Med Clin N Am 86 (2002) xi–xiii Preface Dementia James D. Bowen, MD Guest Editor Dementia is one of the most important yet difficult conditions that physicians are asked to manage. It takes an enormous toll on patients, eventually robbing them of the accumulated wealth of their life experiences, destroying the very essence of their beings. Families likewise suffer from the loss of patriarchs and matriarchs while communities lose the guidance and wisdom of seasoned leaders. With 6% to 10% of those over 65 years of age affected, dementia takes a staggering economic toll that will only worsen as the population ages. Though dementia is common, and despite the severity of its impact, physicians and families often overlook the diagnosis. Recognizing dementia is not the only challenge because identifying the correct diagnosis may be difficult. Finally, the management of these patients can be daunting even for skilled geriatricians. This issue of Medical Clinics of North America is devoted to dementia. It is divided into three sections discussing clinical aspects, recent scientific insights, and treatments. The first article provides an overview of the diagnosis of patients with dementia. The clinical history, examination, laboratory evaluation, and differential diagnosis are reviewed. The next five articles review specific dementing diseases that are of particular importance today. Vascular dementia is reviewed in the second article. This represents the second most common cause of dementia, after Alzheimer’s disease. The third and fourth articles review frontotemporal dementia and dementia with Lewy bodies. These two conditions have recently been distinguished from other types of dementia. New criteria have been proposed, allowing 0025-7125/02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 1 9 - 6 xii Preface / Med Clin N Am 86 (2002) xi–xiii them to be distinguished from other dementing illnesses. Correctly diagnosing frontotemporal dementia and dementia with Lewy bodies can explain otherwise baffling behaviors and can provide important prognostic information to patients and families. These diagnoses also carry important implications for treatment. The fifth article is devoted to AIDS dementia. Dementia in patients with HIV infections can be the result of a number of different causes. Correctly identifying the cause is key to providing optimal treatment. The sixth article rounds out the discussion of specific diseases with a review of human prion diseases. Prion diseases represent a new class of infectious agents that have had dramatic effects on public health policy because of their link to specific food sources. Understanding and recognizing the conditions described in these opening articles should provide the practitioner with valuable tools in evaluating dementia patients. The next section of this issue reviews some of the scientific findings that have advanced our understanding of dementing diseases. The epidemiology of dementia is discussed in the seventh article. Epidemiology studies drive many of the public health care decisions that must be made in caring for the elderly because the incidence and prevalence of dementia point toward society’s present and upcoming healthcare needs. Epidemiology also identifies risk factors for dementia that may provide additional insight into the pathogenesis of dementing diseases. The eighth article describes the many advances in the genetics of dementia that have occurred during the past few years. Many families with genetic risks of dementia have now been recognized. In many cases, the responsible genes have been identified. These genes and the proteins that they encode increase our understanding of dementia at the molecular level, not only for familial dementias, but also for nongenetic dementias. Genetic advances merge into the recent advances in our understanding of the molecular basis of Alzheimer’s disease. We are beginning to understand the molecular causes of two of the prominent pathologic changes found in Alzheimer’s disease: neurofibrillary tangles and plaques. The role of tau in the formation of neurofibrillary tangles and Alzheimer’s disease is described in the ninth article. The role of beta-amyloid in the formation of plaques and Alzheimer’s disease is described in the tenth article. The final two articles address the treatment of patients with dementia. The eleventh article describes some of the nonpharmacologic treatments that may be used to manage the symptoms of dementia. Successful management of these symptoms can greatly reduce the burden on patients and families. In addition, these treatments can avert or delay the need for expensive care in assisted living facilities or nursing homes. The final article describes pharmacologic treatments of dementia. These relatively new medications are the first treatments that can improve cognitive function. I hope this issue will provide the practitioner with the tools needed to diagnose and manage patients with dementia in their clinical practices. It should also provide a basis for understanding the recent scientific advances Preface / Med Clin N Am 86 (2002) xi–xiii xiii that have added so much excitement to this field, and that provide such hope for the future. James D. Bowen, MD Guest Editor Department of Neurology University of Washington Box 356465, Room RR650 1959 N.E. Pacific Street Seattle, WA 98195-6465, USA E-mail address:
[email protected] James D. Webster Ross. 0025-7125/02/$ . Box 356465.hawaii-health. The laboratory and imaging evaluation of the patient with dementia and the various causes of dementia are described. Honolulu. PII: S 0 0 2 5 . Bowen.000. Current clinical practice guidelines and practice parameters are reviewed as relevant for the primary care practitioner. University of Washington School of Medicine. Annual costs for caring for a single patient with Alzheimer’s disease (AD) are reported to be between $35. WA 98195. The emotional impact of the disease on patients and families is devastating. USA b Department of Neurology. This figure is projected to rise as the proportion of the population older than the age of 65 years increases.7 1 2 5 ( 0 2 ) 0 0 0 0 9 . and Department of Veterans Affairs medical research funds. USA Dementia is one of the most costly and disabling diseases associated with aging. Suite 307. Pacific Health Research Institute. This article provides an overview of the bedside and clinic evaluation of patients with complaints of forgetfulness or other cognitive or behavioral disturbances and reviews distinguishing features of dementia and other conditions that may be confused with dementia. This work was supported by National Institute on Aging contract NO1-AG-4-2149. University of Hawaii. these guidelines are similar.*. Seattle. 846 South Hotel Street.000 and $47.W. and no official endorsement should be inferred. For the most part. The information contained in this article does not necessarily reflect the position or the policy of the US government. totaling more than $140 billion dollars per year in the United States assuming there are 4 million people with AD [1–3].com (G. HI 96813.3 . the accurate and early diagnosis of these disorders becomes more crucial. Burns School of Medicine. MDa. MDb a Honolulu Department of Veterans Affairs. E-mail address: ross@phri. and the cost to society is staggering. * Corresponding author. there are important inconsistencies that are discussed.see front matter Ó 2002.Med Clin N Am 86 (2002) 455–476 The diagnosis and differential diagnosis of dementia G. however. Ross). US Department of the Army grant DAMD17-98-1-8621. Elsevier Science (USA). All rights reserved. and John A. As treatments for AD and other dementias that can extend the period individuals have reasonably good cognitive and physical functioning become available. Because there is no diagnostic test to identify dementia. In practice. cognition (the ability to manipulate previously learned information). J.456 G. the clinician must rely on a careful and accurate history from the patient and a reliable informant as well as a good mental status examination. Patients most often pass through stages of intellectual decline that may or may not progress to dementia. require that the intellectual deficits be of sufficient severity to impair social or occupational functioning. and early dementia. Most definitions. it is important to diagnose patients in the earliest phases of disease. and mood/personality [4]. As effective treatments are developed for the common causes of dementia. Bowen / Med Clin N Am 86 (2002) 455–476 Dementia is a clinical syndrome characterized by acquired impairment in multiple neuropsychologic and behavioral domains. Family members can provide information regarding the time and character of onset as well as the pattern of progression of the memory complaints. mild cognitive impairment (MCI). Even in the early stages of dementia. a term used to recognize a transitional phase from normal aging to dementia. These include cognitive deficits thought to occur with normal aging. they do .W.8. taken from the patient as well as from a relative or close friend. According to one recently published population-based study. such as that of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [5]. Another study found that more than 75% of patients in a primary care group practice found to have dementia on cognitive screening had no documentation of cognitive impairment in their medical record [7]. it is often difficult to recognize when a patient with memory complaints has a process that is likely to progress to further intellectual and functional decline. For example. These definitions necessarily draw an arbitrary line between no dementia and dementia. visuospatial ability. Ross. whereas vascular dementia (VsD) may begin abruptly and be associated with a stepwise decline [5. and the course is slowly progressive. Although there are exceptions to these rules. Clinical evaluation of patients with memory complaints History of cognitive impairment Patients who complain of memory problems and those suspected to have memory problems should give a thorough and detailed history. including memory. approximately 20% of family informants failed to recognize memory problems in elderly subjects who were found to have dementia on a comprehensive standardized examination [6]. the onset of AD is insidious. language and speech.D. perhaps even before affected individuals recognize that a memory problem exists. It is thus essential that clinicians inquire about cognitive and functional changes in their elderly patients and administer a brief mental status examination if changes exist so as to identify cognitive decline as early as possible.9]. such as AD or frontotemporal dementia. patients may be unable to recall important aspects of their medical history and may even deny or not recognize significant memory deficits because of lack of insight. Standardized instruments. excessive anxiety. eating. lose items (eg. Patients may forget to pay their bills. become lost in familiar surroundings. especially when physical ailments also contribute to inactivity or decline in functional ability. mail or keys). These assist the clinician in screening for a range of behavioral complications associated with dementia and in measuring the effect that these complications have on the caregiver’s well-being. is not always the presenting feature. taking . loss of interest in usual activities.11]. as well as instrumental activities of daily living (higher order skills required for independent living). including managing money. asking the same question over and over).D. or the Instrumental Activities of Daily Living Scale [16]. such as the Neuropsychiatric Inventory [12] or the Behave-AD [13]. depression).W. disinhibition. This may be a difficult task in the elderly. hallucinations. changes in mood (eg. such as hospitalization. History of behavioral disturbances It should be recognized that memory impairment. bathing. or the loss of a spouse or other family member. and changes in personality (eg. Inquiry should be made regarding ability to learn and recall new information. History of functional impairment An important component of the history is assessing the impact that the intellectual decline and behavioral disturbances are having on the patient’s social and basic functioning ability. providing a base for a more focused history taken by the primary physician. Examples include recall of recent conversations and events. As a result. short shopping lists. such as the informant-rated Blessed Dementia Scale [14].G. telephone messages. the Functional Activity Questionnaire [15]. head injury. may be used for functional assessment. uncharacteristic anger or agitation). These scales assess activities of daily living (personal maintenance activities essential for good health and wellbeing). stroke. Ross. Standardized informantbased questionnaires regarding memory and cognitive decline may be administered by trained interviewers. and use of new appliances or electronic devices. One of these tools is the Informant Questionnaire on Cognitive Decline in the Elderly [10. Behavioral disturbances and decline in functional ability are often the triggers that lead family members to seek medical attention [6]. some knowledge of the patient’s previous activities is necessary. impulsivity. appointments. although a hallmark of the dementia syndrome. or exhibit repetitive behaviors (eg. It is also helpful to inquire about life events temporally related to the onset of the memory complaints. and toileting. Standardized assessments of behavioral complications are also available. preparing meals. Behavioral disturbances include delusions. including dressing. new medications. J. Bowen / Med Clin N Am 86 (2002) 455–476 457 provide useful information for distinguishing these two common dementia syndromes. and three-dimensional geometric shapes. intact learning. Performance of these tasks is highly dependent on educational level. Aphasia may suggest dominant hemisphere disease. category or multiple choice cues may be given to determine if the words have been learned. The bedside mental status examination . cognition. attention. orientation. remote head trauma. attention is preserved until late in most dementias. Bowen / Med Clin N Am 86 (2002) 455–476 medication. These techniques can be helpful for differentiating the forgetfulness (ie. dietary supplements. and performing household tasks. visuospatial skills and mood/personality. impaired learning and retrieval) of AD and other cortical syndromes [4]. A review of the patient’s past medical and psychiatric history for conditions that may contribute to cognitive decline is always necessary. because many dementing diseases have a familial component. During the recall phase. confrontation naming. Family history is important.W. In general. J. Recent memory may be tested by asking the patient to recall a list of words after 3 to 5 minutes. and tremor suggest one of the parkinsonian syndromes. whereas bradykinesia. and mental arithmetic. Thorough reviews of systems and a general physical examination. Cognition or the ability to manipulate previously learned information includes assessment of abstracting ability by interpretation of similarities. speech and language. This should include questions regarding cardiovascular disease. prescription and nonprescription medications. The reader is directed to several references with excellent descriptions of the mental status examination for more detail [4. are needed to identify clues to the diagnosis.458 G. Language assessment begins with listening to the patient’s spontaneous verbal output and includes word list generation. Mental status examination The bedside mental status examination should include assessment of level of consciousness. rigidity. longer lists. Ross. The minimum is three words. alcohol use. performing.22]. and comprehension. recent and remote memory. Executive function refers to judgment and motivation as well as planning. allow the generation of a learning curve. Attention refers to the patient’s ability to maintain focus on the appropriate stimulus while avoiding distraction from irrelevant stimuli. Visuospatial function is tested at the bedside by asking the patient to copy two. including a detailed neurologic examination. impaired retrieval) of normal aging and certain subcortical dementia syndromes from the amnesia (ie. A cardiac murmur or dysrhythmia along with focal neurologic signs may suggest a vascular etiology. This may be tested by digit repetition or by subtracting serial 7’s or 3’s from 100. More detailed discussions of these topics are available in recently published guidelines and reviews [17–20]. proverbs. such as eight words.D. and monitoring complex behaviors. however. impoverished spontaneous verbal output with paraphasic errors (word substitutions) may also be an early indication of AD [21]. however. Impairment in this area is characteristic of subcortical dementia syndromes. repetition. and treatment for depression. 5 5 3 5 3 2 1 3 1 1 1 . and visuospatial ability. Repeat them until the patient learns all three count trials and record. Published normative data allow interpretation of scores according to the patient’s age and education [27]. Attention and calculation Serial 7’s. a specific cutoff score cannot be the sole method of diagnosing dementia.’’ Follow a three-stage command: ‘‘Take a paper in your right hand. When used along with the other components of the history and examination. Because of the variable sensitivity and specificity in different populations and the effects of education on performance. easy to administer. memory. In addition to age and education. or buts. and put it on the floor. fold it in half. It has the advantages of being brief. Give 1 point for each correct answer. or the Neuropsychological Assessment of the Consortium to Establish a Registry for Alzheimer’s Disease [26]. Give 1 second to say each. The Mini-Mental State Examination is the most commonly used cognitive screening instrument (Table 1). and inclusive of multiple domains.G. Copy design [two overlapping pentagrams]. the Alzheimer’s Disease Assessment Scale [25]. Repeat the following: ‘‘No ifs. Write a sentence. impairment in hearing and vision as well as cultural and language background may affect performance on cognitive testing [18. Alternatively.W. Recall Ask for the three objects repeated previously. Nonnative English speakers may have difficulty with Table 1 Mini-mental state examination Maximum score What is the (year)(season)(date)(day)(month)? Where are we (state)(country)(town)(hospital)(floor)? Registration Name three objects. Stop after five answers. Ask the patient all three after you have said them. Give 1 point for each correct answer. the Cognitive Abilities Screening Instrument [24]. These all have the advantage of being quantitative and easy to administer. spell ‘‘world’’ backwards. including orientation.28].19]. language. J. Ross. ands.D. attention. Give 1 point for each correct. Bowen / Med Clin N Am 86 (2002) 455–476 459 provides valuable qualitative information in multiple cognitive domains. however. they are useful for determining if a patient has dementia. the time and expertise to administer the full examination may make it impractical in the average primary care setting. Scores are useful for measuring change over time [18.’’ Read and obey the following: CLOSE YOUR EYES. Clinicians may prefer a brief standardized cognitive assessment instrument such as the Mini-Mental State Examination [23]. Language Names a pencil and watch. D.460 G. requiring interpretation of the test results within culture-specific norms [18. Neuroimaging is essential for the diagnosis of cerebrovascular dementia. J. The recent report from the Quality Standards Subcommittee of the American Academy of Neurology on the diagnosis of dementia recommends neuroimaging at the time of initial dementia assessment ‘‘under most circumstances’’ [20].28]. or hydrocephalus. it was estimated that 12% to 88% of patients with a potentially reversible cause of dementia would not be imaged [31]. Although the guidelines support the use of either a non-contrast-enhanced CT scan or MRI. neoplasm. Bowen / Med Clin N Am 86 (2002) 455–476 cognitive function tests given in English. Ross. Clinically silent (ie. ranged from 12. . The clinical significance of multiple small white matter changes seen on T2-weighted MRI images in the elderly is often uncertain. culturally biased items on the screening test used may still affect performance. These tests may also assist with narrowing the differential diagnosis of the dementia syndrome. ischemic white matter changes. Another study evaluating the usefulness of the prediction rules from the American Academy of Neurology guidelines published in 1994 [30] found that 5% of cases with a meaningful lesion found on neuroimaging had none of the clinical predictors [32]. Diagnostic evaluation of dementia Neuroimaging Although the literature regarding indications for neuroimaging in the evaluation of dementia remains inconclusive.30]. Earlier published guidelines state that neuroimaging is optional [29].W. Imaging analysis techniques that quantify the volume of brain structures or lesions may be useful in the future for diagnosing AD [33]. Depending on the rules used. Formal neuropsychologic testing may be necessary when the bedside assessment fails to differentiate between changes associated with normal aging and early dementia. however. such as subdural hematomas. no recognized focal event) lacunar infarcts. subdural hematomas. MRI is more sensitive than CT for identifying small cerebrovascular lesions and space-occupying lesions that could cause cognitive impairment. Individuals relatively fluent in English may still perform at a higher level in their native language given the stress of cognitive function tests. most dementia specialists suggest that a structural brain image be obtained for a newly diagnosed patient to assess cerebrovascular lesions. A recent evaluation of six published sets of prediction rules for neuroimaging in the evaluation of dementia found that the sensitivity of these rules for identifying potentially reversible causes of dementia.5% to 100%. neoplasms. or hydrocephalus [17]. and some offer prediction rules that dictate when imaging is indicated [19. Cognitive screening instruments translated into the native language should be used when available. Even when assessing cognition in the language most comfortable for the patient. and even cortical infarctions that affect cognition may be present. and inflammatory disorders that can cause neuropsychologic impairment. and human immunodeficiency virus antibody testing. the physician must first determine whether true memory loss is present. J. metabolic. or immunosuppression [30]. When evaluating the patient with complaints of memory loss. tests of electrolyte. An electroencephalogram may identify the periodic sharp wave complexes associated with Creutzfeldt-Jakob disease and may be helpful in distinguishing depression or delirium from dementia [30]. sedimentation rate for suspected infectious or inflammatory disorders. or heavy metals when exposure is suspected. however.G. This includes serum or urine tests for toxins. vasculitis. In a recent study.D.34]. these techniques are expensive and time-consuming. Genetic testing may be useful in those with three or more first-degree relatives with a dementing illness. elevation of the normal brain protein 14-3-3 in the CSF of patients with progressive dementia without CSF pleocytosis has been reported to be 96% sensitive and 99% specific for Creutzfeldt-Jakob disease [20. a lumbar puncture may help to diagnose metastatic cancer. renal. Differential diagnosis of memory and cognitive impairment Not all patients with complaints of memory loss have dementia. Neither single photon emission CT nor positron emission tomography is recommended for routine use in the diagnostic evaluation of dementia [20]. meningitis. Ross. Some have no memory loss at all. Specific tests on cerebrospinal fluid (CSF). the use of these tests affected patient management in 13% of consecutive patients being evaluated for dementia [32]. Further diagnostic testing should be based on clinical suspicion.W.20]. Assuming that mass lesions are absent. toxic. These are listed in Table 2. or hydrocephalus. Lumbar puncture may be particularly useful in dementia patients less than 55 years of age or in those with rapid progression. although not standard. and a serologic test for syphilis [19. and folate levels. may be helpful for diagnosis. For example. drugs. serum glucose. and thyroid function. Bowen / Med Clin N Am 86 (2002) 455–476 461 Presently. These studies can be useful diagnostic adjuncts. syphilis. unusual dementia. A number of conditions can lead to memory complaints or cognitive impairment. Required tests include a complete blood cell count. infection. whereas others have a mild degree of impairment insufficient for a diagnosis of dementia. Laboratory tests Laboratory tests should be performed to identify infectious. Cognitive changes with normal aging Cognitive decline related solely to aging remains a controversial topic. encephalitis. tests of liver. vitamin B12. Normative data from cross-sectional studies examining neuropsychologic . It is not appropriate to assume that memory complaints. Ross. whereas cued recall remains stable [35]. It is reported in this evidence-based review that subjects with MCI followed for up to 4 years have a high risk of progressing to dementia. Although exact definitions vary. and whether the data are cross-sectional or longitudinal [35– 37]. This condition is considered to be a transitional stage between normal aging and dementia. J. they do not meet the criteria for dementia.462 G. Arguments countering these recommendations question the benefit of clinical monitoring considering the fact that not all those with MCI evolve to dementia and . with an annual conversion rate ranging from 6% to 25%.38]. Because the activities of daily living are intact in these patients. at any age. it has been reported that new learning ability or acquisition declines with age. Guidelines for the detection and management of this condition have been published recently [39].W.D. The significance of MCI lies in the identification of patients at high risk for developing dementia and in the potential for treating these patients so as to prevent further decline. and that when they do occur. the tests used. The pattern and severity of deficits across cognitive domains vary widely depending on the population studied. Bowen / Med Clin N Am 86 (2002) 455–476 Table 2 Problems presenting as memory loss Dementia Worried well Normal aging Depression Delirium Stroke syndromes Bradykinesia Abulia Seizure Excessive daytime somnolence Amnestic syndrome performance demonstrate declines in memory with age. are caused by senescence. it is age-related diseases that are often responsible [36. The recommendations are made that persons with MCI be recognized and monitored for cognitive and functional decline because of their increased risk of progressing to dementia and that general cognitive screening instruments be considered for identifying dementia in patients with MCI [39]. Mild cognitive impairment One of the more important clinical concepts to emerge recently in the field of cognitive disorders is MCI. It should be emphasized that all patients with memory complaints need a careful evaluation. MCI exists in patients with memory complaints and objective memory impairment. A clear conclusion from studies of neuropsychologic function in the elderly is that aging-related declines are not inevitable. Specifically. Clinical screening tools for depression are available. depressed patients experience sleep and appetite disturbances. 3. loss of energy. Patients with depression generally have impaired recall with relative sparing of recognition memory. The cognitive and mood symptoms can resolve completely with treatment. delirium requires the following: 1. In addition to memory impairment and poor concentration. disorientation. Disturbance of consciousness (ie. such as the Hamilton Scale or the Geriatric Depression Scale [43. because depression with cognitive impairment may presage the development of dementia. According to the DSM-IV [5]. feelings of worthlessness or guilt. It is important to recognize that patients with dementia are at increased risk for delirium and that delirium and dementia may coexist [46]. established. memory deficit. Features that help to differentiate delirium from dementia include rapid onset. reduced clarity of awareness of the environment) with reduced ability to focus. infections. speech may be incoherent at times. In fact. Additionally. and psychomotor activity is increased or decreased. A change in cognition (eg.D.44]. language disturbance) or the development of a perceptual disturbance that is not better accounted for by a preexisting. memory complaints in the elderly may be more related to depression than to objective memory impairment [42]. or shift attention. The essential features of major depression are sadness that is persistent or anhedonia (loss of interest in usual activities) [5]. Delirium is associated with a variety of systemic illnesses. The disturbance develops over a short period (usually hours to days) and tends to fluctuate during the course of the day. Hospitalized patients in general and surgical patients in particular are prone to delirium. Delirium Delirium or acute confusional state is another condition that is common in the elderly. J. psychomotor retardation. 2. sustain. or recurrent thoughts of death. and disturbance of consciousness that often waxes and wanes between agitation and lethargy. or evolving dementia. short duration.W. Illusions and hallucinations may be seen. Bowen / Med Clin N Am 86 (2002) 455–476 463 suggest that the stigma attached to this label could actually work to the patient’s detriment [40]. . Ross. Depression Memory impairment is commonly associated with major depression in the elderly and may be the presenting symptom of this common and treatable disorder [41]. sleep-wake cycles are often disturbed. although response to treatment may be difficult to assess when dementia and depression coexist. and toxic and metabolic disturbances. it is important to follow patients so as to assess treatment effectiveness and track progression of cognitive deficits [45].G. D. the physician must determine the nature of the dementing disorder. Unlike AD. whereas posterior lesions in Wernicke’s area are associated with fluent verbal output with word substitutions or paraphasias and impaired comprehension [49]. or apraxia suggests frontotemporal dementia. The early onset of behavioral abnormalities.W. or read. usually the left hemisphere. Aphasia Language disturbance or aphasia complicates the evaluation of the cognitively impaired patient. Dominant hemisphere strokes are the most common cause of aphasia. Parkinsonian features in early stages of the disease suggest the presence of Parkinson’s disease or dementia with . the amnestic syndromes are characterized by isolated amnesia with preservation of other areas of neuropsychologic function. however. such as stroke. Detailed information on some of these conditions may be found in other articles in this issue. mamillary bodies. Aphasia is associated with dysfunction in the dominant hemisphere. repeat words or phrases. Table 3 provides a partial list of the many causes of dementia. and head trauma [47].464 G. Ross. such as language and visuospatial ability. herpes encephalitis. anomia may be the earliest feature of AD or frontal lobe degenerative dementia [21]. The following discussion highlights some of the more common and reversible causes. Clues to diagnosing less common conditions include the presence of focal neurologic findings that suggest focal structural lesions. Identifying less common causes of dementia Although AD is the most common cause of dementia. An aphasic patient may be unable to participate in memory testing because of an inability to comprehend instructions. Comprehensive reviews of the causes of dementia are also available [4. Causes of amnesia include Korsakov’s syndrome associated with alcohol abuse and thiamine deficiency. the physician must be vigilant to less common causes. Etiology of dementia Once it has been determined that a patient’s complaints of memory loss are the result of dementia. It is important to recognize that patients with isolated memory loss without apparent cause are at high risk for developing dementia and should be closely monitored [48]. rigidity. Bowen / Med Clin N Am 86 (2002) 455–476 Amnestic syndromes Amnesia is defined as an inability to learn new information and is an early sign of AD. however. and thalamus. Anterior lesions cause nonfluent aphasia with sparse verbal output. tumor. or subdural hematoma. Amnestic syndromes are generally associated with conditions that affect the mesial temporal lobes and their connections with the fornix. language dysfunction. J.18]. comprising over two thirds of all cases in most studies [50].D. J. There is no confirmed biologic marker for AD.or hyperthyroidism Hypo.51].or hyperparathyroidism Hypo or hypermagnesemia Hypo or hypercalcemia Cushing’s disease Addison’s disease Renal failure Liver failure Porphyria Domoic acid poisoning Paraneoplastic syndromes Limbic encephalitis Autoimmune/inflammatory disorders Multiple sclerosis Behcet’s disease Lupus erythematosus Sarcoidosis Temporal arteritis and other central nervous system vasculitides a 465 Dementias associated with parkinsonism Parkinson’s disease Dementia with Lewy bodies Progressive supranuclear palsy Multiple systems atrophy Cortical-basal ganglionic degeneration Idiopathic basal ganglia calcifications Parkinsonism-dementia complex of Guam Other extrapyramidal disorders Wilson’s disease Huntington’s disease Hallervorden-Spatz disease Dementias related to infections Prion diseases Creutzfeldt-Jakob Disease Gerstmann-Straussler-Scheinker Disease Kuru New-variant Creutzfeldt-Jakob Disease Neurosyphilis AIDS dementia Chronic meningitis Fungal Tuberculosis Lyme disease Viral encephalitis Whipple’s disease Trauma-related dementias Dementia related to closed-head injury Chronic subdural hematoma Dementia pugilistica Miscellaneous disorders Normal pressure hydrocephalus Hippocampal sclerosis Central nervous system tumors Mitochondrial encephalopathies Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.W. Onset is insidious. often over a period of minutes.G. Bowen / Med Clin N Am 86 (2002) 455–476 Table 3 Causes of dementia Cortical degenerative dementias Alzheimer’s disease Frontotemporal dementia Vascular dementias Multiple large vessel infarcts Single strategic infarct Lacunar state Binswanger’s disease CADASILa Toxic/metabolic conditions Medication-induced dementia Alcohol-related dementia Dementia related to heavy metal exposure Vitamin B12 deficiency Folate deficiency Hypo. or the presence of visual hallucinations also suggests dementia with Lewy bodies. Fluctuations in performance. and progression . standardized clinical criteria have improved the accuracy of diagnosis to greater than 85% [8. Age of onset less than 50 years or the presence of three or more first-degree relatives with dementia suggests a genetic dementing disorder. Ross. however. Lewy bodies. Alzheimer’s disease AD is the most common cause of dementia. 466 G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455–476 slow. Language disturbances may be an early feature, with anomia progressing to fluent aphasia with word substitutions or paraphasias and impairment in comprehension. Recent memory and the ability to learn new information are also impaired early in AD. Other common disturbances in cortical function include apraxia (impaired ability to perform motor activities despite intact motor function), agnosia (inability to recognize objects despite intact sensory functioning), and alexia (inability to comprehend the written word). Patients with AD commonly lack knowledge of their memory problems. Delusions and hallucinations are common and occur in up to 50% of patients [52]. The results of the elementary neurologic examination are remarkably normal in most cases. Subtypes of AD include those with isolated cognitive impairments that later progress to more widespread cognitive deficits. In addition, another type presents with rigid or bradykinetic symptoms resembling Parkinson’s disease. When present early, extrapyramidal signs suggest a more rapid decline [53]. In those patients with three or more first-degree affected family members, familial AD must be suspected, and appropriate testing should be undertaken. Vascular dementia The concept of (VsD) is evolving as it becomes increasingly recognized that in addition to causing cognitive decline alone, vascular lesions modify the expression of Alzheimer pathologic findings [54]. VsD is clinically recognized in patients with a prior history of strokes, focal neurologic findings, or strokes on neuroimaging. The classic sudden onset with stepwise deterioration of VsD probably occurs in less than half of cases. Because of these clinically silent cases, it is important to obtain neuroimaging in all cases of dementia. The cognitive deficits associated with VsD depend on the lesion location. Large vessel strokes cause cortical deficits, such as aphasia and focal neurologic deficits, such as hemianopia and hemiparesis. Multiple small vessel strokes cause a subcortical clinical presentation with forgetfulness and prominent executive function deficits. Pseudobulbar palsy, gait disturbances, and urinary incontinence are also common. Although several sets of criteria exist for VsD [5,9,55], the clinician should be concerned with stroke prevention in any dementia patient with cerebrovascular risk factors or vascular lesions on neuroimaging. Frontotemporal dementia Frontotemporal dementia consists of a clinically and pathologically heterogeneous group of disorders, including Pick’s disease. These have in common degeneration of the frontal and temporal lobes. Diagnostic criteria for frontotemporal dementia are listed in Table 4 [56]. Behavioral changes, including disinhibition, impulsiveness, social inappropriateness, apathy, and withdrawal, are early and prominent features. These behavioral changes provide the most important clue allowing the differentiation of this condition G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455–476 Table 4 Criteria for the diagnosis of frontotemporal dementia 467 A. Dominant deficits in behavior and conduct appearing early in the course Loss of personal awareness (neglect of hygiene and grooming) Loss of social graces and awareness Disinhibition (sexually provocative or demanding, inappropriate jocularity), overactivity, or restlessness, often with a stereotyped repertoire Impulsivity, distractibility Hyperorality (dietary changes, excessive eating, smoking, or alcohol consumption, preference for sweet foods or food fads, oral exploration of objects) Withdrawal from social contact, apathy or inertia Stereotyped or perseverative behaviors (wandering, repetitive clapping, humming or singing, ritualistic toileting, dressing) B. Speech output changes Progressive reduction of speech (late mutism, economy of speech) Stereotypy of speech (few repeated phrases or themes), perseveration Echolalia C. Physical signs Early or prominent primitive or ‘‘frontal’’ reflexes Early incontinence Late akinesia, rigidity, tremor D. Deficits in social comportment, behavior, judgment, or language are out of proportion to memory deficit. Memory loss is variable, often seems to result from lack of concern or effort; frontal lobe impairments most notable: abstraction, planning, self-regulation of behavior from AD. Language disturbances may also appear early, whereas visuospatial function remains intact until later in the illness [57]. Neuroimaging may allow the visualization of focal atrophy, but the disease can often be recognized clinically before changes on routine imaging are apparent [58]. Single photon emission CT imaging demonstrates hypoperfusion in the frontal and temporal lobes before atrophy in these regions is evident on structural imaging [58]. Dementias associated with parkinsonism Parkinsonism is a syndrome of disturbed motor function characterized by bradykinesia, muscle rigidity, rest tremor, and postural instability. Dementia is often a secondary feature. There are many diseases that cause parkinsonism. The most common of these is Parkinson’s disease, which is characterized by loss of dopaminergic neurons in the substantia nigra of the midbrain. The presence of Lewy bodies, target-shaped inclusions with a dense eosinophilic core, within the degenerating neurons of the substantia nigra confirms the diagnosis of Parkinson’s disease; however, these lesions may also occur in the cortex. Dementias associated with Lewy bodies comprise a spectrum of diseases, including Parkinson’s disease with Lewy body pathologic changes limited to the brain stem, dementia with Lewy bodies associated with Lewy bodies in the cerebral cortex, and AD associated with cortical Lewy bodies as well as typical Alzheimer pathologic findings. Dividing lines between these conditions are somewhat arbitrary; 468 G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455–476 however, the practitioner should be familiar with the basic clinical distinctions, because the correct diagnosis affects patient management. Dementia occurs at some time during the course of the illness in approximately 40% of patients with Parkinson’s disease [59]. Cognitive decline begins at least 1 year after the onset of the movement disorder and is associated with impaired recall that is aided with recognition cues, prominent executive function deficits, and intact language [60]. Dementia with Lewy bodies, in contrast to Parkinson’s disease, is identifiable by fluctuating cognitive performance, well-formed visual hallucinations unrelated to dopaminergic therapy, and parkinsonism that emerges simultaneously with the cognitive impairment. These features allow it to be differentiated from AD and Parkinson’s disease. It is particularly important to recognize dementia with Lewy bodies because of the severe adverse reactions that these patients may have to neuroleptic medications used to treat behavioral problems. Because of this, neuroleptics should be avoided in the treatment of this disease [61]. Diagnostic criteria for identifying dementia with Lewy bodies are listed in Table 5 [62]. Other degenerative parkinsonian syndromes are much less common. Progressive supranuclear palsy begins at the age of 40 years or older and is characterized by a rigid-akinetic form of parkinsonism, dementia, supranuclear gaze palsy, severe dysarthria, neck rigidity (usually in extension), minimal tremor, and frequent falls [63]. Multisystem atrophy refers to a group of adult-onset progressive neurodegenerative disorders (ie, striatonigral degeneration, Shy-Drager syndrome, olivopontocerebellar atrophy) characterized by parkinsonism that Table 5 Criteria for diagnosing Lewy body dementia A. The central requirement is progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. Deficits on tests of attention and frontal-subcortical skills and visuospatial ability may be especially prominent. B. Two of the following are required for a probable diagnosis, and one for a possible diagnosis of dementia with Lewy bodies: Fluctuating cognition with pronounced variations in attention and alertness Recurrent visual hallucinations that are typically well formed and detailed Spontaneous motor features of parkinsonism D. Features supportive of the diagnosis are as follows: Repeated falls Syncope Transient loss of consciousness Neuroleptic sensitivity (deterioration in cognitive function, parkinsonism, drowsiness, and some features of so-called neuroleptic malignant syndrome) Systematized delusions Hallucinations in other modalities E. A diagnosis of dementia with Lewy bodies is less likely in the presence of the following: Stroke disease, evident as focal neurologic signs or on brain imaging Evidence on physical examination and investigation of any physical illness or other brain disorder sufficient to account for the clinical picture G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455–476 469 is poorly responsive to levodopa and is associated with cerebellar dysfunction, pyramidal dysfunction, or symptomatic autonomic failure as well as dementia [64]. Vascular parkinsonism is characterized by the stepwise progression of an akinetic-rigid syndrome in the setting of clinical strokes or other vascular risk factors, such as hypertension, diabetes, or lipid abnormalities. Clinical signs may improve without the use of levodopa [65]. Cortical-basal ganglionic degeneration is characterized by a chronic progressive akinetic-rigid parkinsonian syndrome resistant to levodopa and is associated with dystonic limb posturing and focal myoclonus. There is also evidence of higher cortical dysfunction (apraxia, cortical sensory loss, or alien limb) [66]. Dementia related to chronic subdural hematoma The presenting features of chronic subdural hematoma include focal symptoms, headache, or cognitive/personality changes. Without neuroimaging, the diagnosis is rarely straightforward. A history of trauma is absent in one third of patients. The onset may be sudden with a fluctuating course or may extend over weeks to months. Seventy percent of chronic subdural hematomas occur in patients more than 60 years old, and men are more commonly affected than women [67–69]. Patients may have lethargy or agitation. Cognitive deficits involve multiple domains, including recent memory, language, abstract thinking, calculations, and judgment [68,69]. A contrastenhanced brain CT scan may be required to recognize chronic subdural hematoma, because the density of the lesion may be the same as that of brain parenchyma. Medical management is recommended for small lesions with minimal clinical signs [70]. Surgical management is indicated for the rest. Either burr holes or twist-drill craniotomy is effective and associated with relatively few complications [71]. Dementias associated with infectious disease The prion diseases, including Creutzfeldt-Jakob disease and dementia secondary to human immunodeficiency virus infection, are covered elsewhere in this issue. Creutzfeldt-Jakob disease usually presents with a dementia that progresses over weeks or months. In addition to cognitive impairment, many patients experience depression or emotional lability. Myoclonus, especially in response to stimuli, is seen later in the course of the disease in three fourths of patients. Ataxia is often seen as a late manifestation of the disease. Gait and vision may be affected. The dementia is often rapidly progressive, with the median time from onset of symptoms to death being 4.5 months. Diagnosis may be aided by the electroencephalographic finding of 1- to 2-Hz triphasic sharp waves that are often asymmetric. Elevated levels of the 14-3-3 protein in CSF in the absence of pleocytosis also support the diagnosis. Recently, variant Creutzfeldt-Jakob disease has been found after consumption of beef infected by bovine spongiform encephalopathy. These variant cases generally affect younger patients and have a more prolonged course. Dementia associated with metabolic disturbance Neurologic symptoms related to vitamin B12 deficiency occur most commonly in the fourth through sixth decades and include paresthesias of the . such as the venereal disease research laboratory slide test (VDRL). trihexyphenidyl and meclizine). such as the antipsychotics haloperidol and thioridazine. the results may be negative in some cases. psychosis. an amnestic disorder that may be permanent [72]. Aqueous penicillin G remains the treatment of choice.W. The CSF VDRL test is highly specific. and antihypertensives (eg. Patients with dementia may be particularly susceptible to further cognitive impairment with medication use [75–77]. Prompt thiamine replacement may reverse the delirium and other signs. Patients exhibit memory impairment with confabulation. characterized by delirium. and grandiosity [4]. Although the DSM-IV recognizes alcohol-induced dementia that persists after heavy drinking. Treponemal serology tests. such as the micro hemagglutination assay for treponema pallidum (MHA-TP).D. Ross.73]. is related to thiamine deficiency and is associated with prolonged heavy use of alcohol. Sedatives and hypnotics (eg. Medications used to treat the behavioral complications of dementia. however. analgesics. The lowest possible dose should be used to control the target symptoms. amitriptyline).470 G. Toxin-related dementias Wernicke’s encephalopathy. general paresis is now rarely seen. Cases screening positive by serologic testing should undergo lumbar puncture. dysarthria. ophthalmoplegia. J. causing some to question the utility of routinely screening for treponemal infection [20]. impaired judgment. Once a common cause of institutionalization. beta-blockers) are all commonly prescribed medications that can cause cognitive impairment reversible on withdrawal of the medication [18]. Medications are a common cause of delirium and cognitive decline in the elderly and may be responsible for 1. anticholinergic drugs (eg. Onset may occur many years after the initial infection. antidepressants (eg. and the need for continued use of the medication should be assessed at regular intervals. the lack of pathologic findings in the brain related to alcohol abuse has called into question the direct toxic effect of alcohol on the brain [5. benzodiazepines). and ataxia.5% to 10% of all clinically diagnosed dementias [74]. Bowen / Med Clin N Am 86 (2002) 455–476 General paresis refers to the dementia associated with parenchymatous neurosyphilis. have fewer false-negative results than nontreponemal tests. The increased risk of head injury and association of heavy prolonged alcohol use with blood disorders that can lead to stroke may also cause persistent cognitive impairment. may worsen the memory impairment. although some patients still evolve to Korsakoff’s syndrome. Patients with positive serology and elevated white blood cells in their CSF should be treated. is an unreliable predictor of treatment response and is unlikely to contribute to the . Focal areas of cerebral demyelination characterize the brain pathologic findings much like the loss of myelin in the posterior and lateral columns of the spinal cord associated with this syndrome. Radionuclide cisternography. memory loss. and absent or mild symptoms [82]. Bowen / Med Clin N Am 86 (2002) 455–476 471 feet and hands. and irritability are all features of the neuropsychiatric syndrome that has been described as megaloblastic madness [78. and psychomotor slowing is rarely seen. normal thyroid hormone levels. and neuropsychiatric disturbances. memory impairment. and urinary incontinence. the gait disturbance develops first. Owing partly to the common assessment of thyroid function. paranoia. as many as one fourth do not have the megaloblastic anemia that is classically associated with pernicious anemia [80]. Normal pressure hydrocephalus Normal pressure hydrocephalus is a rare condition characterized by the triad of dementia. MRI or CT demonstrates ventricular dilatation.G. Importantly. hallucinations. the term magnetic gait. loss of vibratory and position sensation. and impaired abstraction. Psychosis may occur [4]. Confusion. treatment with thyroxine has been associated with significant improvement in cognitive function [82]. ataxia. Dementia associated with hypothyroidism is characterized by inattention. with slow initiation giving the appearance that the feet are stuck to the floor–hence. gait disturbance. Onset is rare before 60 years of age. Ross. with forgetfulness. especially of the frontal horns. clinicians encounter patients with elevated thyrotropin levels. This usually results in improvement in the motor and sensory deficits and has been reported to improve language and frontal function in individuals with vitamin B12–related cognitive impairment [81]. that is out of proportion to the amount of cortical sulcal widening. followed by dementia. The diagnosis is made by neuroimaging in patients with the appropriate clinical picture. once the diagnostic test of choice.D. weight gain. The gait is associated with slow and small steps akin to parkinsonism. Incontinence may not occur until the later stages of the disease. Typically. More often.W. thick skin. among those with cognitive and behavioral symptoms and vitamin B12 deficiency. The dementia syndrome is mild. Folate deficiency may cause a similar syndrome that can be treated with oral folic acid supplements. and impaired executive function being the predominant symptoms.79]. depression. the myxedema syndrome of edema. Treatment consists of intramuscular administration of vitamin B12. cold intolerance. psychomotor slowing. Evidence from communitybased studies demonstrates an association between this condition known as subclinical hypothyroidism and cognitive impairment [83]. constipation. J. extremity weakness. Furthermore. The cause is unknown but is thought to be related to ischemic demyelination in periventricular white matter secondary to a combination of vascular insufficiency and intermittent slight increases in CSF pressure [84]. D. and aphasias should be considered in the differential diagnosis of memory impairment. 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Belle S.318:1720–8. Clinical practice. . [74] Bowen JD. [86] Vanneste JA. pathogenesis. have made VaD one of the most controversial. also known as cerebral arteriosclerosis. Kraepelin concluded in 1910 that arteriosclerotic insanity.1 .see front matter Ó 2002. challenging. In 1894. Roman). treatment.7 1 2 5 ( 0 2 ) 0 0 0 0 8 . University of Texas Health Science Center at San Antonio. treatment. Roman. and progress in the understanding of pathogenetic mechanisms as well as new possibilities of early diagnosis. neuronal death. MD* Department of Medicine/Neurology. when the importance of AD as the main cause of senile dementia was ´ * E-mail address: romang@uthscsa. Among other recent developments. TX 78284-7883. a common cause of dementia at that time. and prevention. USA Vascular dementia (VaD) is an etiologic category that includes clinical forms of dementia caused by ischemic or hemorrhagic cerebrovascular disease (CVD) or by ischemic-hypoxic brain lesions of cardiovascular origin [1. 0025-7125/02/$ .C. Murphy Memorial Veterans Hospital. and identified at least four different clinicopathologic forms of VaD [5]. Otto Binswanger and Alois Alzheimer separated VaD from dementia paralytica (neurosyphilis). brain atrophy. Elsevier Science (USA).2]. and prevention ´ Gustavo C. This concept persisted until the late 1970s. and Audie L. VaD is the most common cause of dementia after Alzheimer’s disease (AD) [3].Med Clin N Am 86 (2002) 477–499 Vascular dementia revisited: Diagnosis. Based on their work. and rapidly evolving areas in the field of dementia. This unwarranted simplification of the complexity of the field implied that progressive narrowing and blockage of large cerebral arteries led to decreased cerebral blood flow. the recent identification of genetic forms of VaD. All rights reserved. 7703 Floyd Curl Drive. PII: S 0 0 2 5 . the recognition of the adjuvant role of vascular factors in AD. San Antonio. and dementia. was the most frequent form of senile dementia [4].edu (G. History Thomas Willis first described postapoplectic dementia in the seventeenth century [4]. These ischemic lesions may interrupt the recently described frontal Table 1 Pathological lesions capable of producing vascular dementia 1. Small-vessel disease with dementia Subcortical Binswanger’s disease CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) ´ Lacunar dementia or lacunar state (etat lacunaire) Multiple lacunes with extensive perifocal incomplete infarctions Cortical and subcortical Hypertensive and arteriolosclerotic angiopathy Amyloid angiopathies (including British dementia) Collagen-vascular disease with dementia 4. Likewise. Strategic infarct dementia A single brain infarct. the important role of ischemic-hypoxic white matter lesions in the pathogenesis of VaD has been recognized. damages functionally critical areas of the brain (angular gyrus. . with the advent of new-generation CT and MRI of the brain. cortico-subcortical in location. usually with perifocal incomplete infarction involving the white matter 2. Blessed. VaD includes more than MID. Multi-infarct dementia Multiple large complete infarcts. Ischemic-hypoxic dementia (hypoperfusive) Diffuse anoxic-ischemic encephalopathy Restricted injury due to selective vulnerability Incomplete white-matter infarction Border-zone infarction 5. Pathogenesis VaD may be caused by a number of vascular lesions and pathogenetic mechanisms as listed in Table 1 [8]. Hemorrhagic dementia Traumatic subdural hematoma Subarachnoid hemorrhage Cerebral hematoma Venous thrombosis 6. with permission.478 ´ G. Pathology and pathophysiology of cerebrovascular dementia: pure subgroups of obstructive and hypoperfusive etiology. often lacunar in size. and Roth demonstrated that the loss of more than 50 to 100 mL of brain tissue from stroke resulted in dementia [6]. Concurrently. Of particular importance in the elderly is small vessel disease. Nevertheless. basal forebrain. which causes lacunes and white matter ischemic lesions. posterior cerebral artery and anterior cerebral artery territories) 3. because a single strategic stroke may also result in VaD.5:145–7. Other mechanisms Modified from Brun A. Dementia 1994. the term multi-infarct dementia (MID) was then coined for this condition [7]. Tomlinson. as described later in this article.C. Roman / Med Clin N Am 86 (2002) 477–499 recognized. thalamus. Not surprisingly. modulators.50:873–80. basal ganglia. such as capsular genu lacunes Manifestations Executive dysfunction.18]. impersistence. or subcortical circuit lesions interrupting connections at the level of caudate. mood changes. The last three are the primary behaviorally relevant circuits [12–15. basal ganglia. mania. (2) orbitofrontal subcortical circuit lesions are manifested by disinhibited behaviors and obsessive-compulsive disorders. Ann NY Acad Sci 1995. and difficulty with set shifting (loss of Luria’s kinetic melody) 2. Roman / Med Clin N Am 86 (2002) 477–499 479 cortical-subcortical circuits that underlie executive functions. executive dysfunction. or subcortical circuit lesions interrupting connections at the level of caudate.10]. and thalamus. and (3) medial-frontal (anterior cingulate) cortex subcortical circuit lesions often result in apathy. Dorso-lateral prefrontal circuit lesions Lesions May include cortical strokes involving dorsolateral prefrontal cortex. thalamus or white matter loop links Manifestations Disinhibited behaviors. perseveration. thalamus or white matter loop links Manifestations Apathy.C. dorsolateral prefrontal region.´ G. frontal eye fields. lacunar lesions in putamen or thalamus. and anterior cingulate cortex [11. mood changes. motivation. Medial-frontal (cingulate) cortex-subcortical circuits Lesions May include anterior cerebral artery strokes involving medial frontal cortical territories. or ischemic white matter lesions involving loop segments. infarctions at head of the caudate nucleus. Frontal-subcortical circuits and human behavior. Anatomic and behavioral aspects of frontalsubcortical circuits. apathy. impaired motor programming.769:1–13. Each segment of the circuit has different neurotransmitters. Table 2 Behavioral manifestations of subcortical vascular dementia caused by lesions interrupting prefrontal-subcortical circuits 1.17]. and obsessive-compulsive disorder 3. These frontal circuits originate in the supplementary motor area. or vascular depression Modified from Cummings JL. slowing of information processing. with thalamocortical connections closing the loop [11–15]. with permission. and receptor subtypes that may provide the basis for pharmacologic intervention [18]. .16. There are five parallel anatomic circuits that link regions of the frontal cortex to the striatum (caudate nucleus). Orbito-frontal-subcortical circuit lesions Lesions May include anterior cerebral artery strokes involving lateral orbitofrontal cortical territories. Arch Neurol 1993. and uninhibited behaviors are frequently observed in patients with VaD [19–22]. and Cummings JL. and socially responsive behaviors [9. as follows (Table 2): (1) interruption at any portion of the loop of the dorsolateral prefrontal subcortical circuit results in executive dysfunction. poor word list generation and decreased verbal fluency. globus pallidus/substantia nigra. lateral orbitofrontal area. such as those present in Binswanger’s disease (BD) [21]. For these reasons. For instance. and ischemic periventricular leukoencephalopathy of the Binswanger type. a single small thalamic stroke may cause extensive hypometabolism and decrease of blood flow in the frontal cortical territories and cerebellum as a result of diaschisis [35–37].42]. and the syndromes resulting therein. narrowing of the lumen is produced by senile arteriolosclerosis [28]. Other mechanisms responsible for VaD include cortical disconnection from ischemic white matter lesions [34]. These cases should be classified as ‘‘AD plus CVD’’ instead of the commonly used but incorrect . ´ Recently.38–40]. The end result of these morphologic changes is the loss of the normal autoregulation of cerebral blood flow [29] and hypoperfusion of gray matter and white matter [30]. Cerebrovascular pathologic findings and heart disease are common in the elderly. orthostatic hypotension. and their prevalences increase with age. Roman / Med Clin N Am 86 (2002) 477–499 Vascular and circulatory lesions In addition to acute ischemia from embolic and atherothrombotic large vessel occlusions. Repeated episodes of brain ischemia from chronic hypoperfusion affect the deep white matter territories that are perfused by small vessels (medullary arterioles) [23]. Epidemiology AD and VaD are the most common causes of senile dementia. with VaD ranking second after AD [3. and diaschisis. and congestive heart failure in the elderly increase the risk for the development of cognitive loss and eventual VaD [31–33]. resulting in lacunes. and hypertension. whereby elderly subjects with the presence of one or two lacunar strokes seem to require a lesser amount of senile plaques and neurofibrillary tangles to manifest signs of dementia. Robin [27] and etat crible Also. as a result.C. diabetes. Ageing produces tortuosity and elongation of these arterioles [24–26]. About one third of poststroke VaD patients harbor this dual pathologic profile. cardiac arrhythmias. Henon and her colleagues [44. histologic changes of AD in the elderly often coexist with stroke and vascular pathologic changes [41.480 ´ G. The multiple mechanisms capable of producing VaD. leading to dilatation of the perivascular spaces of Virchow´ ´. represent a major challenge when formulating diagnostic criteria for VaD as well as for case ascertainment in epidemiologic studies and recruitment of subjects participating in controlled clinical trials.45] demonstrated that careful questioning can separate patients with preexisting memory loss and probable AD from pure cases of poststroke VaD. the elderly are also susceptible to ischemic lesions of small vessels. cortical microinfarcts (granular atrophy). Somewhat more unexpected was the observation of the adjuvant role of cerebral infarction in AD [43]. approximately 125. Dubois and Herbert [49] used age-based standardized incidence ratios to analyze data from 10 incidence studies of VaD in comparison to the Canadian Study of Health and Aging. which predominates in women. Poststroke dementia The most common form of VaD is probably poststroke dementia (also known as MID when dementia develops after multiple strokes). VaD was more prevalent than AD in 85-year-olds in Italy and Gothenburg (Sweden) [46]. There are methodologic variations that depend on the definition of dementia and test cutoffs used. In Helsinki [50].42 to 2. Based on these figures.5 years for AD.´ G. Prevalence rates double every 5. at 3 months after ictus).53]. The prevalence of AD versus VaD tends to increase among ethnic Japanese who migrated to Hawaii. Prevalence rates range from approximately 1. environmental. Henon et al [44] found a 16% prevalence of prestroke dementia in possible cases of poststroke dementia. the prevalence of poststroke VaD would be above 1 million elderly people currently suffering from poststroke VaD [53]. Roman / Med Clin N Am 86 (2002) 477–499 481 ´ denomination of ‘‘mixed’’ dementia. Jorm and Jolley [48] performed a meta-analysis of 11 studies of VaD with age-specific incidence data. Prevalence Jorm et al [40] performed a meta-analysis of 47 international studies on VaD prevalence and found that prevalence increases exponentially with age up to the age of 95 years.000 new cases of VaD after ischemic stroke occur every year (approximately one third of the estimated 360. indicating environmental interaction on genetic susceptibility [47]. being more prevalent in Asian populations than in white populations. however. poststroke dementia ranged between 27% and 41%. the figures ranged from 6% to 25. Incidence Incidence data for VaD from longitudinal cohort studies are rather limited. whereas in New York City [51. VaD seems to be more common in men in contrast to AD.C. or methodologic differences between studies. however.52]. This is probably a result of the preponderance of small vessel disease in Oriental races. Age-based standardized incidence ratios ranged from 0. The incidence of poststroke dementia is relatively easy to ascertain when cognitive tests are performed after stroke (typically. . In Europe. This means that in the United States alone. VaD has a peculiar geographic (racial) variation. confirming the geographic variation of VaD.68.5%.000 incident cases of AD) [39.5 per 100 persons from the age of 70 to 75 years to 14 to 16 per 100 persons at the age 80 years and above.3 years compared with every 4. Also. that most cases of poststroke VaD remain undiagnosed. It should be noted. More recently. These variations may be a result of genetic. 57]. from recurrent strokes (MID). Orthostatic hypotension has been correlated with these lesions in a large population-based MRI study of elderly subjects [61]. cardiac arrhythmias. Clinical forms of vascular dementia ´ Roman [62] has simplified the clinical syndromes of VaD into two main groups. Acute-onset vascular dementia This group includes patients with new-onset dementia after a clinically eloquent acute ischemic event as a single ‘‘strategic stroke’’ resulting from occlusion (or rupture) of a large-sized vessel. and urinary impairment. Pohjasvaara and colleagues [50] confirmed that the most important risk factors for poststroke VaD are older age.6. Demented patients were more often current smokers and had lower blood pressure and orthostatic hypotension. dementia is a predictor of poor outcome in patients with stroke [52]. an effect not explained by aphasia) as well as the presence of dysphagia. Risk factor quantification in case-control studies of poststroke dementia have begun to provide an answer [54. or after a symptomatic lacunar stroke caused by small vessel disease. Moroney et al [58] recently found that hypoxic and ischemic complications of acute stroke (eg. Larger periventricular white matter ischemic lesions as detected by MRI are also predictive of poststroke dementia [56.C. acute and subacute. Roman / Med Clin N Am 86 (2002) 477–499 Risk factors for vascular dementia One of the long-time paradoxes of VaD has been why it is that some patients develop dementia after a single stroke. according to the temporal profile of clinical presentation. lower educational level.482 ´ G. Hypoxic and ischemic complications of acute stroke may result in border zone infarcts [59] but also cause Binswanger-type ischemic periventricular white matter lesions [60].9–9. increasing more than fourfold the risk of developing poststroke dementia (odds ratio ¼ 4. and baseline cognitive function). gait limitations. Poststroke multi-infarct dementia The risk factors for poststroke MID have been presented and are summarized in Table 3. seizures. . whereas others seem to tolerate large or recurrent strokes without decline of intellectual function.3 and 95% confidence interval: 1. and left hemisphere stroke (associated with a fivefold increase in the risk of developing poststroke dementia. recurrent stroke. recurrent stroke. after adjustment for demographic factors. aspiration pneumonia) are strong and independent risk factors for poststroke dementia.55]. Consequently. and basal forebrain lesions. posterior association areas such as gyrus angularis. striking psychomotor retardation. current smokers Genetic factors: family history of dementia Stroke type: recurrent strokes Stroke location: left-sided lesions.70] called attention to this characteristic—although relatively uncommon—syndrome manifested by sudden change in cognitive function and often associated with fluctuating attention. 6. Infarctions of the left angular gyrus presenting with right-to-left disorientation. Tatemichi and his colleagues [69.C. 2. 5.67]. The usual cause is a lacune involving . Posterior cerebral artery territory involving the ventral-medial temporal lobe. Dementia from capsular genu infarction In 1992. Infarction in the anterior cerebral artery territory and medial-frontal lobe lesions. occipital structures. finger agnosia. inferior capsular genu stroke producing diaschisis of frontal lobes and cerebellum 7. inattention. ‘‘strategic strokes’’ (ie. and thalamus and presenting with anterograde amnesia. urinary impairment Dementia caused by a single cortical-subcortical infarction A single large vessel stroke in the following locations may produce VaD: 1. posterior cerebral artery territories including paramedian thalamic artery territory. bilateral anterior cerebral artery territories. Stroke volume: lesions larger than 50–100 ml of tissue destruction. often from an anterior communicating artery aneurysm rupture [64]. confusion. and constructional difficulties and on the right side with hemispatial neglect and visuospatial or visuoconstructive disturbances [65]. gait limitations. 3. 4. Bilateral involvement of the basal ganglia and thalamus. Stroke manifestations: dysphagia. and frontal white matter lesions). cardiac arrhythmias. 483 Age: older age Education: lower educational level Personal factors: lower-income. acalculia. abulia. 3. Roman / Med Clin N Am 86 (2002) 477–499 Table 3 Principal risk factors for poststroke vascular dementia 1. hippocampus. and other features of frontal lobe dysfunction but with mild focal findings. larger peri-lesional incomplete ischemic areas involving white matter. visuospatial difficulties. memory loss. such as hemiparesis or dysarthria. and hippocampus. watershed or border-zone infarcts mainly involving superior frontal and parietal regions.´ G. seizures. Stroke complications: hypoxic and ischemic complications of acute stroke (ie. aspiration pneumonia. inferomedial temporal lobes. aphasia. 2. This is the socalled thalamic dementia of vascular origin [66] caused by butterflyshaped bilateral paramedian thalamic polar infarcts [66. larger periventricular white matter ischemic lesions 8. aphasia. anterior choroidal artery strokes. dysgraphia. hypotension) 9. Some cases of caudate stroke may also result in VaD [68]. or constructional apraxia [63]. 4. 13. and abnormal Luria’s kinetic melody test results [12. inattention.78–80]. In addition to lacunes. An unusual case of subcortical dementia resulting from a giant lacune with a unilateral left-sided mammillothalamic tract lesion has been recently reported [72]. Binswanger [76] described as the hallmark of this condition the presence of an ischemic periventricular leukoencephalopathy that typically spares the arcuate subcortical U fibers [21]. executive dysfunction. Memory loss is characterized by . parkinsonian features. globus pallidus. Diagnostic criteria for subcortical VaD have been proposed recently [73]. Senile dementia of the Binswanger type In 1894. slowing of motor function with perseveration. including executive dysfunction. Small vessel disease and multiple lacunes often coexist in BD. impersistence. The main forms of subacute subcortical VaD are lacunar state ´ (etat lacunaire). and some forms of cerebral amyloid angiopathy (CAA).C. and it has been postulated that this condition and the so-called lacunar dementia of patients with a lacunar state may represent a single entity [77]. this is one of the most common forms of VaD and results from small vessel disease with lacunes and white matter lesions that damage structures (caudate nucleus.484 ´ G. depressive mood changes. and pseudobulbar palsy. urinary disturbances. Subacute (subcortical) vascular dementia The temporal profile of presentation of these forms of VaD is typically subacute. inattention. loss of verbal fluency. ventricular dilatation and Binswangertype lesions of the white matter caused by recurrent ischemia-hypoxia frequently coexist. causing ipsilateral blood flow reduction to the inferomedial-frontal cortex by a mechanism of diaschisis [71]. This is considered a thalamocortical disconnection syndrome [69]. Pierre Marie [74] described this clinical syndrome in the elderly. BD. and white matter. Roman / Med Clin N Am 86 (2002) 477–499 the inferior genu of the internal capsule. slow information processing. A lacunar state and BD produce a cognitive and motor syndrome with characteristics of subcortical dementia. As mentioned previously. [21. ´ Lacunar state (etat lacunaire) In 1901. difficulties with set shifting. Their clinical manifestations are similar. motor involvement. thalamus. and connecting fibers) of the prefrontal subcortical circuits [22].17–21. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The latter are also called leukoaraiosis (Greek for ‘‘white rarefaction’’) [75]. pons. impaired memory.76–79] and are discussed jointly. emphasizing the presence of multiple lacunes in the basal ganglia. This group is characterized clinically by a subcortical dementia (subcortical VaD) with frontal lobe deficits. with a chronic course marked by fluctuations and progressive worsening. Numerous pedigrees have been described in Europe and North America [82. mainly lacunar strokes. The brain lesions are ischemic infarcts. and nocturia are also common findings [80. where the mutations result in gain or loss of a cysteine residue [91]. migraine with focal deficits (40%). and accompanied by gait and urinary disturbances and pseudobulbar palsy clinically identical to that of sporadic BD. cognitive deficits and VaD (50%). localized in the basal ganglia. and epilepsy (10%). The vessels show deposits of eosinophilic periodic acid–Schiff-positive material in the arterial media that consists of granular osmiophilic deposits and accumulation of the ectodomain of the Notch3 receptor in the basal lamina of degenerated smooth muscle cells on electron microscopy. culminating in dementia and death usually approximately 20 years after the onset of symptoms [82. Also. centrum ovale. MRI reveals a combination of small lacunar lesions and diffuse white matter abnormalities. The disease is caused by highly stereotyped mutations in the Notch3 gene. The large extracellular domain of Notch3 contains 34 tandem epidermal growth factor–like repeats. Apathy. depression. CADASIL is an autosomal dominant disorder of cerebral small vessels mapped to chromosome 19q12 [83]. slowness of movement. frontal in type. . and are associated with extensive confluent areas of frontal ischemic leukoencephalopathy. primarily in the brain but also in other organs.C. Onset is usually in early adulthood (mean age of 46 years) [87] in the absence of risk factors for vascular disease. in some cases. Roman / Med Clin N Am 86 (2002) 477–499 485 poor retrieval and intact recognition. pseudobulbar palsy. axial rigidity.84. thalamus. particularly BD. The underlying vascular lesion is a unique nonamyloid and nonatherosclerotic microangiopathy involving arterioles (100–400 lm in diameter) and capillaries. cerebral blood flow reactivity to inhaled carbon dioxide is impaired. this condition offers a natural model for the study of subcortical subacute forms of VaD. The dementia is slow in onset. and pons. Extrapyramidal features. dysarthria. mood disorders (30%). Originally called familial BD [85]. particularly in periventricular regions. Mild residual hemiparesis or other discrete focal ` findings are often found as well as a peculiar short-stepped gait (marche a petits pas). and. loss of postural reflexes. and behavioral problems are common. frequent falls. Clinical manifestations include transient ischemic attacks and strokes (80%). astasia-abasia.´ G. such as inexpressive facies. these are often present in asymptomatic relatives [88].87].84.81].87]. The diagnosis may be established by skin biopsy [89] and confirmed by immunostaining with a Notch3 monoclonal antibody [90]. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy One of the most important recent developments in the field of VaD has been the clinical and genetic description of CADASIL [82–84].86. increased urinary frequency. subcortical. which encodes a phylogenetically old transmembrane cell surface receptor that regulates cell fate during embryonic development. C. VaD requires the use of tests for subcortical dysfunction. There are several autosomal dominant forms of CAA with differences in their clinical. and exclusion of other causes of dementia. particularly AD. genetic. In practical terms. and cerebellar ataxia with onset in the sixth decade [92]. the vessels show amyloid deposition. This test is more suitable for patients with cortical forms of dementia. cerebrovascular lesions demonstrated by brain imaging (CT. the National Institute of Neurologic Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN) criteria [94] (Table 4) offer an operative approach to the three basic elements needed to reach a diagnosis of VaD: cognitive loss. Roman / Med Clin N Am 86 (2002) 477–499 Cerebral amyloid angiopathy This is a heterogeneous group of disorders characterized by deposition of amyloid in the walls of leptomeningeal and cerebral cortical blood vessels and demonstrated clinically by recurrent or multiple lobar hemorrhages. A temporal relation (ie. Some of the bedside tests available include clock drawing [96]. is also the major amyloid component in sporadic CAA and AD. microaneurysms. the major amyloid component in the Dutch. Binswanger-type deep white matter hyperintensities and lacunar infarcts are seen. but no intracerebral hemorrhages are apparent. such as AD. including executive function testing [22]. progressive spastic paraparesis. and fibrinoid necrosis. biochemical. internists usually have suspected patients perform a Mini-Mental State Examination (MMSE) [95].486 ´ G. and ischemic strokes. On histologic examination. Familial British dementia with amyloid angiopathy (FBD) is an autosomal dominant condition characterized by VaD. but the amyloid subunit found in FBD brains is entirely different and unrelated to other amyloid proteins. MRI displays diffuse white matter abnormalities along with ischemic or hemorrhagic focal brain lesions. and Iowa type of familial CAA. and pathologic findings. the Trail Making Test Part B [97]. Amyloid b. and the Behavioral Dyscontrol Scale [98] based on Luria’s kinetic melody. Diagnosis of vascular dementia Although a number of diagnostic criteria for VaD have been proposed. The NINDS-AIREN criteria require objective proof of dementia validated by neuropsychologic tests. MRI). The corpus callosum is severely affected and atrophic plaques and tangles are present. On brain MRI. particularly in patients with silent strokes. frequently a subcortical form of dementia. Flemish. cognitive deterioration. These criteria also require a logical link between the vascular lesions and the dementia. A point mutation in the BRI gene has been shown to be the genetic abnormality. development of dementia within 3 months after stroke) has proven to be more difficult to fulfill. FBD combines neurodegeneration and dementia with systemic amyloid deposition [93]. . ´ G.C. Roman / Med Clin N Am 86 (2002) 477–499 Table 4 NINDS-AIREN diagnostic criteria for vascular dementia 487 I. The criteria for the diagnosis of probable VaD include all of the following: 1. Dementia: Impairment of memory and two or more cognitive domains (including executive function), interfering with ADLs and not due to physical effects of stroke alone. Exclusion criteria: Alterations of consciousness, delirium, psychoses, severe aphasia or deficits precluding testing, systemic disorders, Alzheimer’s disease, or other forms of dementia. 2. Cerebrovascular disease: Focal signs on neurological examination (hemiparesis, lower facial weakness, Babinski sign, sensory deficit, hemianopia, dysarthria) consistent with stroke (with or without history of stroke, and evidence of relevant CVD by brain CT or MRI including multiple large-vessel infarcts or a single strategically placed infarct (angular gyrus, thalamus, basal forebrain, or PCA or ACA territories), as well as multiple basal ganglia and while matter lacunes or extensive periventricular white matter lesions, or combinations thereof. Exclusion criteria: Absence of cerebrovascular lesions on CT or MRI. 3. A relationship between the above two disorders is manifested or inferred by the presence of one or more of the following: A. Onset of dementia within 3 months following a recognized stroke. B. Abrupt deterioration in cognitive functions or fluctuating, stepwise progression of cognitive deficits. II. Clinical features consistent with the diagnosis of probable VaD include the following: ` 1. Early presence of gait disturbances (small step gait or marche a petits pas, or magnetic, apraxic-ataxic or parkinsonian gait). 2. History of unsteadiness and frequent, unprovoked falls. 3. Early urinary frequency, urgency, and other urinary symptoms not explained by urologic disease. 4. Pseudobulbar palsy. 5. Personality and mood changes, abulia, depression, emotional incontinence, or other deficits including psychomotor retardation and abnormal executive function. III. Features that make the diagnosis of VaD uncertain or unlikely include: 1. Early onset of memory deficit and progressive worsening of memory and other cognitive functions such as language (transcortical sensory aphasia), motor skills (apraxia), and perception (agnosia), in the absence of corresponding focal lesions on brain imaging. 2. Absence of focal neurological signs, other than cognitive disturbances. 3. Absence of CVD on CT or MRI. Abbreviations: ACA, anterior cerebral artery; ADLs, activities of daily living; CT, computerized tomography; CVD, cerebrovascular disease; MRI, magnetic resonance imaging; PCA, posterior cerebral artery; VaD; vascular dementia. ´ From Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993;43: 250–60; with permission. Demonstration of the presence of vascular lesions by brain MRI or CT is required. Lesions range from a single strategic lacunar stroke, to multiple cortical-subcortical strokes, to periventricular ischemia. Mungas et al [99] determined by MRI that hippocampal atrophy, volume of cortical gray matter, and volume of white matter lesions (but not lacunes) were strong and independent predictors of vascular cognitive impairment. The neuropathologic substrate of these lesions in patients with VaD seems to be widespread ischemia from microvascular disease, including ischemic hippocampal injury 488 ´ G.C. Roman / Med Clin N Am 86 (2002) 477–499 pathologically resembling mesial temporal lobe sclerosis [100]. By definition, absence of vascular lesions by brain imaging excludes VaD. Inclusion and exclusion criteria as well as stratification into levels of diagnostic certainty are also provided in Table 4. Chui [39] has recently reviewed other available diagnostic criteria for VaD. The different criteria are not interchangeable, and the criteria for subcortical VaD are yet to be validated. Separating Alzheimer’s disease from vascular dementia A practical problem that frequently confronts the internist is the elderly patient with cognitive and behavioral disturbances presenting with an abnormal MMSE and the presence of vascular lesions on brain imaging. Does the patient have MID, AD plus CVD, or simply AD? The ischemic score (Table 5) may provide additional elements for the diagnosis of the MID form of VaD [101]. A score greater than or equal to 7 is consistent with MID, a score less than or equal to 4 is consistent with AD, and a score of 5 to 6 is suggestive of AD plus CVD. In a recent metaanalysis [101], the following features were found more often in VaD than in AD: stepwise deterioration, fluctuating course, history of hypertension, history of stroke, and focal neurologic symptoms. As discussed previously, it is possible to successfully diagnose prestroke dementia by means of a careful interview of relatives and caregivers [45]. In most instances, probable AD is a likely etiology for the progressive memory loss occurring before the ictus. Another related method is the application of the concept of mild cognitive impairment [102]. The amnestic form of MCI is easily identifiable and carries a risk of conversion to clinically probable AD at a rate of 10% to 15% per year compared with 1% to 2% per year in healthy age-matched Table 5 Items of the ischemic score Item Abrupt onset Stepwise deterioration Fluctuating course Nocturnal confusion Preservation of personality Depression Somatic complaints Emotional incontinence History of hypertension History of stroke Associated atherosclerosis Focal neurological symptoms Focal neurological signs Score (total: 18) 2 1 2 1 1 1 1 1 1 2 1 2 2 Modified from Hachinski VC, Zilhka E, DuBoulay GH, McAllister VL, Marshall J. Cerebral blood flow in dementia. Arch Neurol 1975;32:632–7; with permission. ´ G.C. Roman / Med Clin N Am 86 (2002) 477–499 489 control subjects. The frequency and severity of CVD in older patients with AD point to the possibility that vascular risk factors may predispose not only to VaD but to the development of AD [103]. Population-based epidemiologic data [104,105] have shown that vascular risk factors, such as hypertension, carotid artery wall thickness, cholesterol, and peripheral vascular disease, often occur in patients who develop AD. The vascular role of the apolipoprotein E e4 allele [105,106], a risk factor for AD, may partially explain this interaction. Treatment and prevention Secondary prevention Patients with VaD have higher morbidity and mortality than age-matched control subjects and patients with AD [52]. Coronary artery disease and recurrent strokes are among the common complications in these patients. Secondary prevention of recurrent stroke must be undertaken in patients with poststroke VaD. Although age, gender, ethnicity, and genetic factors are nonmodifiable stroke risk factors, there is clear class I evidence that treatment of hypertension reduces the risk of recurrent stroke by 28% [107]. Likewise, the use of statins to decrease low-density lipoprotein cholesterol by 25% reduces stroke risk up to 30% [108]. Antiplatelet medications reduce the risk of recurrent stroke by 17% with aspirin and 25% with ticlopidine. Clopidogrel is a safe and effective alternative to ticlopidine but is not superior to aspirin; dipyridamole in combination with aspirin seems to be superior to aspirin alone [109]. Anticoagulation with warfarin [International Normalized Ratio (INR): 2–3] in patients with atrial fibrillation is highly efficacious in preventing recurrent stroke (approximately 70% risk reduction) [110]. For patients with more than 75% carotid artery stenosis, surgery reduces recurrent stroke by 51% [111]. Primary prevention Of significant public health interest are the observations that the treatment of hypertension [112–115] and the use of statins [116–119] have been associated with decreased incidence of dementia in the elderly. Other risk factors Treatment of other risk factors for subcortical VaD is also indicated; these risk factors include smoking, hyperfibrinogenemia, orthostatic hypotension, cardiac arrhythmias, congestive heart failure [32,33,120], and obstructive sleep apnea [121]. Not infrequently, nocturnal hypertension (‘‘nondippers’’), a risk factor for Binswanger-type VaD, frequently occurs in patients with obstructive sleep apnea. Finally, control of hemorheologic factors that increase blood viscosity becomes important in subjects with small vessel 490 ´ G.C. Roman / Med Clin N Am 86 (2002) 477–499 disease and disturbances of the microcirculation. Blood glucose control in patients with diabetes and lowering of fibrinogen and lipids should be beneficial. In patients with hyperhomocystinemia, the use of oral folate is recommended. Increased homocysteine levels may have a role in the pathogenesis of CADASIL [122]. Drug treatments for vascular dementia A large number of medications of purported efficacy for VaD have been available for many years [123]. These drugs responded to prevailing notions about pathogenesis, however, and have been found to be ineffective. For instance, vasodilators (nicotinic acid, cyclandelate, papaverine, isoxsuprine, cinnarizine, buflomedil, naftidrofuryl, and ergoloid mesylates among others) were widely used to counteract ‘‘hardening of the arteries.’’ As pointed out by Cochrane [124], their alleged efficacy was based on open-label trials that lacked masking, controls, randomization, clear inclusion and exclusion criteria, and appropriate outcome measures and endpoints. A comprehensive ´ review by Roman [125] of pharmacologic agents for VaD is available elsewhere. Here, only those agents with demonstrated efficacy in randomized controlled clinical trials (class I evidence) are presented. Calcium channel blockers Nimodipine (Nimotop) and nicardipine have demonstrated moderate efficacy in tests of attention and psychomotor performance in the subcortical (small vessel) form of VaD [126,127]. These agents have effects on autoregulation of cerebral blood flow and block L-type calcium receptors, providing some degree of neuroprotection. Neuroprotective (Nootropic) agents Piracetam [128], oxiracetam [129], and nicergoline [130] seem to be safe and modestly effective in the MID form of VaD as well as in elderly hypertensive patients with leukoaraiosis [131]. Citicoline has been shown to have positive short-term effects on memory and behavior in patients with VaD [132,133]. Citicoline activates the biosynthesis of structural phospholipids in the neuronal membranes, increases cerebral metabolism, and increases noradrenaline and dopamine levels in the central nervous system [134]. Memantine This agent is a potent noncompetitive antagonist of the N-methyl-Daspartate receptor with nootropic properties [135]. Memantine has been shown to be well tolerated and useful in severe dementia [136]. A recently completed pivotal 28-week trial of memantine in patients with mild to moderate VaD enrolled 321 patients who received 2 · 10 mg/d or placebo. The study demonstrated good tolerance and improvement in cognitive tests, including the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and MMSE [137]. randomized.´ G. Of the available cholinergic agents approved for the treatment of AD. placebo-controlled international trial of donepezil in VaD has been completed recently [152].C. The trial . increased sedimentation rate. Pentoxifylline treatment lowered fibrinogen and tumor necrosis factor-a levels and corrected these abnormalities. Antiplatelet agents Aspirin [142]. A large. The multicenter European Pentoxifylline Multi-infarct Dementia Study demonstrated significant cognitive improvement in the MID form of VaD in comparison with placebo [139]. Solerte et al [141] described hemorheologic alterations in patients with AD but not in age-matched controls or in patients with VaD. a mixed dementia [145]. rivastigmine tartrate (Exelon). Cholinergic drugs are effective in VaD because these patients have cholinergic deficits related to ischemic involvement of basal forebrain neurons (nucleus basalis of Meynert) or their projections. Roman / Med Clin N Am 86 (2002) 477–499 491 Pentoxifylline (Trental) This is a xanthine derivative with hemorheologic and immunomodulatory properties [138]. Sometimes. donepezil hydrochloride (Aricept). triflusal [143]. multicenter. and Ginkgo biloba [144] have been used in patients with MID or with AD plus CVD with modest positive results. 24-week. whereas choline concentrations were higher than in controls or AD patients. It seems clear that (at least in the oldest patients) both vascular and degenerative mechanisms contribute to AD dementia [146]. Tohgi et al [150] found acetylcholine concentrations in the cerebrospinal fluid of patients with BD and MID to be significantly lower than in controls. Martin-Ruiz et al [151] demonstrated the relative integrity of nicotinic receptors in definite cases of VaD. Recently. These widespread neurotransmitter deficits probably are not caused by localized brain infarcts per se. Cholinesterase inhibitors The encouraging results obtained with the use of cholinergic agents in VaD may give some clinicians the mistaken impression that VaD is really AD or. only in one third of patients diagnosed with VaD [147]. and galantamine hydrobromide (Reminyl) have been used in patients with VaD. Recently. hyperfibrinogenemia. these findings confirmed previous results [140]. these changes were correlated with increased levels of tumor necrosis factor-a and interferon-c. using postmortem brain tissue materials. Abnormalities included hyperviscosity. This overlap occurs. the patients fulfill the criteria for AD [148]. Wallin et al [149] found pronounced disturbances of the serotoninergic and cholinergic systems in subcortical and cortical gray matter at postmortem brain examination of patients with VaD. It should be noted that the MMSE was the primary endpoint for cognitive evaluation in most of these patients. Nicotinic receptors control cerebral vasodilatation. such as in the case of an anterior choroidal artery occlusion. and increased acute-phase reactants. however. at best. Likewise. 492 ´ G. multicenter. such as risperidone and olanzapine. have been useful in the treatment of agitation and disruptive behaviors. may be required. Patients were randomized to placebo (n ¼ 330). n ¼ 231) for 26 weeks. Patients on the 5-mg/d dose tolerated the drug better than those on the high dose of 10 mg/d. For some patients with depression and anxiety. such as the selective serotonin reuptake inhibitors citalopram or sertraline. Other agents Atypical antipsychotic drugs. and (3) exclusion of other causes of dementia.C. low-dose rivastigmine (1–4 mg/d. or to high-dose donepezil at 10 mg/d (n ¼ 310). and hypoperfusive lesions such as border zone infarcts and ischemic periventricular leukoencephalopathy (Binswanger’s disease). with beneficial effects on activities of daily living and global scores. The use of cholinergic medications often controls these problems. controlled clinical trial of patients with VaD identified by NINDS-AIREN criteria [155]. VaD may be caused by multiple strokes (MID or poststroke dementia) but also by single strategic strokes. or hemorrhagic brain lesions as a result of CVD and cardiovascular pathologic changes. Primary and secondary prevention of stroke and cardiovascular disease decreases the burden of VaD. Treatment . (2) vascular brain lesions demonstrated by imaging. or high-dose rivastigmine (6–12 mg/d. Genetic advice is needed in patients with familial forms. ischemic-hypoxic. n ¼ 233). Summary VaD is the second most common cause of dementia in the elderly after AD. Significant improvement was found on the ADAS-Cog and MMSE in patients treated with high-dose rivastigmine compared with controls treated with placebo. VaD is defined as the loss of cognitive function resulting from ischemic. VaD is excluded by brain imaging showing no evidence of vascular lesions. Diagnosis requires (1) cognitive loss (often predominantly subcortical). Patients were randomized to placebo (n ¼ 235). significant improvement was noted on the ADAS-Cog and MMSE cognitive tests. the use of antidepressants. Rivastigmine tartrate was evaluated in patients with mild to moderately severe AD with or without concurrent vascular risk factors [153]. Rivastigmine has also been found to be effective and safe in a study of 16 patients with subcortical VaD [154]. The results of the trial are awaited with interest. such as CADASIL. Galantamine is also being tested in a large. to low-dose donepezil at 5 mg/d (n ¼ 329). The use of tricyclic antidepressants in the elderly patient with VaD is discouraged because of anticholinergic effects and orthostatic hypotension. 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Cerebrospinal fluid acetylcholine and choline in vascular dementia of Binswanger and multiple small infarct types as compared with Alzheimer-type dementia. Cazzato G. Arch Neurol 1998. [152] Pratt RD.25:187–90.359:1283–90.15:286–90. Lilienfeld S. [144] Oken BS. Torre P. [149] Wallin A. Carlsson A. cases of primary progressive aphasia (PPA) were distinguished as a unique entity [8].Med Clin N Am 86 (2002) 501–518 Frontotemporal dementia Andrew Kertesz. 268 Grosvenor Street. 0025-7125/02/$ . Spain a Frontotemporal dementia (FTD) is a new name for clinical Pick’s disease (PiD). Kertesz). apathy. At the same time. The clinical picture of frontal lobe dementia (FLD) or.see front matter Ó 2002. FRCPCa.1 .kertesz@sjhc. London. neuroimaging evidence of often asymmetric frontal and temporal atrophy. MD. it was recognized that PPA is related to FTD. lack of insight. neuronal loss.on. when dementia of the frontal lobe type was described as a behavioral and personality disorder. Munoz. as later renamed. University of Western Ontario. University of Western Ontario. Ontario. Similar cases were described as ‘‘dementia lacking distinctive histology’’ (DLDH) [6]. and disinhibition. and spongiform degeneration in a superficial area of the frontal and temporal cortex [5]. FRCPCb. Neuropsychologic testing showed poor performance on tests of mental flexibility and executive function. a consensus meeting agreed that PPA and semantic dementia * Corresponding author. The pathologic profile was characterized by gliosis. PII: S 0 0 2 5 . The Lund and Manchester Groups [4] described the core symptoms as personality change. Joseph’s Hospital. St. Nevertheless. most clinicians make the diagnosis on the basis of the striking behavioral and personality changes.*. E-mail address: andrew. and it was also suggested that corticobasal degeneration (CBD) belongs to this group of various overlapping clinical presentations and underlying pathologic findings called Pick complex [9]. All rights reserved.c Department of Clinical Neurological Sciences.7]. FTD. Canada c ´ Banco de Tejidos para Investigacion Neurologica. Less than 25% of the patients with this syndrome had Pick bodies [5]. has been described with emphasis on the personality and behavioral changes [1–3]. The eponymic PiD has been increasingly restricted to the pathologic variant with Pick bodies. Madrid. or decreased activity on isotope single photon emission CT [3. Canada b Department of Pathology and Clinical Neurological Sciences. Universidad Autonoma.ca (A. blunting of emotions. Subsequently. London. Later. Elsevier Science (USA).7 1 2 5 ( 0 2 ) 0 0 0 1 1 . Ontario N6A 4V2. David G.london. MD. A dichotomy of nosology arose. it became apparent that cases of clinical PiD with frontal lobe and temporal lobe symptomatology often do not show this typical histologic picture on autopsy [18–20]. Gans [15] suggested the eponymic term and considered a predilection for the phylogenetically younger frontal and temporal lobes in the etiology. Subsequently. . The recent discovery of autosomal dominant inherited chromosome 17– linked FTD with parkinsonism (FTDP-17) and subsequent description of tau mutations in several families with this linkage created considerable interest [12. stated that the most common form is characterized by early development of aphasia. in his review of PiD. Munoz / Med Clin N Am 86 (2002) 501–518 should be part of the frontotemporal lobar degenerations [2]. This gave rise to the notion that PiD is difficult to diagnose in vivo. and the clinical features were often incompletely described because of the retrospective nature of these studies. Kertesz.18. In this review. and motor neuron type inclusions [10.’’ a favorite and sometimes misleading adjective in many descriptions. The temporal lobe variety of PiD presenting with progressive aphasia was described quite early [14.502 A.’’ followed by aphasia and. D.13]. the considerable overlap is emphasized in addition to the distinctive features. Pick’s initial cases only had gross examination without any microscopic data. Caron [27]. Schneider [21. a ‘‘disturbance of judgement and asocial behaviour. Several of his subsequent articles dealt with progressive aphasia and progressive apraxia on the basis of focal atrophy. Later. Onari and Spatz [17] re-examined the cases of Pick and cases from others emphasizing Pick bodies and Pick cells (large ballooned neurons). FTD is still underdiagnosed and underestimated. because some people use the term Pick’s disease on the basis of histologic criteria. Most series of PiD were based on postmortem examination. It was recognized that FTD or Pick complex could have a number of pathologic substrates.G.11]. by more generalized dementia. including PiD. later.22] described several stages of PiD: first. whereas others describe the clinical picture of focal atrophies as Pick did originally. partly because the individual components of the complex are considered separately or considered ‘‘heterogeneous.23–26]. but the clinical pattern and its relation to focal atrophy are the basis of the syndrome. CBD. and these descriptions are similar to those of PPA appearing later. PiD was defined on the basis of histology as initially described by Alzheimer [16]. and others also emphasized early speech disturbance or aphasia in PiD [28–30]. Pick’s disease Arnold Pick [14] described behavioral and aphasic symptoms associated with frontotemporal atrophy more than 100 years ago. Many of the clinical descriptions had dramatic frontal lobe deficits. The phenotypic and pathologic variations of these mutations closely match sporadic disease and provide powerful evidence for the cohesion of the complex. the inferior frontal gyri. Sometimes. There were larger series of PiD described in the literature in the early 1950s from Europe [47–50]. with air studies. first. Munoz / Med Clin N Am 86 (2002) 501–518 503 There have been several case descriptions of PiD in which the patients had prominent extrapyramidal features [19.31. Munoz-Garcia and Ludwin [36] differentiated the ‘‘generalized’’ variety of PiD from the cortical variety because of the subcortical extent of the pathologic findings. right frontal atrophy was more prominent than left frontal atrophy. The brunt of the atrophy was most often in the medial orbital. The relatively early age of patients has been observed by authors describing the subcortical or generalized varieties of PiD [19. unilateral rigidity and parkinsonism were the first symptoms to attract attention. where 25 of 51 examined members were affected [41] with a mostly behavioral presentation. The clinical description of these patients is quite similar to the description of the cortical variety of PiD. PiD generally has a presenile onset below the age of 65 years in contrast to the age at onset of most AD patients. With the development of neuroimaging. Many of the subcortical varieties of PiD are similar to corticonigral and CBD clinically and pathologically. was subsequently found to have a genetic linkage to chromosome 17 [42]. More than half of the cases showed atrophy on the left side more than on the right side. Ferraro and Jervis [33] stated that extrapyramidal symptoms were common in PiD. but some had features of the Kluver¨ Bucy syndrome [37]. It was recognized that the disease sometimes occurred in families [39]. They believed that ‘‘in spite of the dissimilarities between these forms. . A large family with PiD.38]. Frontal atrophy only occurred in 25% of cases. it seems prudent at present to maintain the uniqueness of Pick’s entity’’ [20]. and Mann et al [34] described extrapyramidal involvement in 8 of 12 of FLD patients. considering the absence of sufficient knowledge about pathogenesis. and in 20% of the cases. and the anterior third of the superior temporal gyrus. occurred in most of 30 cases in one review [35]. It was recognized that subcortical changes occur in PiD even without extrapyramidal symptomatology [19]. None of these patients had prominent extrapyramidal symptoms. and (3) only gliosis. (2) only with swollen neurons. Frontotemporal atrophy was the most common form of the disease (54%). especially in the striatum and substantia nigra in addition to cortical pathologic changes. Constantinidis et al [20] classified PiD as (1) with Pick bodies. Several other families were described with various tau mutations with classic PiD pathologic findings [43–46].A. frontotemporal lobe atrophy was demonstrated with increasing frequency in vivo. and temporal atrophy only occurred in 17% of cases. Kertesz. familial cases tend to have an even earlier onset. More than half of autopsy-diagnosed cases of PiD were familial [40].36.24. Changes in the basal ganglia. They thought the clinical differences between these forms were not related to the nature of histologic alterations but rather to the temporal lobe or frontal predominance of the abnormality.G. In addition. Constantinidis et al [20] described extrapyramidal involvement particularly in ‘‘group B’’ patients. D.32]. so far. . DLDH. They called the pathologic entity without Pick bodies ‘‘frontal lobe dementia type. Frontotemporal dementia In the second half of the 1980s. Munoz / Med Clin N Am 86 (2002) 501–518 then. Knopman et al [6] described a similar clinicopathologic picture as DLDH.5]. only remains a pathologic diagnosis. such as Bodian or Bielchowsky stain. with the largest series being those of Verity and Wechsler [58] and Bergeron et al [59]. to clinical PiD.G.504 A. while reserving the diagnosis of PiD to increasingly restricted histologic criteria. as defined by pathologists. Kertesz. with MRI and single photon emission CT scans. the separation of this variation is hardly justified [11]. two European groups described FLD as a distinct entity and contrasted the clinical features with those of AD [1–3. Additionally. suggesting that complement activation is interrupted before reaching completion and causing neuronal lysis [55]. Large ballooned neurons (Pick cells). is characterized as round argyrophilic inclusions in the neuronal cytoplasm called Pick bodies. The pathologic definition of PiD. Pick body–bearing neurons (but not Pick cells) are surrounded by activated microglial cells and T lymphocytes [56]. They are best demonstrated with traditional silver stains. superficial cortical spongiosis neuronal loss. The in vivo diagnosis of PiD continued to be made sporadically on the basis of frontal and temporal symptomatology supported by the focal atrophy on imaging and a normal electroencephalogram [51]. and other forms of the Pick complex. FTD. and more recently. Complement proteins and complement inhibitors are detected in the neuronal cytoplasm. At the same time. such as FLD. Neocortical Pick bodies are preferentially located in small neurons. the in vivo studies applied new labels. and gliosis occur in the atrophied areas. however. There is variable labeling with tau antibodies. D.’’ which consisted of neuronal loss and gliosis in the frontal cortex with or without spongiform changes or ballooned neurons [5]. Because white matter gliosis is common in other varieties of Pick complex pathologic entities. but do not stain with the Gallyas method [11]. ubiquitin. More than 30 cases have been described in the literature. and these features are common in CBD.52] and long-period twisted fibrils [53]. Both groups recognized that even though some of the cases had Pick bodies and most did not. and chromogranin A. They estimated its relative incidence to be 15% to 20% of degenerative dementias. and PPA. Electron microscopy has revealed bodies made up of 15-nm straight fibrils [36. Instead of shifting the diagnosis of PiD back to the clinic. Progressive subcortical gliosis [38. and they are pathognomonic in the dentate gyrus [53].57] is clinically similar to PiD but. the clinical syndrome was the same. with CT scans in the 1970s. whereas traditional silver stains and tau antibodies identify scattered Pick bodies in the neocortex in CBD as well [54]. are sometimes grouped under the term Kluver-Bucy ¨ syndrome. indifference. money. which originated from the observation of monkeys with bilateral temporal lobectomy [37]. Patients may consume large quantities of candy or cookies in one sitting. There is a group of behaviors that can be characterized as ‘‘negative. wandering. one or the other symptom may be predominant.’’ consisting of apathy. hyperorality. incessant clapping. Munoz / Med Clin N Am 86 (2002) 501–518 505 The groups that described dementia of the frontal lobe type changed the terminology to FTD [4]. The striking alterations in personality and behavior have become synonymous with FTD. The final stages of disinhibition manifest in urinary and stool incontinence. gestures. echolalia. pills. Kertesz. types of clothing. however. Utilization behavior is the need to touch. The hypersexuality may be only verbal and gestural in middle-aged or older individuals. and telephoning people inappropriately. and actions as well as obsessive stereotypic routines. One of the characteristic groups of behaviors is characterized by perseveration of words. it does not distinguish between the clear-cut behavioral presentation of FTD and aphasic presentation of PPA. Disinhibition often refers to social inappropriateness ranging from childish rude behavior to exposure and kleptomania. singing. Others insisted on a diet of milk and bananas or had plum sauce with everything. insisting on eating. although this may occur early in FTD patients who are still oriented. or clock watching while they carry out their stereotypic routines. aspontaneity. The hallmark of this distinctive form of dementia is the combination of disinhibition with apathy. which is one of the most valuable contributions of the recent descriptions of the clinical picture in these conditions. If attempts are made to restrain these behaviors. or extrapyramidal symptomatology. These patients are inflexible. Some patients grab food off the serving plate before anybody else starts or even take food off the plates of others. Patients may be preoccupied with germs. buying. Furthermore. It does reflect. poor judgment. and irritability. or even garbage. pacing. Hyperorality often manifests in gluttony and overeating. and utilization behavior. or doing the same thing at the same time. such as hypersexuality. hoarding objects. and laughing are observed. similar to what others called ‘‘environmental dependence’’ or ‘‘hypermetamorphosis’’ [61]. We had patients who would eat in the same chicken restaurant day in and out. perseverating with stories. anger and violent resistance often occur. In more advanced stages. irresponsibility. The term frontotemporal degeneration or frontotemporal dementia [60] does not include the frequent subcortical involvement. Other manifestations. feel. the frequent combination of frontal and anterior temporal atrophy originally described by Pick. Other disinhibition phenomena. and many patients develop food fads. are also seen. and aggression. particularly for sweets. examine. clothes. although at different stages of the disease. It overlaps with impulsivity. . such as restlessness. or pick up objects within reach and sight. D.A. and emotional flatness. parietal pathologic findings.G. The compulsive eating and drinking sometimes extends to inedible objects as in coprophagia. sex. Lately. In our experience. however. not washing or changing underwear. distractibility. and neuronal loss. Others emphasize the ‘‘loss of self. Pathologic changes are considered to involve the basal ganglia and temporal neocortex. whose behavior is grossly abnormal. only the results of complex executive tests of shifting sets. These patients have pathologic changes in the dorsal lateral convexity as well as in the temporal neocortex. These patients are impulsive and distractible. More apparent extremes of indifference and apathy culminate in personal neglect. Munoz / Med Clin N Am 86 (2002) 501–518 Patients are unable to recognize the extent of their own behavioral disturbance and most often insist there is nothing wrong.G. D. and lack of cooperation tend to interfere with testing rather early in the disease. Similar behavioral inventories for FTD have been used at other centers [65. are abnormal. for example. or planning (the Tower of Hanoi). consisting of focal atrophy with superficial cortical spongiosis. although impulsiveness. and their separation may not be clinically or pathologically feasible. The combination of phenotypes in these families suggests that the various clinical manifestations in the much more . which is often called the ‘‘dysexecutive syndrome. Sometimes. There are patients. several anatomic correlations with the behavioral variants of FTD have been attempted. Kertesz. and obsessive copying or coloring behavior with right temporal atrophy [63]. yet they can perform well on the traditional frontal lobe tests. The ‘‘apathetic inert subtype’’ may be seen at presentation or subsequent to the disinhibited behavior. The pathologic profile of FTD was originally described as a separate entity. with relative sparing of the frontal lobes. seems to be more helpful in the clinical diagnosis and even in the quantitation of severity of the illness [64]. The ‘‘stereotypic rigid subtype’’ of FTD is associated with perseverative and ritualistic behavior and tends to be associated with akinesia and rigidity early in the disease. interference (the Stroop Test). Patients may perform surprisingly well on neuropsychologic tests. gliosis. Several families with FTD have been described with linkage to chromosome 17 [68]. Another negative behavior is the lack of ability to plan complex activity or pay attention in a sustained manner so as to complete a task.506 A. Their social and personal disinhibitions are embarrassing to families. The pathologic changes tend to be in the orbital surface of the frontal lobes and the temporal neocortex.66]. such as that designed in our clinic. which may eventually resemble progressive aphasia resulting in mutism. Progressive aphasia was also renamed the left temporal variety of FTD. such as the Wisconsin Card Sorting Test.’’ a serial criminal behavior.’’ Decreasing language and communication is also part of this negative cluster of symptoms. but this is generic to all the varieties of Pick complex pathologic findings [11]. A striking disinterest in family matters or in the plight of others is sometimes the presenting feature. these variants tend to overlap a great deal. The more general Neuropsychiatric Inventory has also been used to differentiate AD from FTD but has less specific items for FTD [67]. Snowden et al [62] distinguished the ‘‘disinhibited overactive’’ variety of FTD. A behavioral inventory. which tends to be the frontal type.25. D. and semantic aphasia (dementia) in which speech output remains preserved. the aphemic variety with verbal apraxia and stuttering initially. Mesulam and Weintraub [79] found that most cases have a PiD or Pick variant pathologic profile.26. neuronal loss. Several varieties of PPA have been described. whereas the naming and comprehension of objects seem to be lost [82]. Progression of the illness results in eventual mutism in all varieties. but the pathologic or clinical features may not be typical [80]. Although much has been made of the heterogeneity of the underlying pathologic changes. with the more common nonfluent variety leading to mutism (most of the published cases). Other cases had histologic findings characterized by gliosis. There are a few cases with underlying focal AD. If one includes the cases with only focal atrophy and superficial cortical spongiform degeneration or those with motor neuron type inclusions in this group. Munoz / Med Clin N Am 86 (2002) 501–518 507 common sporadic illness are also related. Ubiquitin-positive and tau-negative inclusion bodies in the dentate gyrus and nonmotor cortex were described as a marker of this MND type of FTD [72.78]. and subcortical involvement with neuronal achromasia similar to that in CBD [9. An association of FTD with motor neuron disease (MND) has been increasingly recognized [70. but tau-negative families with motor neuron type inclusions are also described [69].23. It is defined as progressive language impairment without dementia for at least two years [75]. but even those patients who are mute may have relatively well-preserved memory and visuospatial orientation and may function surprisingly well in the community if they do not develop . pathologically.73]. layer II and III spongiosis in the cortex [77] identical to that described in FLD. and genetically. It must be kept in mind that the fluency-nonfluency distinction is relative and greatly depends on when the patient is seen in the course of the illness. When MND supervenes.76]. In the original series. however. Primary progressive aphasia PPA was described as a distinct clinical entity [8]. however. only one patient had a biopsy showing ‘‘nonspecific’’ pathologic changes with lipofuscinosis. Strong et al [74] reviewed the neuropsychologic deficit in amyotrophic lateral sclerosis. although it is recognized that other modalities are affected subsequently. particularly behavioral changes suggesting frontal deficit. Many subsequent (and preceding) cases of PPA were described with classic PiD [9. Kertesz.G.71].A. Mesulam [81] also recently argued that the syndrome is connected to FTD clinically. Some of these families have taupositive pathologic findings and tau mutation. the pathologic findings become far less heterogenous. the rapid course precludes development of full-blown FTD. The major distinction is the early loss of comprehension in semantic dementia and the early loss of fluency in primary nonfluent aphasia. isolated progressive aphasia can be seen for a decade before other symptoms develop. which is usually superimposed on memory and visuospatial loss.83]. As a result. Patients with semantic dementia become nonfluent later in their illness. without the Gallyas stain.’’ and vertical gaze palsy. At times. Kertesz. extrapyramidal complications [9. The loss of comprehension and naming and the retained fluency and repetition are distinct and could be classified as transcortical sensory aphasia. These cases often begin with difficulty in naming and comprehending single nouns—in other words. but common words seem to be involved later on. D. although the features overlap with primary progressive nonfluent aphasia and FTD. apraxia. Semantic dementia or aphasia deserves to be described separately.508 A. and the inclusions often have a ring or kidney shape and are less homogenous than in Pick bodies. The abundance of tau-positive oligodendroglial inclusions and astrocytic plaques is characteristic.90]. however. but they begin asking stereotypic questions. There are . CBD patients suffer from a dichotomy similar to that of PiD patients in that the pathologic and clinical descriptions do not fully overlap. thus. FTD and CBD. they may be difficult to distinguish. Sometimes. Munoz / Med Clin N Am 86 (2002) 501–518 the behavioral disturbance in contrast to aphasia in AD.G. CBD has certain distinctive features. ‘‘alien hand. The variety associated with MND tends to be more rapidly progressive [87].86] and even MND supervene in PPA [87]. Most of the literature concerning this condition acknowledges the clinical and pathologic overlap between CBD and PiD [91–93]. losing the meaning of words. The cortical neuronal inclusions are positive by Gallyas stain.85. The syndrome was ignored for 20 years and then resurrected using the term corticobasal degeneration or corticobasal ganglionic degeneration [89. such as ‘‘What is a steak?’’ or ‘‘What is a vehicle?’’ At first. Corticobasal degeneration When Rebeiz et al [88] described corticodentatonigral degeneration. they considered it to be a distinct entity characterized by an akinetic extrapyramidal syndrome. Similar cases were described as ‘‘loss of semantic memory’’ [84]. this occurs for relatively low-frequency words. in turn. Most of the pathologic changes are subcortical. frequently have a progressive language disturbance. In addition to the ballooned neurons (Pick cells) and superficial layer (cortical spongiosis). not only the pathologic findings but the symptomatology of PPA overlaps among the entities belonging to the Pick complex. and their speech remains quite fluent. but they recognized the similarity of the pathologic findings to those of PiD (alien hand refers to one hand interfering with the other among other phenomena). Affected patients retain good articulation and syntax. indicating a multimodality loss of meaning for objects. and the hippocampus is usually spared. Some cases have associated visual agnosia. the term semantic dementia [82. and they also develop behavioral disturbances relatively frequently. hereditary dysphasic dementia [85]. and PPA has been accumulated. Pick complex designates both the pathologic and clinical overlap between the variations. The Pick complex Because FTD is used to designate the behavioral abnormality of disinhibition dementia in most instances and the use of PiD has been accepted by many to designate a specific histopathologic profile with Pick bodies. An alternative is to use the lengthy and redundant term frontotemporal lobar degeneration [62]. Munoz / Med Clin N Am 86 (2002) 501–518 509 some case reports describing patients who presented clinically with CBD as defined by unilateral rigidity. D. Further evidence of the clinical and neuropathologic overlap between CBD. In a recent study.96. The evidence is overwhelming that CBD is also part of the Pick complex [101].78. and disinhibition dementia–parkinsonism–amyotrophy .95]. Conditions combining several features of the Pick complex continue to be published under different names. atypical presenile dementia or DLDH [6]. we suggested the term Pick complex to avoid the confusion that continues to surround the term Pick’s disease [9]. suggesting that PSP may be considered in the same biologic spectrum as CBD [102–105]. however. Typical CBD pathologic findings can be seen with a clinical picture of PPA [9.97]. It has an advantage over FTD in that it avoids the restriction of pathologic and clinical symptomatology to the frontotemporal cortex and acknowledges the relation of PiD. such as dementia with nonspecific pathologic findings. The third alternative is to return to the term Pick’s disease. There is also a significant overlap between CBD and progressive supranuclear palsy (PSP) clinically and pathologically. Kertesz. Other cases. Pick complex is a unifying concept of the overlapping clinical syndromes of FTD. regardless of the pathologic findings.A.98–100]. falls.G. and alien hand syndrome but had the pathologic findings of PiD with Pick bodies [31. Typically. PPA. this has been done with a degree of equivocation [108]. emphasizing the commonalities rather than differences between them. The increasingly frequent recognition of gaze palsy in CBD also contributes to the clinical similarities of these entities. FTD. axial dystonia. Nevertheless. to date. have a frontal type of dementia without the presenting extrapyramidal features [91. unilateral presentation of extrapyramidal symptoms in combination with apraxia leads to the diagnosis of CBD. but this term does not consider the extrapyramidal or subcortical manifestations or CBD [107]. these distinctions are not mutually exclusive. pathologically typical of CBD. we suggested that the clinical syndrome of prominent apraxia unilateral extrapyramidal syndrome with the alien hand phenomenon should be designated as CBD syndrome. and CBD with the underlying neuropathologic findings. and bilateral rigidity are considered more typical of PSP [106]. apraxia.94. 13. a revision of the mistaken belief that the disease is rare and difficult to diagnose should result in increased recognition. 4. Circumscribed cerebral atrophy Pick’s disease (PiD) Lobar atrophy Progressive subcortical gliosis (PSG) Corticodentatonigral degeneration Generalized Pick’s disease Frontal lobe dementia (FLD) Primary progressive aphasia (PPA) Corticobasal degeneration (CBD) Dementia lacking distinctive histology (DLDH) Semantic dementia Frontal lobe dementia with motor neuron disease Frontotemporal dementia (FTD) Primary progressive apraxia Nonspecific familial dementia Atypical presenile dementia Spongiform encephalopathy of long duration Hereditary Dysphasic Dementia Pallido-Ponto-Nigral Degeneration Disinhibition-Dementia-Parkinsonism-Amyotrophy . Table 1 summarizes the terms used to describe similar conditions. the entity becomes much less of a rarity. and CBD as part of the Pick complex. Nevertheless. If one considers all the cases of FTD. and we frequently continue to see suspected cases. According to some estimates. successful treatment will follow. 20. This number would be further increased by the inclusion of CBD cases. and a selection bias is playing a role in centers with an interest in the disease. and PPA reports may represent another 10%. 14. 12. 8. epidemiologic studies are lacking. half have PPA (language) presentation. The numbers match or surpass those of patients with vascular dementia. 18. and a smaller number (7%) start with the movement disorder of CBD. D. Kertesz. 16. 9. 19. the incidence of FTD may be as high as 20% of degenerative dementias [2. Approximately half of these patients have FTD (behavioral). The ratio of Pick complex to AD may turn out to be 1:4 or approximately 25% of degenerative dementias rather than the estimates of PiD based on autopsy material using restrictive histologic criteria. The percentage is higher if only presenile cases are considered [108]. with a variable amount of discussion and reference to the clinical and pathologic overlap. Admittedly. 5. PPA with and without MND.510 A. We have now examined over 150 patients with Pick complex in our clinic compared with 600 patients with probable AD. Table 1 Glossary of Pick complex 1.40.110]. 17. 15. even considering the substantial overlap with FTD. 3. 11. 2. including all pathologic variants. hopefully. Munoz / Med Clin N Am 86 (2002) 501–518 complex [109]. 6. 10. 7.G. and PTP is sometimes absent. Abnormally phosphorylated PTPs form three bands on Western blot studies with a molecular weight of 55. different band compositions are obtained from different parts of the brain [113]. There is tau reactivity in the oligodendroglial cells and astrocytic processes. Tau-negative ‘‘hereditary dysphasic disinhibition dementia’’ and some sporadic cases of DLDH with prominent language and behavioral deficits have been more recently attributed to the loss of tau in the brain. and express phosphorylated neurofilament episodes. and ubiquitin-positive and tau-negative inclusions in MND type dementia. CBD. the parkinsonismdementia of Guam (Lytico-Bodig). The amount of abnormal tau can be low in FTD. although their distinctiveness is also argued [111].’’ but we have found ubiquitin-positive and tau-negative inclusions of the amyotrophic lateral sclerosis type in many of these cases previously considered to represent DLDH [69]. but they. At times. Various distinctive features. Other monoclonal antibodies label other bands indicating variously phosphorylated amino acids [112]. Cases lacking any of these distinctive features are often labeled ‘‘dementia lacking distinctive histology. in turn. have been described. and triplets were seen in the hippocampal neurons of PSP.G. Kertesz. Sometimes. with the same effect as the tauopathies with tau-positive pathologic findings [114]. FTD has a tau triplet as in AD [112]. D. can occur with each of the other clinical varieties. Ballooned neurons or Pick cells occur with variable frequency in all varieties. astrocytic plaques in CBD. Biochemistry Pathologic tau proteins (PTPs) are biochemical markers of various forms of degenerative dementia. two bands were seen in brain stem neurons. . but they strongly predict the complex. There is also underlying neuronal loss. Neurofibrillary tangles of AD contain all six human tau isoforms. however. The superficial layer spongiosis is seen in layers II and III of the cortex in contrast to the spongiform changes of Creutzfeldt-Jakob disease. and 69 kd using certain immunologic probes in AD. which tend to be visible throughout. lack Nissl substance (neuronal achromasia) of the cytoplasm.A. which are collectively called tauopathies. PiD has 64-kd and 55-kd doublets. tufted astrocytes in PSP. Munoz / Med Clin N Am 86 (2002) 501–518 511 Neuropathologic findings The underlying commonality of Pick complex neuropathologic findings is the initially asymmetric focal atrophy of the frontotemporal regions. the clinical varieties do not predict the histologic variety. including AD. gliosis. PSP. They appear swollen pink on hematoxylin-eosin staining. and dementia pugilistica. and superficial linear spongiosis in affected cortical areas. In some studies. There is substantial overlap between all varieties of the Pick complex. As mentioned previously. Tau mutations have been discovered only in FTDP-17. and CBD and PSP have 69-kd and 64-kd doublets. such as Pick bodies. PiD. 64. The AO allele is overrepresented in both PSP and CBD [119]. but the association of apolipoprotein E4 with FTD is controversial [120]. Kertesz. several tau mutations were discovered [13. to CBD. Selective serotonin reuptake inhibitors and . Although different tau mutations differentially alter biochemical properties of tau isoforms [118]. more than 20 tau mutations in more than 50 families have been identified [117]. Normal tau proteins contribute to axonal transport by binding to microtubular protein. Treatment There is evidence that cholinergic receptor binding is decreased in PiD in affected cortical regions [121–123]. a similar interaction was found in FTD. The exon 10 splice mutations alter the ratio of fourrepeat to three-repeat tau isoforms. the term frontotemporal dementia with parkinsonism linked to chromosome 17 was accepted [68]. Serotonin and Imipramine binding were decreased in the hypothalamus and frontal and temporal lobes associated with PID [124]. with relative preservation of memory are also compatible with serotoninergic dysfunction [125].G. parkinsonism. and unbound tau becomes abnormally phosphorylated and polymerized into filaments and inclusions. making three or four repeats of the microtubular binding domain of tau. A few years later. resulting in Alzheimer-type tangles. irritability. A consensus conference summarized the clinical features of 12 families and the pathologic characteristics resembling those of the sporadic cases.115. and amyotrophy [109].116]. and 13 lead to accumulation of all six isoforms of tau. most often resulting in pathologic findings resembling those of CBD or PSP. Six tau isoforms are created by the differential splicing of exon 10. Although each family was described under different terminology (see Table 1). but they do predict the overall clinical morphologic picture resembling sporadic FTD or Pick complex. or to a predominance of three-repeat tau and Pick body dementia. Munoz / Med Clin N Am 86 (2002) 501–518 Genetics Wilhelmsen et al [12] discovered a linkage to chromosome 17 q21–22 in a large family with variable symptomatology of FTD. Mutations in exons 9. The decreased serotonin binding could correlate with the overeating and weight gain observed in some patients with PiD/FTD/Pick complex. To date. 12. Other behavioral impairments. with the same mutation often resulting in a different clinical presentation [43]. such as depression. The missense mutations disrupt the interaction between tau and microtubules. D. Tau polymorphisms from the two main haplotypes of tau were also associated with various phenotypes. these mutations do not predict the clinical presentations. aphasia. to PiD. 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New York: Wiley-Liss. 243–58. A polymorphism in the tau gene associated with risk for Alzheimer’s disease. [112] Delacourte A. et al. [119] Houlden H. et al. Ann Neurol 2001. Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau. [117] Hutton M. [121] Yates CM. [125] Mann JJ. Huang R. [113] Schmidt ML. Stanley M. ´ [120] Jesus Bullido M.518 A.55:534–9. et al.487:114–21. McBride PA. Goddhardt MJ. Bird TD.131:507–18. editors. J Clin Psychiatry 1997. Box 356465. USA b Department of Neurology. Seattle. MDa. Education and Clinical Centers. University of Washington. that ‘‘The intellect is at first unaffected.Med Clin N Am 86 (2002) 519–535 Dementia with Lewy bodies James B.’’ The French physicians Trousseau and Charcot appear to have been the first to recognize the cognitive impact of PD. Columbian Way. in part. USA d Department of Old Age Psychiatry. 116MIRECC.c. RO1-AG10845.see front matter Ó 2002. Leverenz. This work was supported by NIA U01AG06781. Seattle. MD. such as tremor and gait disturbance. Northwest Network Mental Illness and Parkinson’s Disease Research. Seattle. Wolfson Research Centre. and University of Newcastle upon Tyne. his initial description of PD specifically notes ‘‘…the senses and intellects being uninjured. Box 356560. Trousseau noted. Newcastle General Hospital. but his description was significant in bringing together the major motor manifestations of this disease. UK a Historical perspective Parkinson’s disease James Parkinson’s classic monograph of 1817 is generally considered the first full description of the clinical disorder now bearing his name. Elsevier Science (USA). McKeith. Newcastle upon Tyne. Institute for the Ageing and Health. Education and Clinical Centers. E-mail address: leverenz@u. caused by the fact that three of his six cases were ‘‘…noticed casually in the street’’ or were ‘‘…only seen at a distance. WA 98195. WA 98108. USA. 1660 S. Seattle. in his Lectures on Clinical Medicine. but gets * Corresponding author. Physicians prior to Parkinson had described various patients with components of the syndrome. WA 98195. 0025-7125/02/$ . Westgate Road. Columbian Way. 116MIRECC. Department of Veterans Affairs (JBL). All rights reserved. and NNNT Mental Health NHS Trust (IGM). 1959 NE Pacific Street. Interestingly.’’ This failure to recognize any intellectual impairment may have been. WA 98108.b. Leverenz).*. Ian G. USA c Department of Psychiatry and Behavioral Sciences.washington. FRCPsychd Department of Veterans Affairs. University of Washington.7 1 2 5 ( 0 2 ) 0 0 0 1 2 . Northwest Network Mental Illness and Parkinson’s Disease Research.edu (J. NE4 6BE. PII: S 0 0 2 5 . 1959 NE Pacific Street. 1660 S. Parkinson’s disease (PD) [1]. Department of Veterans Affairs.3 . 1. he reported a tendency to ‘‘delusions. and Greenfield and Bosanquet fully characterized the substantia nigra lesions in the brains of PD patients. Klaue. Lewy first described these intracytoplasmic inclusions in the basal forebrain (substantia innominata) [6]. Lewy neurites detected by antibody to alpha-synuclein (c. Hassler.4]. LB are often elliptical or irregularly shaped and are without a halo. . Leverenz. He did not describe.G. such Fig.B. Lewy body inclusion (arrow) in a pigmented neuron of the substantia nigra (a. any LB pathology in other regions such as the substantia nigra or cortex. hematoxylin and eosin).’’ perhaps the first description of the now well-recognized propensity for psychotic symptoms in patients with PD and dementia with Lewy bodies (DLB). This appearance of extra-brainstem LB makes them difficult to identify using standard pathological stains. I. The English physician Sir Edward Gowers later noted that there could be ‘‘mental weakness’’ and ‘‘loss of memory’’ [5].520 J. LB in the substantia nigra and other brainstem nuclei. Tretiakoff appears to have been the first to describe LB in the substantia nigra [7]. McKeith / Med Clin N Am 86 (2002) 519–535 weakened at last. such as the locus coeruleus. the patient loses his memory …precocious caducity set in’’ [2]. Friederich H. however. arrows). In addition. such as the cortex. and LB inclusions [8–11]. Lewy bodies (LB) are the characteristic pathology associated with idiopathic PD. Immunohistochemical staining of multiple Lewy body inclusions (arrows) in substantia nigra neurons using antibodies to ubiquitin (b) and alpha-synuclein (c). have a characteristic spherical appearance with an eosinophilic core and clear halo on standard hematoxylin and eosin staining (Fig. Subsequent reports by Foix. Charcot also recognized that in the later stages of disease ‘‘…the mind becomes clouded and memory is lost’’ [3. gliosis. 1a). In extra-brainstem regions. small arrows). including neuronal loss. Lewy body inclusions detected using alpha-synuclein antibodies in CA-3 neurons of the hippocampus (d. I.B. the ‘‘Lewy body variant’’ [25]. Clinical parkinsonism was also variably present. Subsequent reports by Lewy in 1923. . and they have been classified as ‘‘synucleinopathies’’ [18].13]. Others found. throughout the nervous system. These cases often had only modest. and d).20]. Dementia with Lewy bodies As previously noted. Woodard labeled cases with LB and psychiatric disease as having ‘‘Lewy body disease’’. Leverenz. the report of ‘‘Lewy neurites’’ in the CA2 region of the hippocampus of only LB-containing dementia cases suggested that these cases with combined pathology were pathologically different and therefore a pathophysiologically unique and separate disorder from Alzheimer’s disease. McKeith / Med Clin N Am 86 (2002) 519–535 521 as hematoxylin and eosin. c.19. and alpha-synuclein have been found to label inclusions and other LB-associated pathologies. 1b. Because most of these cases had concomitant AD pathology. the correct classification of cases has important implications for research on the fundamental pathogenesis of the disorders characterized by LB pathology.24]. however. 1d) [12. such as ubiquitin or alpha-synuclein. that these cases with AD and LB pathology generally had less severe AD pathology than that observed with AD alone [26]. AD pathology (senile plaques and neurofibrillary tangles) to account for the dementia. such as neurites (Fig. Hassler in 1938. Because of the diffuse distribution of LB pathology in these cases. Subsequent neuropathological reports confirmed a seemingly high frequency of LB pathology in cases of AD [23. these cases were frequently interpreted as being patients with a variant of AD. ‘‘Diffuse Lewy body disease’’ [27]. and Woodard in 1962 also noted dementia or psychiatric disorders associated with LB pathology [10. The discovery of alpha-synuclein mutations in familial Parkinson’s disease and the finding of distinct alpha-synuclein pathology in diseases such as multiple system atrophy and DLB has suggested to many investigators that these comprise a group of disorders characterized by synuclein abnormalities. In fact. In the 1970s. Although it was suggested that the difference in the diagnostic labeling of these cases with combined AD and LB pathology was semantic [28].G. Many neuropathologists now use antibodies to protein components of LB. and occasionally no. to detect extra-brainstem LB (Fig. the cases were diagnosed with ‘‘Diffuse Lewy body disease’’. several groups reported significant numbers of clinically diagnosed AD cases as having clinical parkinsonism. In addition. Research utilizing biochemical analysis and highly specific antibodies have found a number of potential protein constituents of LB [14–17]. Antibodies raised against neurofilaments. nineteenth-century French and English physicians recognized that late-stage PD patients often developed neuropsychiatric symptoms.J. both in brainstem and cortical regions. ubiquitin. The Japanese in the 1960s were the first to recognize that some patients who present with a dementia syndrome have a predominant LB pathology at autopsy [21.22]. G. it is clear that the pathology and clinical symptoms of DLB comprise a large proportion of dementia cases. getting lost in one’s own neighborhood) or on examination by the inability to perform tasks such as clock drawing or copying figures. This progression generally occurs over years. The cognitive profile of patients with DLB. Thus. Some of these cases would also fulfill pathological criteria for AD and thus would have that additional classification. Clinical diagnosis of DLB Clinical-pathological studies have revealed a complex set of clinical signs and symptoms in DLB. The clinical criteria for DLB will be reviewed in the next section. .31]. McKeith / Med Clin N Am 86 (2002) 519–535 In 1995. can be very similar to AD and in fact accounts for the frequent misdiagnosis of DLB patients as having AD [29]. Despite the lack of diagnositic clarity inherent in any disease process that is not yet fully understood.522 J. however.B. The results of this conference were published in 1996 by McKeith et al.31]. Loss of the ability to retrieve already encoded information (long-term memory) may be more severe in DLB than AD [30]. this can manifest as the loss of the ability to navigate in well-known locations (eg. It is an ongoing research objective to more fully understand the pathophysiology of DLB and thus improve the appropriate diagnostic classification scheme. Leverenz. DLB patients will also generally have more severe visuospatial dysfunction than observed in AD patients [30. Similar to AD. We will outline the cognitive. memory impairment can involve loss of ability to encode new memories (short-term or recent memory). second perhaps only to AD [13]. DLB required only the presence of LB pathology with a history of dementia. Pathologically. and motor signs and symptoms observed in pathologically confirmed cases of DLB patients and will then review the current consensus criteria used by many researchers to make a clinical diagnosis of DLB. the consensus group was unable to come to an agreement on a single disease classification of cases with both LB and AD pathology. Clinically. I. although it may proceed more rapidly than typically observed in AD. although this type of memory impairment is generally less severe than that observed in AD patients [30. behavioral. the First International Workshop of the Consortium on Dementia with Lewy Bodies met in the United Kingdom. DLB is an important focus for both research and clinical care. who outlined the consensus guidelines for the clinical and pathological diagnosis of DLB [13]. Because of the unclear pathophysiological relationship between DLB and AD. Cognitive The primary clinical feature of DLB is progressive loss of cognitive function and associated decline of social or occupational function [13]. Emotional responses can vary. This latter problem might present clinically with loss of ability to problem-solve or plan and successfully execute a task. although the bedside neuropsychological testing (eg. Thus.32]. persistent. Recurrent visual hallucinations (VH) are one of the hallmarks of DLB and are one of three core symptoms in the consensus criteria for DLB (Table 1). Patients with DLB can have episodes of severely reduced levels of arousal and also may have histories of increased somnolence. In addition to fluctuations in cognition. with patients able to describe fine details. Short Blessed) is important. Psychotic symptoms are more frequent. this pattern of neuropsychological dysfunction should increase the clinician’s suspicion of DLB. Although there is some overlap with the cognitive impairments in AD. formal neuropsychological testing can provide a more detailed profile of cognitive deficits that may be helpful in differentiating DLB from other disorders such as AD. Finally. ranging from indifference to significant distress and agitation. it is important to recognize that these cognitive differences may be most evident in the early stages of disease.G. Recent work with computerized attention and vigilance tasks in DLB patients have confirmed this increased frequency of fluctuation in performance on some tasks on a second-by-second basis [33]. Level of insight may be an important factor in the emotional response. it is worth noting that these fluctuations can be helpful diagnostically and can also account for visit to visit variability in patient cognitive and functional performance. Besides specific neuropsychological deficits.B. and tend to occur earlier in DLB patients. I. patients with DLB can also have significant problems with frontal lobe-associated cognitive skills such as executive function. the . VH are characteristically well formed in DLB. Leverenz. patients with DLB can exhibit marked fluctuation in attention and cognition with cognitive impairment alternating from near-normal performance to severe confusion within periods ranging from minutes to days and weeks [13. Neuropsychological distinctions between DLB and other neurodegenerative dementias are less clear as a patient moves into a more severe stage of disease and cognitive deficits become much broader. This is distinct from normal variations in function observed in all patients with neurodegenerative disorders in which the severity of the fluctuations are less severe and more predicable. this may appear as a decline in the ability to perform tests such as the Wisconsin Card Sorting and Trail Making Tests [30. Mini-Mental State Exam. alterations in levels of attention and vigilance are also seen. As will be discussed in the treatment section. when compared with patients with AD [35–37]. McKeith / Med Clin N Am 86 (2002) 519–535 523 Similar to patients with Parkinson’s disease.J. Behavioral Behavioral and psychiatric disturbances in dementia are a significant source of morbidity and increase the risk for institutionalization [34]. On neuropsychological testing.31]. For clinicians. Repeated falls b. Neurology 1996. Hallucinations in other modalities 4. Deficits on tests of attention and of frontal-subcortical skills and visuospatial ability may be especially prominent. and one is essential for possible DLB: a. delusions of theft) [13]. in contrast with AD where delusions are less well formed or related to misidentification or memory impairment (eg. A large crosssectional study of behavioral symptoms in DLB has revealed high frequency of apathy.G. that these latter behavioral symptoms are sufficiently unique to DLB to warrant use in diagnosis. and . rigid. Fluctuating cognition with pronounced variations in attention and alertness b. evident as focal neurologic signs or on brain imaging b. Spontaneous motor features of parkinsonism 3. patients with DLB can be bradykinetic. Neuroleptic sensitivity e. Stroke disease. When delusions occur. Leverenz. Unlike VH in delirium. Transient loss of consciousness d. A diagnosis of DLB is less likely in the presence of: a. however.524 J. Evidence on physical examination and investigation of any physical illness or other brain disorder sufficient to account for the clinical picture From McKeith IG. but with lesser frequency and with a distribution of symptoms that differs from typical PD [39]. 2. Features supportive of the diagnosis are: a. I. Recurrent visual hallucinations that are typically well formed and detailed c. It is not clear. Systematized delusions f. are less frequent and less specific for DLB. McKeith / Med Clin N Am 86 (2002) 519–535 Table 1 Consensus criteria for the clinical diagnosis of probable and possible DLB 1. et al: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. these symptoms are important as a source of morbidity and effects on caregiver burden. such as auditory hallucinations. bradykinesia.B. Two of the following core features are essential for a diagnosis of probable DLB. As with other dementias. Other behavioral symptoms are also common in DLB. anxiety. Other types of hallucinations. emotional response can be used as a guide to help determine whether psychotropic medications are required. rigidity. and postural instability) can be observed in DLB. Syncope c. Motor The four major motor symptoms of PD (resting tremor. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. 47:1114. and depression [38]. those in DLB are recurrent and not associated with a systemic illness [37]. The central feature required for a diagnosis of DLB is progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function. In particular. they are frequently complex and bizarre. Delusions are also less unique to DLB than VH. however. On the other hand. whereas resting tremor is a comparatively uncommon motor symptom. whereas other clinical features such as a focal neurological deficit or stroke make a diagnosis of DLB less likely. These core features include fluctuating cognition with pronounced variations in attention and alertness. Leverenz. The gait disturbance can include slow shuffling steps.G. Unlike PD. I. it has also been reported that some autopsyconfirmed DLB patients never exhibited motor symptoms of PD [41]. there is a high likelihood (greater than 80%) that there will be LB pathology at autopsy. Thus. Good prospective studies of the parkinsonian symptoms in DLB and other degenerative disorders are needed to further our understanding of the timing of these motor symptoms and their diagnostic utility. Consensus criteria for the diagnosis of DLB Currently. Included in the consensus guidelines are a series of supportive features. and one recent prospective study. most investigators utilize the consensus guidelines provided by the First International Conference on Dementia with Lewy Bodies for the clinical diagnosis of DLB [13]. Supportive symptoms have not. as yet. Multiple studies have examined the diagnostic accuracy of the published clinical criteria for DLB [42–49]. Most of these studies have demonstrated high specificity and positive predictive value of the criteria for the diagnosis of DLB.B. and decreased arm swing. though still lower than the specificity rates [46. Second. the clinical diagnosis of DLB is based on a set of required ‘‘core’’ symptoms and assisted by the presence of supportive signs and symptoms (Table 1).48. The first required feature is the presence of dementia. such as falls and neuroleptic sensitivity. and one of three for a diagnosis of possible DLB. in addition to postural instability. In these guidelines. however. these motor symptoms may be less responsive to dopaminergic agents [39]. en bloc turns. two of three core features are also required for a diagnosis of probable DLB. the timing of onset of motor symptoms may be an important feature in helping to distinguish DLB from other dementias.49]. In most retrospective studies. These results would suggest that the consensus DLB criteria . and spontaneous motor features of parkinsonism. Thus. the consensus criteria were found to have a relatively low sensitivity (the clinical criteria correctly identifying pathologically confirmed DLB cases) [42–45. VH. when a case of dementia is clinically diagnosed with DLB. Two other prospective studies have found higher sensitivity rates for the diagnostic criteria.J. although differences in the nigrostriatal dopaminergic systems in DLB and PD may be important [40].47]. It is worth noting that PD symptoms are relatively common in the later severe and terminal stages of several other dementias including AD and fronto-temporal dementia. The reasons for this discrepancy in patterns of motor symptoms and response to treatment are unclear. McKeith / Med Clin N Am 86 (2002) 519–535 525 have significant gait disturbance. been shown to clearly improve on the diagnostic accuracy of DLB [13]. it is important to look prospectively for the core and supportive signs and symptoms of DLB and to know that once a patient fulfills these criteria. Postmortem pathological assessment of temporal lobe volume provides a clear correlate of this with in vivo imaging data [54]. as these symptoms are difficult to operationalize. very good at correctly identifying patients who will have LB pathology at autopsy (high positive predictive value). Clinical management of DLB Clinical management of DLB patients can be very challenging. I. Dementia A focus of treatment of dementia in AD has been the reversal of the wellcharacterized loss of cholinergic activity in the brain. Ancillary studies including special imaging studies (eg. More systematic approaches to identifying fluctuating cognition may improve the clinical diagnosis of DLB.56].526 J. the patient is likely to have DLB pathologically. PET and SPECT studies show consistent evidence of occipital hypometabolism (reduced O2 uptake and reduced glucose utilization) compared with AD [55.B.G. reliable identification of fluctuating confusion and cognition may also be a problem. Additionally.58]. At this point. . in general. In addition to their dementia. in part. This lower sensitivity is likely. Exclusion of these latter patients lowers the ability of the presence of this core feature to identify patients with dementia and LB pathology [13.50]. From a clinician’s point of view. In the United States. patients develop frequent behavioral disturbances that are a source of significant morbidity for patients and are quite problematic for their caregivers. The lower sensitivity values would suggest that DLB is under-diagnosed clinically. because of the inconsistent presence of clinical parkinsonism and is exacerbated by the criteria’s exclusion of patients who present with parkinsonism more than 12 months before dementia (these patients are currently classified as PD with dementia). although there is no significant difference in the overall rate of brain atrophy in DLB compared with other dementia syndromes [53]. additional prospective investigations into the clinical characteristics of DLB should help improve our ability to accurately diagnosis DLB. McKeith / Med Clin N Am 86 (2002) 519–535 are. Several MRI studies have emphasized the relative preservation of medial temporal lobe volume in DLB compared to AD [51. Whether other ancillary studies such as spinal fluid testing will be helpful is less clear [60]. The degeneration of the nigrostriatal dopaminergic projection in DLB is demonstrable by FP-CIT SPET imaging of the pre-synaptic dopamine uptake site [57. Leverenz. Appropriate clinical management can lead to substantial improvement in the quality of life for both the patient and caregiver.52]. PET and SPECT imaging) may be particularly helpful in the future. This investigation has been proposed as a diagnostic procedure to distinguish DLB from AD [59]. Double-blind placebo-controlled treatment trials of psychotic symptoms in DLB are nonexistent (however. a more extensive literature investigating treatment of psychosis in PD. this latter finding has particular importance in the treatment of patients with DLB. in this issue) [97].B. As with other behavioral disturbances. delusions. Several open-label trials have suggested that patients with DLB can tolerate cholinesterase inhibitors. to have significant positive cognitive and behavioral effects in AD (see Bonner and Peskind. Neuropsychological tests for executive function and planning also showed significant improvement with treatment. McKeith et al found a significant positive treatment effect of rivastigmine [73]. and aberrant motor behavior. There does exist. was administered as a primary outcome measure and demonstrated significant improvement with rivastigmine treatment on ratings of apathy. Further evaluation of the cholinesterase inhibitors for patients with DLB and PD with dementia will hopefully be available in the future. Leverenz. McKeith / Med Clin N Am 86 (2002) 519–535 527 there are currently four medications (three of these in Great Britain) available to clinicians for treatment of the cholinergic deficit in mild to moderate AD (see also Bonner and Peskind. I. hallucinations. only double-blind study of cholinesterase inhibitor treatment in DLB. psychotic symptoms are associated with significant morbidity and early nursing home placement. three additional cholinesterase inhibitors (donepezil. a systematic behavioral assessment scale. All are cholinesterase inhibitors that increase availability of central nervous system acetylcholine by blocking its metabolism by the cholinesterases. The Neuropsychiatric Inventory (NPI). and episodic memory. rivastigmine and galantamine) have become available with improved ease of administration and more favorable side effects profiles than tacrine [61]. Tacrine was the first available cholinesterase inhibitor approved for use in AD in the United States in 1993. Psychiatric features Psychotic symptoms present a common and challenging clinical problem in the treatment of DLB. working memory. Chapter 12). which suggests that the newer atypical antipsychotic agents . Examination of the cholinergic system in DLB has also demonstrated a significant reduction in activity that appears to be more severe than that observed in AD [62]. Since that time. note rivastigmine trial in previous section [73]).G. in double-blind placebo-controlled studies. with few reports of worsened parkinsonism. and can have a positive clinical response [64–72]. Given the significant morbidity associated with behavioral disturbance in dementia and the high frequency of these symptoms in DLB.J. thus far. anxiety. All of these ‘‘second generation’’ cholinesterase inhibitors have been shown. Only case reports or small case series are available. These findings in DLB suggest that this group of patients may also respond well to cholinesterase inhibitors [63]. however. DLB patients treated with rivastigmine had significantly better performance on a computerized cognitive assessment system examining attention. indifference. In the first and. Treatment of psychotic DLB patients with atypical antipsychotics can be successful but can also be associated with either significant side effects.G. in that there tends to be less resting tremor than observed in PD. studies in PD suggest that even some atypical antipsychotic agents. in comparison with the almost universal response in PD [39]. The results from the rivastigmine trial would suggest that treatment with cholinesterase inhibitors might be an effective treatment for not only cognitive but also behavioral disturbances in DLB [73]. Unfortunately. Further blinded and controlled studies of atypical antipsychotic medications and cholinesterase inhibitors are needed to guide treatment strategies. Unfortunately. in DLB has not been performed and is clearly needed. given the unique motor profile of DLB patients. Based primarily on the PD literature. As a final caveat. the treatment of psychosis in DLB remains problematic. In this latter circumstance.B. The Lewy body ‘‘cluster’’ of symptoms from the NPI (delusions. I. McKeith / Med Clin N Am 86 (2002) 519–535 may be the most useful ones [74–77]. Despite the encouraging findings in the rivastigmine study. In addition. cognitive symptoms were improved with treatment. Research in DLB Clinical The focus of much of the clinical research in DLB has been on diagnostic and clinical characterization.528 J. whereas quetiapine needs further study [76]. hallucinations. As elaborated in previous sections. it generally wise to avoid medications that specifically target psychotic symptoms. Motor symptoms in DLB patients are somewhat unique. and depression) was significantly improved with treatment. such as confusion or parkinsonism.78]. In contrast with most antipsychotics. In addition. studies of treatments in PD are not necessarily applicable. treatment of parkinsonian motor features in DLB has been incompletely studied. or a lack of response. Motor symptoms As with psychosis. in some patients. and postural instability [39]. apathy. A randomized and blinded prospective study of levodopa. bradykinesia. the clinical response of motor symptoms to levodopa is modest in DLB. as can be observed with antipsychotic use. while there are similar levels of rigidity. rivastigmine was not associated in treatment with a significant increase in extrapyramidal symptoms (except for the appearance of new tremor in 4 of 59 subjects). the consensus . psychotic symptoms do not appear to be a significant stressor to the patient or caregivers. can have significant associated extrapyramidal and cognitive side effects [74. such as risperidone and olanzepine. rather than impaired. Leverenz. or other antiparkinsonian agents. clozapine may be the most effective atypical antipsychotic medication available for patients with psychosis and parkinsonism. alterations in the substantia nigra-based dopaminergic system have been demonstrated in DLB.G.B. and disruption of this system in DLB may also be important in the development of hallucinations and delusions.85]. McKeith / Med Clin N Am 86 (2002) 519–535 529 criteria for DLB have been successful in accurately identifying patients with DLB pathology. alterations in the dopamine system have been implicated in psychotic disorders. I. Norepinephrine levels are also significantly reduced in the striatum of DLB. it has been established that DLB patients have substantial loss of cholinergic function [62]. Pathological Pathological characterization of DLB using new histological techniques has been a major focus of recent clinical-pathological studies [79–81]. There is some evidence that dopaminergic changes in DLB differ from those observed in PD and may account for the differential clinical response of DLB patients to dopaminergic agents [40]. Of course. This latter problem has led to continued efforts to improve characterization of the clinical symptoms of DLB patients and to identify biomarkers that may help in improving diagnostic sensitivity of DLB clinical criteria. As already mentioned. Leverenz. and receptors for norepinephrine are abnormally increased in locus coeruleus projection sites [85.84. Understanding of the alterations of these systems including potential compensatory mechanisms . As would be expected. Neurobiological Neurochemistry Neurobiological investigations have focused on understanding the pathophysiological basis of the unique clinical symptomatology of DLB. The clinical and pathophysiologic significance of the high frequency of alphasynuclein lesions in the amygdala of AD patients remains unclear. In addition to the abnormalities of the dopaminergic and cholinergic systems in DLB.J. are complex and incompletely understood. the locus coeruleus and its neurotransmitter norepinephrine are also affected. Recent evidence suggests that specific alterations in cholinergic receptors also occur in DLB and that regionally specific alterations in receptor density are associated with delusions and hallucinations [82. with reduction in dopamine transporter sites and dopamine levels in the striatum [40. Neurotransmitter system alterations in dementia. but not as successful in identifying clinically subtle cases. and particularly in DLB. Further evaluation of alpha-synuclein pathology and examination of other pathological markers are needed (See also Neurobiology below). Neuronal counts of the locus coeruleus in DLB show a substantial loss of neurons [86].83].86]. The well-established cholinergic disturbance in DLB and the beneficial response to cholinesterase inhibitors are important findings and clues to future directions of DLB research. Biology of alpha-synuclein The discovery of alpha-synuclein mutations in a subset of cases with familial PD and the presence of this protein in LB has led to an exploration of synuclein biology in both normal brain function and in disease. Genetics Mutations in alpha-synuclein and parkin genes in familial PD would appear to be important in helping understand the pathophysiology of PD and its relationship to DLB. in fact. McKeith / Med Clin N Am 86 (2002) 519–535 will be important. PD motor symptoms are also associated with a dementing syndrome [90]. In these families. individuals have presented with PD symptoms and/or dementia. In these families with alpha-synuclein and parkin mutations. however. Identification of additional cases of familial DLB and of mutations could be critical to our understanding of the etiologic processes that lead to the development of this disease.and beta-synucleins that influence the development of LB pathology [92]. dementia was the predominant presenting symptom and LB pathology was confirmed at autopsy.and gamma-synuclein) [91]. There may. however. It is unclear at this time whether these animals will serve as useful models for the clinical-pathologic components of DLB. The frequent presence of AD and LB pathology together in familial AD would also suggest a possible pathophysiologic connection between AD and DLB [80]. such as parkin and synphilin. At this time. I. only a few families with familial DLB have been described [96].89]. Mutation in the gene is associated with a form of familial PD characterized by LB inclusions [88. insights into the pathophysiology of the synucleinopathies. Additional recent investigations have suggested an abnormal posttranslational modification of alpha-synuclein in synucleinopathies [94]. in advancing the understanding of the pathophysiology of clinical symptoms. may also play a role in the development of LB pathology [93]. there is no mutation that has been associated with DLB. Interactions between alpha-synuclein and other proteins implicated in the synucleinopathies. Alpha-synuclein appears to play an important role in normal vesicular function in the presynaptic terminals of neurons [87]. beta. in at least one of these families with an alpha-synuclein mutation. Further work in PD and DLB has also suggested a more widespread dysfunction of all of the synuclein proteins (alpha-. suggesting that the same mutation can lead to a variety of clinical phenotypes [90]. In contrast to PD and AD.B. These findings also appear to blur the distinctions between DLB and PD.G. they certainly should provide important. Transgenic mouse models are currently under development.530 J. more general. Leverenz. be critical interactions between alpha. these mice have the mutated form of alpha-synuclein inserted into their genome and have shown associated alpha-synuclein abnormalities in the brain [95]. . Interestingly. Lecture XV: Senile trembing and paralysis agitans. Contribution a l’etude de l’anatomie pathologique du locus niger [Thesis]. Tu PH. Am J Pathol 1998. A manual of diseases of the nervous system. Perry EK. London: Churchill. Trojanowski JQ. Bosanquet FD.49:387. [11] Klaue R.47:1113–24. Synucleinopathies: clinical and pathological implications. James Parkinson.16:213–26.816. Growdon W. I.J. 1995. Paris: University of Paris. 1872. Perry RH. Further research is needed to improve our understanding of the pathophysiology of this important dementing disorder. Lecons sur les maladies du syseme nerveux faites a la Salpetriere.95:6469–73. Jakes R. An essay on the shaking palsy. 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Uryu K. ophthalmology.Med Clin N Am 86 (2002) 537–550 AIDS dementia David B. The neurologic impact of HIV-1 has been recognized since quite early in the development of the clinical description of HIV infection [2] and includes opportunistic complications as well as those primarily associated with the HIV infection itself. Primary HIV-associated conditions include peripheral neuropathy. progressive multifocal leukoencephalopathy. Further. this infection affects in excess of 36 million people. USA Human immunodeficiency virus type 1 (HIV-1)–associated complications were first reported in 1981. myelopathy. and its rapid growth in the poorest parts of the world. including but not limited to infectious diseases. All rights reserved. toxoplasma encephalitis. MO 63110. oncology. immunology. and the virus was identified in 1983 [1]. Louis. Elsevier Science (USA). Clifford). and primary central nervous system (CNS) lymphoma are the most prominent of the serious secondary neurologic complications. PII: S 0 0 2 5 . Worldwide. 660 South Euclid Street. MD* Department of Neurology. St. Washington University School of Medicine. nephrology. and * E-mail address: cliffordd@neuro. threatens profound economic and political consequences while causing unthinkable human suffering. notably in Africa and Asia. it provides insights into human pathobiology that may assist in the development of treatments for many other afflictions. Box 8111. This tragic epidemic also represents an opportunity for mankind. the complicated ramifications of this infection in society seem to require that broad societal improvements be included in the response to the infection. Cryptococcal meningitis. As a model of the interaction between viral infections and hosts.7 1 2 5 ( 0 2 ) 0 0 0 0 5 . metabolism. and neurology. Improvements in general health care and in the social and economic status of the world’s peoples are required to control this epidemic. Clinical diagnosis of HIV-infected subjects must always include careful exclusion of opportunistic complications. 0025-7125/02/$ .see front matter Ó 2002.edu (D. Clifford. neurosyphilis.wustl. A detailed understanding of the manifestations of the infection is thus of considerable importance. cytomegalovirus (CMV) encephalitis and radiculomyelitis.B. gastroenterology.6 . The subsequent scientific battle that has been a major part of medicine in the past 20 years has expanded knowledge in many areas of medicine. Systematic classification of these HIV-associated cognitive processes is most widely performed using the American Academy of Neurology criteria [4]. and this sector of the epidemic has been especially hard to stem. myalgia. The latter is associated with clinical dementia that has been called AIDS dementia complex (ADC) [3]. fever. the infection is spread predominantly through heterosexual contacts and by contaminated needles most commonly used in illicit intravenous drug abuse. including fever. headaches. leading to more than a decade of asymptomatic infection in some ‘‘nonprogressors.B. in maternal milk. The success of the host immune response governs the course of untreated infection. and viral load in the serum declines to a variable degree. less complete control of the infection results in higher viral loads and more rapid onset of clinical symptoms associated with increasing immunodeficiency. The CD4 lymphocyte count declines over time in infected hosts and is a useful indicator of the degree of immunosuppression. most commonly during sexual intercourse. viral loads fall to low levels. The social stigmas of homosexual lifestyles and drug abuse have compounded the medical problems associated with the disease.538 D. Although the epidemic in the United States began with a preponderant cohort of male homosexuals. or on contaminated needles. Human immunodeficiency virus HIV-1 is an RNA virus that is spread by person-to-person tissue transfer. Behavior modification in the face of drug abuse has been particularly challenging. the spread of the virus has gradually been decreasing in the initial male homosexual cohort and more heavily affecting drug abusers and persons of both sexes. Characterization of the clinical state and outlook has been refined by the development of routine monitoring of CD4 counts and HIV RNA viral loads in the plasma. and clinical signs with weight loss. a notable increase in opportunistic infections is more commonly encountered. Clifford / Med Clin N Am 86 (2002) 537–550 encephalopathy. HIV-1 has several important characteristics that have an impact on the natural history of the infection. Effective therapy generally results in significant increases in CD4 counts (rarely to .’’ In others. In the United States. When this count falls below 200 cells per cubic millimeter. After introduction of the virus. and sometimes a rash. from mother to child. Where hosts generate a good immune response. A milder clinical presentation that may be a precursor of full-blown dementia is minor cognitive motor disorder. which is recognized by a complaint of neurologic dysfunction accompanied by changes in neuropsychologic test performance. and clinical progression is absent or slow. Other names for this condition are HIV-associated cognitive motor complex and HIV-associated dementia. during blood transfusion. globally. and thrush often develop. diarrhea. As the host immune response develops. most hosts experience a viral illness. serologic tests for HIV become positive. Motor slowing is a virtually uniform feature of this process. This step is a critical target for antiretroviral therapy. Cognitive decline is subacute with a course of at least 6 months in most cases. A depressed affect may be particularly pronounced in this setting. generally for relatively brief intervals. It generally involves the arms and legs. to the extent that clinical trial testing can be heavily weighted to timed motor tasks that reliably monitor the severity of the disorder. frank psychotic changes are observed. however) and decline of viral loads to levels that are not detectable by current RNA assays. Also important is a high mutation rate that allows rapid change in the genetics of the virus even in the same individual over time. Replication requires a viral reverse transcriptase step in which viral RNA is transcribed to DNA. Patients often discover that they have increased problems with concentration interfering with their ability to perform tasks. Rarely. and eventually concentrate on hobbies and avocations. but the performance deficits can generally be clearly separated from an affective disorder.D.B. Motor slowing affects patients’ ability to get around and to accomplish tasks as well as their independence. The virus has a half-life of only a few days in the plasma compartment. A second important aspect of HIV is the rapid and persistent rate of viral replication that typifies this infection [5]. implying that the large amount of virus correlates with a huge synthesis rate estimated at 109 to 1010 virions per day. Clinical characteristics of acquired immunodeficiency syndrome dementia complex The full manifestations of ADC are characteristic of a subcortical dementia in which cognitive decline and motor slowing are the predominant characteristics. Abrupt changes in cognition are generally not attributable to HIV itself. colored by a variable degree of behavioral change. it is possible for this virus to generate resistant versions in a distressingly rapid and efficient manner. Other neurologic manifestations that accompany ADC include some increase in the frequency of seizures and increased complaints of headache. With the high mutation rate and high turnover rate. Symmetric involvement is typical of ADC. Language involvement is variable but generally not prominent. Behavioral changes are variable. . one finds that there is often insight into the progressing cognitive decline. Clifford / Med Clin N Am 86 (2002) 537–550 539 normal levels. Patients often compensate by writing reminders and making lists. this modulating characteristic of the virus explains in part why the immune response alone is unable to control the infection and why antiviral medications cannot eradicate it. enjoy reading. which may then be inserted into the host DNA. Presumably. and any major degree of lateralized asymmetry should arouse serious suspicion that additional opportunistic processes are involved. In questioning subjects. now representing a greater proportion of AIDS-defining clinical events [7]. it complicates the disease course of subjects who often have multiple medical problems because of the broad impact of immunodeficiency. In the hippocampus. neuronal cell loss has been demonstrated in frontal [18] and temporal regions [19]. Although it may be the presenting complaint leading to the diagnosis of AIDS. Instead. The more recent introduction of highly active antiretroviral therapy (HAART) has further reduced the incidence to considerably less than 10% of AIDS patients.15]. constitutional symptoms. In advanced stages. . In HAART-treated patients.20. Similarly. Quantitatively. Cortical atrophy develops as HIV infection progresses. Pathologic characteristics and mechanisms The pathologic characteristics of HIV infection in the brain often seem to be less impressive than the functional impact would predict. Additional factors that are associated with an increased risk of dementia include anemia.540 D. The onset of neurocognitive dysfunction in HIV is likely associated with modification of synaptic architecture in the cortex [14. Advancing age has been suspected as a risk but has not been clearly demonstrated as such. dual nucleoside therapy resulted in a decline in ADC to the range of 20% [6].B. this is grossly apparent and is obvious in loss of thickness of the cortical mantle [17]. ADC has declined less than other complications. but careful analysis of the brain reveals many pathologic changes [11–13]. Further. Because ADC has the appearance of a subcortical dementia. it is notable that ADC is now encountered more commonly in patients with a higher CD4 count. Before effective antiviral therapy was developed. subsequently. Not all neuronal types are equally likely to be killed [17. however. a stereologic study demonstrated cell atrophy without loss of cell numbers [16].21]. The introduction of zidovudine (ZDV) therapy and. it has not been clear that exposure through intravenous drug use is associated with a risk different from that of sexual exposure for the development of ADC [9]. ADC developed in more than 60% of patients developing AIDS [3]. The impact of viral replication is clearly important. Dore et al [7] report that the median CD4 count in subjects with ADC rose from 70 to 170 cells per cubic millimeter after the introduction of HAART.23] is probably a common pathway for cell loss and is somehow accelerated in the setting of HIV. it is not surprising that there is ample evidence of involvement in subcortical structures. this is rarely the case. Apoptosis [22. Clifford / Med Clin N Am 86 (2002) 537–550 Epidemiology ADC is seen primarily in advanced HIV patients in whom immunodeficiency has developed. this is supported by the declining incidence of ADC with increasingly effective treatment and by the observation that ADC patients have a higher HIV viral load in the cerebrospinal fluid (CSF) than patients without ADC [10]. and wasting [8]. may not be an important aspect of the clinical syndrome. Early positron emission tomography scans demonstrated the earliest stages of ADC associated with hypermetabolism in deep gray structures [24]. they do not seem to be a source of replicative infection.D. Clifford / Med Clin N Am 86 (2002) 537–550 541 From the earliest descriptions of the brain in HIV. there is an association with multinucleated macrophages and leukoencephalopathy seen on pathologic examination. HIV is primarily replicated in monocytes and macrophages in the brain [26]. infected. In groups. including a recent report linking it to the metabolic balance of low-density lipoprotein receptor–related protein ligands as well as to direct activation of neuronal genes [32]. Pulliam et al [39] reported significant elevations of peripheral CD14/CD16 and CD14/CD69 monocytes associated with the development of AIDS dementia.37]. When messenger RNA was analyzed in brains of ADC patients. notable involvement of the subcortical white matter has been described. the protective CNS benefits for HIV therapy remain. neopterin [36. The hypothesis that the development of dementia may be initiated outside the brain would be consistent with this observation. with most evidence accruing to the impact of the envelope glycoprotein. In individual cases. tumor necrosis factor-a message was found to be most closely associated with the development of dementia [33]. and some patients with dementia have low brain viral loads. b2-microglobulin [34. but. so critical to maintaining the brain environment. Although therapeutic drug activity within the CNS seems to be of critical importance to understanding AIDS dementia treatment. with the presence of multinucleated giant cells often loaded with the virus and change in the staining characteristics of white matter being prominently described. the presence and severity of ADC correlates with the levels of productive HIV replication within the brain [27]. It is thus implied that the changes in neuronal performance that must underlie behavioral changes are indirect rather than direct. again. it has been surprising that even with regimens that penetrate the CNS and CSF compartments relatively poorly. Although astrocytes may be infected. these findings are not uniformly seen in patients with ADC. Recent evidence has linked Tat with neurotoxicity by a number of mechanisms [29–31]. In ADC. The subcortical gray matter also seems to be preferentially involved. Neurons are rarely. Portions of the HIV virus have been postulated to have critical importance. Cytokines have also been implicated in the indirect mechanisms resulting in neuronal dysfunction in ADC. Indirect mechanisms that may be responsible for this changed neuronal behavior are probably myriad. if ever. Gartner [40] has proposed the hypothesis that peripheral events may be primary in triggering . This does not mean that viral-induced changes in astrocytic function. high viral load is sometimes found without dementia.35]. and this is followed by loss of volume that is notable in MR scans when basal ganglia atrophy develops in association with ADC [25]. however. and quinolinic acid [38] have been demonstrated to be elevated in CSF in proportion to progressing ADC when other causes of activation are excluded. gp120 [28].B. and primary CNS lymphoma have notable abnormalities on MRI that should turn the clinician’s attention to these alternative causes of neurologic abnormality. and motor skills. It could be that bone marrow populations are activated in late-stage disease.542 D. including toxoplasma encephalitis and lymphoma. but it is a critical means of helping to rule out alternative diagnoses. CNS complications such as toxoplasma encephalitis. whereas neuropsychologic testing may be used to quantify performance measures. with its greater sensitivity for pathologic changes. leading to the development of monocyte subsets associated with ADC. Absence of massive space-occupying CNS lesions also augments the safety of performing lumbar puncture. CSF evaluation is important. Most HIV neurology studies have used widely available neuropsychologic tests. MR scanning is optimal for screening for other diagnoses. particularly in the white matter. although CT scanning allows reliable exclusion of most mass lesions. Diagnosis and monitoring Diagnosis of ADC is made by recognition of a compatible clinical picture in the setting of HIV infection and exclusion of alternative causes for these clinical changes. progressive multifocal leukoencephalopathy. Research criteria have been articulated in the report of the American Academy of Neurology AIDS Task Force [4]. CMV encephalitis is one of the most serious considerations in the differential diagnosis. The activated cells probably transmigrate into the brain. Recent reports suggest that focusing on white matter by the use of diffusion tensor imaging might further enhance the ability of MR to detect the subtle white matter changes caused by HIV [41]. If this were true. including representative measures of attention/working memory. Ancillary measures that are essential include brain imaging studies and CSF evaluation.B. Ideally. speed of information processing. readily setting up the physiologic changes leading to dementia. learning. peripheral control of the disease should protect subjects from dementia. Longitudinal data to assess the peripheral and CSF compartments (and the brain after death) are critical to a more certain understanding of the dynamic interaction between peripheral and central viral infection in the genesis of neurologic disease. Brain imaging is not diagnostic. MR brain scanning detects more lesions than CT. an informant should assist in corroborating the change in cognitive and motor functions typifying ADC. manifesting neurologic complications particularly in late disease. The alternative scenario that remains of great concern to investigators is that the CNS represents a distinct compartment in which HIV infection can develop less impeded by drug treatments and that it becomes the nidus of treatment failure. Cryptococcal meningitis may mimic ADC and is best excluded when cryptococcal antigen is absent from the CSF. Clifford / Med Clin N Am 86 (2002) 537–550 AIDS dementia. and it can be excluded by absence of . Recent studies with perfusion MR scanning also suggest that MR techniques allow monitoring of cerebral blood flow.35]. One of the promising means of tracking HIV brain involvement uses MR spectroscopy [45–47]. The unique aspects of the brain and CSF compartment. Therapy HIV therapy has evolved rapidly over the past decade. but elevated viral loads are not necessarily associated with dementia. ADC subjects have higher viral loads than undemented controls [10. Clifford / Med Clin N Am 86 (2002) 537–550 543 CMV DNA on polymerase chain reaction testing of CSF [42].B. . a few mononuclear cells are found (as they are throughout HIV infection). HIV viral loads have been studied in the CSF. neopterin [36. inability to completely clear this viral infection and the potential of indirect mechanisms to cause complications even when the replicative viral infection is largely controlled make it critical to continue to study the evolution of ADC in the HAART era. Typically. Correlates of ADC in the CSF include b2-microglobulin [34. CSF cannot confirm the diagnosis of ADC. which involve barriers to drug penetration and a different immunologic milieu. Advancing ADC has been accompanied by declining N-acetylaspartate and early elevations in choline reflecting neuronal loss and gliosis. Fas is involved in the execution of apoptotic programs and thus may be a rationale link to neuronal loss causing neurologic impairment. Oligoclonal bands may be found in the CSF in the setting of HIV infection but are not limited to ADC patients. Neurosyphilis should also be considered when sexually transmitted disease–related dementia is being considered. Further. and quinolinic acid [38]. make it critical to maintain additional vigilance for incongruity of response in these compartments compared with plasma.D. Improvements in general therapy for HIV have led to marked improvements in life expectancy and quality of life and have been accompanied by improvements in the neurologic complications. elevations of neopterin and b2-microglobulin correlating with increasing dementia have been reported [37]. Elevated levels of soluble Fas and Fas ligand in the CSF [44] were recently described. and CSF protein may be slightly elevated. although glucose is generally in the normal range. CSF testing for syphilis is important in excluding this consideration.43].37]. Overall. which seems to diminish as ADC progresses [49]. These elevated levels associated with ADC declined with successful treatment and decreasing viral loads. propelled by the urgent need to address this devastating viral disease. This MR-based technique allows noninvasive measurement of several brain metabolites reflecting neurons and glia. and dementia is sometimes seen in the absence of elevated viral loads. respectively [48]. because findings are nonspecific. In advanced disease. where most observations informing drug development occur. The best point after infection for initiation of therapy remains uncertain. Combivir) Nonnucleoside reverse transcriptase inhibitors (NNRTIs) • Delavirdine (Rescriptor) • Efavirenz (Sustiva) • Nevirapine (Viramune) Protease inhibitors (PIs) • Amprenavir (Agenerase) • Indinavir (Crixivan) . the goal is to achieve maximal viral suppression with minimal toxicity. For asymptomatic subjects. Most subjects should reach undetectable levels of HIV virus in the plasma with currently available HAART therapy. Combivir) Stavudine (Zerit) Zalcitabine (Hivid) Zidovudine (Retrovir. with 15 approved drugs available as follows: Nucleoside reverse transcriptase inhibitors (NRTIs) • • • • • • Abacavir (Ziagen) Didanosine (Videx) Lamivudine (Epivir. It is thus best for HIV patients to be managed by clinicians with extensive practice in this area. therapy should be offered when viral loads are high (>55. the role of therapeutic drug monitoring in dose selection.B. Evolving recommendations may be studied as they are developed by a panel of experts working with the International AIDS Society—USA (http://www. Ongoing research probes the ability of resistance testing to improve drug selection by genotypic or phenotypic techniques.org). Some of the drugs required have complicated and important drug interactions. and inevitably results in evolution of resistant virus over long periods of use. three classes of antiretroviral medications are approved. is expensive. The current trend in academic centers is moving toward delayed initiation of drug therapy because of these concerns. leading to inferior clinical outcomes.544 D. Once therapy is undertaken. This therapeutic decision must balance the rational desire to treat infections early when involvement may be minimal and complications have not occurred with the recognition that current therapy has substantial long-term toxicities. care is often suboptimal. Current recommendations suggest initiation of therapy in acute infection or symptomatic infection. and tools to enhance compliance. Currently. HIV specialists have the incentive and opportunity to stay abreast of current therapeutic knowledge. Clifford / Med Clin N Am 86 (2002) 537–550 HIV therapy is rapidly evolving.hivatis. which is absolutely essential to therapeutic success. Without this investment.000 copies per milliliter) or the CD4 count has fallen to levels less than 350 cells per cubic millimeter. Major toxicity of NRTI drugs includes bone marrow toxicity (ZDV). Because resistance tends to develop within classes of drugs. delaying exposure to other classes of drugs has a significant theoretical benefit. with more than half of subjects reporting a detectable change in sleep. lamivudine. and exploration of a triplenucleoside HAART regimen also seems to be acceptable [50]. nelfinavir. The combination therapies originally including PIs were referred to as HAART. this is mild in most cases and tolerated well enough to allow continuation of the therapy. or alertness [51]. These are potent compounds that are highly specific for HIV-1 alone. amprenavir. They are extremely important components of HAART. revolutionized HIV therapy when they were introduced. ddC. delavirdine. rashes (most serious hypersensitivity reaction with ABC). distal sensory peripheral neuropathy (ddI. including insulin resistance and the . ddI). Approved drugs in this class include nevirapine. These drugs. ritonavir. The chief toxicities of this class are hypersensitivity reactions with rashes. and hepatic toxicity. diarrhea. As potent NNRTI and NRTI drugs have been introduced. stavudine (d4T). The second class of drugs developed was the NNRTI class. and efavirenz. Metabolic complications. dreaming. and improved quality of life. Fortunately. The third class of antiretroviral agents is the PI class. Their marked efficacy when combined with NRTI drugs vastly increased the ability to achieve prolonged viral inhibition. which includes ZDV (also known as AZT). d4T. didanosine (ddI). attention. resulting in fewer opportunistic complications. zalcitabine (ddC). Gastrointestinal toxicity with nausea. including saquinavir. and lopinavir. indinavir. Long-term complications associated with these drugs in conjunction with the other antiretroviral agents are a growing source of concern. These drugs specifically block the active site of HIV-1 reverse transcriptase.B. and lactic acidosis.D. and abacavir (ABC). because resistance develops quite rapidly in monotherapy. They are drugs useful only in combinations. and hepatic toxicity has been seen with drug regimens that contain PI drugs. Improvements in the overall health of HIV patients associated with HAART are not without a price in toxicity. Symptoms tend to recede over the initial weeks of therapy. the concept of HAART has been broadened to include the numerous triple or more drug-containing regimens that typically can achieve undetectable HIV RNA viral loads. Neurologic toxicity has been the most common issue with efavirenz. pancreatitis (d4T. however. Clifford / Med Clin N Am 86 (2002) 537–550 545 • • • • Lopinavir / ritonavir (Kaletra) Nelfinavir (Viracept) Saquinavir (Fortovase) Ritonavir (Norvir) The first class of drugs developed was the NRTI class. These drugs are important components of most standard treatment combinations. Other less common neurologic toxicities include myopathy (ZDV) and headache (especially ZDV). ddC). longer life. simplified drug regimens are easier to follow and may be of particular value with cognitively impaired populations or where directly observed therapy is tried. working closely with patients to achieve the most tolerable set of medications may also pay handsome dividends in clinical success. PIs are highly protein bound and enter the CSF and CNS only in low concentrations. The study did provide evidence of ABC antiretroviral activity in CSF studies. Nevirapine seems to cross the blood-brain barrier quite effectively [54].546 D. and thus is seen as a good drug to use in this situation. At present. Extended-release forms of some of the drugs are in development. construction of a treatment program with these specific drugs is probably optimal. Clifford / Med Clin N Am 86 (2002) 537–550 development of diabetes. Achieving strict compliance with therapy is crucial to success for HIV therapy. elevated cholesterol. but d4T [52] also seems to be efficacious in lowering viral load in the CSF [52]. Design of antiviral therapy for ADC should consider other criteria as well. Because ADC seems to be triggered by HIV replication in the CNS. a placebo-controlled trial of this drug in patients with ADC failed to demonstrate efficacy when it was added to optimal therapy in the setting of ADC. efforts to enhance CSF and CNS penetration would be appropriate. the needed focus on compliance goals may threaten therapeutic success. . Nevertheless. The least protein bound of these drugs is indinavir. A supportive environment designed to ensure compliance should be sought for ADC patients. Consequently. Finally. ZDV has the best evidence of efficacy against ADC [56]. and the once-a-day dosing of efavirenz should make these formulations of particular value if they are otherwise satisfactory. If this did not occur and ADC were suspected. ABC is potent. Generally. With cognitive function impaired. As with other patients. are active areas of research associated with the use of HAART. and elevated triglycerides as well as osteopenia and lipodystrophies. Comparative trials of different antiviral regimens have not been undertaken for neurologic disease. however [57]. In the NRTI class. because the rapid turnover of the virus means that even brief lapses of therapeutic efficacy allow time for viral replication and selection of resistant mutants. a successful response in plasma is accompanied by a decline in CSF viral load as well [52]. has good CSF penetration. side effects routinely encourage noncompliance.B. selection of optimal antiretroviral therapy is an important consideration. optimizing the efficacy of the treatment for full control of the plasma viral load would appear to be the primary goal of therapy. whereas efavirenz has been documented to at least achieve therapeutic free drug concentrations in the CSF [55]. Some of these complications may combine to accelerate atherosclerosis with the risk of premature cardiovascular and cerebrovascular disease. and its CNS efficacy is better established than that of the other PI drugs [53]. Many neuroAIDS specialists are monitoring the response of HIV viral load in the CSF as a part of such therapy. thus. Use of NNRTI drugs may be of advantage in the setting of neurologic disease. edu/narc). and a larger trial is currently enrolling subjects sponsored by the Neurologic AIDS Research Consortium and the AIDS Clinical Trials Group to further investigate this drug. the brain may become a recurrent source for infection or that accelerated degenerative processes may result in more serious and common neurologic disease later in the course of infection. AIDS—the first 20 years. it remains a concern that over the extended survival time now achieved by our patients. We still are challenged by an incomplete understanding of the pattern of trafficking of the virus across the blood-brain barrier and by the potential pathologic mechanisms resulting in ADC and other neurologic consequences of infection. N Engl J Med 2001.41:778–85.neuro. and memantine [67].344:1764–72. Major questions HIV infection has resulted in many opportunities to learn more about medicine and neurology. Price RW. The belief that indirect mechanisms are important in developing the neurotoxicity underlying ADC suggests that other forms of therapy might be quite helpful. Clifford / Med Clin N Am 86 (2002) 537–550 547 At present.58–60]. Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection.19:517–24. The most promising results to date have been seen in the small trials of selegiline.14:403–18. A substantial group of small clinical trials have explored some of these mechanisms. and toxicity of viral components. [4] Working Group of the American Academy of Neurology AIDS Task Force. peptide T [63]. The AIDS dementia complex: I. et al. Updates on clinical trials for ADC may be obtained by consulting the web site of the Neurologic AIDS Research Consortium (www. clinical evidence primarily supports efforts to optimize antiretroviral therapy without clear evidence that other forms of therapy improve the outcome for patients with ADC. including gp120 and Tat [28. CPI-1189 [66]. Neurology 1991. . References [1] Sepkowitz KA. Ann Neurol 1983. Because the CNS compartment represents a challenge to treatment. selegiline [64. Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. oxidative stress. platelet activating factor–mediated neuronal injury. lexipafant [62]. including trials of nimodipine [61]. Mechanisms of toxicity for which there is at least in vitro evidence include calcium-mediated toxicity. Ann Neurol 1986.B.D. Ongoing studies focusing on the CNS and CSF are continuing to unravel the virology. Simpson DM.wustl. 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Transdermal selegiline in HIV-associated cognitive impairment: pilot. Cleveland. The clinical presentations of these diseases as well as the levels of histopathologic lesions and their distribution in the central nervous system (CNS) vary from case to case. GSS has a unique phenotype with the presence of multicentric amyloid plaques. In Fore language.4 . Cleveland. FFI is a much more recent disease that was first described in 1986 by Goldfarb and colleagues [4]. From the onset. Room 933 Biomedical Research Building.6]. Institute of Pathology. Some histopathologic features of this group of diseases are spongiform vacuolation. such as GSS. it was recognized that some of these spongiform diseases.see front matter Ó 2002. USA a Transmissible spongiform encephalopathy (TSE) is a group of rare. School of Medicine.7 1 2 5 ( 0 2 ) 0 0 0 0 4 . These variations hampered earlier histopathologic and clinical diagnose of these diseases. was first reported in the 1950s by Gajdusek [1]. human TSE diseases have been classified on the basis of pathogenic mechanisms instead of histopathologic and clinical observations [2]. ¨ and kuru. All rights reserved. Human TSE diseases were divided into three basic categories: the * Corresponding author. OH 44120-1712.cwru. CJD and GSS have been known since the 1920s [2]. In human beings. 0025-7125/02/$ . fatal neurodegenerative diseases in human beings and animals [1–3]. Gerstmann-Straussler-Scheinker disease (GSS). PhDb Division of Neuropathology. a disease confined to the Fore linguistic group. USA b Division of Neuropathology. and neuronal loss [2]. It has been suggested that there are variants in each disease [5.-S. Boon-Seng Wong.*. Sy). and Cancer Research Center. fatal familial insomnia (FFI). Institute of Pathology.Med Clin N Am 86 (2002) 551–571 Human prion diseases Man-Sun Sy. Elsevier Science (USA). E-mail address: mxs92@po. astrocytic proliferation. 10900 Euclid Avenue. OH 44120-1712. Kuru. Case Western Reserve University. subacute. In recent years. 10900 Euclid Avenue. TSE includes Creutzfeldt-Jakob disease (CJD).edu (M. occur in clusters in an inherited familial manner [2]. a tribe in Papua–New Guinea. School of Medicine. PhDa. Pierluigi Gambetti. kuru means ‘‘to tremble or shake’’ and graphically describes a symptom of the disease. PII: S 0 0 2 5 . MDb. Case Western Reserve University. surgical instruments. Based on this lead. as in 85% of human TSE cases. Subsequent studies revealed that the natural transmission of kuru most likely occurred through cannibalism. some herds of sheep were susceptible. a TSE disease [1]. however. In 1936. Gibbs and Gajdusek demonstrated the transmissibility of kuru and then of CJD in the 1960s. from human beings to primates [1.3]. major TSE diseases include scrapie in sheep and goats. which occurs sporadically via unknown mechanisms (Table 1). followed by that of GSS in 1981. Cuille and Chelle demonstrated that scrapie was a transmissible disease [8]. and the sporadic form. the infectious form. that is. Experimental transmission was most efficiently achieved by injecting homogenates into the brain of recipient animals.552 M. as in kuru and iatrogenic CJD. It was commonly thought to be a genetic disease [7]. TSE has also been found in captive animals in the zoo as well as in domestic cats. bovine spongiform encephalopathy (BSE) in cattle. In animals. and chronic wasting disease (CWD) in deer and elks (see Table 1). which was practiced as part of the funereal ceremony common to the Fore linguistic group [1]. A major breakthrough in our understanding of these diseases was the serendipitous discovery of histopathologic similarities between the brains of kuru patients and the brains of sheep and goats with scrapie. The homogenates were prepared using brains from affected subjects.-S. Sy et al / Med Clin N Am 86 (2002) 551–571 familial form. transmissible mink encephalopathy in mink. The incubation period of kuru could be as long as four to five decades [1]. whereas others were resistant. as in GSS and FFI cases and some CJD cases. hormones) Kuru (contaminated food) Variant Creutzfeldt-Jakob disease (contaminated food?) Scrapie Bovine spongiform encephalopathy Chronic wasting disease Transmissible mink encephalopathy Transmissible spongiform encephalopathy of domestic and captive animals Acquired by infection Animals Probably all acquired by infection . Scrapie has been known in the United Kingdom for more than 200 years. Cessation of Table 1 Transmissible spongiform encephalopathy diseases in human beings and animals Form Human beings Sporadic Inherited Phenotype Creutzfeldt-Jakob disease Fatal familial insomnia Creutzfeldt-Jakob disease Fatal familial insomnia Gerstmann-Straussler-Scheinker disease ¨ Undefined or mixed ‘‘Iatrogenic’’ Creutzfeldt-Jakob disease (tissue grafts. Recently. a novel form of CJD called variant CJD (vCJD) that is believed to be acquired from cattle affected by BSE (commonly known as mad cow disease) has emerged in the United Kingdom [9]. By jumping the species barrier. The mean survival time for patients with sporadic diseases is approximately . The mechanisms of neuroinvasion are not clear. geographic location. kuru can be acquired exogenously. Clinical laboratory results reveal no evidence of inflammation. It is believed that the infectious agent can travel from the peripheral to the CNS either via the peripheral nervous system or via the circulatory system [3].10]. or malfunctions of hepatic or renal systems. TSE diseases are rare in human beings. Immune responses also have not been detected in affected individuals. The infectious agent spreads from the digestive tract to the CNS. including psychiatric and behavior abnormalities. there is no conclusive evidence to suggest that the frequency of the disease is linked to gender. or environmental factors. All patients with sporadic TSE diseases suffer from cognitive deficits. Despite the relative rarity of the cattle-to-human transmission route. a process known as neuroinvasion.-S. No transmission of scrapie to human beings has yet been reported. Like other infectious diseases caused by microbes or viruses. Sy et al / Med Clin N Am 86 (2002) 551–571 553 cannibalism since the 1950s has gradually eliminated the disease. It became infectious in the 1980s when rendering plants abandoned the use of organic solvents that inactivated the infectious agent.5 per 1 million people per year. and it can also be penetrated outside the laboratory [8]. abnormal blood chemistry. This dietary supplement was contaminated by scrapieinfected ovine. a rate that has remained stable over the last few decades [2. transmission of scrapie was thought to be impossible because of the existence of this ‘‘species barrier’’ between the agent and the host. These cases represent the familial form of the TSE diseases. Scrapie has a 200-year history in the United Kingdom and is endemic [7]. Dietary supplement contaminated with scrapie-infected ovine is also the culprit for transmissible mink encephalopathy in mink and for most of the TSE cases in captive animals in the zoo. In the past. It is now clear that this species barrier can be violated in experimental animals. however. The barrier is not permanent. the infectious agent has transmitted scrapie from sheep to cattle and from cattle to human beings. Many case-control studies have attempted to identify the risk factors in these diseases [8]. experimental animal models showed that the infectious agent is highly species specific [3]. because the agent of TSE can cross the species barrier after repeat passages in the host. For sporadic diseases.M. The development of BSE in England in the 1980s has been traced to the consumption of meat and bone meal fed to cattle [9]. specifically by the ingestion of contaminated foods. Overall. TSE diseases have captured considerable attention because of their unique pathogenic mechanism and their potential threat to public health. Hence. So far. The exception occurs in cases where there is a familial link between affected individuals. The annual rate is approximately 1. occupation. the onset of disease most frequently occurs between the fifth and seventh decades of life. The electrodes were ‘‘sterilized’’ with 70% alcohol and formaldehyde vapor. The incubation period for iatrogenic diseases ranges from 6 months to 19 years. Human TSE is clearly transmissible. human TSE diseases have been acquired via infectious mechanisms. Based on studies carried out over a span of 30 years involving 300 cases of human TSE and close to 2000 primates. Similar to patients with sporadic disease. have a shorter incubation period. These cases are commonly referred to as iatrogenic CJD [2]. and most patients die within 1 year. The inherited form of the diseases has an earlier age of onset and a more protracted disease course than the sporadic form [2]. patients with iatrogenic disease develop ataxia and movement disorders followed by dementia. Extracranial infections. the risk of contracting TSE as a result of surgery must be low. Transmission best correlated with the presence of spongiform pathologic findings . These variations reflect differences in the levels of exposure as well as in the route of infection. tend to have a much longer incubation period.L. personal communication. but the rate of transmission from human beings to primates varies from disease to disease. It is presumed that the dura maters and the hormones were harvested from donors who might have died of unrecognized TSE diseases. Sy et al / Med Clin N Am 86 (2002) 551–571 5 months. as in the cases of electrode implantation or dura mater transplants. Human transmission was most convincingly demonstrated when TSE disease developed in two young patients who underwent stereotactic electroencephalographic exploration with silver electrodes. Furthermore. 2001). All seven patients are unrelated. Intracranial infections. Brown and colleagues [11] found that the transmission rates were higher for iatrogenic CJD (100%). At variance with other neurodegenerative diseases. Masters.000 in Australia (C. More recently. Physicians have also inadvertently transmitted the disease to patients as a result of medical procedures. and duration of the iatrogenic form of the diseases are much more variable than those of either the sporadic form or the inherited form. frequency. Nevertheless. as most vividly demonstrated by kuru. more than 80 cases of iatrogenic diseases have been reported after neurologic transplants of human cadaverderived dura mater. More than 100 cases of iatrogenic diseases have also been linked to injection of cadaver-derived growth hormone and gonadotropic hormone [2]. as in the cases of growth hormone injection. and sporadic CJD (sCJD) (90%) and lower for the familial form of diseases (68%). The onset. It is clear that TSE can be transmitted by invasive medical procedures under some conditions. based on the number of surgical procedures that have been carried out and the number of iatrogenic TSE cases that have been reported.-S. and the common feature of the group is that three of the seven patients have visited the same ophthalmologist. The electrodes had previously been implanted in a patient with TSE disease [2]. a cluster of seven TSE cases surfaced in a small village with a population of approximately 70.554 M. which was sufficient to eliminate microbes and viruses but did not destroy the TSE agent. kuru (95%). The brain. Later. It has been known since 1936 that scrapie is a transmissible disease. The confusion and frustration are best summarized by the names assigned to this elusive pathogen (eg. A number of CJD patients have been known to donate blood over extended periods of time. This observation is consistent with the findings of epidemiologic studies. spinal cord. in experimentally infected animals. The normal human cellular prion protein (PrPC) is encoded by a single gene in the short arm of chromosome 20 [13]. and infectious) are believed to share the same pathogenic mechanism. It was resistant to agents that destroy nucleic acids but was sensitive to agents that destroy protein [3]. In contrast. which is based on the conversion of the normal PrPC into the pathogenic prion protein (PrP). and many positive reports were never confirmed [3]. although the infectious agent has been reported to be present in non-CNS locations. The infectious agent was too small to carry nucleic acid and tended to copurify with proteins [3]. slow virus. PrPSc has the unique and fundamental property of being . Sy et al / Med Clin N Am 86 (2002) 551–571 555 (80%). In 1982. there is no evidence to suggest that the agent is present in the blood of affected human beings. infectivity in other tissues was much lower and was only detectable in a limited number of inoculated animals. Since then. and eye consistently have the highest infectivity [11]. commonly called scrapie PrP (PrPSc). however. Prion concept and protein-only hypothesis In 1967. the most susceptible host. Accumulated evidence suggested that the infectious agent in scrapie was highly unusual. The absence of spongiform change was a better indicator of nontransmissibility. As a result. No infectivity has ever been detected in any body fluids. Prusiner [3] made the fundamental discovery that led to our current understanding of these diseases. Neither patients with hemophilia nor intravenous drug users have increased risk. Many attempts to isolate the pathogen were unsuccessful. virino. Griffith [12] was the first to propose that the agent for TSE is a self-replicating protein rather than a bacteria or virus. simply. the same group found that the prion is an aberrant isoform of a protein that is normally expressed and highly conserved in all mammals [13]. The nature of the etiologic agent remained elusive and controversial until the mid-1980s. sporadic. which have failed to uncover any link between blood transfusion and human TSE to date [9]. Stanley Prusiner and his colleagues isolated and tentatively identified the infectious pathogen.M. virods [plant virus] or. All three forms of prion diseases (hereditary. including blood.-S. The tracking of the blood recipients has failed to uncover any development of CJD in this group so far [9]. which they termed a proteinaceous infectious particle or prion. including the transfusion of full units of blood from CJD donors into chimpanzees. unconventional viruses) [3]. Therefore. however. the name prion disease has been used synonymously with TSE. however. which has two highly conserved nonobligatory N-linked glycosylation sites and a disulfide bridge between residues 179 and 214 (Fig. Pathogenic mutations are broadly divided into those that cause point mutations and those that cause insertion mutations in the coding region. Two different lines of evidence provide the strongest support for the prion concept. In the human brain. can be inherited in an autosomal dominant fashion [2]. but only the CNS has the capacity to accumulate PrPSc. PrPC knockout mice that do not express PrPC are resistant to infection [14]. It has been known for decades that some human spongiform diseases. which is located approximately between amino acids 110 and 125. PrPC is expressed at high levels in many non-CNS tissues. which migrates at 27 kd . 1) [3]. Some skeptical investigators still question whether prion by itself is sufficient for the pathogenesis of the diseases [15]. PrPC is a small glycoprotein bound to the cell surface by a glycosyl-phosphatidyl-inositol (GPI) anchor [16]. lymphoid tissues. and (3) the unglycosylated form. the brain is the only site where the conversion from PrPC to PrPSc could occur. can be arbitrarily divided into three subregions: (1) the N-terminus region. FFI. (2) the monoglycosylated form.556 M. The first line of evidence came from studies in transgenic animals. Whereas it is generally accepted that normal cellular PrPC is critical for the pathogenesis of prion diseases. PrPC is expressed in three glycoforms [5]. and (3) the C-terminal region. In all human prion diseases. which migrates at 33 to 42 kd. which encompasses approximately the first 90 amino acids and has a highly conserved motif of five repeating octapeptides. Sy et al / Med Clin N Am 86 (2002) 551–571 a self-replicating and infectious agent that lacks nucleic acid. The mechanism by which PrPSc targets the CNS is not known.-S. It is believed that these three glycoforms represent: (1) the diglycosylated form. more than 20 pathogenic mutations have been found in the coding sequence of the PrP gene in patients with the inherited form of the diseases [3]. which includes 209 amino acids (residues 23–231). the mechanisms by which PrPSc causes neurodegeneration remain unclear. it should be noted that the prion concept or the ‘‘protein-only hypothesis’’ is not universally accepted. Although the conversion hypothesis provides a mechanism for the propagation of PrPSc. Normal cellular prion protein In human beings. conversion may occur in other tissues. The identification of the prion gene suddenly permits investigators to determine whether any of the inherited forms of human prion disease are linked to the PrP gene. Indeed. no PrPSc has ever been detected in non-CNS tissues. such as GSS and. and muscle [3]. The second line of evidence came from clinical studies in human beings. with the exception of vCJD. The full-length PrPC. Pathogenic mutation represents approximately 15% of the human prion diseases. which migrates at 29 kd. In addition to the CNS. the presence of the PrPC is essential for PrPSc propagation. (2) the central region. more recently. Therefore. Alternatively. Therefore. including the heart. 2). This variety indicates that the glycans play a complex role in the physiology of PrPC and may be important in the pathogenesis of the diseases [18]. The normal cellular prion protein can be divided into three regions: the N-terminus region. The N-link glycans are complex. and the C-terminus region. PrPC knockout mice are normal. 2) [23]. the PrP is inherently unstable. and other intermediate conformers. and the a-helix decreases to 30%. and b-sheet structures are located in the C-terminus as well as two potential Nlinked glycosylation sites and the disulfide bonds. Recent in vitro and in vivo studies suggest that PrPC is a metalbinding protein and may be important in oxidative stress responses [22]. which form a well-structured core domain when combined (see Fig. Most of the secondary structure elements. which leads to the formation of new PrPSc through an autocatalytic process [3].’’ recruiting the unstable PrP forms. the a-helices. as exemplified by the murine PrPSc. PrPC has 42% a-helix content and 3% b-sheet content.-S. Sy et al / Med Clin N Am 86 (2002) 551–571 557 Fig. the C-terminus region includes three a-helices and two short antiparallel b-strands. In contrast. According to the most recent model. fluctuating between the dominant native state. PrPC. (Fig. the b-sheet content of infectious PrPSc increases to 43%.20]. This structure then acts as a ‘‘seed. It also shows that the central region is partially structured and hydrophobic. thus. PrPSc. Nuclear magnetic resonance analysis of recombinant PrPC shows that the N-terminus region is highly flexible. 1) [19. The exact cellular compartment where the conversion processes takes place is not clear. the central region. one or more of which can self-associate to produce a supramolecular structure. expression of PrPC is not obligatory for survival in mice [21]. Diagrammatic representation of human prion protein after posttranslational modifications.M. The initial interaction between infectious PrPSc and PrPC . Pathogenic mechanism: conversion of normal cellular prion protein to scrapie prion protein The PrPC-to-PrPSc conversion is based on a conformational change from the predominantly a-helical structure of PrPC to the predominantly b-sheet structure of PrPSc (see Fig. In contrast. which has over 60 different carbohydrate structures [17]. 1. The accumulation in the brain of PrPSc that is resistant to proteases has . One of the consequences of the conformational change is that although the N-terminal region of PrPSc remains sensitive to treatment with proteases. the C-terminal region from residues 80 to 231. NY: Cold Spring Harbor Press. The GPI anchor may be needed. however.558 M. In contrast. Extensive cell model stud ies support this interpretation [27]. Cold Spring. also known as PrP27–30. because GPI-anchored proteins occupy microdomains on the cell membrane known as detergentinsoluble complex in a concentrated and multimeric form. The conformational changes in PrPSc also result in drastic alterations in its biochemical properties. 1999. Disulfide bonding is also important in the conversion process [26] and seems to be inversely related to the glycosylation in PrPC [18]. Prion biology and diseases. Some of these changes are summarized in Table 2. Sy et al / Med Clin N Am 86 (2002) 551–571 Fig. the entire PrPC is protease sensitive. The presence of the GPI anchor is important for the conversion processes to occur [16]. 1–68. Indirect evidence suggests that the conversion process requires PrPSc to interact with PrPC either directly or through the ‘‘help’’ of protein X or chaperones [28]. The PrPC-to-PrPSc conversion is based on the change in conformation from the predominantly a-helical form of PrPC (light ribbons) to the predominantly b-sheet structure of PrPSc (dark ribbons). a molecular chaperone has not been identified. An introduction to prion biology and diseases. To date.) is believed to occur first in the plasma membrane and then in the endosome [24]. Ribbon models of the tertiary structures of hamster cellular prion protein (PrPC) (A) and scrapie prion protein (PrPSc) (B) based on nuclear magnetic resonance studies of PrP108– 231 and major biochemical differences between PrPC and PrPSc. p. editor. with permission.-S. Conversion of PrPC by exogenous PrPSc has been demonstrated in vitro in a cell-free system [29]. becomes protease resistant. 2. In: Prusiner SB. (From Prusiner SB. the process is inefficient because of the absence of cofactors or the chaperone protein [30]. and the detergent-insoluble complex may facilitate the initial interaction [25]. 31]. provided a useful diagnostic test for prion diseases [6. Sy et al / Med Clin N Am 86 (2002) 551–571 Table 2 Differences between normal human cellular prion protein and scrapie prion protein PrPC Monomer More a-helix Relatively more soluble in detergent Sensitive to in vitro digestion with proteinase K Noninfectious Present in CNS and many non-CNS tissues PrPSc 559 Oligomeric or polymeric More b-sheet Less soluble in detergent Relatively more resistant to proteinase K Infectious Only in CNS Abbreviations: PrPC. In a small number of cases. all samples were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunoblotted with an anti-PrPC monoclonal antibody as described [47]. Resistance to PK is the only in vitro test by which one can distinguish PrPSc from PrPC. lanes 7 and 8 from CJD). After treatment. Brain homogenates were prepared from two nonCreutzfeldt-Jakob disease (CJD) cases and two confirmed CJD cases. central nervous system. Sensitivity to PK in vitro is relative rather than absolute. no PK-resistant PrPSc was detected [32]. 3. PrPSc. Each sample was divided into two tubes: one sample was either not treated (lanes 1 and 2 from non-CJD. the presence of PKresistant PrPSc might not be required for pathogenesis in some situations. lanes 5 and 6 from CJD) or treated with PK (lanes 3 and 4 from non-CJD.M. normal human cellular prion protein. and the levels of PK-resistant PrPSc vary greatly between different prion diseases. . 3). The commonly used protease is proteinase K (PK) (Fig. In contrast. Resistance of scrapie prion protein (PrPSc) but not cellular prion protein (PrPC) to proteinase K (PK) digestion in vitro. Therefore. strong immunoreactivity remained detectable after PK treatment of samples from CJD cases (lanes 7 and 8) (unpublished results) [47]. CNS. scrapie prion protein. No immunoreactivity is detected in non-CJD samples after PK digestion (lanes 3 and 4).-S. Brown and colleagues [11] have also evaluated the relation between transmissibility of diseases and the presence of PK-resistant PrPSc in human Fig. In the hereditary form. This discrepancy may be a result of the presence of variable amounts of PrPSc in the different parts of the brain that were used for in vivo transmission and in vitro immunoblots. NY: Cold Spring Harbor Press. which is based on the conversion of the endogenous PrPC (or its conformational variants) into PrPSc [2]. Although resistance to PK is a reliable diagnostic test for human prion diseases. Alternatively.) . Goldfarb L. Most of the point mutations are located in the C-terminal regions of the PrP protein (Fig. Cold Spring. This mutation destabilizes the mutant PrP and facilitates its inevitable conversion to PrPSc [2]. and posttranslational modifications. and infectious) are believed to share the same fundamental pathogenic mechanism. with permission. (From Gambetti P. In: Prusiner SB. More than 20 pathogenic mutations have been found in the human PrP gene. 1–68.560 M. sporadic. p. Capellari S. Petersen RB. Only laboratories with the necessary expertise can perform the test. editor. S-S ¼ disulfide bond. H ¼ a-helix. 4. Accumulated evidence also suggests that the conversion involves one or more intermediate conformers [32]. including mutations. 1999. the disease is believed to be triggered by the presence of a germline mutation in the PrP gene. b ¼ b-sheets. Sy et al / Med Clin N Am 86 (2002) 551–571 prion diseases. Prion biology and diseases. secondary structures. Parchi P. Approximately 80% of the transmissible cases contain PKresistant PrPSc. the in vivo bioassay may be much more sensitive than the in vitro immunoblots. which represents about 15% of human prion diseases. Mutations resulting in the heterogeneous and Gerstmann-Straussler-Scheinker ¨ disease phenotypes are indicated below the diagram. it is time-consuming and technically demanding. a fact that has been demonstrated in animal models. This residue is normally removed during the Fig.-S. Mutations resulting in Creutzfeldt-Jakob disease and fatal familial insomnia as well as polymorphisms (long arrows) are indicated above the diagram. Another pathogenic mutation has been identified in the GPI anchor signaling peptide at residue 231. Chen SG. Inherited prion diseases. polymorphisms. CHO ¼ N-glycans. All three forms of prion diseases (hereditary. Diagram of prion protein (PrP). et al. A pathogenic point mutation in residue 145 has been found to result in the generation of the stop codon and in premature termination of the PrP. 4). transgenic mice lacking the N-terminus are susceptible to infectious PrPSc. One of the most intriguing findings regarding the inherited form of prion diseases comes from studies revealing that a common polymorphism in aminoacid residue 129 of the human PrP gene can greatly modulate disease phenotypes [4]. The mechanisms by which residue 129 influences the disease phenotype are not clear.-S. which leads to the formation of PrPSc. As a matter of fact. Two groups of patients were identified with an identical mutation in residue 178 with a change from aspartic acid to asparagine. Lesions were less severe in the thalamus. with extensive spongiosis. Experimental mutations of the PrP gene in some transgenic mice have led to neurodegeneration in the absence of detectable PrPSc [35]. It is unclear whether PrPSc is solely responsible for all aspects of the pathogenesis and whether all hereditary prion diseases share the same pathogenic mechanism.M. Goldfarb. The clinical presentations and histopathologies of the two groups differed dramatically. insertion mutations have only been found in the octapeptide repeat region [33]. neuronal loss. An individual can be homozygous with methionine (M/M) or valine (V/V) or heterozygous (M/V). These results suggest that a mutation in the PrP gene may not be sufficient to cause neurodegeneration and that other factors unique to human brain may be required for the manifestation of the disease. Also noteworthy. Microsatellite analysis searching for E200K mutation–associated haplotypes reveals that this mutation is derived from two families. and astrogliosis in the cerebral cortex region. It should be noted that another transgenic mouse line bearing the same human pathogenic mutation failed to develop neurodegeneration [36]. Sy et al / Med Clin N Am 86 (2002) 551–571 561 attachment of the GPI anchors to the protein and is absent in the mature protein. the phenotype was that of FFI. personal communication. 2001). Sixty percent of pathogenic mutations found in human prion diseases involve residue 200.G. In the group with the 129 V/V genotype. In the group with the 129 M/M genotype. the phenotype was more consistent with CJD. All E200K cases reported in the United States and Canada are descendants of the Slovakia family. one in Spain and the other in Slovakia. Conversely. deletion mutation in the same region does not. albeit at a reduced efficiency [34]. Collectively. these results suggest that there are multiple pathways in the pathogenesis of the inherited form of human prion diseases. whereas the Spanish family is the origin of the cases in Europe (L. with preferential thalamic and olivary atrophy. a single octapeptide repeat deletion is a polymorphism in 1% to 2. The number of insertions ranges from one to nine octapeptide repeats. which results in a change from glutamine (E) to lysine (K). . The reason for this discrepancy is not known. however.5% of the population [2]. It is interesting to note that although insertion mutations in the octapeptide repeat region cause diseases. Sporadic prion diseases are thought to be triggered by a rare and stochastic change of the PrPC conformation. These findings show that a difference in one amino acid can drastically alter disease phenotype. The mechanism by which the PrPSc travels from the peripheral to the CNS is not clear. one cannot rule out the possibility that some sporadic prion diseases may be caused by non-germline mutations or by unrecognized infectious mechanisms. Most of the sCJD patients are homozygous with M/M or V/V [10]. Accumulated evidence in animal models suggests that the successful transmission of a prion disease depends on several factors: (1) the degree of homology between the exogenous PrPSc and the PrPC of the recipient. Ann Neurol 1999. V/V represents 12% of cases. the frequency of M/M is 37%. and (3) the expression of PrPC at the portal entry of the exogenous PrPSc as well as in the various intermediate stations between the portal entry and the CNS of the recipient. all vCJD cases so far were from individuals homozygous with M/M at residue 129 [9]. Interestingly. methionine. Sy et al / Med Clin N Am 86 (2002) 551–571 Even so. Windl O. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. and the remaining 51% of cases are heterozygous (Table 3). Once the initial conversion occurs. Other investigators believe that blood cells are involved in the process. it is the endogenous PrPSc that propagates and accumulates. The first confirmed vCJD case was reported in 1996. Data from Parchi P. valine. with permission. Giese A. Prion diseases contracted by an infectious mechanism are believed to result from exposure to exogenous PrPSc. suggesting an incubation period of approximately Table 3 Polymorphism at amino-acid residue 129 and incidences of sporadic Creutzfeldt-Jakob disease 129 Genotype Normal Sporadic M/M 37% 71. Accumulated results suggest that homozygosity at residue 129 predisposes an individual to prion diseases. (2) the dose of the PrPSc. which may be necessary for the initial binding. . Rise of variant Creutzfeldt-Jakob disease BSE was first reported in 1986 in England [9].7% V/V 12% 16. Schulz-Schaeffer W. Homozygosity presumably provides more PrPC substrates with similar conformation for conversion. In the general population. the 129 polymorphism also influences the incidence of sCJD in Caucasian patients. Some investigators believe that the peripheral nervous system is the route of PrPSc entry into the CNS. Brown P. In contrast. it suggests that residue 129 is important either directly or indirectly in the overall conformation of PrPC. which binds to endogenous PrPC. et al. causing its conversion to PrPSc [3].562 M. If this interpretation is correct.7% Abbreviations: M. Capellari S. heterozygous individuals have two different PrPCs with different conformations.46:224–33. V. Either individuals with M/M are uniquely susceptible to vCJD or other genotypes are also susceptible but with a much longer incubation period. Interestingly.6% M/V 51% 11. causing the disease.-S. variant Creutzfeldt-Jakob disease. CWD was first recognized as a prion disease in deer and elks in 1980. Available evidence does not indicate that the prion disease was acquired via exposure to CWD through the consumption of contaminated deer or elk meat. Since 1996. CWD is endemic in north central Colorado and southeastern Wyoming. which set this disease apart from conventional CJD. appendix) of vCJD patients but not in patients with conventional CJD [8. however. age at onset of the disease. PK-resistant PrPSc is detectable in non-CNS tissues (eg. and CNS pathologic findings seen in patients with vCJD differed greatly from those seen in patients with conventional CJD. or V/V 60 years old 5 months No ‘‘daisy’’ plaques Type 1 or 2 None vCJD M/M only 29 years old 14 months Plaques with ‘‘daisy’’-like feature Type 2 only In tonsil and appendix Abbreviations: sCJD. In addition. M/V. PrPSc. suggesting that similar pathologic mechanisms are involved in these two diseases (ie. PrPC. sporadic Creutzfeldt-Jakob disease. Table 4 Differences between sporadic Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease sCJD Residue 129 genotype Disease onset (mean age) Mean duration of disease CNS histopathology PrPSc type PrPSc outside of CNS M/M. scrapie prion protein. The unusual clinical signs of vCJD patients are prominent behavior changes at the time of clinical presentation. close to 100 confirmed cases of vCJD have been reported. four cases of prion disease in unusually young patients have been reported [39]. normal human cellular prion protein. followed by ataxia. dementia. and myoclonus at the terminal stage of disease. No vCJD has been reported in the United States. . vCJD. PK-resistant PrPSc is detectable in tonsil before the manifestation of clinical signs. tonsils. CNS. consumption of contaminated meat or meat products).M. At least three of these patients (whose tissue has been examined by us) had regularly consumed deer or elk meat. M.38]. but considerable evidence points to BSE [37]. Some of the differences between vCJD and conventional CJD are summarized in Table 4. methionine. most of which occurred in the United Kingdom with a few exceptions [9]. (3) the similar histopathologic lesion profile in mice inoculated with either BSE or vCJD preparations. V.-S. Early on. valine. Interestingly. however. The histopathologic changes seen in the vCJD cases are reminiscent of those seen in kuru. and (4) the similar ‘‘molecular signatures’’ shared between BSE and vCJD. Four major lines of evidence associate vCJD with BSE: (1) the outbreak of vCJD with a time delay from and in the same geographic location as the BSE epidemic. Sy et al / Med Clin N Am 86 (2002) 551–571 563 10 years in vCJD. central nervous system. it was recognized that the clinical signs. (2) the distinct clinical features of vCJD. The origin of the infection in vCJD has not been firmly established. 94). PrP from four of the sporadic Creutzfeldt-Jakob disease cases was indistinguishable from that of the control sample. and immunoblots were carried out as described. Molecular and biochemical typing of human prion strains Early on. in turn. with permission. the unglycosylated form of scrapie prion protein type 1 migrated at approximately 21 kd. type 1 PrPSc migrates at 21 kd and type 2 PrPSc migrates at 19 kd (Fig.564 M.004). Aberrant metal binding by prion protein in human prion disease. which. Recent reports indicate that the size of the PK-resistant PrPSc fragment and the ratio of the three glycoforms vary depending on the type of prion diseases or the strain of prion. Xie Z. reflects the size of the main PrPSc fragment generated by PK digestion in vitro [6]. Separated proteins were then transferred onto nitrocellulose membranes and blotted with anti-prion protein (PrP) monoclonal antibody 8H4 as described [47]. each strain of scrapie produces characteristic pathologic lesions and has a distinct incubation time. Because of the small sample size. Two major types of PrPSc have been identified in human prion diseases based on electrophoretic mobility. Molecular typing of human prion stains. whereas that of type 2 migrated at approximately 19 kd. 5). After electrophoresis. this study should be duplicated before drawing any definitive conclusion. Chen SG. J Neurochem. (A) Brain lysates were prepared and separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis. When inoculated into susceptible animals. 5. Pan T.) . (B) Aliquots of lysates were treated with 50 lg/mL of proteinase K (PK). Colucci M. with individuals who eat venison at least once per year having an eightfold increased risk of sCJD compared with individuals who never eat venison (P ¼ 0. et al. After PK treatment. Sy et al / Med Clin N Am 86 (2002) 551–571 Can sCJD also be caused by ingestion of infected meat? Case-control studies involving 206 cases of sCJD disease identified between 1990 and 1997 in England have provided statistical evidence that the risk of CJD increases with the frequency of consumption of certain types of meat [40]. Li R. it was recognized that the infectious agent of scrapie exists in multiple strains in a manner similar to microbes and viruses. Fig. (From Wong BS.-S. in press. The greatest odds ratio is for venison (odds ratio ¼ 7. 4% 54. which results in the exposure of different PK cleavage sites. Giese A. Some of the clinical and pathologic features of these six phenotypic variants are summarized in Table 6. et al.46:224–33.M. The differences in the size of the PK-resistant fragments along with differences in glycosylation may account for some of the heterogeneity seen in the clinical presentation of the human prion diseases.9% 14. Sy et al / Med Clin N Am 86 (2002) 551–571 565 Microsequencing shows that PrPSc type 1 is cleaved by PK at (or around) residue 82 and that PrPSc type 2 is cleaved at (or around) residue 97 [6]. This analysis provides a classification of disease variants based on biochemical analysis rather than on histopathologic and clinical evaluations. metals. Hydrogen peroxide (H2O2) is the most common ROS. Capellari S. the biochemical pathways that lead to neurodegeneration remain unknown. such as Alzheimer’s disease and Parkinson’s disease. with permission. Both PrPSc type 1 and type 2 have been transmitted to transgenic mice and are considered to represent human prion strains. play a critical role in the pathogenesis of neurodegenerative diseases.4% V/V 1.6% Abbreviations: M.7% 31. They subdivided 300 cases of the most common sporadic diseases into six phenotypic variants. as well as in experimental prion diseases [41]. five distinct subtypes of CJD. . Ann Neurol 1999.0% M/V 3. This difference in size is likely caused by conformational differences between these two prion strains. and prion diseases It is clear that PrPC and PrPSc are important in the pathogenesis of prion diseases. methionine. Approximately 95% of the subjects with PrPSc type 1 are homozygous for methionine at 129 (M/M). Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Oxidative stress is an abnormal physiologic condition caused by overproduction of reactive oxygen species (ROS) [41]. Windl O. ROS is generated during normal metabolic processes such as the reduction of oxygen to water by the mitochondrial Table 5 Preferential association of type 1 diseases with methionine/methionine homozygous and Type 2 diseases with valine/valine homozygous 129 genotype Type 1 Type 2 M/M 94. V. valine. Nevertheless. It has been speculated that metallochemical alterations. Schulz-Schaeffer W. Parchi and colleagues analyzed the physiochemical properties of PrPSc in conjunction with the 129 genotype. Brown P.10]. and the sporadic form of FFI. whereas 86% of those with the type 2 are either homozygous for valine (V/V) or heterozygous (M/V) (Table 5). which result in oxidative stress. The type of PrPSc also correlates with the 129 genotype [6. Oxidative stress.-S. Data from Parchi P. The MM. Ann Neurol 1999. More interestingly. Recently.3 15.46:224–33. such as proteins. Capellari S. this SOD-like activity is lost when Cu is replaced with manganese (Mn) [43]. electron transport chain. we observed a striking elevation of Mn accompanied by a significant reduction of Cu bound to PrP in all . Both recombinant PrP and brain-derived PrP have been reported to have SOD-like activity when they carry bound copper (Cu) [42]. The numbers (1 or 2) are the PrPSc types as determined by immunoblots. with permission. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Brown P. VV represent 129 genotype. Giese A. MV.3 17. valine. they were grouped together. We found that the levels of protein oxidation and lipid peroxidation were greatly increased in the brain of all sCJD cases [44]. V. They can readily combine with other molecules. Overproduction of ROS may be attributed to either an increase in pro-oxidant activity or a decrease in antioxidant availability.-S. and nucleic acids. MM1 and MV1 cases have similar phenotypes.9 6. PrPSc. two families of molecules tightly regulate the levels of ROS: the pro-oxidants and the antioxidants. ROS can also chemically modify proteins and lipids.6 67% 0% 0% 17% MV2 23 59. Sy et al / Med Clin N Am 86 (2002) 551–571 Table 6 Some of the clinical features at presentation and immunohistochemical staining patterns of the five subgroups of sporadic Creutzfeldt-Jakob disease and sporadic fatal familial insomnia cases based on 129 genotype and type of scrapie prion protein Subtypes of sporadic human prion diseases MM1/MV Number of cases Age of onset (years) Duration (months) Cognitive loss Myoclonus Aphasia Insomnia PrPSc staining pattern in immunostaining Synaptic Cerebellar kuru plaques Plaque-like deposits 186 65. ROS are potentially quite toxic to cells. methionine.5/62. we investigated whether these markers are detectable in sporadic human prion diseases. Attack by ROS can result in breakage of proteins and nucleic acids.9 75/50% 18/12% 23/25% 8/0% VV1 3 39.5 100% 0% 33% 0% MM2-C 6 64. scrapie prion protein. Because of their highly reactive nature. One of the most important antioxidants is superoxidedismutase (SOD). This family of enzymes converts damaging superoxide anion free radicals to H2O.1 3.3% 0% 0% 100% 100% 100% 100% 0% 100% Abbreviations: M.566 M. Protein oxidation and lipid peroxidation are two of the best-characterized markers of oxidative stress. thus. In normal conditions.4 15.3 27% 0% 0% 9% 100% 0% 0% 100% 0% 0% 0% 0% 0% 33. Schulz-Schaeffer W. Data from Parchi P.3 15. et al. and MM2-T represents sporadic fatal familial insomnia with prominent thalamus involvement. Windl O. MM2-C represents a subgroup with cortical involvement.7 74% 0% 11% 15% VV2 43 61. which results in the loss of their normal functions. In contrast.1 100% 0% 33% 0% MM2-sFI 6 52. lipids. the diagnosis of human prion diseases is based on a set of established clinical. infarct) . immunohistochemical. Whether alteration in metal binding is the cause of the diseases or the consequence of the diseases remains to be determined. correlating with the increases in the markers of oxidative stress. time-consuming. No diagnostic test based on PrPSc detection in peripheral tissues (eg. other tissues. the diagnosis is much more cumbersome for the most common sporadic human prion diseases.10]. As a result. This is because the infectious agent. and organs. Diagnosis and surveillance of human prion diseases Currently. The British experience indicates that unchecked animal prion diseases may be transmitted to human beings.M. Since the discovery of vCJD in 1996. Furthermore.-S. The loss of antioxidant function associated with increased oxidative stress suggests a change in the metal-ion occupancy of PrP. Human prion diseases should be diagnosed as early as possible so as to avoid the potential transmission of infectious prions through the donation of blood. PrPSc. In contrast. manuscript submitted). It also relies exclusively on the availability of brain tissues. is not present in the peripheral tissues or the level of PrPSc in peripheral tissues may be much too low for currently available assays [9. The sensitivity and specificity of this test was reported to be greater than 90%. Recent studies in an animal model suggest that alterations in metal binding can be observed in experimentally infected mice at a presymptomatic stage (Wong et al. the need for a rapid. it may also contribute to the diversity of PrPSc and disease phenotype in sCJD [44]. For example. Sy et al / Med Clin N Am 86 (2002) 551–571 567 sCJD patients. and relatively early diagnostic test for the detection of human and animal prion diseases is of obvious importance. neoplasm. they are also present in a variety of conditions other than prion diseases. This screening can be carried out with non-CNS tissues (eg. and biochemical criteria [2. This change might play a pivotal role in the pathogenesis of prion diseases. effective. it is just as important to develop tests that can detect PrPSc in animals before the animals reach the food chain. blood) is available for human or animal prion diseases. Because the 14-3-3 proteins are essentially markers of brain parenchymal damage. PrPSc detection by histochemistry or Western blot analysis is nonquantitative. and technically demanding.31]. Recently. Cu and Mn changes were pronounced in sCJD subjects homozygous for methionine at codon 129 and carrying PrPSc type 1 (sCJD M/M1). These metal imbalances varied according to the PrP 129 genotype and PrPSc type [44]. Advances in molecular biologic techniques have allowed rapid screening of individuals with pathogenic mutations. a diagnostic test for the presence of a family of proteins known as 14-3-3 proteins was introduced [45]. peripheral blood). the PrP-associated SOD-like activity was reduced by approximately 85% in each of the sCJD variants. they are present in conditions that affect the CNS both focally (eg. Because the metal change is different in the sCJD variants. the challenge for human prion diseases is in the diagnosis. Sy et al / Med Clin N Am 86 (2002) 551–571 and with widespread distribution (eg. to identify any potential case of human prion disease that might have been transmitted from animals. we have not uncovered any vCJD case in the United States. monitoring disease incidence is important in public health. it is currently unclear whether the 14-3-3 protein test is positive in all five variants of sCJD and in sporadic FFI or only in typical CJD [46]. In 1997. finding a cure for prion diseases is likely to be difficult. Identification of the infectious agent is only the first step in a long and arduous process. and eventual prevention of the diseases. Future challenges Like all other human diseases.568 M. and to collect and provide human tissues for research on the pathogenesis of prion diseases. Human prion diseases belong to a group of heterogeneous diseases. So far. Only time can tell whether any of these approaches reaches clinical application. Alzheimer’s disease). Since the appearance of vCJD. and other prion diseases. many European counties have established surveillance centers to monitor the appearance and spread of vCJD. significant progress has been made in the diagnosis of prion diseases. the development of a more reliable and rapid diagnostic test is the easiest task. The major purposes of this center are to monitor the incidence of prion diseases in the United States. we established a National Prion Diseases Pathology Surveillance Center in the United States. we have received and diagnosed more than 326 cases of human prion diseases (Table 7). Of these three challenges.-S. We must endeavor to unravel the mechanisms by which this Table 7 Cases of human prion diseases received and diagnosed by the National Prion Diseases Surveillance Center at Case Western Reserve University Human prior diseases Year 1997 1998 1999 2000 2001 (3/1) Sporadic 54 45 65 97 31 Familiar 4 5 9 12 1 Iatrogenic 0 1 0 2 0 Total 58 51 74 111 32 . Many attempts have been made to identify compounds that might interfere with the PrPC-toPrPSc conversion in in vitro and in vivo experimental models. cure. To find a cure and prevent human prion diseases. we must focus on a better understanding of the molecular mechanisms that are responsible for the diseases. Conversely. After the discovery of vCJD in the United Kingdom. In addition to diagnosis. Since then. like all other neurodegenerative diseases. Furthermore. This is because most patients with sCJD do not have obvious clinical signs until they are close to the terminal stage of the diseases. Capellari S.197:943–60. [3] Prusiner SB. Nature 1997. Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: background. Petersen RB. clinicians.8:286–93. References [1] Gajdusek DC. Oesch B. [8] Culle J.46:417–28. Burlingame AL.40:3759–66. Biochemistry 1999. Emerg Infect Dis 2001. Sy et al / Med Clin N Am 86 (2002) 551–571 569 small protein causes diseases. Tabaton M. 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[44] Wong BS. [46] Green AJ. Neurology 2001. Pan T. Morillas M. Clive C. Glassmith LL. Pan T. Pocchiari M. Chen SG. Xie Z. Swietnicki W.344:1–5. Macleod MA. Lowman A. EMBO J 2000. Misleading results with the 14–3-3 assay for the diagnosis of Creutzfeldt-Jakob disease. [45] Zerr I. Jones IM. Brandel JP. Free radicals in biology and medicine. Wong BS. J Mol Biol 2000. O’Rourke K. de Pedro Cuesta J. Sy et al / Med Clin N Am 86 (2002) 551–571 571 [41] Halliwell B. Collins S. [42] Brown DR.55:811–5. Hafiz F. Haswell S. Gutteridge JMC.-S. J Neurochem 2001.M. Will RG. however. emotional. such as stroke.A. Approximately 2. Elsevier Science (USA).7 1 2 5 ( 0 2 ) 0 0 0 1 0 . extracting an enormous social. Our success in preventing and controlling the acute diseases that strike between childhood and early middle age has led to greater longevity and the aging of our population. James D. Kukull). As with other scientific fields. safer working conditions. This has allowed us to develop a wide array of interventions. and once found. families. The enormous burden that dementia inflicts on individuals. The past few decades have seen remarkable success in treating some acute illnesses and in reducing the incidence of others. WA 98195-7286. how accurately are they diagnosed? The diagnosis of dementia is difficult because specific antemortem biologic markers for * Corresponding author.*. Box 357236. and society underlies the increased emphasis medical science has placed on the study of these diseases. Kukull. PhDa.see front matter Ó 2002. such as antibiotics. Of these chronic illnesses.Med Clin N Am 86 (2002) 573–590 Dementia epidemiology Walter A. WA 98195-7286. Seattle. dementia is one of the most common. In other words. and economic burden on society.X . In the developed world. University of Washington. At least 6% to 10% of persons in the United States aged 65 years or older may suffer from some form of dementia [1]. Case detection and identification (or diagnosis) are critical to the epidemiologic study of dementia. All rights reserved. Bowen. E-mail address: kukull@u. MDb a Department of Epidemiology. USA b Department of Neurology. chronic diseases are the leading causes of morbidity and mortality. 0025-7125/02/$ . Epidemiology has played a central role in identifying the risk factors and potential causes of these acute illnesses. PII: S 0 0 2 5 .edu (W. University of Washington School of Medicine. and improved sanitation. Seattle. how are new dementia cases found. USA Dementia has become one of the leading public health concerns facing our society. The epidemiologic study of dementia has some unique challenges. whereas clinical medicine has provided new and more effective treatments.washington.32 million persons in the United States were estimated to be living with Alzheimer’s disease (AD) in 1997 [2]. Box 356465. there is great interest in studying causes and risk factors for dementia with all the tools that epidemiology can bring to bear. could cause serious selection bias and lead to spurious conclusions. for example. For example. leaving the picture additionally confusing. Failure to start with a cohort that is free of the disease of interest can potentially bias results. Biopsy of the affected tissue is not available in most dementia diagnoses. relative to disease onset. which is the gold standard for the diagnosis of many dementias. and autopsy. Frailty. an exposure may have been able to influence disease is complicated by the often insidious and indeterminate onset of disease. potentially leading to diagnostic heterogeneity and misclassification of those patients with dementia. age. if associated with exposure history.D.574 W. may reflect cumulative disease processes. Kukull. in practice. Instead. J. Case identification methods are also critical to cohort studies (and intervention trials). As one leaves major research institutions or attempts to begin epidemiologic research studies in less developed countries. do not exist. Case detection is a further problem for most epidemiologic studies. gender. The method of identifying and including cases. there are too many extraneous factors affecting whether dementia might or might not be entered as a cause of death. especially in diseases that affect memory. Exposure measurement (valid determination of risk factor information) is critical for analytic risk factor studies. low serum cholesterol levels in existing/prevalent cases may be a function of the impact of disease on diet or may be influenced by physical wasting. education. For dementia. Cases identified using death certificates alone are simply not comparable to those identified by direct patient examination. however. and specifically for AD. Long past exposure histories are difficult to construct and validate.A. There can be considerable variation in making the diagnosis of dementia based on a clinical examination. and some may be affected by the disease itself. Actual records. Standardization of clinical criteria can limit the amount of misclassification. Potential markers obtained from analysis of peripheral blood may not correspond to marker exposure levels in neuronal tissue. ethnicity. Fortunately. some of this heterogeneity has been reduced by the recent introduction of clinical criteria for the diagnosis of various types of dementia. Lack of sensitivity or specificity in screening or diagnosing disease during follow-up leads to incorrect estimates of incidence and to distorted risk factor relations. standardization is difficult to achieve. determining when. Biologic markers of exposure (except for genotype) are difficult to obtain. the diagnosis must be made on the basis of clinical evidence. because many persons (or their families) decline to participate in research studies. the problems grow in mag- . and a host of other factors also influence participation. this does not happen. an uncontrolled bias may result. of medication history or occupational exposures are seldom available. Bowen / Med Clin N Am 86 (2002) 573–590 most dementias. Self-reported histories and those obtained from proxies are often the basis for risk factor inference but may be flawed by distorted recollection or recall bias. Can all identified cases from a particular study base be enrolled in a study? Usually. If any of these participation factors is systematically related to exposure status. Memory may not always be the first domain affected. but the difficulty in obtaining acceptable levels of each is increased substantially. Clinical overview Dementia can sometimes occur suddenly as the result of a stroke. dementia with Lewy bodies. . or problems with activities of daily living that many might ascribe to aging but progress to more serious socially and functionally debilitating cognitive impairment. medications. planning. Various definitions of dementia have been used in past research studies. sequencing. apraxia (impaired ability to carry out motor activities despite intact motor function). To date. personality change. and risk factor exposure measurement remain critical to valid research in these settings. without memory loss. caused by illness. Bowen / Med Clin N Am 86 (2002) 573–590 575 nitude. These include aphasia (language disturbance). case identification. abstracting). including agitation.A. vascular dementia. Valid early identification of true disease would be most helpful in linking exposures and risk factors to the disease. Beyond the umbrella category of ‘‘dementia. There is some controversy concerning whether memory loss should be the cardinal feature of dementia (ie. and depression. Kukull. Moreover. Behavioral changes may be prominent. Differences in available facilities and local practices are likely the easiest to overcome.’’ AD.’’ there are clinical and sometimes histopathologic criteria for differentiation of dementia subtypes. J. More often. diagnostic criteria have been developed for ‘‘mild cognitive impairment. patients may be completely dependent on others. Leaders in the study of vascular dementia have raised interest and debate concerning this question. In late stages. Cognitive loss may begin with mild memory problems. or intoxicants). ‘‘necessary’’ for the diagnosis) or whether loss in a combination of other cognitive domains. should be considered sufficient for diagnosis. it is especially difficult to determine whether dementia is present in people with only some mild indications of cognitive impairment and whether that mild impairment is benign and nonprogressive or a prodrome of the progressive disease. The cognitive deficits must be severe enough to cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning. but that of the Diagnostic and Statistical Manual: Edition IV (DSM-IV) is the most commonly used now [3]. language difficulties.D.W. and disturbances in executive functioning (ie. Case detection. The usually insidious nature of most dementia makes it difficult to determine the point of disease onset. it presents with a slowly progressive loss of cognitive function as with AD. agnosia (failure to recognize or identify objects despite intact sensory function). organizing. wandering. The causes of dementia are listed in Table 1. Dementia must be differentiated from delirium (eg. Addressing political concerns and suspicions to gain the cooperation necessary to begin a study may take additional time and preparation. The DSM-IV criteria for dementia require memory impairment and one or more additional cognitive disturbances. single site Gliomatosis cerebri Abscess Subdural malformation Hydrocephalus Infections AIDS (HIV) Chronic meningitis Encephalitis Progressive multifocal leukoencephalopathy Subacute sclerosing panencephalitis Syphilis Lyme disease Prion disease (kuru. J. multiple sites Tumors.576 W.A.D. Creutzfeldt-Jacob) Toxins Drugs Alcohol Heavy metals Industrial toxins Domoic acid Inherited disease Huntington’s disease Gerstmann-Straussler syndrome ¨ Porphyria Propionic aciduria Adult-onset lysosomal storage diseases Hexosaminidase Arylsulfatase (metachromatic leukodystrophy. Bowen / Med Clin N Am 86 (2002) 573–590 Table 1 Causes of dementia Idiopathic Alzheimer’s disease Frontal temporal dementia Focal/central nervous system pathologic findings Multi-infarct dementia Binswanger’s disease Multiple sclerosis Mass lesions Tumors. or MLD) Kuf disease Adrenoleukodystrophy Others Myotonic muscular dystrophy Down’s syndrome Hereditary ataxias Hereditary spastic paraplegias Cerebrotendinous xanthomatosis Systemic disease Cardiac Pulmonary Renal Renal failure (continued on next page) . Kukull. often. or SLE) Giant cell arteritis Sarcoid Amyloid Neoplastic Metastasis Carcinomatous meningitis Paraneoplastic (limbic encephalitis) Associated movement disorder Huntington’s disease Parkinsonian diseases Parkinson’s disease Progressive supranuclear palsy Postencephalitic dementia Posttraumatic (dementia pugilistica) Diffuse Lewy body disease Myoclonus Creutzfeldt-Jakob disease Alzheimer’s disease Metabolic derangement Other movement disorder Hereditary ataxias Hereditary spastic paraplegia Kuru Wilson’s disease Seizures Kuf disease Deficiency Vitamin B12 deficiency Thiamine Niacin (Pellagra) 577 frontotemporal dementia. there is often more than one diagnostic criteria set for each condition. Parkinson’s disease. vitamin B12 deficiency. they do not agree. Bowen / Med Clin N Am 86 (2002) 573–590 Table 1 (continued ) Dialysis dementia Hepatic Hepatic failure Hepatocerebral degeneration Wilson’s disease Endocrine Hyper/hypothyroid Hyper/hypoparathyroid Hyper/hypoadrenalism Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Rheumatologic Vasculitis (including systemic lupus erythematosus. Unfortunately. Although AD is the most common form of dementia. stroke. for the researcher seeking a common standardized definition.W. neurosyphilis. J. many other disorders must be considered. Kukull. hypothyroidism. including drug-induced conditions. hydrocephalus. subdural hematoma. and HIV dementia.D. brain tumors. Huntington’s disease. alcoholism.A. . too. In frontotemporal dementia. and echolalia. The prevalence of dementia is affected by differences in length of survival. risk or rate) is calculated as the new cases per population at risk per time period. however. Often. stereotypy of speech.578 W. The clinical identification of stroke is surpassed by CT. Vascular dementia is difficult to differentiate from AD because of the common occurrence of cerebrovascular disease and stroke with AD in the elderly. hyperorality. have been separated from AD based on their clinical presentations and pathologic characteristics. emigration. disinhibition. and stereotyped or perseverative behaviors. Many different criteria have been developed to diagnose vascular dementia [3. Speech output changes occur. the more likely it is that some strokes are found. withdrawal from social contact. or language are out of proportion to the memory deficit.A. changes in behavior dominate the early course of the disease These include loss of personal awareness. In addition. Deficits in attention.6]. late akinesia. rigidity. and visuospatial ability predominate. The memory loss is variable and often seems to be caused by lack of concern or effort. overactivity. perseveration. behavior. Memory impairment may not necessarily be prominent in the early stages of the disease. and self-regulation of behavior. Much of the pioneering work in the definition and recognition of vascular dementia can be attributed to Hachinski and his colleagues [7–15]. The false-positive identification of stroke also increases. incidence is presented as a ‘‘cumulative’’ figure (eg. Recently. It represents a cross-sectional picture of the population—the burden of that disease on society.5. two additional types of dementia. dementia with Lewy bodies [16] and frontotemporal dementia [17]. judgment. impulsivity. Kukull. Frontal lobe impairments are notable. and institutionalization as well as by the occurrence of new disease cases. frontal subcortical skills.D. Physical signs include early or prominent primitive or ‘‘frontal’’ reflexes. There are several pathologic findings that may lead to frontotemporal dementia. early incontinence.4]. Deficits in social comportment. visual hallucinations. The more sophisticated the search for stroke. and parkinsonism are suggestive of this disease. Bowen / Med Clin N Am 86 (2002) 573–590 and HIV infection. Two commonly used criteria for the diagnosis of AD have been proposed [3. apathy or inertia. and tremor. including abstraction. J. which is surpassed by MRI. distractibility. fluctuating cognitive performance. including some with dominantly inherited mutations related to the protein tau. Dementia with Lewy bodies presents with cognitive losses. effectiveness of treatment. planning. Prevalence is useful in determining the needs for resources and societal burden from a disease. Current cases versus risk of dementia and Alzheimer’s disease The prevalence of dementia is the proportion of persons in a population suffering from dementia at a particular time. The incidence of dementia (ie. restlessness. including progressive reduction of speech. 15 new . loss of social graces. D. Evans et al [18] reported the results of a community study in East Boston.5 per 1000 person-years for the same age groups in the United States.0% in 60. Jorm and Jolley [21] gathered data from 23 studies and produced a meta-analysis of dementia incidence. Kukull. Rocca et al [22] reanalyzed dementia and AD incidence data for 1975 through 1984 based on charted data from the Rochester Epidemiology Project at the Mayo Clinic. and prevalence is not useful in determining disease risk. the United States. a meta-analysis of prevalence studies worldwide was conducted [20]. and East Asia.2 per 1000 person-years in 65. and they are linked by disease duration. ranging from 2. for AD. rates rose from 1. Because of the diagnostic criteria and screening procedures.to 69-year-olds rising to 40.3 million persons would have AD in the year 2050. J.8 per 1000 person-years in those aged 90 years or more.7 per 1000 person-years (in persons aged 85–89 years) in Europe and from 2.2 to 33. 12 new cases per 1000 person-years). Incidence rates for the United States and Europe were quite similar: ‘‘moderate’’ dementia incidence rose from 3. The prevalence estimates for dementia and AD were based on a complex community sampling scheme [19].1 to 74. More than 80% of the observed dementia cases were classified as AD.W.to 64-yearolds to 43% to 68% in persons aged 95 years or older. the results of this study have been somewhat controversial.4 to 27.6 per 1000 person-years (in persons aged 65–69 years) to 37.7 to 39. These investigators noted that annual incidence seemed to stay rather stable during the 1975 to 1984 time interval. Recently. that would result in 2 million fewer cases in the future. Similarly. dementia. Evans later applied the observed rates to census data. Rocca et al [22] . The dementia prevalence proportion in the population is a function of disease incidence and disease duration (or survival). they are useful descriptors of disease occurrence. Brookmeyer et al [2] have estimated that if disease age-specific incidence curves could be shifted generally to delay onset by 2 years. prevalence is often reported as 6% to 10% among persons aged 65 years or older in North America [1].5 per 1000 person-years for the United States and 0. After disaggregating the data for the oldest people. Bowen / Med Clin N Am 86 (2002) 573–590 579 cases per 1000 persons older than 65 years of age in 1999) or as a ‘‘density’’ or instantaneous rate (eg. projecting that 10. Prevalence proportions rose from 0.A. Incidence is less useful in determining societal burden. but kept in their own arena.9 per 1000 person-years.5 per 1000 person-years (in persons aged 65–69 years) to 46. Incidence was estimated for Europe. and vascular dementia incidence rates were computed. The results showed dementia incidence overall as 2. but they are widely accepted as an observed but high estimate of the potential dementia prevalence in East Boston.3% to 1. Prevalence proportion rose from 3% among those 65 to 74 years of age to 47% in those older than 85 years of age. which concluded that the prevalence proportions and incidence rates observed across studies were geographically consistent.1 per 1000 person-years for Europe compared with 6. ‘‘Mild’’ AD incidence was also computed.7 per 1000 person-years for East Asia. AD. except for variations caused by methodologic differences. As a summary figure. 6 per 1000 personyears. France. consistent.600 person-years). Careful. the overall incidence of dementia was 14. The combined analysis of four large ongoing European cohort studies of dementia and AD was recently reported by Launer et al [23]. it seems that perhaps 50% of such cases may progress to become dementia [37–41]. Approximately two thirds of these cases were attributed to AD. Application of the diagnostic criteria has been shown to be difficult and unreliable in practice. . As more cohort studies begin to report incidence. Distinguishing between normal persons. the Netherlands. Kukull.6].2 years (comprising approximately 28.A. however.580 W.31–36].D. Early forms of pre-AD or predementia are difficult to distinguish from the relatively benign cognitive decline associated with aging. Cohorts enrolled in Denmark. AD rose from 1. when mild cognitive decline can be identified. There is a growing realization that a vascular component can contribute to the dementia seen in AD [26. as a result. Late-stage dementia and AD hold little hope for treatment or the identification of consistent risk factors. The report by Launer et al [23] is one of the first using data from the large cohort studies that are now underway in Europe and the United States.5 per 1000 personyears across the same age groups. this syndrome remains an area of controversy and uncertainty [24–29]. and those with incipient dementia/AD may provide important clues about risk factors and critical periods of exposure before disease onset. We cannot be sure of this at present.000 members aged 65 years or older at enrollment. Similarly. consistent estimates are likely to emerge. Despite the compilation of several competing diagnostic criteria for vascular dementia [5. those with mild cognitive impairment. interest has continued to shift toward early and valid identification of disease. Incidence of dementia was 2. They also noted that rates were similar for men and women. and the United Kingdom totalled more than 16. Exposures associated with the onset of Alzheimer’s disease Studying dementia and its relevant exposures presents many methodologic and logistic challenges. Most of the difference between dementia and AD incidence rates reported here likely represents the next most common form of dementia. Reliable and valid distinctions may also help to determine whether mild cognitive impairment is a treatable and reversible phenomenon. J. and valid case identification and detection (discussed previously) must always be addressed by researchers. Bowen / Med Clin N Am 86 (2002) 573–590 also reported that rates seemed to continue to rise with age after the age of 84 years. Nevertheless. After a mean follow-up of 2. vascular dementia.2 per 1000 person-years to 63. Many of the reliability and validity problems experienced by investigators in classifying a case as ‘‘vascular’’ or AD may stem from the mutual exclusion of the two conditions imposed principally by the DSM-IV diagnostic criteria. even by experienced research investigators [30].6 per 1000 person-years in those aged 90 years and older.5 per 1000 person-years in 65.to 69-year olds and rose to 85. Most of these studies were of the case-control design. smoking). The relevant time window may vary for each exposure. Most early analytic observational studies of AD were based on a casecontrol design. the more remote the risk factor exposure must be. findings that were viewed as consistent in case-control studies are being questioned or refuted. Kukull. If a case series includes substantial misclassification of disease. and exposure measurement may have caused at least some results to be biased or spurious.W. In the case of AD (and dementia). In the absence of a biologic marker identifying all cases of AD.A. When case-control studies rely on crosssectional samples to obtain cases. The design itself is well accepted and valid as a method of study. the ability to recognize risk factors is reduced. as cohort studies of AD and dementia are beginning to emerge. AD case smokers had a threefold . A meta-analysis of studies of smoking and AD showed a consistent decreased risk associated with smoking [43]. there is considerable difficulty in ascertaining all cases and in ensuring that everyone identified as having AD truly does as well as in ensuring that all who clinically do not show symptoms truly do not have the disease. cases of disease were identified. Also. but it is sometimes the best we have to work with. Complicating the situation is the lack of verifiable records for most exposures coupled with the patient’s and patient proxy’s difficulty in recalling a specific exposure or the details surrounding it. and their exposure histories were compared with those of persons without the disease.D. some exposures could cause a disease change immediately after a single exposure. They found that although mortality between smokers and nonsmoking control subjects was rather similar. Bowen / Med Clin N Am 86 (2002) 573–590 581 Comparison groups must also be carefully defined and enrolled to avoid spurious associations as a result of bias. a potential spurious excess of exposure among controls may be observed. they are more likely to encounter those patients with the longest survival after diagnosis [44–46]. The use of caregivers as proxies is an imperfect solution to the patient’s loss of recall. case selection for study. Now. J. Exposure to risk factors for AD could possibly occur many years before the recognition of clinical disease or rather close to recognition. The argument for that potential bias is described as an example that could apply to risk factors other than smoking. In this design. In other words. Wang et al [47] conducted a cross-sectional and longitudinal study to observe the relation between smoking and AD. when decreased postdiagnosis survival among patients is associated with the exposure of interest (eg. whereas others may take years of sustained exposure. The later in the clinical course a patient is identified as having dementia. problems with case identification and detection. either by themselves or in combination with one or more other factors. however. It is subject to bias if not judiciously applied. One example of a potential bias concerning a potential protective effect for AD associated with cigarette smoking was addressed in a recent article [42]. the observed relative risk estimate tends to be biased toward the null (assuming the misclassification is nondifferential). to cause disease changes. and the more difficulty there is in recognizing it. 53. results have shown no indication that estrogen replacement therapy is an effective treatment for AD [78.57–65]. and sociodemographic experiences. These factors include anti-inflammatory medications [1.81]. because of the individual’s ability to respond correctly in testing situations. This result does not address estrogen as a preventive measure. Kukull. Several recent longitudinal studies now show a negligible risk of AD associated with head injury [23. Most of the strict genetic ‘‘causes’’ of disease have been limited to familial AD. Educational level influences the diagnostic process. Bowen / Med Clin N Am 86 (2002) 573–590 increase in risk of death compared with AD nonsmokers.56]. Although the initial associations seemed relatively consistent across studies. Aside from the observable effect of aging dramatically increasing the risk of dementia and AD. even though risk of death or continued cognitive impairment immediately resulting from the injury is substantial [52]. Genetics and Alzheimer’s disease Great progress has been made in the genetics of AD. Recently. genetic constitution. success in finding environmental risk factors has been limited and potentially related to design and selection factors. primarily based on case-control studies [50.51]. Higher educational level has been proposed as influencing a decreased risk of AD. AD is likely to be heterogeneous both diagnostically and etiologically.54]. smoking would be less common in a cross-sectional sample of AD patients than among controls. Educational level influences a subject’s likelihood of participating in epidemiologic studies. As a result of mortality. and conclusions are still tentative. The biologic plausibility of this association has been reviewed [66].47–49].A. selective recall or recall bias may be more important than the effect of survival. What results in the AD phenotype may be the sum or product of aging.D. estrogen replacement therapy [74–88]. Here. although others still find some potentially increased risk [55. environmental factors. Familial AD behaves similar to an autosomal dominant genetic pattern and predom- . Randomized trials to test the observed associations are either proposed or underway. Head trauma has also been shown to be a relatively consistent risk factor for AD. Several ‘‘protective’’ factors for AD have been raised in the past 10 years. however. however. J. Education may influence health care use and may result in greater income or a higher occupational level. designs differ.582 W. The idea that higher education confers greater ‘‘cognitive reserve’’ to be accessed when disease strikes is tantalizing. but the relation between education and AD may be quite complex [1.67–73]. and antioxidants such as vitamin C and vitamin E [89]. although biologically unsubstantiated. Cohort studies where this selection bias is minimized now report either ‘‘no association’’ or a potential increased risk of AD associated with smoking [23. an important idea was raised concerning the importance of early life development in increasing susceptibility to AD [42]. at least in the early stages of disease. In the case of estrogen as a potential treatment for AD. presenilin 2. Familial AD. which pair to form one of six genotypes for each individual. Bowen / Med Clin N Am 86 (2002) 573–590 583 inantly tends to affect persons younger than 60 years of age. Farrer et al [112] provided a meta-analysis of the age and gender effects.118]. Recently. ApoE naturally occurs as three different alleles (e2. which may apply to the more common form (often called sporadic.W. J. forming the amyloid-b 1–42 protein.100–105]. Kukull. important work has been published concerning the identification of enzymes that cleave the precursor protein abnormally. and Mayeux et al [113] later described caveats for the potential value of ApoE genotype in AD diagnosis. Genotypes containing the e4 allele are associated with an increased risk of AD. Evidence for the effects of other genes on AD has also been presented. This work may ultimately help to identify sites for drug intervention not only for familial AD but for nonfamilial AD [93. Perhaps one quarter to one half of the genes for familial AD have yet to be identified [95–98]. but a number of other investigators failed to replicate the association [114–116.119–129]. The largest proportion of familial AD is attributed to mutations in the presenilin 1 gene (chromosome 14). The association was first described from Allen Roses’ laboratory [106–111]. so defined. Despite the huge volume of studies that include ApoE genotyping. Progress continues. but it may also have undiscovered genetic causes). many investigators have observed the association. A small proportion of cases are caused by specific mutations in the amyloid precursor protein gene (chromosome 21). forming the characteristic plaques of AD. Since the initial description of increased risk associated with the e4 allele. e3. and e4). homozygous e4 greatly increases the risk (>8-fold). Even . a2Macroglobulin was first shown as a potential risk factor by Blacker et al [117]. but important clues may be learned from the study of familial disease.A. Several current reviews of AD genetics are available [90–99]. and there is considerable hope for the discovery of important genes that may provide indications for prevention or therapy.D. and e4 alleles actually work to influence the risk of AD. seems to account for less than 5% of all AD. Amyloid-b protein aggregates in the brain. relatively little is known concerning how the e2. Discussion of ApoE genotype is now included in most risk factor studies of AD either as a focus or as a potential confounder/effect modifier of an association. the strongest and most consistent risk factor for nonfamilial AD (other than age) is apolipoprotein E (APOE) genotype. Other genetic associations have been studied but with limited impact to date [96. It is abnormal cleavage of the amyloid precursor protein that results in the formation of amyloid-b protein(1–42). and the next largest known contribution is from mutations in a homologous gene on chromosome 1. 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Davidson M.277:29–32. Heath P. Bowen / Med Clin N Am 86 (2002) 573–590 [125] Lilius L. Neurosci Lett 2000. Mayeux R. Sinclair A. Proc Natl Acad Sci USA 1997. [127] Hirano M. et al. Forsell C. Aldudo J. Biochem Biophys Res Commun 1997. Valdivieso F. Mattila K. c. 116MIRECC. gait.washington.W.2 . Seattle. More women than men are affected even after adjustment for the greater longevity of women. USA b Alzheimer’s Disease Research Center. aphasia. AD is characterized by diffuse cerebral atrophy associated with b-amyloid (Ab) neuritic plaques. The typical age of onset is older than 65 years. Interested readers should refer to the texts by Pulst [1] and Terry et al [2] for detailed descriptions regarding specific disorders.edu (D. PII: S 0 0 2 5 . Pathologic features Pathologically. Seattle. Mental Illness Research. Seattle. University of Washington. USA c Veterans Affairs Puget Sound Health Care System. Veterans Affairs Puget Sound Health Care System. Seattle. and behavioral disturbances. The average duration of illness ranges from 4 to 20 years. WA 98108.see front matter Ó 2002. Clinical. 116MIRECC. and Education Center. and amyloid * Corresponding author. Bird. MSca. 0025-7125/02/$ .7 1 2 5 ( 0 2 ) 0 0 0 0 3 . WA. Tsuang. University of Washington. E-mail address: dwt1@u.*. 1660 South Columbian Way. USA a This article reviews seven of the most prominent examples of dementing disorders for which genes have been identified. Mental Illness Research. however. MDb. confusion. Medical Genetics. WA. Tsuang). and Psychiatry and Behavioral Sciences. MD. Additional symptoms include executive dysfunction. WA 98108. These disorders comprise the most common causes of dementia in the elderly.Med Clin N Am 86 (2002) 591–614 Genetics of dementia Debby W. USA. It is a slowly progressive disease that initially presents with short-term memory loss. WA. Clinical. 1660 South Columbian Way.c.b. USA d Departments of Neurology. Elsevier Science (USA). Seattle. University of Washington.d Departments of Psychiatry and Behavioral Sciences and Epidemiology. Thomas D. All rights reserved. neurofibrillary tangles. and Education Center. Alzheimer’s disease Clinical features Alzheimer’s disease (AD) is the most common cause of dementia [2]. this list is not exhaustive. The lack of complete concordance in monozygotic twins suggests that environmental components are also important in the etiology of AD. AD occurs as a single-gene autosomal dominant trait. although more recent European studies do not report such high estimates [7]. Neurofibrillary tangles are dense bundles of helically wound abnormal fibers composed of a modified form of a normally occurring neuronal protein. Although the sample sizes are small. approximately 20% to 40% of individuals older than 85 years have clinically significant dementia. Epidemiologic studies show that individuals who have an affected first-degree relative with AD have an approximately fourfold greater risk of developing AD and a total lifetime risk of 23% to 48% [6]. The risk for AD is even higher if there are individuals in more than one generation with the disease. To date. A higher density of these lesions in specific brain regions along with the presence of a clinical history of dementia consistent with AD confirms the diagnosis of AD. and more than half of these patients have AD [5]. Disease duration is usually 6 to 10 years but can range from . Senile plaques are complex structures consisting primarily of a core of abnormal aggregates of a small protein molecule known as Ab. Further proof for a genetic basis in AD is that all persons with trisomy 21 (Down syndrome) who survive beyond the age of 40 years invariably demonstrate the neuropathologic features of AD [9]. The presence of either senile plaques or neurofibrillary tangles is not pathognomic of AD [4].D. In some of these rare families. In addition. Although there are fewer than 20 families worldwide with APP mutations. Bird / Med Clin N Am 86 (2002) 591–614 angiopathy as first described by Alois Alzheimer in 1911 [3]. Tsuang. These observations led to the finding of mutations in the amyloid precursor protein (APP) gene on chromosome 21. they suggest that genetic components play an important role. the discovery of these mutations confirmed that genetic factors are important in AD. Approximately 10% of the white population over the age of 70 years have dementia. Familial Alzheimer’s disease Although there is no universally accepted definition of familial AD (FAD). T. the microtubule-associated protein tau. a working definition is three or more affected first-degree relatives (with at least one individual’s diagnosis confirmed at autopsy). the first documented genetic cause of AD [10]. They are both known to occur in other neurodegenerative disorders as well as in normal aging.W. The clinical features of FAD are typically indistinguishable from nonfamilial (or sporadic) AD [11].592 D. especially when the disease is of early onset (age <65 years). The next most important risk factor for AD is family history. Epidemiology The risk for AD increases with advancing age. reports on monozygotic and dizygotic twin pairs have suggested higher concordance rates in monozygotic twins than in dizygotic twins [8]. Familial AD is typically divided into early-onset (<65 years old) and late-onset (>65 years old) types.W. Note that cleavage by the a-secretase interrupts the Ab peptide. Ann Neurol 1996. (From Levy-Lahad E. three causative genes have been found in early-onset families. The predominant species. respectively. Genetic factors in Alzheimer’s disease.and late-onset AD. whereas cleavage by only the b. Bird TD. Schematic representation of the amyloid b (Ab) peptide portion of the amyloid precursor protein (APP) demonstrating mutation sites associated with familial Alzheimer’s disease (positions 670-671 and 717) and hereditary cerebral hemorrhagic amyloidosis of the Dutch type (positions 692 and 693). It is hypothesized that Ab42 is the pathogenic Fig. followed by c-secretase cleavage.) . Tsuang. Ab42 only accounts for 10% of the totally secreted Ab. Amyloid precursor protein The APP gene maps to the long arm of chromosome 21. the discovery of these genetic mutations has been critical in designing studies to investigate the underlying pathophysiology in AD. Other important genetic and environmental risk factors remain to be discovered. one of the neuropathological hallmarks of AD.and c-secretases allows the Ab peptide to remain intact. Two b-secretases have been identified and are referred to as BACE 1 and BACE 2 [14]. Ab is destroyed by this cleavage. A fourth gene. b-secretase cleaves APP first. Although these genes account for less than 2% of all cases of AD. Ab40. b-. Thus far.and c-secretase cleave APP to form the N (amino) and C (carboxy) termini of Ab peptide. which can result in Ab peptides of different lengths [13]. The three normally occurring sites for processing this portion of the APP are also indicated by the a-. is formed by cleavage after the fortieth amino acid of Ab.40:829–40. T. the apolipoprotein E (APOE) e4 is a major genetic risk factor for both early. Ab is a 39 to 43 amino-acid peptide that is the major component of the neuritic plaque. The first is cleavage within the Ab sequence by a protease referred to as a-secretase [12]. Enzymes called b. 1). Bird / Med Clin N Am 86 (2002) 591–614 593 2 to 20 or more years. It encodes for a precursor protein that is proteolytically cleaved to form Ab protein. c-secretase cleavages occur within the predicted transmembrane domain of APP. meaning that this pathway does not contribute to Ab formation. The second cleavage is on either side of the Ab sequence.D. with permission. 1. Conversely. resulting in the Ab40 and Ab42 species. Two proteolytic pathways for APP processing have been shown to occur normally (Fig. and c-secretases.D. a mutation in the APP gene was first discovered in the rare condition called cerebral hemorrhagic amyloidosis of the Dutch type [17]. There is evidence that presenilin-1 has c-secretase activity and may be the major c-secretase [16]. PS-1 mutations are more common than APP mutations. The gene. was subsequently discovered in 1995 [19]. However.D.and c-secretases are potential therapeutic targets. Penetrance is nearly complete by the age of 65 years. In 1990.W. A commercial test is available for PS-1 mutations. It is critical that genetic counseling take place before genetic testing in asymptomatic individuals. Disease onset ranges from 35 to 55 years of age. In the Val717Ile mutation.8 years) [6]. more than 20 different families have been identified with diseasecausing APP mutations. suggesting that the mutations likely cause a change or gain in protein function rather than a loss of function. Subsequently. T. because plasma exhibits a selective increase in Ab42 and because Ab42 is the major constituent of amyloid plaque deposits in the brain [13.8–6. Most of the mutations are missense mutations (ie. There is no commercially available test for APP mutations. More than 70 different mutations in PS-1 have been identified worldwide [20]. presenilin 1 (PS-1). very few of these mutations result in a truncated normal protein.15]. representing approximately 30% to 60% of early-onset FAD and less than 5% of all AD [6]. Disease duration is usually short (5.594 D. Tsuang. Clinically. Of the three genes known to cause FAD. There is no evidence that APP mutations are responsible for lateonset FAD. however [22]. Because cerebral amyloidosis is also a hallmark of AD. Bird / Med Clin N Am 86 (2002) 591–614 species in FAD. this led to the search for APP mutations in FAD. which is typically fully penetrant by the time an affected individual reaches his/her early sixties. a single base-pair change that results in a single amino acid substitution). it was discovered that a valine-to-isoleucine substitution existed at codon 717 (Val717Ile) in two families [10]. APP mutations are a rare cause of early-onset FAD (which is itself uncommon).21]. genetic linkage of FAD to a chromosome 14 locus was established and confirmed [18]. The clinical picture associated with PS-1 mutations is typically characterized by severe dementia associated with language disturbance and myoclo- . PS-1 mutations are associated with the earliest age of onset and cause the most rapidly progressive disease. The function of PS-1 remains unknown. 2). but it may have c-secretase–like activity [16. b. because inhibition of their activity would decrease Ab production. In 1991. age of onset ranges from 41 to 64 years (mean ¼ 50 50 years). This gene is predicted to encode a 467–amino acid protein with 7 to 10 hydrophobic transmembrane domains (Fig. They account for probably less than 10% of early-onset FAD and certainly less than 1% of all AD. Presenilin 1/chromosome 14 gene In 1992. APP mutations result in autosomal dominant early-onset AD. however. the genomic similarity between PS-1 and PS-2 suggests that they arose by duplication. The arrow at the top left of the figure points to the Volga German PS-2 N141I mutation. 2).D. 2) [25]. This diagram shows eight transmembrane domains. It was found in FAD kindreds with Volga German (VG) ancestry [26]. only four or five mutations in PS-2 have been discovered. although the exact number of transmembrane domains remains unknown. The arrow at the bottom of the figure points to a PS-1 mutation (an exon 9 deletion) that is often associated with early spasticity. The highest degree of conservation is within the hydrophobic/transmembrane domains. Presenilin 2/chromosome 1 gene The third AD gene was discovered shortly after the discovery of the PS-1 gene. A single mutation (N141I) occurs in all the reported early-onset VG . 2. including PS-1 (filled circles) and PS-2 (open circles). the first PS-2 mutation discovered. Many of these families subsequently immigrated to the United States. These families are ethnic Germans who migrated to Russia but remained separated from the native Russian population.W. but other configurations remain possible. a single common affected ancestor). To date.24]. Tsuang. and eight of these families were found to have FAD presumably on the basis of a genetic founder effect (ie. which appear relatively early in the course of the disease [23. Schematic representation of one possible form of the transmembrane proteins encoded by the presenilin-1 (PS-1) gene on chromosome 14 and presenilin-2 (PS-2) gene on chromosome 1. PS-2 is predicted to encode a 448–amino acid protein that is 67% identical to PS-1 (see Fig. Several known mutations are indicated. making this the least common known genetic cause of AD [20]. Furthermore. The presenilin 2 (PS-2) gene was cloned through its homology with the PS-1 gene [27].D. suggesting that these regions are important in the normal functioning of the protein. Not all mutations are shown. One mutation in the PS-1 gene (an exon 9 deletion) is often associated with early spasticity (see arrow in Fig. It was also called STM-2 (seven-transmembrane domains). nus. Bird / Med Clin N Am 86 (2002) 591–614 595 Fig. T. Ths PS-2 mutation is highly penetrant (>95%). AD risk associated with APOE is dose dependent [29. several studies suggest a reduced frequency of the APOE e2 allele in AD patients [37. which is consistent with the founder effect hypothesis.D. there is high variability in age of onset. Studies suggest a different e4 allele effect in men than in women. A community-based study suggests that such testing only adds a small amount of certainty to diagnostic accuracy [40].596 D.3 for subjects with two e4 alleles [33. although Hispanics with an e4 allele and blacks who are e4 homozygous remain at increased risk for developing AD [35]. Within the VG families. The APOE e4 risk seems to be more pronounced in women [32]. Bird / Med Clin N Am 86 (2002) 591–614 pedigrees. Some have advocated APOE testing as an adjunct in the diagnostic evaluation of demented persons [39].6 ± 3. A strong allelic association between APOE e4 and AD was established in 1993 [29. Clinical features associated with PS-2 mutations have been reported primarily in the VG families. This study reported that women with the e4/e4 genotype (approximately 1% of the general population) have a 40% risk of developing AD by the age of 73 years. The dementia in PS-2 AD is clinically and neuropathologically indistinguishable from that of sporadic AD. Individuals with an e4 allele may not develop AD.9 ± 8. whereas those without an e4 allele sometimes develop AD. In men. ranging from 40 to 75 years [26]. and mean disease duration is 7. these observations made APOE a plausible candidate gene. Not all studies support these findings.0 to 19. Tsuang. only e4/e4 homozygotes have a younger age of onset. All PS-2 mutations are also missense mutations. These risk estimates are not as strongly observed in blacks or Hispanics (reviewed by Farrer et al [33]). because the presence or absence of e4 is not highly predictive of future AD.2 years. .4 for AD subjects with one e4 allele compared with normal controls.34]. Because APOE was known to be present in amyloid plaques and neurofibrillary tangles. The mean age of onset in these families is 54.30] and was rapidly confirmed in autopsy-proven sporadic and familial lateonset AD cases. the odds ratio increases from 7. The presence of the e4 allele seems to modify the age of onset of AD [32]. odds ratios range from 2.5 years. however.W.38]. Apolipoprotein E genetic testing in Alzheimer’s disease APOE genotyping is not recommended in asymptomatic persons without dementia.31]. Compared with the most common APOE genotype (e3/e3). whereas one e4 allele is sufficient to reduce the age of onset in women [36]. T. In addition. Apolipoprotein E The APOE gene was initially identified as a genetic risk factor in AD by genetic linkage analysis of late-onset FAD pedigrees [28].8 to 4. 53]. there is substantial clinical overlap between DLB and AD as well as PD. systematized delusions or hallucinations) that require neuroleptic treatment.45]. thereby including (1) diffuse LB disease. these conditions were categorized as . which is also the hallmark of PD. Tsuang. Linkage studies suggest that chromosome 12 contains such candidate genes. The boundaries of DLB are still far from being clearly defined because of its shared clinical and neuropathologic features with PD and AD. (2) LB variant of AD.D. a1-antichymotrypsin. T. Clinically. Ab deposition [49]. and additional genetic and neuropathologic studies are necessary to further investigate the role of genetic factors in DLB. Twenty to fifty percent of cases with neocortical LBs also have substantial AD pathologic findings. Bird / Med Clin N Am 86 (2002) 591–614 597 Late-onset Alzheimer’s disease More than 50 genes have been implicated in late-onset AD [41]. parkinsonism (either de novo or neuroleptically induced). These factors include interleukin-6. Vascular dementia Clinical features Binswanger (1894) and Alzheimer (1911) described behavioral disorders related to arteriosclerosis. Over half of the patients with autopsyproven DLB have hallucinations or systematized delusions during the course of their illness [49]. there are several reports in which LB disease seems to be familial [50. Dementia with Lewy bodies Dementia with Lewy bodies (DLB) [48] encompasses any case that exhibits clinical dementia and has Lewy bodies (LBs) on autopsy. Other studies requiring further evaluation have suggested the involvement of genes on chromosome 10 [46.51]. Two genes have been shown to cause rare genetic types of PD: a-synuclein and parkin. DLB is characterized by the presence of LBs. human leukocyte antigen. but most have not been confirmed or replicated. however [44. Numerous association studies have implicated other potential genetic factors in AD. present therapeutic challenges for clinicians. As anticipated. Families with a-synuclein mutations have LB pathologic findings and may develop dementia [52. Patients with parkin mutations do not necessarily have dementia or LB pathologic findings [54]. and angiotensin converting enzyme [41]. as well as (3) dementia associated with classic Parkinson’s disease (PD). Neuropathologically. Behavioral disturbances (ie. Neither has been clearly established as an AD gene. which can worsen parkinsonian signs and symptoms. namely. Although most cases with DLB are considered sporadic. including the a-2 macroglobulin gene [42] and low-density lipoprotein receptors [43]. no genes have been identified that cause DLB.D.W. and psychosis with prominent visual hallucinations. DLB is characterized by progressive and fluctuating cognitive impairment. Initially.47]. To date. assessing the genetic contributions of each of the risk factors is extremely complicated. including inattention. it is the first genetic form of geriatric dementia and depression to be identified. there is a narrowing of small arteries throughout the brain caused by smooth muscle layer hypertrophy. depression (30%–50%).D. later. Vascular dementia typically does not have a distinct genetic risk factor. Bird / Med Clin N Am 86 (2002) 591–614 subcortical arteritis. and pseudobulbar affect. T. Subsequent studies reported that these mutations may be present in individuals without a positive family history [56]. this disorder should be considered in the differential diagnosis of geriatric patients presenting with these symptoms. . perseveration. hyperlipidemia. asymptomatic. mutations in the APP and cystatin-b genes are rare causes of cerebral amyloid angiopathy and hemorrhagic strokes. Clinically. As a result. The frequency of Notch3 mutations in sporadic and familial cases with vascular dementia remains unclear but seems to be rare. and are initially similar to patients with multiple sclerosis. although multiple cerebrovascular risk factors are heritable (eg. with electron microscopy showing osmophilic densities in the arteriolar media. Transient ischemic attacks begin to occur when patients are in their 40s and 50s. Notch3 Linkage analysis mapped the CADASIL gene to the short arm of chromosome 19. Although this is a rare form of vascular dementia. The patients are not hypertensive. however. Pathologically. with some cases showing extensive lacunar infarcts. Mutations in the Notch3 gene were first reported in 1996. they were classified as Binswanger’s disease. Cognitive impairment in CADASIL is best characterized as frontal lobe disturbance.598 D. An autosomal dominant syndrome of hereditary multi-infarct dementia has been described with subsequent gene identification [55]. the typical age at death is 64. patients with CADASIL have areas of high signal in the periventricular and deep white matter as well as in the basal ganglia. hypertension). Tsuang. small vessel ischemic disease is now commonly observed in geriatric patients. On T2-weighted MRI. Hyperintensities increase over the next two decades of life until confluent areas of high signal in the subcortical white matter are observed. apathy. The genetics of vascular dementia is likely multifactorial. These abnormalities may be observed while patients are in their 20s. The diagnosis of CADASIL can sometimes be confirmed by skin biopsies showing the arteriolar pathologic changes. In addition. With newer neuroimaging techniques. For the purposes of this article. we focus on a rare cerebrovascular disease associated with dementia for which a gene has been discovered. As a result. and migraine with an aura (30%) during the course of their disease. False-negative skin biopsies have been reported. The contribution of small vessel atherosclerotic disease to clinical dementia remains controversial.5 years. This disorder is called cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). patients with CADASIL can have dementia (80%).W. The typical age of onset is in the 50s or 60s. The diagnosis of HD is indicated by the presence of a positive family history of an autosomal dominant degenerative disorder consistent with HD. Chorea is the main motor sign in HD. including voluntary and involuntary movements. Suicide is more common in patients with HD than in the general population. Caudate . Aspiration secondary to dysphagia is the most common cause of mortality and morbidity.D. although the age of onset ranges from 2 to 80 years. Psychiatric symptoms may precede motor signs and symptoms by many years and do not necessarily relate to the severity of chorea or dementia. Typically. Pathologic features The primary pathologic feature in HD is neuronal loss in the corpus striatum.W. Huntington’s disease Clinical features The clinical triad in HD includes chorea. Changes in mood and personality are common. T. and a lack of awareness of one’s own disability. In the future. rigidity. DNA analysis confirms the diagnosis. cognitive impairment. Each of these risk factors is influenced by diverse pathogenetic mechanisms. sexual disinhibition. occurring first in the caudate and later in the globus pallidus. The duration of HD is typically 15 years. Orientation to time and place remains intact until late in the illness. cognitive decline. whereas verbal memory remains preserved until late in the course of the disease. These involuntary movements are present only during waking hours. and alcohol abuse. with the age of death ranging from 51 to 63 years. and hypertension should result in prevention of and intervention in dementia associated with cerebrovascular disease in the future. Some patients may develop bradykinesia. additional knowledge regarding the genetic and environmental risk factors related to conditions such as atherosclerosis. particularly new motor skills. and behavioral disturbances. Visuospatial memory is particularly affected.D. and behavioral disturbances. and words but have difficulty copying designs on the Mini-Mental State Examination. ranging from irritability to prolonged periods of depression as well as psychosis [57]. presence of progressive motor disability. and dystonia. Bird / Med Clin N Am 86 (2002) 591–614 599 Regardless of their prevalence. aggressive behavior. Caudate atrophy on CT or MRI provides additional support for the diagnosis. Patients may be able to remember facts. stories. Finally. The mean age of onset in HD is approximately 40 years [58]. The interaction of the multitude of risk factors related to stroke remains unclear. Other symptoms commonly observed include apathy. Tsuang. A typical pattern of cognitive decline includes slowness of thought and impaired ability to integrate new knowledge. they cannot be voluntarily suppressed and can increase with stress. the discovery of these mutations provides an opportunity to explore the genetics of cerebrovascular disease. diabetes mellitus. Genetic testing issues in HD are complex and require careful thought and counseling [70. George Huntington. HD became the first genetic disorder to be linked by restriction fragment length polymorphism markers to a locus on chromosome 4. Individuals with the greatest number of repeats (>60) are more likely to have juvenile-onset illness. Neurons containing gamma-aminobutyric acid and enkephalin are the most severely affected. noted clear familial aggregation in HD. China. A significant correlation between the number of CAG repeats and age of onset of HD has been demonstrated [64–67]. A neuropathologic grading system rates the macroscopic and microscopic appearance of the striatum [59]. Most adult-onset HD cases have 38 to 50 CAG repeats. Bird / Med Clin N Am 86 (2002) 591–614 atrophy is evident on MRI. The discovery of intranuclear inclusions in HD brains that contain the protein encoded by the HD gene (huntingtin) [60] has resulted in new avenues of animal research.D. The association was the greatest in patients with higher CAG repeats (>60). and the most consistent neurochemical findings suggest low levels of these two neurotransmitters.69]. HD is the first of numerous neurodegenerative disorders associated with a trinucleotide repeat expansion. Individuals with symptomatic HD have more than 36 CAG repeats in the HD gene. however. fragile X mental retardation. who first described the syndrome in 1872 [61]. with the medium spiny neurons being preferentially lost. Whether these inclusions interfere with nuclear function or whether they are markers for neurodegeneration remains unknown.71]. with characteristic concavity of the ventrolateral aspect of the lateral ventricles. There is general agreement that the prevalence of HD in Western European countries is between 3 and 10 cases per 100. This highly polymorphic CAG repeat is located in the 5¢ region of the HD gene (Fig. A novel gene containing a trinucleotide repeat (CAG) that is repeated beyond the normal range is associated with HD. In 1983. T. Tsuang.600 D. hereditary ataxias) that exhibit anticipation are also trinucleotide repeat disorders [68. an international research consortium reported the successful cloning and sequencing of the HD gene [63]. Epidemiology Many epidemiologic studies have been performed worldwide.W. But the number of CAG repeats is not useful in predicting the age of onset or type of symptoms at presentation in individual patients. who tended to have a lower age of onset. Anticipation is .000 persons. the discovery of dynamic repeat mutations helps to account for the long-observed clinical phenomenon of anticipation. Interestingly. The rates are lower in Japan. Genetics HD is inherited as an autosomal dominant trait. Several other neuropsychiatric disorders (eg. 3). [62] Ten years later. and Finland as well as in African black populations. The neuronal loss seems to be selective. Because most patients with dementia and prominent frontal lobe dysfunction do not have Pick bodies. (CAG)n. Terminology has included Pick’s disease. which was called Interesting Transcript-15. the observation that a disease becomes more severe and appears earlier with each successive generation. parkinsonismlinked to chromosome 17 [FTDP-17]) has resulted in new diagnostic categories (see below). Sweden). PhD. (Courtesy of Elisabeth Almqvist. Pick described a clinical syndrome with dementia. including progressive . and parkinsonian features. paternal HD alleles are more likely to undergo significant expansion than maternal alleles. Stockholm. In the 1970s. Tsuang. This novel gene contains highly polymorphic trinucleotide repeats. FTD. Typically. The bold lines indicate the HD gene. there may be marked confusion. Neuronal cytoplasmic inclusions (Pick bodies) were observed later in neuropathologic studies of some cases. and frontal cortical atrophy [72]. Specifically. this is a result of the unstable expansion of the CAG trinucleotide repeats when the disorder is passed from parent to offspring. D4S10 was the initial marker linked to HD. the clinical presentation of FTD includes personality or behavioral change (often disinhibition) with a relatively intact memory. the discovery of genetic mutations in some FTD families with taupathies (eg.D. and frontal lobe degeneration with spinal motor degeneration. non-AD dementia. Frontotemporal dementia Clinical features Initially. at the 5¢ end of the HD gene. Pick complex. In addition. disinhibition-dementia-parkinsonism-amyotrophy complex. confusion has reigned in the nosology of frontotemporal dementia (FTD). The Huntington’s disease (HD) gene on chromosome 4. Bird / Med Clin N Am 86 (2002) 591–614 601 Fig. Genetic markers are indicated at the top of the figure. progressive aphasia. Later in the course of disease. resulting in the observation that those individuals with larger repeat sizes are more likely to have affected fathers. 3. mutism. As in other trinucleotide repeat disorders. Individuals with symptomatic HD have more than 36 CAG repeats at this locus.W. clinical and pathologic studies helped to solidify consensus diagnostic criteria for FTD [73–75].D. There are at least three subtypes of FTD. T. T. The only available sample estimating disease incidence is based on clinician referrals. sometimes resembling neurofibrillary tangles. Other cases have cytoplasmic inclusions that may be typical Pick bodies or other varieties of tau-positive material. Genetics Familial aggregation was the first feature of FTD suggesting that there may be an underlying genetic cause. Bird / Med Clin N Am 86 (2002) 591–614 aphasia. and frontal lobe degeneration [76]. In this study [77].5 times more likely to develop dementia than first-degree relatives of normal controls. FTD is the most common syndrome with prominent frontal lobe degeneration. Pathologic features Pathologically. Epidemiology Incidence and prevalence estimates of FTD are not well established. In the Consortium to Establish a Registry for Alzheimer’s Disease neuropathologic studies. Patients with progressive aphasia have progressively nonfluent speech with agraphia.2 to 28 cases per 1 million persons from the third decade to the sixth decade.W.80]. distractibility. It is commonly misdiagnosed as AD. there is frontal or temporal lobar atrophy. and acalculia with preservation of word meaning. alexia. The frequency of FTD in autopsy case series with dementia varies from 0% to 15% [79].D.602 D. and less commonly as DLB or AD with vascular disease. patients with inferior-frontal lobe involvement tend to be more disinhibited. whereas patients with involvement of dorsolateral-frontal regions tend to be abulic. Most FTD cases are misdiagnosed as AD. In general. Several groups reported a positive family history in 10% to 60% of cases [77. It has also been suggested that age of onset in relatives of FTD patients is. FTD is thought to comprise approximately 10% of cases (and probably more in younger age groups). Many cases have only gliosis and neuronal loss without distinctive features. and task impersistence. Among all patients with dementia. Segregation analyses have suggested that first-degree relatives of FTD patients are 3. partly due to the clinical heterogeneity of the disorder. Patients with frontal lobar degeneration have a marked loss of personal and social awareness with hyperorality. this is probably an underestimate. the prevalence rises from 1. Patients with semantic dementia have predominantly temporal lobe abnormalities with progressive loss of word meaning but a preserved ability to read and write regular words. Classic Pick’s disease with Pick bodies is considered a subtype of FTD. semantic dementia. Some cases also have anterior horn cell loss in the spinal cord. on average. FTD-like pathologic findings were observed in 3% to 9% of patients with a clinical diagnosis of AD [78]. Tsuang. . But because this was not a populationbased study. however. Interestingly. these syndromes were classified as FTD and FTDP-17 [84]. Since then. whereas other mutations appear to change the ratio of tau isoforms in the brain (3 and 4 repeat tau). Bird / Med Clin N Am 86 (2002) 591–614 603 11 years younger than in other dementia patients [77]. The discovery of tau mutations in families with FTDP-17 has confirmed the fact that genetics plays a role in a subgroup of FTD cases. appearing in the coding regions as well as in the noncoding regions (introns). Tsuang.89]. The causative gene in this family is yet to be identified.D.W. This mutation (V337M) is located in exon 12 of the tau gene (Fig. Because tau is a major component of NFTs and the tau gene is located in the critical region. 4). T. Some mutations are believed to cause disease by producing functional changes that interfere with the normal binding of microtubules.000 base pairs of DNA and 15 exons. more than 20 tau mutations have been identified in FTDP-17 families [88. many other families with FTDlike features also showed linkage to the same region. several other clinically distinct syndromes also mapped to 17q21-22. The success of gene identification (see below) in families with atypical dementia not only confirmed the genetic basis of FTD but established it as a distinct clinical and pathologic entity. There are commonly six alternatively spliced isoforms of the tau gene involving exons 2. it has been considered an important candidate gene for FTDP-17. Other families not linked to chromosome 17 have been identified. There are clearly a few large families with multiple affected individuals in which FTD seems to segregate in a highly penetrant and autosomal dominant fashion. with 100. Some of these aggregates have similar morphology to the neurofibrillary tangles (NFTs) seen in AD. pathologic similarities between the various syndromes include tau protein aggregates in the absence of amyloid plaques. and linkage to chromosome 3 has been reported in one such family [90]. . Subsequently. More work needs to be done to determine the range of tau mutations in FTD and related disorders. including parkinsonism [82] and schizophreniform features [83]. It also exhibits complex splicing (see Fig.87]. 3. Tau gene The modified product of the tau gene is a major component of NFTs seen in AD. the first tau mutation was identified in a family with familial presenile dementia with psychosis [85] and was confirmed in additional studies [86. Most of these mutations are missense. Frontotemporal dementia and parkinsonism-linked to chromosome 17 The first systematic linkage study of FTD families mapped the causative gene to chromosome 17 [81]. After some failed attempts to identify mutations in this gene. The tau gene is large. and 10. 4). Even though many clinical differences exist. All but one of the currently identified mutations affect microtubule binding domains.D. At the consensus meeting on chromosome 17-linked dementia in 1996. the frequency of tau mutations increases to as high as 30% to 40%. such as Guamanianamyotrophic lateral sclerosis-parkinsonism-dementia complex and progressive supranuclear palsy. and 10 are alternatively spliced. 3. which was discovered in exon 12. 4. T.D. and molecular findings are necessary to better understand the role of tau and the frontal lobes in behavior and cognition. pathologic. Seattle. Bird / Med Clin N Am 86 (2002) 591–614 Fig. If FTD is familial and affected individuals have tau-related neuropathologic findings.95].W. Tau mutations have not been found in AD or sporadic cases of FTD. Scrapie was shown to be experimentally transmissible in 1936 [96]. WA). Exons 2. there are genetic association data that suggest that tau may play a role in the disease process [91–93]. What we now know as prion diseases were first described in the 1800s. The tau gene on chromosome 17 has a complex genomic structure with more than 15 exons spread over 100. In conditions with tau aggregate pathologic findings. making up six commonly alternatively spliced isoforms of the tau gene. It undergoes complex differential splicing.604 D. Tsuang. Prion disease Although prion diseases are relatively uncommon. Understanding the in vivo processing of the tau gene is likely to be important in the eventual development of therapeutic treatments. PhD.000 base pairs of genomic DNA (top of figure). Explanations for these various clinical. Human prion diseases were recognized in the 1920s by Creutzfeldt and Jakob and . The large bold arrow points to the first tau mutation (V337M) associated with frontotemporal dementia. But most FTD cases are sporadic and are not associated with mutations in the tau gene [94. (Courtesy of Parvoneh Poorkaj. with reports of scrapie in sheep. they exemplify both transmissible and heritable forms of dementia. new variant CJD) can be both vertically (heritable) and horizontally Fig. Bird / Med Clin N Am 86 (2002) 591–614 605 were called spongiform encephalopathies [97. Gerstmann-Straussler-Scheinker syndrome (GSS). but the protein structure undergoes a three-dimensional configuration change. The prevalence of CreutzfeldtJakob disease (CJD) is approximately 1 case per 1 million persons. fatal familial ¨ insomnia (FFI). the occurrence of bovine spongiform encephalopathy (mad cow disease) further increased the recognition of these disorders. The identification of the prion protein (PRNP) gene that encodes the prion protein (PrP) [102] has rapidly transformed neurobiologic and genetics research in this area. and new variant CJD (Fig. Interestingly. GerstmannStraussler-Scheinker disease. The normal cellular prion protein (PrPC) is a membrane protein primarily expressed in astrocytes [99–101]. and bovine spongiform encephalopathy. Tsuang. T. Because these diseases all share the property of transmissibility and the characteristic pathologic finding of spongiform changes. CJD.98]. The animal prion diseases include ¨ scrapie. 5. some prion diseases (eg. and fatal familial insomnia. including kuru. . Six human diseases associated with prions have been described. The human prion diseases include Creutzfeldt-Jakob disease. most sporadic cases have no known cause. The mechanisms by which PrPC converts to the scrapie isoform (PrPSc) remain unclear. In the 1990s.W. transmissible mink encephalopathy. kuru. CJD. atypical prion disease. kuru (a deadly neurodegenerative disorder transmitted through ritualistic cannibalism) was recognized to be similarly transmissible. they are often collectively referred to as transmissible spongiform encephalopathies. 5). Although some families have mutations in the PRNP gene that are transmitted in an autosomal dominant fashion and other cases are caused by known exposure to contaminated tissue.D.D. Prions are small proteinaceous particles that resist inactivation by conventional proteinases. In the 1960s. The classic symptoms occur in less than 60% of cases. In families with the D178N mutation and valine at position 129. The most common PRNP mutation associated with familial prion disease is the E200K (glutamic acid [GAG] to lysine [AAG]) mutation. T.W. Tsuang. and FFI. PrPSc-positive kuru plaques and other PrP-containing amyloid plaques are pathognomic of prion disease.D. Another missense mutation (D178N) in the PRNP gene has been reported in a number of different families. the presentation is that of fairly typical CJD with memory loss. such as ‘‘familial prion disease with a P102L mutation and predominant ataxia. Other clinical features may include psychotic symptoms resembling schizophrenia as well as extrapyramidal and cerebellar dysfunction or akinetic mutism. The diagnosis of CJD should be entertained in individuals with rapidly progressive neuropsychiatric disorders. ataxia. A cerebrospinal fluid test for the 14-3-3 protein has been found to be diagnostically useful. The largest known cluster is a group of Libyan Jews living in Israel. In families with inherited prion diseases. Prion protein mutations The human PRNP gene is located on the short arm of chromosome 20. Current nosology may be replaced in the future by specific DNA mutations. although definitive diagnosis can only be made on neuropathologic or biochemical examination of the brain. and astrocytic gliosis. This gene is highly conserved throughout many species. The cellular function of PrPC remains unknown. suggesting that its function is critical. Surprisingly. however. Clinical diagnostic criteria have been established by a large CJD surveillance group in Europe [103].606 D. . GSS. the phenotype depends heavily on the genotype present at an entirely different codon (codon position 129). Up to 50% of familial cases have this mutation. This mutation has been found in more than 50 families worldwide.’’ Creutzfeldt-Jakob disease Sporadic CJD most often affects patients in their 50s and 60s. who have an incidence of CJD 100-fold greater than the population worldwide [105]. There are no systematic studies that provide frequency estimates of known mutations in different patient samples. The neuropathologic hallmarks of CJD include spongiform degeneration. more than 15 types of mutations have been described [104]. we review the genetics of CJD. however. neuronal loss. They are almost exclusively found in familial CJD cases with PRNP mutations. Bird / Med Clin N Am 86 (2002) 591–614 (infectious) transmitted. and myoclonus) and characteristic synchronous spikes on the electroencephalogram in an afebrile individual. In this section. The typical clinical presentation includes rapid progressive cognitive decline (<2 years to death) accompanied by a variety of neurologic signs (most commonly rigidity. the phenotype is that of FFI. and mutism. dystonia. Neuropathologically. ¨ The clinical and neuropathologic characteristics of these families are indistinguishable from those of sporadic CJD. Neuropathologic findings include diffuse spongiform degeneration in the cerebral cortex and basal ganglia with relative sparing of the thalamus. Alternatively. FFI is characterized by neuronal loss and astrocytic gliosis preferentially affecting the thalamus. in families with the same D178N mutation but with methionine at position 129. family members with the same PRNP mutation may have either phenotype. and pyramidal tract dysfunction. GSS is always considered to be solely genetic and often has a longer disease duration than CJD. T. More than 30 affected families in the Northern Hemisphere have been described to date [108]. This finding is similar to the results observed in experiments using brain tissue from sporadic CJD cases. Clinical symptoms often overlap.D. The most common mutation associated with GSS is the P102L mutation. but transmission has not been demonstrated in other families with different mutations [110]. Bird / Med Clin N Am 86 (2002) 591–614 607 ataxia. Tsuang.D. and myoclonus. patients exhibit complete insomnia. dementia. GSS is distinct from CJD in that GSS is characterized by the presence of large multicentric PrPcontaining amyloid plaques with variable spongiform changes. and hyporeflexia. As such. The age of onset is in the 50s and 60s. the GSS syndrome. They may later show signs of ataxia. dysarthria. This was the first mutation to be formally linked to a human prion disease and is the causative mutation originally described by Gerstmann. rigidity. dysphagia. These patients often present with insomnia and dysautonomia. the disease was transmitted in most trials. myoclonus. dementia. dysarthria. At least 21 families with FFID178N mutations have been reported [106]. Straussler. In the later stages.W. The electroencephalogram shows generalized slowing rather than periodic triphasic waves. Clinical symptoms include early ataxia. Conversely. however. Neuropathologically. and do not always ‘‘breed true’’ within families. Patients with GSS are more likely to exhibit ataxia than patients with CJD. with the disease duration ranging from 9 months to 4 years. It is unclear why the codon 129 genotype dramatically influences the phenotype associated with the D178N mutation. Another phenotype. patients with CJD are more likely to have dementia and myoclonus. but it presumably affects the three-dimensional structure of PrP. is caused by several different mutations in the PRNP gene [107]. when infected brain tissue from CJD E200K patients was injected into primates. Interestingly. The duration of illness is short (mean ¼ 13 months). and Scheinker [109]. Mitochondrial disorders Mitochondrial disorders are clinically diverse and are defined by structural or functional abnormalities in the mitochondria or mitochondrial DNA . including the brain. These are not specifically germline mutations but accumulating mutations that may increase over time in any organ. we have made tremendous advances in our under- . younger AD patients (<75 years old) are more likely to have an increased level of common mtDNA mutations than age-matched controls. Because mtDNA has a poorly developed repair system. Screening for mtDNA mutations is not recommended for any neurodegenerative conditions until these frequency of these mutations is better established [112]. T.608 D. Summary Many neurodegenerative diseases are exceedingly complex disorders (Fig. mutations are rarely repaired. In addition. Bird / Med Clin N Am 86 (2002) 591–614 (mtDNA). some clinical symptoms may improve as a child ages. It has been hypothesized that several different mutations may ultimately contribute to functional impairment. it is postulated that mtDNA mutations may lower the oxidative efficiency of critical neuronal populations early in life [111]. mitotic segregation. Heteroplasmy refers to the mixture of both mutant and wild-type molecules within mitochondria. The characteristics of inherited mitochondrial disorders include maternal inheritance. Mitochondrial disorders have been implicated in prevalent neurodegenerative disorders (eg. 6). Aging is associated with an increase in mtDNA mutations. Tsuang. In AD. Although infrequent. the data need to be confirmed. In normal cells. Because mtDNA is almost exclusively maternally inherited.D. In the past decade. As a result. the proportions of mutant and normal mtDNA allocated to daughter cells shift. There is evidence that mtDNA mutations may be involved in neurodegenerative conditions such as AD. Mitotic segregation explains the markedly different levels of mutant mtDNA in members of the same family as well as among different tissues in a single individual. and the threshold effect. heteroplasmy. but the evidence is controversial. It remains unclear whether these observations are the consequences of the disease or whether they contribute to the pathophysiology. an increasing number of mtDNA mutations have been described in several neurologic disorders. all mtDNA molecules are identical. These mutations are not genetically transmitted to the next generation but may cause dysfunction of the organs in which they occur. Nevertheless. As heteroplasmic cells undergo cell division. analysis of large families is often necessary to establish the pattern of maternal inheritance. AD. An increase in oxidative damage to mtDNA in AD brains has been reported. Because of the clinical heterogeneity associated with mitochondrial disorders. all mtDNA mutations are passed on by mothers.W. The precise effects of these mutations are not known. Variability in onset and severity of clinical manifestations results from a changing balance between the energy supply and oxidative demands of different organ systems. The threshold effect is the observation that a certain level of mutant mtDNA must be achieved before a cell expresses a defect. PD) as well as in aging itself. In summary. This diagram demonstrates the concept that the Alzheimer’s disease (AD) phenotype (as well as the other neurodegenerative conditions) is phenotypically heterogeneous. One common characteristic of these disorders is the existence of rare families in which a given disease is inherited as a Mendelian trait. genetic predisposition.D. Such research should facilitate new strategies for therapeutic interventions. Future clinical and molecular genetics findings hold many clinical implications. standing of the genetic basis of these disorders. the bottom arrow shows that most cases of AD in the general population may be the result of a complex interplay between environment. On the right are four potential nongenetic causes of AD that presently remain speculative.W. . Further genetic analysis should clarify the roles of known genes in the pathogenesis of common sporadic forms of these various diseases. Although molecular genetics has helped to clarify the etiology of these disorders. clinicians have played a critical role in the careful identification and classification of many families who were involved in the eventual mapping and cloning of causative mutations. Investigation of the normal and aberrant functions of these genes should provide insight into the underlying mechanisms of these disorders. 6. On the left are the four known genetic factors associated with AD.D. T. and aging. It is likely that new diagnostic and therapeutic strategies for dementing disorders are just on the horizon. Bird / Med Clin N Am 86 (2002) 591–614 609 Fig. Tsuang. 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PII: S 0 0 2 5 . E-mail address:
[email protected] (J. All rights reserved. Maloney Building.-Y. 3rd Floor. Despite their diverse phenotypic manifestations. Philadelphia. Elsevier Science (USA). Virginia M.upenn. Trojanowski). see [1–3]). University of Pennsylvania School of Medicine. Department of Pathology and Laboratory Medicine.7 1 2 5 ( 0 2 ) 0 0 0 0 2 .0 . However.see front matter Ó 2002. this was controversial until 1998 when multiple tau gene mutations were discovered in families with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and provided unequivocal evidence that tau abnormalities alone are sufficient to cause neurodegenerative disease [4–8]. USA Growing evidence over the past decade has led to the realization that many sporadic and familial neurodegenerative diseases are characterized by distinct hallmark brain lesions formed by filamentous deposits of abnormal brain proteins. Trojanowski. Normal tau biology and functions Tau proteins are low Mr microtuble associated proteins (MAPs) that are expressed predominantly in axons of central nervous system (CNS) * Corresponding author. these dramatic discoveries re-focused attention on the role of tau pathologies in mechanisms of brain degeneration in AD.med. This opened up new avenues for investigating the role of tau abnormalities in mechanisms of brain dysfunction and degeneration in Alzheimer’s disease (AD) and related neurodegenerative disorders [1–3]. and here we review recent insights into these aspects of the pathobiology of AD. and the absence of other disease-specific neuropathological abnormalities in several tauopathies provided circumstantial evidence implicating tau abnormalities in the onset/progression of neurodegeneration [1–3]. Lee. and a group of heterogeneous disorders characterized neuropathologically by prominent intracellular accumulations of abnormal tau filaments may share common disease mechanisms (for recent reviews. 0025-7125/02/$ .Q.Med Clin N Am 86 (2002) 615–627 The role of tau in Alzheimer’s disease John Q. PA. HUP. 19104. PhD Center for Neurodegenerative Disease Research. PhD*. 18. alternative splicing of exons (E) 2 (E2). Further. tau is developmentally regulated leading to expression of only the shortest tau isoform (3R/0N) in fetal brain. tau binds to and stabilizes microtubules (MTs). Several functions of tau have been extensively characterized (for review [1–3]). 3 (E3) and 10 (E10) generates six tau isoforms ranging from 352 to 441 amino acids in length which differ by the presence of either three (3R-tau) or four (4R-tau) carboxy-terminal tandem repeat sequences of 31 or 32 amino acids that are encoded by E9. In the adult human brain. and the CNS isoforms are generated by alternative mRNA splicing of 11 exons [15–17]. Lee / Med Clin N Am 86 (2002) 615–627 Table 1 Neurodegenerative disease with tau pathology Alzheimer’s disease Amyotrophic lateral sclerosis/parkinsonism-dementia complex* Argyrophilic grain dementia* Corticobasal degeneration* Dementia pugilistica* Diffuse neurofibrillary tangles with calcification* Down’s syndrome Frontotemporal dementia with parkinsonism linked to chromosome 17* Multiple system atrophy Myotonic dystrophy Neurodegeneration with brain iron accumulation type 1 (formerly Hallevorden-Spatz disease) Niemann-Pick disease.616 J. For example. Human tau is encoded by a single gene consisting of 16 exons on chromosome 17q21. 0N and 2N tau isoforms comprise about 54%.23]. and they also are found in axons of peripheral nervous system (PNS) neurons. but all six isoforms are expressed in the adult human brain.M. but the 1N.10–14]. Additionally. in addition to promoting MT polymerization through MT binding domains in the carboxy-terminal half of tau that are composed of highly conserved . In the PNS.21]. 37% and 9% of total tau. inclusion of E4a in the amino-terminal half results in the expression of the largest tau isoform [12. the ratio of 3R-tau to 4R-tau isoforms is 1.19]. Trojanowski. neurons. V.-Y. E11 and E12 [15. In the adult human brain. E10. respectively [20. type C Pick’s disease* Post-encephalitic parkinsonism Prion diseases Progressive subcortical gliosis* Progressive supranuclear palsy* Subacute sclerosing panencephalitis Tangle only dementia* * Diseases in which tau pathologies are the most predominant neurodegenerative brain lesions.22. but they are barely detectable in CNS astrocytes and oligodendrocytes [9.Q. the three 3R-tau and 4R-tau isoforms differ due to alternative splicing of E2 and E3 that results in tau isoforms without (0N) or with either 29 (1N) or 58 (2N) amino acid inserts of unknown functions. 11. The major candidate tau kinases include mitogen-activated protein kinase [36. The binding of tau to MTs is a complex process mediated by several MT binding sites distributed throughout the MT binding repeats and the inter-repeat sequences as well as sequences flanking the repeats [1–3. cyclindependent kinase 2 (cdk2) [46]. Trojanowski.36. and a large number of Ser/Thr protein kinases have been suggested to play a role in regulating tau functions in vivo. this aspect of tau biology remains controversial (reviewed in [1–3]). but the inter-repeat sequence between the 1st and 2nd MT binding domains has >2 times the binding affinity of any of the MT binding repeats.M.31–35]. For example. However.41].24–27]. The tau phosphorylation sites are clustered in regions flanking the MT binding repeats.Q. glycogen synthase kinase 3b (GSK-3b) [42–45]. while the degree of phosphorylation of the six adult tau isoforms decreases with age [1–3. However. Further. recent data suggest that GSK-3b and cdk5 plausibly regulate the in vivo phosphorylation of tau. the increasing phosphorylation of tau negatively regulates MT binding [1–3. Lee / Med Clin N Am 86 (2002) 615–627 617 18-amino acid long binding elements separated by less conserved 13-14 amino acid long inter-repeat sequences [1–3. Tau phosphorylation is developmentally regulated and fetal tau is more highly phosphorylated in the embryonic compared to the adult CNS.54–57]. The 4R-tau isoforms are more efficient at promoting MT assembly and have a greater MT binding affinity than 3R-tau isoforms.-Y. and cell culture studies indicate that GSK3b induces hyperphosphorylation of tau followed by dimished MT binding [45. but a similar role has been ascribed to phosphorylation of Ser-396 [31]. In cultured neuronal cells. and 79 potential serine (Ser) and threonine (Thr) phosphate acceptor residues are present in the longest tau isoform. 31.28–30]. Although the kinases and protein phosphatases that regulate tau phosphorylation are the focus of intense investigation. MT-affinity regulating kinase [50]. both sites are phosphorylated in fetal tau and they are hyperphosphorylated in all six adult human brain tau isoforms that form paired helical filaments (PHFs) in AD neurofibrillary tangles (NFTs). cyclin-dependent kinase 5 (cdk5) [46.47] . phosphorylation of Ser-262 has been reported to play a dominant role in reducing the binding of tau to MTs [38].20.40. while phosphorylation at 30 of these sites has been reported in normal tau. and stress-activated protein kinases [51–53]. which may account for the higher MT binding affinity of 4R-tau versus the 3R-tau isoforms. GSK3b .26.24. V. it has been suggested that a sequence of residues aminoterminal to the MT binding domains (224KKVAVVR230) promotes MT binding in combination with the repeat regions. and it is likely that phosphorylation at multiple phosphate acceptor sites regulates the binding of tau to MTs. Ca2þ/calmodulin-dependent protein kinase II [49]. Although the relative importance of individual sites for regulating the binding of tau to MTs is unclear. while other studies suggest that neither of these sites dominantly regulate binding of tau to MTs [39]. cAMP-dependent protein kinase [48].J. and this region is unique to 4R-tau. GSK3b is a Ser/ Thr kinase that is abundant in brain and associates with MTs.37]. Pathological tau in AD In contrast to tauopathies. although their role in vivo is unclear (reviewed in [1–3]).Q.-Y. but more than 20 years earlier [76] electron microscopical (EM) studies had revealed that the major structural components of NFTs were PHFs and to a lesser extent straight filaments (SFs). However. For example. selective destruction of stable MTs and rapid axonal degeneration of axons [73]. wherein filamentous neuronal and/or glial tau inclusions are the only defining neuropathological features in affected brain regions.54. cdk5 complexes with tau and anchors cdk5 to MTs while cdk5-mediated tau phosphorylation stimulates further phosphorylation of tau by GSK3b [64– 66]. the specific role of individual phosphatases in the in vivo regulation of tau phosphorylation remains to be determined. and PP2A shows the major activity in brain on tau phosphorylated by a number of kinases [41. Trojanowski. Both PP2A and PP2B are present in human brain tissue and they dephosphorylate tau in a site-specific manner. the building block subunits of both PHFs and SFs were shown to be abnormally phosphorylated tau proteins [16. cdk5 is a Ser/Thr protein kinase highly enriched in neurons that colocalizes with the cytoskeleton and contributes to the phosphorylation of tau. PP1 and PP2A bind to tau. biochemical analysis of . Moreover. decreased tau binding to MTs. V.44.62. On the other hand.M. and inhibition of GSK-3b by lithium salts or ATP inhibitors reduces tau phosphorylation and affects MT stability [43.78–83]. and it is activated by regulatory subunits such as p35 [46. but PP2A also dephosphorylates tau at additional sites. after the appearance of a number of conflicting reports on the composition of these filaments in the early 1980s. 2B (PP2B) and 2C (PP2C) in regulating tau phosphorylation.47.68. 2A (PP2A). tau-rich NFTs and neuropil threads co-occur with deposits of Ab fibrils in the extracellular space as diffuse and senile plaques as well as in blood vessel walls of AD brains (reviewed in [1–3]).618 J. However. For example. although inhibition of PP1 and PP2A by okadaic acid in cultured human neurons was followed by increased tau phosphorylation.75].63]. The neurofibrillary tau lesions in AD brains were first shown to be stained with anti-tau antibodies more than 15 years ago [74. and PP2A also binds directly to MTs [70–72].67–69]. the relative contributions of individual kinases to tau phosphorylation in vivo remain to be elucidated.58–61]. Subsequent EM studies demonstrated that PHFs contain two strands of fibrils twisted around one another with a periodicity of 80 nm and a width varying from 8 to 20 nm. Finally. Protein phosphatases also have been the focus of research on tau since they counterbalance the effects of tau kinases. possibly mediating an association with MTs. both enzymes dephosphorylate Ser396. while SFs do not demonstrate a similar helical periodicity [77]. Lee / Med Clin N Am 86 (2002) 615–627 mediated tau phosphorylation is inhibited by insulin and IGF-1 via a phosphatidylinositol 3-kinase and protein kinase B dependent pathway. and studies have implicated protein phosphatse (PP) 1 (PP1). 108] and arachidonic acid [109] also were shown to induce fibrillization of full-length recombinant tau. Nonetheless. and the detetion of GAGs and RNA co-localized with PHFtau in NFTs suggests that these in vitro findings may be relevant to tau fibrillization in the AD brain [103. In subsequent studies. although PHFs from AD brain consist of full-length tau [99–101]. the relative abundance of each of the six tau isoforms in AD PHFs (PHFtau) was indistinguishable from the six soluble tau isoforms in the normal adult human brain [3. since increasing the ability of pathological tau to intereact with MTs may be beneficial. Indeed.93–95]. six protein bands corresponding to the six adult human brain tau isoforms were evident. most phosphorylated residues in PHFtau also were found in tau isolated from biopsies of normal human brain [69]. While the role of tau phosphorylation in AD brain degeneration remains uncertain. RNA [107.21. in addtion to a minor 72-kDa band. but relative to normal.and 60-kDa. a number of early studies of tau fibrillogenesis showed that PHF-like filaments can be assembled in vitro from bacterially expressed non-phosphorylated 3R-tau fragments. indirect evidence of a causative role for tau protein abnormalities in brain degeneration .84. although there is no consenus on this at this time [1–3. but after enzymatic dephosphorylation. a truncated form of p35.M. but cdk5 abnormally activated by p25. Moreover. Numerous kinases and protein phosphatases were implicated in the aberrant phosphorylation tau in the AD brain (for detailed reviews see [1–3]). may play a mechanistic role in the conversion of normal tau into PHFtau in AD [89–92]. it is unclear if it directly mediates tau fibrillogenesis in vivo. V. Nonetheless. while tau hyperphosphorylation is likely an early step in the generation of PHFtau from normal soluble tau [98]. Trojanowski. Implications of other neurodegenerative tauopathies for AD Despite controversies about the role of tau pathology in AD. sulphated glycosaminoglycans (GAGs) were shown to stimulate phosphorylation of tau by a number of protein kinases and induce fibrillization of full length tau [102–104]. thereby increasing the pool of unbound tau which then may aggregate into insoluble filamentous inclusions. hyperphosphorylated) at these sites [85–88]. the organic osmolytes trimethylamine N-oxide (TMAO).85]. tau fibrillization may occur in a nucleationdependent manner [106]. 64. Further. while a short amino acid sequence (VQIVYK) in the third MT-binding repeat was suggested to be essential for heparin-induced filament assembly [105].110–112].97]. soluble adult brain tau isoforms. Lee / Med Clin N Am 86 (2002) 615–627 619 PHFs purified from AD brains revealed three major bands of approximately 68-.-Y. betaine or related compounds could have therepeutic potential in AD and related tauopathies because they appear to increase tau mediated MT assembly and restore the ability of phosphorylated tau to promote this assembly [96. Indeed. Moreover.Q. PHFtau was more extensively phosphorylated (ie.J. it is possible that hyperphosphorylation of tau disengages tau from MTs. Trojanowski. E342V) and E13 (G389R. three silent mutations in E10 (L284L. see [1–3]). while experimental confirmation of this notion is emerging from studies of a number of transgenic mouse and other model systems of tauopathies (see [1–7. S305S) and a deletion mutation (DK280). function and biochemistry of tau. E12 (V337M. as well as the identification of potential disease-modifying . N296N. The finding that specific tau gene mutations lead to diverse FTDP-17 phenotypes raises the possibility that the clinical and pathological expression of hereditary and related sporadic tauopathies may be influenced by tau gene polymorphisms. studies of FTDP-17 brains from several laboratories add increasing support to the hypothesis that FTDP-17 mutations lead to tau dysfunction and neurodegenerative disease by one or more distinct mechanisms including losses of tau functions and gains of toxic properties. However.113] for further details. þ13. Further. and additional citations). but overlapping.M. E10 (N279K. Summary Despite earlier uncertainties about the role of tau patholgy in AD. but further investigation into the mechanisms of tau dysfunction. P301L. As reviewed elsewhere [1–3]. and these disorders are characterized neuropathologically by prominent filamentous tau inclusions in neurons and/or glial cells (for recent reviews. However. þ14. reviews of other studies. in 1998. these include 11 missense mutations in coding regions of the tau gene involving E9 (K257T.Q. including altered expression. more compelling evidence for this notion came from studies of a group of syndromes known as FTDP-17 that are autosomal-dominantly inherited neurodegenerative diseases with diverse. P301S. For example. The mutations lead to specific cellular alterations.620 J.21. S305N). G272V). and within three years more than 20 distinct pathogenic mutations in the tau gene have been identified in a large number of new FTDP-17 families. R406W). other genetic factors and epigenetic events. clinical and neuropathological features. and this is exemplified by sporadic tauopathies such as progressive supranuclear palsy and corticobasal degeneration (for which specific tau haplotypes appear to be genetic risk factors). while five substitutions in six different positions of the intron following E10 have been identified (at positions þ3. the discovery of multiple mutations in the tau gene that lead to the abnormal aggregation of tau and the onset/progression of FTDP-17 demonstrates that tau dysfunction is sufficient to produce neurodegenerative disease. þ12. the precise mechanisms whereby tau assembles into filaments and causes neurodegeneration in the human brain remain to be elucidated.-Y. þ16) and other mutations have been reported in recent meetings. V. several groups identified pathogenic mutations in the tau gene that segregated with FTDP-17 [4–8]. I260V. Lee / Med Clin N Am 86 (2002) 615–627 comes from studies of pure tauopathies wherein there is abundant filamentous tau pathology and brain degeneration in the absence of extracellular amyloid deposits or other brain lesions (Table 1). and Pick’s disease (reviewed in [1–3]). 43(6):815–25.95(13): 7737–41. References ´ ` ´ [1] Buee L.7(11):1825–9.M. the support of the families of our patients have made this research possible. Proc Natl Acad Sci USA 1998. Trojanowski JQ. Murrell JR.J. Annu Rev Neurosci 2001. et al. Work done in the laboratories of the authors is supported by grants from the National Institute of Aging of the National Institutes of Health and the Alzheimer’s Association. [4] Clark LN. Nature 1998. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Rizzu P. Buee-Scherrer V. will provide additional insight into novel strategies for the treatment and prevention of AD and related disorders. J Chem Neuroanat 2000. 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RNA sequestration to pathological lesions of neurodegenerative diseases. et al. Trojanowski.-Y. van den Heuvel LP.amyloid protein-containing lesions of Alzheimer’s disease and Down’s syndrome. Acta Neuropathol (Berl) 1998. et al.155(6):2115–25. [112] Verbeek MM. Biochem 2000. Am J Pathol 1999. V. Dawson H.Q. Galvin JE. Mar H.96(5):487–94. et al.137(5):1253–70. et al. Otte-Holler I. Lee / Med Clin N Am 86 (2002) 615–627 627 [110] Ginsberg SD.M.J. Chiu TS. Nochlin D. Elsevier Science (USA). PII: S 0 0 2 5 . which have been shown to be composed of the abnormally phosphorylated microtubule-associated protein tau [2]. They occur as intraneuronal. both identified by Alois Alzheimer in 1906. CA 94080.sinha@elan. ultrastructurally shown to occur as interwound paired-helical filaments (PHF). Neuritic plaques are composed of extracellular fibrillar deposits of the beta-amyloid peptide.com (S. and activated astrocytes. the senile or neuritic plaque.see front matter Ó 2002. But all cases of clinical AD that have been analyzed for neuropathology have been shown to have Ab deposits. upon postmortem analyses of the brain. Although both of these prominent pathologic lesions often occur simultaneously in the majority of AD cases. and are often associated with dystrophic neurites. although the nature and extent of these varies widely in both sporadic and familial forms of the disease. 0025-7125/02/$ .6 . Neurofibrillary tangles. 800 Gateway Boulevard. cytoplasmic inclusions. are found extensively in all of the brain areas affected in AD. PhD* Elan Biopharmaceuticals. Amyloid precursor protein (APP) and its metabolism Remarkable progress in understanding the underlying pathology of this disease has been made over the last fourteen years.Med Clin N Am 86 (2002) 629–639 The role of beta-amyloid in Alzheimer’s disease Sukanto Sinha. remarkably resistant to solubilization even in strong chaotropic agents. or NFTs. NFTs are sometimes found in diseases other than AD. especially some of the ‘‘taupathies’’ without coincidental beta-amyloid plaques. as well as in the hippocampus. Ab. Sinha). and neurofibrillary tangles. They are found widely in the limbic and association areas of the temporal cortex. a structure that is affected dramatically in the disease [1].7 1 2 5 ( 0 2 ) 0 0 0 2 2 . dating approximately * E-mail address: sukanto. by the presence of two major pathologic lesions. All rights reserved. USA Alzheimer’s disease pathology Alzheimer’s disease (AD) is characterized. activated microglial cells. South San Francisco. and that alternate. and that tissue culture cell lines. in their culture medium [6]. the b-sAPP made up as much as 40–50% of total sAPP derived from culture medium of the neuronal cells. Shortly thereafter.630 S. This ‘‘a-secretase’’ cleavage also leads to the loss of the intact Ab peptide region. ubiquitous pathway of mature APP processing. Sinha / Med Clin N Am 86 (2002) 629–639 from the time that the protein precursors to the Ab peptides. as well as Ab11-40. enriched in neuronal cells. led to the dogma that this represents ‘‘normal’’ APP metabolism. This cleavage takes place between Met671-Asp672 (using the APP770 codon numbering). collectively called APP. releasing a b-sAPP [7] that is C-terminally truncated compared with a-sAPP. such as HEK293 that are transfected with APP also release Ab peptides into their culture medium as well. which is detected not only in the culture medium of cells expressing APP. and its recognition as the major. pathologically triggered pathways must be responsible for the aberrant generation of the Ab peptides. which are then subsequently deposited as insoluble amyloid during the disease process. and also generating a cell-associated 99 aa long C-terminal fragment (CTF) which starts with Asp672 (¼Ab1) (Fig. which leads to the release (secretion) of the bulk of the N-terminal ectodomain of the protein as sAPP [4]. The early identification of this pathway. were cloned [3] and subsequently expressed in cell culture. but also in physiologic fluids such as plasma and cerebrospinal fluid (CSF). This alternate secretory cleavage was found to be far more prevalent in primary neuronal cultures than in peripherally derived tissue culture cells. 1). It turns out that most of the sAPP generation takes place as a consequence of cleavage of the membrane-bound protein approximately 12 amino acids N-terminal to the membrane interface [5]. The recognition that the Ab peptides are actually normal metabolites of APP came about as the consequence of the discovery that primary human neuronal cells release Ab peptides. Studies of the metabolism of the APP from various laboratories have conclusively established that following maturation of the protein in the secretory pathway. could initiate the normal production of Ab by the cellular turnover of the 99 aa b-CTF. Ab1-40. proteolytic cleavages take place in the extracellular or luminal domain of the protein. It therefore appeared that b-secretase cleavage of APP. the site of endoproteolysis being 16 aa C-terminal to the start of the Ab peptide sequence. compared with 5% or less as found in culture medium from HEK293 cells transfected with APP. Familial Alzheimer disease mutations and genetic risk factors Concurrent with the elucidation of these cellular pathways of APP metabolism that lead to the release of Ab peptides into the extracellular milieu came the identification of rare missense mutations in APP that lead . it was shown that a subset of sAPP is generated by an alternate ‘‘b-secretase’’ activity that cleaves the full-length membranebound APP immediately N-terminal to the Ab peptide sequence. These classified into two groups. however. 1. changing the Lys670Met671 sequence of the b-secretase cleavage site to a Asn670Leu671 motif (‘‘Swedish’’ mutation. Sinha / Med Clin N Am 86 (2002) 629–639 631 Fig. Phe or Gly (‘‘London’’ mutations. or with a more complex interaction among multiple hereditary and extrahereditary factors. The higher levels of the cell-associated b-CTF generated as a consequence of this gives rise to the higher levels of Ab peptide released. APP717). appear to be transmitted in . consistent with either incompletely penetrant singlegene defects. there is an increased age-dependent risk for AD among primary relatives of patients with AD [11]. Approximately 10% of AD cases. The increased Ab peptide release was accompanied by increased levels of b-sAPP as well. indicating that the Swedish double mutation at the b-secretase site leads to an increased cleavage of the full-length APP molecule at the altered sequence. to the familial inheritance of AD. This was demonstrated dramatically on transfection of the Swedish APP forms into HEK293 cells. The a. one in which Val717 was found to be mutated into either Ile [8]. epidemiologic data have long pointed to the strong contribution of genetic factors to the overall population risk for AD. The identification of such disease-causing mutations that framed the Ab peptide region suggested that they somehow alter the metabolism of APP. such as possible environmental modifiers. leading to increased Ab production.S. APPNL). which led to a five to sixfold overproduction of the Ab peptides compared with Wt APP [10]. Although missense mutations in APP account for a very small number of total AD cases. For example.and b-secretase cleavage pathways for APP. and a second pedigree [9] with a double mutation. in a Volga-German family [13]. The utilization of such assays in the analysis of the effect of the various FAD mutations in PS-1. the numbers in parentheses indicating their approximate prevalence in a Caucasian population. As demonstrated in vitro. and the ‘‘London’’ mutations in APP. Immunohistochemical analyses of AD brain sections with such antibodies have revealed that the majority of diffuse plaques. Ab1-42.632 S. S182 [12]. . with three commonly occurring variants. Multiple studies have gone on to establish that the e4 allele is over-represented in patients with late-onset AD (40% in postmortem or clinically diagnosed AD). e2 (10%). was predicted to traverse the membrane multiple times (polytopic) and was shown to be widely expressed in all cells and tissues surveyed. consistent with its increased presence in insoluble amyloid plaques. Current estimates suggest that the apoe4 allele may account for only 7–9% of all AD cases. STML2. and most senile plaques. and CSF indicate that the predominant form of Ab is Ab1-40. named presenilin-1 (PS-1). called presenilin-2 (PS-2). the additional 2 amino-acid extension at the C-terminus renders this form much more prone to aggregation. Ab42 and AD pathogenesis Although the analysis of Ab isoforms from primary cells. PS-2. the majority of cases of familial Alzheimer’s disease (FAD) were found to map to chromosome 14. The inheritance of two e4 alleles correlates with an earlier age of onset in patients with AD than with a single allele [15]. to a locus that was identified as a new gene. and the identification of the genes that account for the predominant numbers of such cases have provided key insights into the etiology of AD. The protein product of the S182 gene. Sinha / Med Clin N Am 86 (2002) 629–639 familial pedigrees in a classical Mendelian autosomal dominant manner. With the exception of the small number of families that map to APP on chromosome 21. A homologous gene. it has turned out that a relatively minor form. transfected cells. e3 (75%) and e4 (15%). has led to the emergence of a central hypothesis for the cause of AD. Apo E in humans is a polymorphic protein. Distinct from these autosomally inherited single gene defects in PS or APP that lead to early onset AD. and also to the shorter Ab40 peptide. The generation of antibodies specific to this form of the Ab peptide. genetic linkage studies of other familial pedigrees led to the identification of the apolipoprotein E (apo E) locus on chromosome 19 as a potential AD susceptibility gene [14]. inheritance of any of which leads to fully penetrant AD at an early age (35–65 age of onset). although it appears that the apo E polymorphism remains a risk factor and is not causative for AD. is the primary constituent of the amyloid burden in AD [16]. More than 80 separate missense mutations have been cataloged in PS-1. and 5 in PS-2. made possible the development of sensitive and specific assays for both of these forms [17]. was concurrently mapped to chromosome 1. Biochemical analyses of AD brain plaque composition have provided more quantitative confirmation of this as well. senile plaques label with antibodies to Ab40 as well [16]. The increased APP levels. the first FAD mutation identified was the ‘‘London’’ mutation. Plaques at this time label prominently with antibodies to the N-terminus of Ab. has also confounded the issue of what forms of the Ab peptides make up the senile plaque [17]. show up in DS individuals who are 20–30 years old. and the translation of this increased gene dosage at the protein level has been confirmed by analyzing for APP levels in the body fluids of persons with Down’s syndrome. Down’s syndrome is accompanied. Effect of FAD APP mutations on Ab42 As described earlier [8]. or with antibodies specific to the N-terminal region of the Ab peptide [19]. it has been a difficult proposition to precisely nail down the exact composition of senile plaques in AD. although the mature. A roundabout approach to this problem has evolved as a consequence of careful analysis of Ab forms deposited in the various FAD families and the analysis of brains from individuals with Down’s syndrome. approximately 12 years old. vesselassociated amyloid. they show no reactivity with either antibodies to Ab40. as well as with antibodies to Ab40.S. with neurofibrillary tangles being evident by age 30. even though it makes up a relatively small proportion of normally secreted Ab peptides. Trisomy 21 theoretically leads to an extra copy of the APP gene. essentially without exception. Sinha / Med Clin N Am 86 (2002) 629–639 633 label strongly with antibodies specific to the 42 form of the peptide. More Ab42 reactive plaques. That said. Postmortem examination of brains from a Japanese family with this mutation showed dramatic and extensive presence of both diffuse and neuritic amyloid plaques. the Ab42 appears to be a preponderant constituent of neuropil amyloid in AD. and although these diffuse ‘‘plaques’’ label readily with Ab42 antibodies. The earliest amyloid deposits seen in very young individuals. using a variety of different methodologies. Inheritance of this led to an autosomally dominant. leading to substitution of Phe and Gly for the naturally-occurring Val at . accompanied by dystrophic neurites and activated microglial cells. Other APP717 mutations have since been identified. renders the biochemical problem quite formidable. which resulted in the substitution of an Ile for a Val at codon 717 of APP. with DS have a diffuse morphology. and the heterogeneity of the Ab forms that have been identified from AD brain. and the availability of postmortem brain tissue from trisomy 21 individuals at various ages has enabled the ‘‘reconstruction’’ of the likely temporal progression of AD. At this level of analysis. early onset form of AD. with the progressive acquisition of AD-like pathology. leads to increased levels of circulating Ab peptides [18]. not surprisingly. which prominently labeled with antibodies specific to the Ab42 epitope. The concurrent presence of cerebral amyloid angiopathy. prompted the analysis of the mechanism by which APP717 leads to disease. . an increased level of Ab42 peptides were secreted [20]. PS-1. Compared with cells transfected with Wt APP. relative to the Ab40 species. The identification of this gene. the PS-1 holoprotein. Most cells appear to have a saturable capacity for forming the stable NTF:CTF complex [24]. Sinha / Med Clin N Am 86 (2002) 629–639 that position. such mutations were very infrequent. increased levels of total Ab (both Ab40 and Ab42) also cause early onset AD.634 S. and that this was sufficient to cause early onset AD. The pathologic observation of the preponderance of Ab42 plaques. The in vivo and in vitro data provided very strong evidence for the hypothesis that increased levels of Ab42 are produced from the mutated APP. A twofold increase in total Ab was found in the plasma of individuals carrying the APPNL mutation. in both sporadic as well as in this first FAD disease. Analysis of plasma Ab from individuals with codon 717 mutations also showed an approximately twofold increase in Ab42 levels. although the mechanism via which it causes AD was established chronologically earlier than that with the APP717 mutations. and not to be incorporated in a functionally relevant complex. The second FAD mutation identified was also in APP. PS-2 is processed in a similar manner as well. accompanied by a large increase in the b-secretase-cleaved secreted APP. b-sAPP [10]. PS-1 is widely expressed in various tissues and cells and exists in cells as a noncovalent yet stable complex [22]. providing a very strong basis for the hypothesis that Ab is causative for AD. and transfection of PS-1 in cell culture usually leads to only a relatively small (about twofold) increase in the levels of the cleaved forms detected. the ‘‘Swedish’’ or APPNL. Thus. and the consequent stable complex appears to be the functionally relevant form of PS-1. appears to be rapidly degraded. of a 30 kDa N-terminal fragment (NTF) and a 15 kda CTF. The observation that a single point mutation in APP can lead to AD provided the first direct genetic evidence for Ab as a causative factor in AD. Transfection of APPNL into 293 cells led to a very large increase in the total amount of Ab secreted into the conditioned medium. Analysis of Ab species derived on transfection of the mutated APP717 form into 293 cells showed that a small yet significant change in the composition of the Ab species secreted into the conditioned medium. confirming the cellular results [21]. under these conditions. The NTF and CTF are derived by intracellular proteolytic cleavage of the intact PS-1 holoprotein [23]. and the locus on Chromosome 14 (APP is on Chromosome 21) seemed to account for the vast majority of FAD cases around the world. opened up a new field of investigation for AD researchers. resulting in an 50% increase in the Ab42/Ab40 ratio. Presenilins and AD Although the APP mutations provided strong evidence for the amyloidcentric view of AD. including the cellular maturation. and the extracellular release of a. Nicastrin has recently been identified as another necessary component of this complex [29].S. however. Knockout of the PS-1 gene in mice leads to severe developmental abnormalities and consequential fetal lethality. thus underscoring in vivo the likely pathogenetic mechanism deduced from the cellular observations. A variety of experimental approaches have subsequently established that this is indeed the case. diffuse and . noncompacted form. Transgenic models for AD pathology The APP FAD mutations have also been utilized to obtain transgenic mice that overexpress in neuronal cells. without affecting total levels of Ab (Ab40 + Ab42). Transfection of the disease-causing mutant forms invariably leads. Sinha / Med Clin N Am 86 (2002) 629–639 635 The transfection of Wt PS-1 or PS-2 into cells has no detectable effect on Ab40 and 42 levels. Postmortem analysis of brains of PS-1 FAD individuals have demonstrated very high levels of Ab42-positive plaques [17]. although the effect of the FAD mutations are restricted to an increased cleavage of APP at the Ab42 site.and b-CTF fragments is also observed. Potent inhibitors of cellular Ab production have been shown to interact directly with PS-1 [28]. The disease-causing PS-1 and PS-2 mutants thus selectively increase cleavage at the Ab42 site. as well as the mature neuritic plaques. The difficulty of demonstrating increased levels of Ab production on overexpression of the presenilins has suggested the existence of as yet unidentified cellular factors [24] that may be necessary for the saturable formation of the high-molecular-weight presenilin complex.and b-sAPP. at high levels. PS-1 appeared to have a much bigger role in c-secretase cleavage of APP-derived CTFs. All other aspects of APP metabolism appear to remain virtually unchanged. Mutation of either of two highly conserved aspartic acid residues in PS-1 and PS-2 leads to a dominant negative phenotype on Ab production on transfection of such forms into cells [27]. in a age-dependent manner. either APPNL (Tg2576) [30] or the Val fi Phe APP717 (PDAPP) [31].and b-secretory cleavages. Both of these lines of transgenic animals develop. although its biochemical role remains unelucidated.and b-CTFs. An elevation of the steady state levels of the a. and the consensus opinion in the field is that the presenilins are essential biochemical components of c-secretase. without measurable effects on a. but primary cortical cultures generated from premorbid embryonic stages have been used to conclusively demonstrate that the absence of PS-1 leads to a 80% reduction of both Ab40 and Ab42 [26]. to an elevation of Ab42. both of the diffuse. accompanied by the stabilization of APP-derived a. turnover. usually measured as an increase (50–200%) of the Ab42/Ab42 ratio [25]. Thus. suggesting that the absence of PS-1 leads to a reduction in c-secretase cleavage of the CTFs generated by the action of a.and b-secretases. the APPNL FAD family suggested that b-secretase cleavage of APP is important for Ab generation. The ability to test potential drugs and therapeutic approaches directed toward the lowering of Ab peptide levels and the associated aggregated amyloid deposits has opened up the way in utilizing these animal models of AD pathology toward identifying and testing strategies for treating AD. and ancillary pathologies seen in AD. In a separate approach. but not in other regions spared in AD such as the cerebellum. Sinha / Med Clin N Am 86 (2002) 629–639 compact amyloid plaques in the cortex and hippocampus. b-secretase cleavage of APP. these animal models have also proven to be useful in identifying pharmacologic agents that modulate the production or clearance of the Ab peptide. Peripheral administration of antibodies directed to the human Ab was also shown to result in a similar clearance [34]. though observable in cultured cells. although these mice are totally deficient in . other neurofibrillary changes highly reminiscent of AD have been shown to occur in the PDAPP mouse with age [32]. This indeed turned out to be the case. an inhibitor of c-secretase. along with a reduction of the neuritic pathology and glial pathology.636 S. and b-secretase was independently identified by (1) biochemical purification from human brain [36]. The unique protein sequence identified by these different approaches turned out to encode a novel. Studies of APP metabolism in cell culture established that b-secretase cleavage precedes that by c-secretase. membrane-bound aspartic protease. identified using cell culture models. as evidenced by the higher proportion of b-sAPP relative to a-sAPP. Immunization of the PDAPP transgenic mice with human Ab42 was shown to result in the clearance of existing plaques by microglial cells by an antibody mediated mechanism [33]. was shown to inhibit the production of Ab in young PDAPP animals. In addition to demonstrating that the APP FAD mutations do result in the production of amyloid plaques. (2) expression cloning in HEK293 cells [37]. b-Secretase: initiation of Ab production Although the overwhelming majority of FAD cases manifest themselves via PS-1 mutations (increased Ab42). occurs at a much higher level in primary neuronal cultures. in a dose. and (3) homology based cloning and expression of novel human aspartic proteases [38]. as well as neuritic changes in the vicinity of plaques that are remarkably similar to that observed in sporadic AD.and time-dependent manner [35]. Although it has been difficult to measure frank cell loss in these transgenic lines. and pharmacologic agents that disrupt b-secretase cleavage of APP selectively inhibit Ab production without inhibitory effect on a-secretase cleavage. This suggested that the enzymatic activity is enriched in the CNS. Knockout of BACE in mice is without any detectable developmental consequence. BACE. The pathologic changes observed in these transgenic mice lines also include microglial activation and astrogliosis. Although the precise etiology of AD still remains poorly understood. [7] Seubert P. [5] Esch FS. Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. cleavage of APP by BACE is absolutely required for the generation of the Ab peptide. Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. [2] Grundke-Iqbal I. et al. Heinriksson T. Crawford F. et al.56: 321–39. 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Suite 507. consensus conference documents have concluded that nonpharmacologic treatment is the most appropriate first step to treating behavioral disturbances in patients with dementia [8]. Highly associated with greater functional impairment in the patient and increased burden in the caregiver [4–6].washington. Problems such as depression. Logsdon.Med Clin N Am 86 (2002) 641–656 Nonpharmacologic treatment of behavioral disturbance in dementia Linda Teri. We also discuss the role of the caregiver in nonpharmacologic treatment. wandering.8 . Consequently. however. McCurry. health care providers routinely receive little training in the direct care management of behavioral problems in dementia. Practical suggestions abound in the literature. University of Washington. and sleep disturbance.edu (L. agitation/aggression. All rights reserved. PhD. Furthermore. including depression. Despite this. WA 98115. such problems critically impede effective care and are often cited as the most difficult aspect of caregiving [7]. MH01644). agitation/aggression. Susan M. PhD Department of Psychosocial and Community Health. Teri). Elsevier Science (USA). * Corresponding author.7 1 2 5 ( 0 2 ) 0 0 0 0 6 . E-mail address: lteri@u. 0025-7125/02/$ . PII: S 0 0 2 5 .see front matter Ó 2002. and although still relatively sparse. wandering. Preparation of this manuscript was supported in part by grants from the Alzheimer’s Association (PIO-99-1800) and the National Institutes of Health (AG10483. This article provides an overview of the treatment of behavioral problems with nonpharmacologic means as well as guidelines for assessing and treating the most common behavioral problems seen in dementia. 9709 3rd Avenue NE. and sleep disturbances affect most if not all patients at some point in the disease course [1–3]. Teri et al / Med Clin N Am 86 (2002) 641–656 Assessment The most common method for assessing behavioral disturbance in cognitively impaired older adults is a detailed clinical interview with the patient and an informant familiar with the patient’s day-to-day functioning. such as the patient’s family or caregiver. the Revised Memory and Behavior Problem Checklist [3]) rate behaviors on the frequency of their occurrence and provide information about caregiver reactions to symptoms when they do occur. anxiety. and psychosocial measures. such as dementia caregivers [24]. and specific behaviors of concern for their clinical population. its reported sensitivity to change. In the interview. including the length of the measure. Table 1 shows a representative sampling of instruments that have been used to measure depression. A variety of mood and behavior assessment measures with good psychometric properties have been developed. and verbal or physical threats or abuse. As can be seen from Table 1. By asking the caregiver about the presence or absence of a variety of potential problems. a standardized inquiry list is a valuable tool. agitation. including wandering. In addition. Both researchers and health care providers interested in using screening instruments should consider a number of factors. or general psychiatric disturbance in clinical controlled trials with dementia subjects. frequency. the Cornell Scale for Depression in Dementia [15]) provide information on the severity of symptoms. to discuss these concerns privately with the clinician. The instruments also vary in the data format they yield. This process is similar to the preliminary health screening forms used in many clinics. the caregiver is given an opportunity to express concerns on paper and. the clinician can then focus on the ones that are of concern. and behaviors are often included as part of a comprehensive assessment with other cognitive. the patient and informant are typically asked about the occurrence. others (eg. Some measures are based on paper-and-pencil informant report. The selection of appropriate measures varies according to the outcomes targeted by each study. To ensure that the full spectrum of problems is assessed in an efficient and thorough manner. agitation. whereas others require structured interviews with trained clinicians or direct behavioral observation. suspiciousness.642 L. Providers caring for populations that include nonEnglish-speaking individuals from multicultural backgrounds or persons . Such a list may be administered by a trained staff person (eg. functional. aggression. there is no single instrument that has gained universal use in clinical trials with dementia patients. the Neuropsychiatric Inventory [29]). For some measures (eg. paranoia. later. depression. and severity of typical problems. a medical assistant) or provided to an informant to complete while the patient is being examined. Some (eg. sleep disturbances. summary subscale information is computed from a combination of frequency and severity ratings for individual behavioral symptoms. There are also a number of self-report instruments that have been shown to be valid when completed by surrogate informants. 26] X X [16] X [14.31–35]. environmental triggers. injury. In assessing behavioral disturbances. Readers interested in a comprehensive review of behavioral screening instruments used in dementia care and research are referred elsewhere [17.19] X X [17.18] X X [10. medication side effects. the clinician must consider possible medical triggers. such as a urinary tract .17] X [18.or dementia-related triggers. Common causes of behavioral disturbance may include medical illness. restlessness may be triggered by an acute medical condition. For example. and interpersonal conflicts.L.21] X [22] X X X [24] X [24] X [19] X [19.13] X [14] X X [16. The same behavioral disturbance may be triggered by a variety of different causes. environmental changes.17] X [26] X X X [17] X [10] X [30] X [19. with limited education or reading skills particularly need to evaluate the validity of a given instrument for their situation. and caregiver issues. a thorough assessment of their possible causes is essential.26] CERAD: Consortium to Establish a Registry for Alzheimer’s Disease. Teri et al / Med Clin N Am 86 (2002) 641–656 Table 1 Common mood and dementia screening instruments for dementia Informant report questionnaire X Interviewer administered Reliability/ validity data X [10] 643 Title Agitation Agitated behavior in dementia scale (ABID) [9] Cohen-Mansfield agitation inventory (CMAI) [12] Depression Cornell scale for depression in dementia (CSDD) [15] Dementia mood assessment scale (DMAS) [20] Geriatric depression scale (GDS) [23] Hamilton depression rating scale (HDRS) [25] General behavioral disturbance Behavioral pathology in Alzheimer’s disease (BEHAVE-AD) [27] CERAD behavior rating scale for dementia (CERAD-BRSD) [28] Neuropsychiatric inventory (NPI) [29] Revised memory and behavior problem checklist (RMBPC) [3] Used in clinical controlled trials X [11] X X [10. Once specific problems are identified. cognitive. informational handouts. such as lack of appropriate activity. or it may be related to environmental triggers. Later. support. Restlessness may also result from changes in brain functioning caused by dementia. Providing education. One provided a focus on behavioral training to reduce patient depression [19]. too much noise or stimulation. and has been used in three controlled trials thus far. and another compared nonpharmacologic . Three investigations included behavior training as part of a larger psychoeducational and social support program and examined general behavioral outcomes and delayed patient institutionalization [44–46]. and the increased involvement of caregivers often has a secondary benefit of providing overburdened caregivers with an opportunity to receive support. For example. and Italian.644 L. support. confusing or noisy surroundings) or interpersonal factors (eg.36. environmental factors (eg.37]. The 36 Hour Day [38]. or conflicts with people with whom the patient comes into contact. is in its second printing with over one-half million copies sold worldwide. Attention to these factors through nonpharmacologic approaches (caregiver education. The earliest reports showed that caregivers were able to learn specific techniques and successfully reduce problematic behaviors [40–43]. A videotape training program entitled ‘‘Managing and Understanding Behavior Problems in Alzheimer’s Disease and Related Disorders’’ [39] has been used in Alzheimer Association support groups worldwide. case-controlled and randomized controlled trials investigated the effectiveness of nonpharmacologic treatment in reducing behavioral problems or delaying institutionalization in patients with dementia. videotapes and worldwide web technology. and training in behavioral strategies for management) can be quite effective in alleviating or preventing behavioral problems in patients with dementia. arguing with the patient) are frequently the primary triggers of behavior problems. has been translated into Japanese. or by a change in medication. information. The risk of adverse side effects or interactions with other medications is nonexistent. It is also part of standard training in numerous long-term care facilities. Korean. and advice to help families better understand and cope with the disease process has a long clinical history and often represents the core of any treatment whether it is nonpharmacologic or pharmacologic. Practitioners often advise families to use strategies to adapt the environment and modify their own behaviors so as to better care for patients. Published reports of nonpharmacologic treatment span two decades. training materials. Furthermore. Treatment Nonpharmacologic treatments are often recommended as the most appropriate initial strategy for managing behavioral disturbances in persons with dementia [7. The amount and popularity of this kind of information have grown exponentially in recent years as is evident in the proliferation of books. Teri et al / Med Clin N Am 86 (2002) 641–656 infection. and skills. long considered a staple of information to families. caregivers are provided with methods to change either the antecedents or the consequences so as to change the problem behavior. Didactic information along with vignettes of specific problems and solutions guides caregivers through a systematic approach called the ‘‘A-B-C’s of Behavior Change. the reader is referred to the article by Teri [51]. and identify and address the special needs of caregivers.) Once the caregiver understands and can identify the A-B-C’s of a problem. Gather information about the circumstances surrounding the problem. teach caregivers skills to modify behavior problems that interfere with proper care.) The Seattle Protocol A comprehensive behavioral training program for reducing behavioral problems in patients with dementia As mentioned earlier. Identify what happens immediately before the problem occurs and what happens immediately . The program consists of a series of 10 videotapes and a written trainer’s guide designed to provide background information about dementia and related disorders. This is defining the ‘‘A’’ and ‘‘C’’ of the A-B-C’s. decrease patient depression [19]. results thus far suggest that nonpharmacologic interventions can significantly reduce general patient behavioral problems [46. Although certainly not conclusive. (For more information on this program. Teri et al / Med Clin N Am 86 (2002) 641–656 645 with pharmacologic approaches to reduce patient agitation [11. ‘‘arguing all the time’’ may seem clear to the caregiver. but ‘‘arguing’’ can take many forms. caregivers learn that ‘‘A’’ is the antecedent or triggering event that precedes the problem behavior. ‘‘B’’ is the behavior of concern.’’ or are they more common at certain times of the day or with certain people? What specifically is said? The more clearly a caregiver can define a problem. (For more detailed reviews of nonpharmacologic treatments.’’ In this approach. the reader is referred to articles by Bourgeois et al [49] and Teri et al [50]. For example. What is the nature of the arguments? Do they really occur ‘‘all the time.47]. and ‘‘C’’ is the consequence of that behavior. the more likely it is that he or she can carry out an effective course of action. This is defining the ‘‘B’’ of the A-B-C’s. Once the chain of behavior occurrence and response is understood.47]. and increase caregiver satisfaction [48].L. a videotape training program entitled ‘‘Managing and Understanding Behavior Problems in Alzheimer’s Disease and Related Disorders’’ [39] teaches clinicians and caregivers to use a systematic behavioral approach to behavioral problems. The caregiver needs to articulate exactly what the problem is in a specific and informative manner. a step-by-step problem-solving strategy is implemented involving six steps: Identify the problem. and the health provider may even think he or she understand what that means. delay institutionalization [45]. Depression Depressive symptoms occur in 30% to 70% of individuals diagnosed with Alzheimer’s disease. and loss of interest can all signify depression. For example. they can effectively deal with new problems that may develop over the course of the disease. The 36 Hour Day [38] and Alzheimer’s Disease: A Guide for Families [53]). For a plan to work. Encourage rewards for the patient and the caregiver for small successes. Goals of ‘‘increasing pleasant activity’’ and ‘‘not discussing upsetting topics’’ are more realistic and more achievable. fatigue.’’ this goal is too broad and unstructured. and because of their cognitive impairment. Changing behavior is hard work for everyone involved. and proceed step by step. Start with small achievable goals. For additional suggestions (although not framed within an A-B-C approach). Set realistic goals and make plans to achieve those goals. Teri et al / Med Clin N Am 86 (2002) 641–656 after the problem begins. 1-800-272-3900). they may be unable to identify replacement activities. the more likely it is that they can successfully intervene. One goal of the A-B-C approach is to help teach caregivers to develop strategies on their own so that once treatment is concluded. Methods for modifying antecedents and altering consequences to depressive behaviors include: . We now provide some suggestions for management of several of the most common and troubling behavior problems. including depression.646 L. and materials available from the Alzheimer’s Association (www. or they may disengage from activity altogether. the most common form of dementia in older adults [54– 56]. self-help books (eg. these suggestions are again framed in an A-B-C approach. and the more caregivers understand how the A-B-C’s fit together. It is important for caregivers to reward themselves and their patients for their accomplishments no matter how small. Strategies need to change as caregivers discover some that do and do not work. the reader is referred to the books by Robinson et al [52]. Consequently. expressions of guilt and worthlessness. it must be creative but realistic and tailored to the individual patient and caregiver. Many problems have more than one antecedent and consequence. they may spend much of their time in activities that are not gratifying or meaningful. Patients with dementia gradually lose the ability to engage in enjoyable hobbies or activities. Unhappiness. tearfulness. withdrawal. It is important that caregivers be consistent in carrying out plans but flexible in trying new approaches. wandering.org. specific suggestions can be helpful.alz. Continually evaluate and modify plans. In addition. whereas a caregiver may ‘‘want the patient to be happy. inactivity. In the Seattle Protocol. agitation/aggression. and sleep disturbances. listening to music. As with depression. By ensuring that patients are not continually challenged and frustrated. including physiologic. affect between 70% and 90% of patients with dementia at some point during the course of the disease [3. these causes often interact. If the patient has had to stop driving. Patients with depression and dementia are often incapable of ridding themselves of depressing thoughts. • Depressed patients often have depressed caregivers [60]. helping around the house. physical and verbal aggression. such as irritability. sources of conflict and frustration can be alleviated (and sometimes eliminated). For example. pacing. exercising. • Redirect and refocus. and going for a ride in the car. Plan outings with someone whose company the patient enjoys. environmental.61]. was designed to help caregivers identify simple everyday pleasant activities that might be incorporated in the daily care of patients with dementia.58]. Improving caregiver mood is likely to have a positive outcome on patient behavioral problems. resulting in a more contented patient. arrange transportation to activities the patient enjoys but is no longer able to attend without assistance. having meals with family or friends. reminiscing of pleasant experiences. and interpersonal triggers. • Eliminate sources of conflict and frustration. They need assistance in distracting themselves and thinking nondepressing thoughts. thus reducing their frequency or impact. being bathed by a caregiver they do not know or remember). Teri et al / Med Clin N Am 86 (2002) 641–656 647 • Increase and encourage enjoyable activities. evaluate and discuss the caregiver’s own affective state. or having cheerful conversations can be quite helpful. resisting needed assistance.L. a 53-item inventory. Patients with depression often are asked to engage in activities they can no longer do. The key to nonpharmacologic intervention for episodes of agitation or aggression is to identify and avoid their triggers. If the patient lives with a caregiver. . Memory books [59] with pictures of happier times. particularly if the patient complains of feeling isolated or lonely. Furthermore. Agitation Agitated behaviors. such as overstimulation or activities they do not understand (eg. agitation may have a variety of causes. and wandering. The Pleasant Events Schedule-AD [57. restlessness. Items include being outside. patients may have decreased tolerance for stimulation or decreased inhibition of inappropriate behaviors as a result of neurologic changes. They may experience agitation or catastrophic reactions in response to environmental triggers. • Increase social activities. Identifying activities that the person has enjoyed in the past and modifying them to be appropriate for the patient’s current level of functioning is a good way to begin. Initiating pleasant social activities that keep the patient alert and involved can significantly improve a depressed mood. Stand or sit at eye level rather than standing over the person. and try not to startle him or her. Use touch judiciously and gently. Recognition of problems and early intervention can help to prevent agitation and catastrophic reactions. rate of cognitive decline [66]. There have been no published randomized controlled trials of interventions for wandering in dementia [70].72]. or leave the situa tion. but greater frequency of wandering was associated with significantly more impairment in cognition. • Redirect and refocus.648 L. (Some patients do not find touch reassuring. Methods for modifying antecedents and altering consequences of wandering include: • Environmental modification. they may lash out. and decreased length of survival [67. Visual cues and labels can be used to direct wanderers in a particular direction or away from potential dangers. • Stay calm. For example. Distract the patient with questions about the problem. Wandering occurred in subjects at all levels of cognitive impairment. Tell the person what you are going to do. 24% of subjects had wandered at least once. Change activities. Caregiver distress increased significantly with increased frequency of wandering [69]. Wandering Cognitively impaired individuals who wander pose a danger to themselves and are of considerable concern to their care providers and family [62. • Prevent aggression. Arguing almost always causes the agitation to escalate. In an investigation of disruptive wandering behavior in a population-based sample of 193 individuals with Alzheimer’s disease. electronic alarm systems [74].63]. Remain calm yourself as you strive to calm the patient. Research on strategies for preventing dangerous wandering has been conducted primarily in long-term care settings.68]. day-to-day functioning.) Avoid arguing or trying to reason while the person is agitated. and promising approaches include environmental modification [71. go to another room. and reinforcement of nonwandering behaviors [75]. and gradually turn his or her attention to something unrelated and pleasant. activity programming [73]. In these samples. • Get help immediately if there is imminent danger. clear and unambiguous labels on bathrooms and bedrooms may . and behavior. Use a reassuring and gentle voice. wandering occurs in up to 65% of patients at some point in the disease process and is related to severity of cognitive impairment [63–65]. Approach an agitated person slowly from the front. Most research on wandering has focused on nursing home– or dementia clinic–based samples. and 12% had wandered within the past week. Teri et al / Med Clin N Am 86 (2002) 641–656 Methods for modifying antecedents and altering consequences to agitated or disruptive behaviors include: • Intervene early. whereas visual barriers. Many individuals with dementia seem to wander because of boredom or loneliness. disturbed sleep. Interesting displays or seating areas help by inviting individuals to stop pacing and enjoy them. and nighttime incontinence care practices. such as floor grids or stop signs. There is evidence that environmental and behavioral factors. environmental noise and light. but they have not been systematically studied in persons with dementia. drug-related sleep disorders. Teri et al / Med Clin N Am 86 (2002) 641–656 649 direct residents to appropriate areas. and social interaction may decrease wandering and other problem behaviors. and disguising exits by blending them in with surrounding walls may help to prevent individuals from banging on doors or repeatedly attempting to leave. and its associated impact on physical and emotional health. The Alzheimer’s Association’s ‘‘Safe Return’’ program is a resource for educational materials and identification labels for wanderers and their caregivers. bedtime agitation.82]. • Have a safety plan. Cognitive-behavioral and psychoeducational strategies are readily available and known to be effective in normal older adults [81. • Install electronic alarm systems. When present.78]. There is general agreement that hypnotic treatments for sleep problems should be used sparingly in the elderly so as to minimize falls. such as time spent in bed during the day. These alarms do not prevent wandering but alert care providers so that dangerous consequences of wandering can be prevented. This exhaustion. Removing objects or cues from the environment that suggest leaving. or aggravation of a preexisting sleep apnea syndrome [79. is one of the most common reasons why caregivers are forced to institutionalize their loved ones [77. including coats or hats. exercise. One recent study in 29 nursing . are associated with sleep disturbances in institutionalized older adults [83–86].L. Programs that engage individuals in meaningful activities.80]. Have the person wear an identification bracelet with contact information and clearly marked with the statement ‘‘memory impaired. such problems are quite stressful for family members. Clothing labels with this information may also be sewn into the person’s clothing. Keep a current photograph for reference in case the person should get lost. Caregivers who are awakened frequently during the night to reassure or assist the dementia patient eventually become exhausted.’’ Secure it so that it cannot be easily removed or slipped off. • Provide activities. discourage wanderers from crossing into areas that are off limits. impaired memory. and night-day reversal are common problems for persons with dementia [76]. Sleep disturbances Wandering at night. Electronic alarms are in wide use in dementia residential care programs and range from a key code box and alarm that sounds when doors are opened to special radio transmitters that track the movements of individuals who wear them. and outside traffic noise. • Restrict use of alcohol and caffeinated beverages (including chocolate products). When consumed close to bedtime. live-in adult children or grandchildren. Although there have been no clinical trials demonstrating the value of consistent sleep habits in dementia patients. In community home settings. may produce a worsening in nighttime sleep. such as milk. A light bedtime snack comprising foods that promote sleep. keeping patients out of bed in the late afternoon and evening or providing quiet nighttime incontinence care) produced significant improvements in measures of percentage of total sleep and duration of sleep episodes [87].650 L. teaching caregivers strategies to use with the patient on a daily basis is the focus of most nonpharmacologic treatments. Role of the caregiver Practically speaking.94]. Try to plan ahead. these can disrupt sleep and exacerbate the preexisting tendency of dementia patients to awaken more often and spend less time in deep (slow wave) sleep [93. caregiver snoring.92]. such as family get-togethers or holidays. many persons with dementia spend a significant proportion of their daytime hours asleep [91. particularly in combination with an increase in physical activity. may reduce patient awakenings that are caused by nighttime hunger. potential environmental causes of disturbed patient sleep that should also be evaluated include the impact of household pets. or cheese. sleep regularity is considered an important aspect of the treatment and prevention of sleep disturbances in all older adults [80]. bananas. In the later stages of disease. and build in some quiet ‘‘catch-up’’ time after any out-of-theordinary planned activity. There is also a growing amount of literature suggesting that timed bright light exposure may be helpful in reducing the sleep disturbances found in Alzheimer’s disease patients [88. Care- . Reductions in light levels and nighttime noise have been shown to be critical for the alleviation of sleep disturbances for nursing home residents [83]. • Limit daytime napping. Methods for modifying antecedents and altering consequences associated with sleep disturbances in persons with dementia include: • Strive for consistent bedtime and rising times. Reductions in daytime napping. Regular sleep time habits and routines help to reinforce time cues for demented individuals and may also promote circadian rhythmicity by maximizing cues to the brain’s time-keeping system [90]. • Be aware that changes in daily routine.89]. • Eliminate or reduce environmental nuisance factors that may interrupt sleep. can increase the likelihood that the dementia patient has longer and more consolidated nighttime sleep. Teri et al / Med Clin N Am 86 (2002) 641–656 home residents found that a combination of light physical exercise and other behavioral strategies (eg. extensive clinical experience exists indicating their utility. The past and present relationship between patient and caregiver influences the manner in which the patient and caregiver interact and. or paid caregivers who have a role in the patient’s day-to-day care. Although such strategies have been subjected to few rigorous controlled clinical trials. pervasive. Treatment must be tailored to meet the needs of both the patient and the caregiver to be most effective. Persons with either frontotemporal or subcortical dementia often exhibit prominent impairment in executive functioning (eg. problem solving. behavioral problems are prevalent. unpaid caregivers. Conclusion Most if not all patients with dementia experience behavioral problems. For example. it is important to respect the dignity of the patient and the caregiver when developing treatment plans.L. potentially. it is important to have a good understanding of the resources. Finally.98]. Teri et al / Med Clin N Am 86 (2002) 641–656 651 givers may include family members. the degree of stress and burden the caregiver is currently experiencing influences the caregiver’s willingness and ability to carry out a behavior change plan. whether they . Caregivers. It is important for health care providers to assess the occurrence and impact of these behaviors so as to best care for their patients with dementia. and energy of these individuals. often leading to patient institutionalization and caregiver burnout. Some forms of dementia seem particularly prone to behavioral disturbances. skills. Some caregivers have physical or mental health problems of their own that interfere with their ability to follow through with treatment. In planning management strategies. Once identified. Whatever the cause.96]. Measurement tools can augment the clinical interview to help the practitioner obtain a thorough assessment of behavioral problems. and disruptive. A variety of factors have an impact on the caregiver’s ability to carry out recommended changes. individuals who have dementia with Lewy bodies may present with psychotic symptoms early in the course of dementia [95. flexibility and creativity are needed to modify and adapt strategies as problems evolve. For example. Health care providers must spend time talking with the caregiver about their own concerns and well-being and address these problems when they are identified. Many caregivers are employed or have other family responsibilities in addition to caring for their relative with dementia. and results thus far support the use of these strategies in patients with dementia. mood and personality changes are also common [97. the occurrence and treatment of behavioral problems. these problems may be amenable to nonpharmacologic treatments designed to prevent or alleviate such problems. Because dementia is a progressively worsening condition. planning) that affects patient care and safety. and these factors must be addressed for successful nonpharmacologic treatment. They adversely affect patient and caregiver alike. judgment. 1:132–9. Peskind E. Uomoto J. Sunderland T. Russo J. Oftentimes. agitation/aggression. and the American Geriatrics Society. Weiner MF. including depression. [3] Teri L. they must be able to impart this knowledge to those caregivers providing essential daily care of patients with dementia. The Institute of Psychiatry Alzheimer’s disease cohort 1986–1992: part 1—clinical observations. long-term care staff. J Am Geriatr Soc 1994.278:1363–71. JAMA 1997. We have also provided specific suggestions as to how to begin a treatment plan for common problems. et al. Teri L. Depression. Young HM. Int J Geriatr Psychiatry 1996.6:77–88. 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Psychiatric morbidity in dementia with Lewy bodies: a prospective clinical and neuropathological comparative study with Alzheimer’s disease. Am J Psychiatry 1999;156:1039–45. [96] Raskind M, Peskind E. Alzheimer’s disease and related disorders. Med Clin North Am 2001;85:803–17. [97] Levy ML, Miller BL, Cummings JL, Fairbanks LA, Craig A. Alzheimer disease and frontotemporal dementias: behavioral distinctions. Arch Neurol 1996;53:687–90. [98] Perry RJ, Miller BL. Behavior and treatment in frontotemporal dementia. Neurology 2001;56(Suppl 4):S46–51. 7 1 2 5 ( 0 2 ) 0 0 0 0 7 . USA Alzheimer’s disease (AD) and other forms of dementia are estimated to affect millions worldwide. prevalence rates should increase as our population continues to age. Is it estimated that AD. and Clinical Center. with pneumonia or sepsis as the usual cause of death. PII: S 0 0 2 5 . accounts for nearly 70% of dementias [1]. accounting for 15% to 25% of dementia cases [2]. By the year 2050. Elaine R. Bonner). Short-term memory is affected early in the course of the illness.see front matter Ó 2002. AD is estimated to affect 4 million Americans [4]. with an estimated 30% to 50% of Americans aged 85 years and older suffering from the disorder [1]. This work was supported by the Department of Veterans Affairs and NIA AG05136 and AG18644.gov (L. WA 98108. Elsevier Science (USA). approximately 5% of Americans aged 65 years and older suffer from AD. all cognitive functions are impaired. Visuospatial deficits and executive dysfunction also appear early in the illness. The * Corresponding author.T. Education. the most common cause of dementia. E-mail address: lauren. MD Department of Psychiatry and Behavioral Sciences. The duration of the illness is 5 to 10 years. the number of Americans suffering from AD is estimated to rise to 14 million [4]. global cognitive deterioration. Recent neuropathologic studies have demonstrated that dementia with Lewy bodies (DLB) may be the second most common cause of dementia. Peskind.Med Clin N Am 86 (2002) 657–674 Pharmacologic treatments of dementia Lauren T. Because AD and other forms of dementia are diseases of the aged. 1660 South Columbian Way. University of Washington School of Medicine.X . Bonner. Mental Illness Research. and Veterans Affairs Puget Sound Health Care System. Currently. All rights reserved. the true number of people affected by dementia in the United States is unknown. and functional deterioration.bonner@med. Seattle. as the disease process advances. AD is characterized by a gradual insidious onset of memory loss. MD*. Because estimates of the incidence and prevalence of dementia are criteria dependent. 0025-7125/02/$ . Gradually. 116 MIRECC. Other sources consider vascular/multiinfarct dementia (VaD) to be the second most common cause of dementia [3]. reflecting early involvement of the hippocampus and medial temporal lobes. There is still debate about the second and third most common forms of dementia.va. in the patient with a dementing disorder. which exert their effects by increasing the availability of intrasynaptic acetylcholine. and nutrition helps to maximize function and promote general health. In addition. Alcohol puts endangered neurons at even greater risk. Caregivers should be encouraged to utilize the resources of their local Alzheimer’s Association chapter. Optimizing vision. Caregivers need to be provided with education. alcohol use should be minimized. the anticholinergic tricyclic antidepressants amitriptyline and imipramine. Cholinesterase inhibitors. In this article. The clinician should inquire about the presence of depressive symptoms in the AD caregiver and provide treatment or appropriate referral. The antioxidant vitamin E (a-tocopherol) slows functional deterioration in AD [17]. certain classes of drugs should be avoided if possible. and practical advice. neurofibrillary tangles. the efficacy data presented were derived from analysis of observed cases. encouragement. Although there is no cure for AD. The list of drugs that may contribute to cognitive impairment is large. Minimizing excess disability Before consideration of pharmacologic management of the cognitive impairments of dementia. have been demonstrated to be more effective than placebo in the treatment of the cognitive deficits of AD [5–16]. use the fewest number and lowest effective doses of medications for comorbid medical and behavioral conditions. Bonner. Unless otherwise specified. with special emphasis on the use of nonpharmacologic approaches to treatment. sources of excess disability and comorbidity should be eliminated or reduced. when specific effect sizes are described. Provision of appropriate referrals for needed services is important as well. E. AD is often described as causing more suffering in caregivers than in the AD patients themselves. Periodic respite for the caregiver is often beneficial.T.658 L. Common offenders include oxybutynin used for treatment of urinary incontinence. Avoid polypharmacy. that is. and neuronal loss. and depression in AD caregivers is common. two pharmacologic treatment options can provide symptomatic improvement in cognitive and functional deterioration: cholinesterase inhibitors and vitamin E. Peskind / Med Clin N Am 86 (2002) 657–674 typical findings on neuropathologic examination include hippocampal and neocortical neuritic plaques. such as depression. Comorbid medical and psychiatric conditions. should be identified and optimally treated. Caregiver support is a crucial component of managing the dementia patient. and the benzodiazepine antianxiety and hypnotic drugs.R. This includes instructing caregivers in providing an appropriate environment for the demented patient and in the fundamentals of behavior management techniques. particularly those with anticholinergic or sedating side effects. . hearing. we review data supporting the use of cholinesterase inhibitors and vitamin E in the treatment of AD and related dementias and present recommendations for incorporating their use into clinical practice. By inhibiting the degradative metabolism of acetylcholine released by presynaptic cholinergic neurons. Several strategies have been attempted to increase cholinergic transmission in the brain. with higher scores reflecting increased severity of cognitive impairment. donepezil. and are involved in memory and other cognitive functions. These findings provide a scientific rationale for the consideration of cholinergic strategies as a treatment for AD. in target areas in the cortex and other brain regions as well as overall reductions in other markers of cholinergic activity [18–20. The ADAS-Cog. and galantamine (Table 1). and cholinesterase inhibitors [5–16. defined as having a Mini-Mental State Examination (MMSE) [34] score between 10 and 24.33]. muscarinic and nicotinic cholinergic receptor agonists [32]. Cholinesterase inhibitor use in Alzheimer’s disease Cholinesterase inhibitors for which data from large-scale placebo-controlled clinical trials support efficacy in the treatment of AD include the US Food and Drug Administration (FDA)–approved drugs tacrine. Drug-placebo differences of approximately 3 to 4 points on the . the basal forebrain nucleus that is the site of origin of the cholinergic neurons that project widely to many brain regions. there is well-documented loss of neurons in the nucleus basalis of Meynert [21. Peskind / Med Clin N Am 86 (2002) 657–674 659 Cholinergic systems and memory: cholinergic hypothesis of Alzheimer’s disease There have been clear demonstrations of presynaptic cholinergic deficits in AD [18–21]. In addition to loss of cholinergic neurons. In AD. placebocontrolled. The criteria used to diagnose AD included the Diagnostic and Statistical Manual III–Revised [35] and Diagnostic and Statistical Manual IV [36] of the American Psychiatric Association and the National Institute of Neurologic and Communicative Disorders and Stroke–Alzheimer Disease and Related Disorders Association criteria [37]. The efficacy measures used in these trials were generally uniform and included the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) [38] as a primary efficacy measure. rivastigmine. there is a marked decrease in the activity of choline acetyltransferase.R. These strategies are analogous to the dopaminergic enhancement strategies that have proven successful in ameliorating the motor disturbances of Parkinson’s disease. cholinesterase inhibitors increase the amount of synaptic acetylcholine available for neurotransmission. generally declines approximately 6 to 10 points per year in the mild to moderate stages of AD.22–26]. scored from 0 to 70.22]. randomized trials in AD are the cholinesterase inhibitors. The only drugs that have demonstrated efficacy and safety in large-scale. Bonner. These include choline and phosphatidylcholine precursor loading [27–31]. with 8 points as the average decline over 1 year. use acetylcholine as their neurotransmitter. Multicenter trials were conducted in patients with mild to moderate disease.L.T. the synthetic enzyme for acetylcholine. E. bid. Various measures of quality of life. on average. Weight loss has also been demonstrated with some cholinesterase inhibitors.8. Patients were followed for approximately 800 days. These effects are dose dependent. preexisting bradycardia. activities of daily living. the drugplacebo differences on the ADAS-Cog obtained from intent-to-treat analysis (ITT) were approximately four points.39–42]. The most frequent adverse events experienced by subjects in cholinesterase inhibitor trials reflect effects of increased cholinergic activity on the gastrointestinal system. interpreted as delay of cognitive decline by approximately 6 months [7. This difference represents approximately 6 months of cognitive and functional ability. 102 patients on low-dose or no tacrine (80 mg or less/d) were compared with 198 patients on high-dose tacrine (>80 mg/d). At the end of this period.T. current alcoholism. Caution is advised with use in patients who have a previous history of allergy or adverse reactions to prior cholinesterase inhibitors. 45% of patients in the low-dose or no-tacrine group had undergone nursing home placement as compared to approximately 21% of patients in the higher dose tacrine . In this study. at bedtime. followed by vomiting and diarrhea.5 mg bid 4–6 weeks/4 mg bid Maximum dose 10 mg qhs 6 mg bid (total of 12 mg) 12 mg bid (total of 24 mg) Abbreviations: qhs. It is becoming increasingly clear that. Bonner.8. E.660 L. cholinesterase inhibitors stabilize cognitive function and activities of living for at least 1 year in the AD patient with mild to moderate cognitive impairment [11.R. Peskind / Med Clin N Am 86 (2002) 657–674 Table 1 Cholinesterase inhibitor titration schedule Cholinesterase inhibitor Donepezil Rivastigmine Galantamine Starting dose 5 mg qhs 1. asthma. Nausea is the most common adverse effect. peptic ulcer disease. twice daily. was shown to have modest efficacy in improving cognition in several large-scale placebocontrolled trials in AD [7. the ‘‘first generation’’ cholinesterase inhibitor. ADAS-Cog over 6 months have been accepted as indicating drug efficacy. and noncognitive behavioral disturbances supported drug efficacy in various trials. The only absolute contraindication to use of cholinesterase inhibitors is severe hypersensitivity to the specific drug or its derivatives. Tacrine Tacrine. or chronic obstructive pulmonary disease.5 mg bid 4 mg bid Titration period/maximum dose increase per titration period 4–6 weeks/5 mg 4–6 weeks/1.10]. After 6 months of treatment. A retrospective analysis of the tacrine trial data suggests that tacrine doses of greater than 80 mg/d may delay time to nursing home placement and provides evidence for long-term cost-effective use of tacrine [42].10]. severe liver disease. T. Significant and equivalent drug-versus-placebo group differences were found for both the 5.and 10-mg donepezil groups on the ADAS-Cog. 8. including cimetidine.9 points.5 and 2. Peskind / Med Clin N Am 86 (2002) 657–674 661 group. Donepezil is metabolized in the liver. recommending measuring alanine aminotransferase levels weekly for the first 18 weeks. randomized. A trial in 468 patients consisting of a 12-week treatment phase followed by a 3-week washout phase compared 5 and 10 mg of donepezil with placebo and . with no significant difference in occurrence of adverse events between the 5-mg and placebo groups. function. and digoxin. E. Tacrine has been demonstrated to have clinically significant drug-drug interactions with cimetidine and theophylline [44].10]. the use of tacrine is limited to patients with an initial good response to this agent. respectively. Four hundred seventy-three patients with AD were randomly assigned to three treatment groups: placebo or 5 or 10 mg of donepezil. Weekly monitoring should be resumed for an additional 6 weeks if the dosage is adjusted up. An international study of 818 patients with the same study design demonstrated similar results [5].12. During the tacrine trials. warfarin.and 10-mg doses. Donepezil at doses of 5 and 10 mg was compared with placebo in a 30-week treatment trial [13]. theophylline. The mean difference between active treatment and placebo groups was approximately three points.46]. and behavior translate into caregivers being able to provide care at home longer. Donepezil was well tolerated. lack significant drug-drug interactions. In clinical practice. tacrine-induced reversible hepatotoxicity occurs in up to 50% of patients [43]. a high incidence of reversible hepatotoxicity and gastrointestinal adverse effects resulted in poor study completion rates [7. and have more convenient dosing regimens. Donepezil The piperidine derivative donepezil is a noncompetitive reversible acetylcholinesterase inhibitor with specificity for the brain [45]. Because of the availability of other cholinesterase inhibitors that are not hepatotoxic.and 10-mg donepezil groups were 1. Bonner. These trials all used ITT analyses.L. donepezil metabolism is inhibited by ketoconazole and quinidine [44. Because transaminase levels may reach up to 10 times the normal level. its half-life is approximately 70 hours. Donepezil has no significant effect on the metabolism of other drugs. The mean drug-versus-placebo differences for the 5.R. Donepezil has been demonstrated to be modestly effective in stabilizing the cognitive function of AD patients in three large. These findings suggest that benefits of cholinesterase inhibitors on stabilization of cognition. There was no difference between the 5. the FDA requires monitoring of transaminases during dose titration and maintenance therapy. placebo-controlled trials [5.13]. There were significant drug-versus-placebo differences on the ADAS-Cog. furosemide. with monitoring every 3 months after a stable dose is reached. 52]. rivastigmine may have increased selectivity for the hippocampus and neocortex.51]. Rivastigmine has been shown to have no effect on the metabolism of other drugs. fluoxetine. In the United States. The clinical relevance of this differential property remains unclear.5 mg/d allowed during the 12-week dose escalation phase.R. 6 to 12 mg of rivastigmine. In this trial. During weeks 8 through 12. with a maximum dose increase of 1. Rivastigmine is metabolized by the cholinesterases in brain.5 points for the 5-mg group and 3. Rivastigmine has relatively more inhibitory activity for butyrylcholinesterase than acetylcholinesterase compared with other cholinesterase inhibitors [51]. high-dose rivastigmine . There was a 13-week maintenance phase during which the dose could be adjusted with the goal of administering the highest tolerated dose. Bonner. diazepam. Seven hundred twenty-five patients with mild to moderate AD were randomly assigned to three treatment groups of 1 to 4 mg of rivastigmine. Compared with other cholinesterase inhibitors. and digoxin [50. reflecting a difference equivalent to appropriately 6 months of cognitive deterioration. Rivastigmine Like donepezil and tacrine. because the duration of inhibition of acetylcholinesterase induced by rivastigmine is longer than its half-life [49.50. or placebo. and liver transaminase monitoring is not necessary [5. E. and intestine and is renally excreted [50. with mean drug-versus-placebo differences of 2. Mean drug-versus-placebo differences on the ADAS-Cog were 0. donepezil is considered a ‘‘second-generation’’ cholinesterase inhibitor with several clear advantages compared with tacrine.662 L. the dose may be increased to 10 mg after 4 to 6 weeks.50]. no dose changes were permitted. double-blind. both treatment groups demonstrated improvement in ADAS-Cog scores when compared with placebo. Peskind / Med Clin N Am 86 (2002) 657–674 demonstrated similar results [12]. Donepezil is not hepatotoxic. Only the high dose differed significantly from placebo. Clinical trials indicate that rivastigmine is modestly effective in the treatment of the cognitive impairments of mild to moderate AD [6. which are the areas of the brain preferentially affected by AD [47.1 points for the 10-mg treatment group. Gastrointestinal side effects and occasional sleep disturbance are the most common adverse effects.13]. Dose increases occurred weekly. liver.14].17 for low-dose rivastigmine and 2. rivastigmine is a noncompetitive reversible inhibitor of acetylcholinesterase [47.51]. placebo-controlled trial of 699 patients compared low-dose rivastigmine (1–4 mg).14. ‘‘Pseudoirreversible’’ enzyme inhibition has also been used to describe its mechanism of action. with or without food. a 26-week.58 for high-dose rivastigmine. Rivastigmine was compared with placebo in a 26-week international treatment trial [14]. including warfarin. It has not been shown to affect hepatic enzymes or other laboratory parameters [6.48]. If the drug is well tolerated.T.51.12. Because of its safety and ease of administration. Donepezil is administered in a single bedtime dose. the recommended starting dose of donepezil is 5 mg at night.51]. L.T. Bonner, E.R. Peskind / Med Clin N Am 86 (2002) 657–674 663 (6–12 mg), and placebo [6]. Patients in the 6- to 12-mg rivastigmine group demonstrated significantly better cognitive function than patients treated with placebo. The mean drug-versus-placebo difference in the ADAS-Cog between the 6- to 12-mg group and the placebo group was 4.94 points. In addition, patients receiving high-dose rivastigmine demonstrated better preservation of functional ability as measured by the Progressive Deterioration Scale [53] when compared with the placebo group. There was an additional 6-month extension phase of the US trial in which all patients who completed the double-blind phase were eligible for treatment with a flexible maintenance dose of rivastigmine, ranging from a minimum of 1 mg administered twice daily to 6 mg administered twice daily [41]. Initially, all patients were treated with open-label rivastigmine at a rate of 1 mg administered twice daily for the first week, with maximum allowed dose increases of 1 mg administered twice daily per week for a maximum allowed total dose of 6 mg administered twice daily. Decreases in dose were allowed per patient tolerability, with a minimum required dose of 1 mg administered twice daily. The change in ADAS-Cog score at week 52 was compared in four groups: the three original treatment groups given placebo, 1 to 4 mg of rivastigmine, or 6 to 12 mg of rivastigmine, and a fourth group consisting of a theoretic 52-week placebo group based on a modeling procedure of the projected decline if placebo had been continued for the full 52 weeks. Mean treatment differences on the ADAS-Cog at week 52 for the original placebo group were 1.4 points versus the original 6- to 12-mg/d rivastigmine group, 0.3 points versus the original 1- to 4-mg/d rivastigmine group, and 4.3 points versus the theoretic 52-week placebo group. The theoretic 52-week placebo group versus the original 6- to 12-mg/d rivastigmine group mean difference in ADAS-Cog scores was 5.7 points. These data suggest that rivastigmine may modify the course of AD and are consistent with data for other cholinesterase inhibitors [11,39,40,42]. The recommended starting dose of rivastigmine is 1.5 mg administered twice daily given with breakfast and dinner. Administration of rivastigmine at mealtime helps to minimize nausea. Although the rivastigmine package insert recommends titration increases at 2-week intervals, gastrointestinal adverse effects may be minimized by using a slower 4- to 6-week titration schedule. The dose should be increased to 3 mg administered twice daily, then to 4.5 mg administered twice daily, and finally to 6 mg administered twice daily at 4- to 6-week intervals as tolerated. As with all cholinesterase inhibitors, the dose should be titrated slowly upward to the maximum tolerated dose. If rivastigmine therapy is interrupted for more than a few days, it is recommended that treatment be restarted at 1.5 mg administered twice daily (the lowest starting dose) and then titrated up again every 4 to 6 weeks to the highest tolerated dose. Nausea, the most common side effect, can be minimized by adequate hydration. If necessary, an antiemetic may be used. As with other cholinesterase inhibitors, the incidence of gastrointestinal side effects is dose dependent. Rivastigmine is the only cholinesterase inhibitor with which weight loss is a clinically meaningful problem. 664 L.T. Bonner, E.R. Peskind / Med Clin N Am 86 (2002) 657–674 Galantamine Galantamine hydrobromide, a derivative of the snowdrop plant, is the most recently approved cholinesterase inhibitor. Unlike tacrine, donepezil, and rivastigmine, it is a competitive and reversible acetylcholinesterase inhibitor. It has little effect on butyrylcholinesterase, being more selective for acetylcholinesterase [54]. Galantamine is unique among cholinesterase inhibitors in having a potential second mechanism of action as an allosteric modulator at the nicotinic cholinergic receptor [55,56]; this effect is separate from cholinesterase inhibition [55]. In vitro, galantamine acts as an ‘‘allosterically potentiating ligand,’’ increasing the likelihood of acetylcholine-induced channel opening and decreasing the rate of receptor desensitization [55]. This additional mechanism of action is a possible explanation for the finding that the amount of cholinesterase inhibition induced by galantamine and other cholinesterase inhibitors does not correlate well with their clinical ‘‘potency’’ [55]. The clinical relevance of this property is unknown, however. Galantamine is metabolized by the liver [44,57] and has no effects on the metabolism of other drugs. It is renally excreted. The half-life of galantamine is 7.5 hours. Absorption is not affected by food. The results of three published large-scale placebo-controlled trials indicate that galantamine is modestly effective in the treatment of the cognitive impairments of mild to moderate AD [11,15,16]. These trials also demonstrate that galantamine preserves the activities of daily living. All trials demonstrated that doses of 16, 24, and 32 mg were significantly statistically superior to placebo. Galantamine at doses of 8, 16, and 24 mg administered in divided doses twice daily was compared with placebo in a 21-week treatment trial in 978 patients with AD [15]. Doses were started at 8 mg/d (4 mg twice-daily dosing) and were increased by 8 mg/d every 4 weeks. Significant drug-versus-placebo group differences were found for both the 16- and 24-mg galantamine groups on the ADAS-Cog. The mean differences between the 16- and 24-mg–versusplacebo groups were 3.3 and 3.6 points, respectively, on the ADAS-Cog, which is equivalent to approximately 6 months of cognitive function. There was not a statistically significant difference between the 16-mg versus 24-mg dose groups. Both doses were well tolerated. The number of discontinuations secondary to adverse events in the placebo and active treatment groups was similar (7% in the placebo group and 6%–10% in the active treatment groups) and increased in a dose-dependent fashion. In addition, galantamine had similar beneficial effects on global function and behavior. Galantamine at doses of 24 and 32 mg was compared with placebo in two 26-week treatment trials—one in the United States and the other international [11,16]. Both studies demonstrated that galantamine significantly improved cognitive function relative to placebo. Mean differences between the 24- and 32- mg–versus-placebo groups on the ADAS-Cog were 3.9 and L.T. Bonner, E.R. Peskind / Med Clin N Am 86 (2002) 657–674 665 3.8 points in the US trial and 3.1 and 4.1 points in the international trial, a difference equivalent to approximately 6 months of cognitive function. There was no statistically significant difference between the 24-mg versus 32-mg groups. In the US trial, there was an additional 6-month extension phase during which all patients who completed the double-blind phase were eligible for open-label treatment with 24 mg of galantamine [11]. Patients taking 24 mg of galantamine for 12 months demonstrated preservation in activities of daily living compared to patients who received placebo for six months followed by 24 mg open-label galantamine for six months. Activities of daily living were evaluated by using the Disability Assessment for Dementia [58]. Those patients who were randomized to placebo in the 26-week parallelgroup design who then went on to open-label active galantamine in the 6-month extension formed, in effect, a delayed-start design group. Interestingly, this group of patients’ cognitive function then stabilized but never reached the level of the patients who had received 12 months of continuous active drug. Thus, at the 12-month time point, there remained a statistically significant difference in the ADAS-Cog scores between patients on 12-month continuous galantamine versus 6 months of placebo followed by 6 months of galantamine (2 points on the ADAS-Cog). These data and similar data from other cholinesterase inhibitor studies suggest these agents may have disease-modifying effects that may slow disease progression in AD. All trials demonstrated that galantamine had no effect on liver transaminases or other laboratory parameters. As with other cholinesterase inhibitors, gastrointestinal adverse events were the most common side effects and increased with increasing dose. Mild weight loss was also common. The recommended starting dose of galantamine is 4 mg administered twice daily given with breakfast and dinner. Administration of galantamine at mealtime helps to minimize nausea associated with its use. The dose is increased by 4 mg administered twice daily every 4 to 6 weeks as the patient tolerates it. If galantamine therapy is interrupted for more than a few days, it is recommended that treatment be restarted at 4 mg administered twice daily, with the patient then titrated up every 4 to 6 weeks to the highest tolerated dose. Nausea, the most common adverse event, usually resolves within a week and can be further minimized by adequate hydration. If necessary, an antiemetic may be used. Cholinesterase inhibitor use in moderate to severe Alzheimer’s disease A small international trial [9] evaluated the use of donepezil in patients with moderate to severe AD. In this 24-week trial, 290 AD patients with MMSE scores between 5 and 18 were randomly assigned to two treatment groups: 5 to 10 mg of donepezil or placebo. The primary efficacy measure was the Clinician’s Interview-Based Impression of Change with caregiver input [59], a seven-point scale ranging from markedly improved to markedly 666 L.T. Bonner, E.R. Peskind / Med Clin N Am 86 (2002) 657–674 worse based on a semistructured interview performed with the patient and caregiver. Various secondary efficacy measures of cognition, global functioning, and behavior were also obtained. Last observation carried forward analysis revealed significant differences between the donepezil and placebo groups. Sixty-three percent of donepeziltreated patients received Clinician’s Interview-Based Impression of Change with caregiver input ratings of improved or no change in comparison to 42% of placebo patients. There were significant drug-versus-placebo differences in all secondary efficacy measures as well. This study suggests that donepezil may stabilize or improve cognition and functional status in patients with moderate to severe AD. Larger studies are needed to confirm these results. Summary In summary, the cholinesterase inhibitors have provided the first known effective treatments for the cognitive deficits of AD. Symptomatic efficacy is modest and may include positive effects on memory, language, praxis, and problematic noncognitive behaviors, such as pacing, delusions, and uncooperativeness. It should be noted, however, that only approximately one third of patients have clinically meaningful improvement in cognitive function. It is much more common for patients to have stabilization of their cognitive, behavioral, and functional status. This is the message that should be conveyed to patients and their families: the goal of treatment is stabilization. Currently available data suggest that this period of stabilization at or near baseline function lasts at least a year [11,29,39–42]. Vitamin E and antioxidants in Alzheimer’s disease Vitamin E Vitamin E (a-tocopherol) administration is a second pharmacologic approach to slowing progression in AD. Vitamin E has been demonstrated to protect cell membranes from oxidative damage and, in animal models, to reduce hippocampal neurodegeneration [60,61]. The production of neurotoxic free radicals during oxidative metabolism has been suggested as a potential mechanism of neurodegeneration in AD [62]. This neurobiologic consideration, plus the demonstration that the monamine oxidase inhibitor selegiline seems to slow disease progression in Parkinson’s disease, another late-life neurodegenerative disorder, has stimulated investigation of drugs with antioxidant activity as therapeutic agents for AD. Several small placebo-controlled trials and a much larger Alzheimer’s Disease Cooperative Study clinical trial [17] provide evidence for the efficacy of antioxidant strategies in slowing disease progression in AD. The Alzheimer’s Disease Cooperative Study consisted of a four-arm parallel-group study in which 341 patients with moderate-stage AD were randomized to and behavior-altering properties.14 points.R.L.64] and may alter vitamin K–dependent coagulation factors [65. cognitive-enhancing. its use is contraindicated in patients with vitamin K deficiency. vitamin E is now recommended in addition to a cholinesterase inhibitor for slowing progression in AD. Its theoretic properties include anti-inflammatory and antioxidant effects [67. ginkgo biloba is a modest anticoagulant [68]. feeding.68]. Because vitamin E inhibits platelet adhesion [63. When compared with placebo. EGB 761 at a dose of 40 mg three times a day demonstrated a small but statistically significant difference in the ADAS-Cog with a drug-versus-placebo difference of 1. nursing home placement. There was also a statistically significant drug-versus-placebo group difference in the GERRI of 0. The number of adverse events was similar in the placebo and active treatment groups. The effects of EGB 761 on agitation and mood were assessed but not reported.4 points. The GERRI is a 49-item inventory that includes a range of scores from 1 to 5 in which an increasing score indicates poorer patient functioning. Primary outcome measures included the ADAS-Cog and the Clinical Global Impression of Change. was evaluated in a 52-week. or a combination of vitamin E and selegiline. and toileting. EGB 761. There was no difference demonstrated in the Clinical Global Impression of Change. ie. grooming.66]. and cautious use is recommended in patients receiving anticoagulant therapy. selegiline (1-deprenyl) at a dose of 10 mg (given as 5 mg twice a day). Ginkgo biloba Ginkgo biloba is a traditional Chinese herbal medicine with reputed mood-elevating. The active treatments consisted of vitamin E at a dose of 1000 IU administered twice a day. E. was used as an outcome measure. Peskind / Med Clin N Am 86 (2002) 657–674 667 receive one of three active treatments or placebo for a 2-year period. Primary outcome measures were indices of functional decline: progression from moderate to severe dementia. double-blind.T. Bonner. . Although its safety profile has not been fully characterized. In addition. Vitamin E is started at a dosage of 400 IU/d and is increased by 400 IU as tolerated each week until the maximum dose of 2000 IU in divided doses administered twice daily is reached. An ITT analysis was used to compare data. the nonvalidated Geriatric Evaluation by Relative Rating Instrument (GERRI) [70]. loss of two of three basic activities of daily living. a caregiver-rated measure of patient functioning. randomized. Vitamin E and selegiline both delayed progression to the outcome endpoints. only 137 of the 309 subjects included in the ITT analysis completed the trial. There was a high attrition rate during the 52-week trial. Because of its low cost and relative safety. a standardized extract of the Ginkgo biloba tree. or death. The average delay for vitamin E was approximately 230 days compared with placebo. placebo-controlled trial to assess efficacy and safety in patients with AD and VaD [69]. The maximum length of the titration period was 8 weeks.T.668 L. the manufacture of ginkgo biloba and other herbal supplements is unregulated and lacks FDAmandated standards for potency and purity. Treatment of dementia with Lewy bodies DLB is characterized by a cluster of signs and symptoms distinct from AD. including picture recognition reaction times. the use of ginkgo biloba in AD is not supported by the available data. cortical neurons of DLB patients exhibit Lewy bodies—spherical intracytoplasmic inclusions [2].72]. Because the cholinergic deficit in DLB is thought to be greater than in AD. DLB patients demonstrate more severe deficits of choline acetyltransferase activity and more functional and upregulated postsynaptic muscarinic receptors when compared with AD patients [72–74]. case reports and open-label studies as well as one recent double-blind placebo-controlled clinical trial have suggested efficacy of cholinesterase inhibitors in the treatment of DLB [75–77]. Differences between the rivastigmine and placebo groups on the NPI-4 and computerized cognitive assessment system . including a decreased numbers of neurons in the substantia nigra and abnormalities of the dopaminergic. Until the results of this study are replicated and the safety profile of ginkgo biloba is further clarified with regard to potential for causing significant bleeding events.73]. Patients with DLB demonstrate a number of neuroanatomic and neurochemical deficits. E. DLB was defined by consensus guideline criteria. McKeith and colleagues [76] reported a 23-week European study of 3 mg (1. Bonner. Although there are no FDA-approved treatments for DLB. early-stage parkinsonian motor features. Neuropathologically. cholinergic. Mild to moderate disease was defined by an MMSE score of greater than 9.73]. A 20-week titration and treatment phase was followed by a 3-week washout phase. Fifty-six percent of patients reached the maximum daily dose of 12 mg. In addition. and 92% reached doses of 6 to 12 mg. patients with DLB have been hypothesized to have a better response to cholinesterase inhibitors than patients with AD [2. hallucinations. and word recognition) were the primary efficacy measures [76]. and noradrenergic neurotransmitter systems [2. There are a number of methodologic flaws that render interpretation of the data somewhat difficult. and hallucinations.71.5 mg twice a day) to 12 mg (6 mg twice a day) of rivastigmine versus placebo in 120 patients diagnosed with mild to moderately severe probable DLB. Peskind / Med Clin N Am 86 (2002) 657–674 The results of this study must be interpreted with caution. The Neuropsychiatric Inventory (NPI) [78] and a ‘‘computerized cognitive assessment system speed score’’ (a sum of scores reflecting various parameters. serotonergic. including dementia. MMSE scores and other global index measures were used as well as the NPI-4. depression. spatial memory.R. and fluctuating cognitive deficits [2. delusions. a subscale cluster of the four items on the NPI identified as a DLB cluster: apathy. Prompt identification and treatment of hypertension. Cholinesterase inhibitors are the only FDA-approved pharmacologic treatments for AD. the major risk factor for stroke.T. Providing caregivers with education. such as depression and delirium. Large-scale placebo-controlled trials of tacrine. Donepezil. placebo-controlled trials. and mild to moderate side effects. Identification of comorbid medical and psychiatric conditions. treatment of VaD has focused on controlling the risk factors for cerebrovascular disease [79. and practical advice is a critical component of the management of the demented patient. Because the cause of VaD is a consequence of cerebrovascular disease. E. One small placebo-controlled trial demonstrated that rivastigmine was effective in the treatment of behavioral deficits of DLB [76]. behavioral. and functional deficits of AD. Large-scale placebo-controlled trials are necessary to confirm these results. management and modification of lifestyle factors are crucial. behavioral. rivastigmine. In summary. few significant drug-drug interactions. rivastigmine. weight reduction. Before pharmacologic intervention is instituted. Summary The management of dementia patients encompasses pharmacologic. donepezil. however. double-blind. including the elimination of cigarette smoking. and galantamine have demonstrated moderate benefits in patients with mild to moderate AD. should be identified and appropriately treated. The rivastigmine and placebo groups did not differ with respect to MMSE scores or global function.80]. differences between the placebo. and treatment of hypercholesterolemia and hypertriglyceridemia [79. Sixty-three percent of patients in the rivastigmine group demonstrated at least a 30% reduction from baseline in NPI score as compared to 30% in the placebo group.80]. This standard is based on the results of large-scale. The current standard of care for pharmacologic management of the cognitive and functional disabilities of AD consists of the combination of a cholinesterase inhibitor and high-dose vitamin E. are critical in the prevention of stroke and VaD [79. support. Peskind / Med Clin N Am 86 (2002) 657–674 669 speed score were statistically significant.80]. ease of administration. Treatment of vascular dementia There are currently no FDA-approved treatments for VaD.L.R. Bonner. and galantamine are the first-line choices in the treatment of AD because of their lack of hepatotoxicity. and psychosocial intervention strategies. . In addition.and rivastigmine-treated groups on the NPI were no longer significant. After the 3-week study medication washout period. nutritional education. cholinesterase inhibitors may also be effective in the treatment of DLB. it is important that sources of excess disability and comorbidity be eliminated or reduced. Cholinesterase inhibitors have been shown to be effective in the treatment of the cognitive. current alcoholism. [2] McKeith IG. Kosaka K. 278:1363–71. and management of cerebrovascular disease and vascular risk factors.47:1113–24. the Alzheimer’s Association. E. et al. The indications for the use of cholinesterase inhibitor drugs are eventually likely to broaden to include DLB. MD: US Department of Health and Human Services. JAMA 1997. Bonner.T. and AD in its more advanced stages. Veach J. [3] Costa P. Int J Geriatr Psychopharmacol 1998. et al. and the American Geriatrics Society. Known hypersensitivity to a specific drug or its derivatives is the only true contraindication. et al. 1:55–65. Williams T. Cautious administration of cholinesterase inhibitors is advised in patients who have a previous history of allergy or adverse reactions to prior cholinesterase inhibitors. severe liver disease. peptic ulcer disease. asthma. early reports suggest that these agents may also be effective for mixed AD/VaD. There are no FDA-approved treatments for DLB and VaD. Hecker J. Diagnosis and treatment of Alzheimer disease and related disorders. The effects of donepezil in Alzheimer’s disease—results from a multinational trial. and anorexia are the most common side effects of cholinesterase inhibitors. Rockville. diarrhea. adequate hydration. . 1996. a new acetylcholinesterase inhibitor. Dement Geriatr Cogn Disord 1999. References [1] Small GW. Summerfield M. mixed AD/VaD.R. Estimated prevalence of Alzheimer’s disease in the United States. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate). preexisting bradycardia.670 L. administration with food. Anand R. Treatment of VaD focuses on the control. [6] Corey-Bloom J. Vitamin E has been demonstrated to slow the progression of AD in several small and one large placebo-controlled trials. Although there are no peer-reviewed reports on the efficacy of cholinesterase inhibitors for VaD or mixed AD/VaD. or chronic obstructive pulmonary disease. Rossor M. Recognition and initial assessment of Alzheimer’s disease and related dementias. Neurology 1996. Because of its low cost and safety. Nausea. Public Health Service. in patients with mild to moderately severe Alzheimer’s disease. Rabins PV. vomiting. Peskind / Med Clin N Am 86 (2002) 657–674 There are few contraindications to the use of cholinesterase inhibitors. Consensus statement of the American Association for Geriatric Psychiatry. it is recommended in addition to a cholinesterase inhibitor for the treatment of AD. More large-scale placebo-controlled trials are needed to confirm the results of this study.10:237–44. 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