BPSD Journal 1

REVIEW ARTICLEpublished: 07 May 2012 doi: 10.3389/fneur.2012.00073 Behavioral and psychological symptoms of dementia J. Cerejeira 1 *, L. Lagarto 1 and E. B. Mukaetova-Ladinska 2 1 2 Serviço de Psiquiatria, Centro Hospitalar Psiquiátrico de Coimbra, Coimbra, Portugal Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK Edited by: João Massano, Centro Hospitalar de São João and Faculty of Medicine University of Porto, Portugal Reviewed by: Federica Agosta, Vita-Salute San Raffaele University, Italy Luísa Alves, Centro Hospitalar de Lisboa Ocidental, Portugal *Correspondence: J. Cerejeira, Serviço de Psiquiatria, Centro Hospitalar Psiquiátrico de Coimbra, Coimbra 3000-377, Portugal. e-mail: [email protected] Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms, represent a heterogeneous group of non-cognitive symptoms and behaviors occurring in subjects with dementia. BPSD constitute a major component of the dementia syndrome irrespective of its subtype. They are as clinically relevant as cognitive symptoms as they strongly correlate with the degree of functional and cognitive impairment. BPSD include agitation, aberrant motor behavior, anxiety, elation, irritability, depression, apathy, disinhibition, delusions, hallucinations, and sleep or appetite changes. It is estimated that BPSD affect up to 90% of all dementia subjects over the course of their illness, and is independently associated with poor outcomes, including distress among patients and caregivers, long-term hospitalization, misuse of medication, and increased health care costs. Although these symptoms can be present individually it is more common that various psychopathological features co-occur simultaneously in the same patient.Thus, categorization of BPSD in clusters taking into account their natural course, prognosis, and treatment response may be useful in the clinical practice. The pathogenesis of BPSD has not been clearly delineated but it is probably the result of a complex interplay of psychological, social, and biological factors. Recent studies have emphasized the role of neurochemical, neuropathological, and genetic factors underlying the clinical manifestations of BPSD. A high degree of clinical expertise is crucial to appropriately recognize and manage the neuropsychiatric symptoms in a patient with dementia. Combination of non-pharmacological and careful use of pharmacological interventions is the recommended therapeutic for managing BPSD. Given the modest efficacy of current strategies, there is an urgent need to identify novel pharmacological targets and develop new non-pharmacological approaches to improve the adverse outcomes associated with BPSD. Keywords: behavioral and psychological symptoms, dementia, neuropsychiatric symptoms, Alzheimer’s disease INTRODUCTION During the natural course of dementia a heterogeneous group of clinical phenomena is subjectively experienced by the patient and/or observable by an examiner (e.g., caregiver, physician) consisting in disturbed emotions, mood, perception, thought, motor activity, and altered personality traits. These “neuropsychiatric symptoms,” according to the terminology most used in the United States, or “behavioral and psychological symptoms of dementia” (BPSD), as designated by the International Psychogeriatrics Association (Finkel et al., 1996), are very common and associated with high levels of distress both in dementia sufferers and their caregivers, as well as with adverse outcomes and increased use of health care resources. Thus, in addition to cognitive deterioration, BPSD are a relevant and meaningful clinical target for intervention (Katona et al., 2007). BPSD: CONCEPTUAL OVERVIEW BPSD IN THE CURRENT CLASSIFICATION SYSTEMS Despite being almost universally present during the course of dementia, BPSD have not been included in the defining criteria of dementia in the current classification systems. The core features of dementia according to DSM-IV-TR and ICD-10 consist www.frontiersin.org of gradual onset of multiple cognitive deficits (involving memory and at least one additional cognitive domain) not occurring exclusively during delirium and representing a decline from a previous level of functioning (American Psychiatric Association, 1994). In DSM-IV-TR the presence or absence of a clinically significant behavioral disturbance can be coded, but no guidance is provided about the diagnostic criteria of these symptoms. It is also possible to code dementia (e.g., Alzheimer disease, AD) in axis III and specific mental disorders (e.g., mood or psychotic disorder) in axis I with the advantage of better characterizing prominent clinical features related to dementia (American Psychiatric Association, 1994). PSYCHOPATHOLOGICAL FEATURES Neuropsychiatric symptoms in subjects with dementia are heterogeneous and largely unpredictable, affecting the emotional experience, thought content, perception, and motor function. While some symptoms can be more often recognized in a specific pathological sub-type, the clinical presentation has a wide variation within each sub-type and even within each dementia individual. The first step to better understand the psychiatric manifestations of dementia is to appropriately recognize and describe May 2012 | Volume 3 | Article 73 | 1 Cerejeira et al. the psychopathology and accurately distinguish between similar symptoms (e.g., depression vs. apathy). This can be challenging considering the overlap between symptoms and the lack of proper definitions and consensus criteria for their diagnosis. Secondly, it is useful to evaluate whether specific symptoms occur in association and to group them in syndromes with common clinical evolution, neurobiology, and management. Disturbances in emotional experience As the symptoms of depression are frequently masked by dementia, the patient rarely is able to express the typical pathological feelings of sadness, unhappiness, and preoccupation with depressing topics, hopeless (strongly associated with suicidal ideation) and loss of self-esteem (Prado-Jean et al., 2010). Instead, the prominent symptoms can be anhedonia (lost of interest in previous pleasurable stimuli), expression of somatic concerns and anxiety, a subjective unpleasant experience of fear manifested as apprehension, tension, panic, or worry associated with autonomic activation and observable physical and motor manifestations of tension. In the context of dementia, apathy has been defined as a disorder of motivation with additional loss or diminished goal-directed behaviors, cognitive activities and emotions (Robert et al., 2009). Apathy may be mistaken for depression because both symptoms can manifest themselves as diminished interest, slowing and lack of energy (Mulin et al., 2011). Although lack of motivation occurs both in apathy and depression, apathy denotes a lack of motivation without dysphoria. Elated mood, ranging from hypomania to severe mania, refers to a sustained and exaggerated feeling of well-being, cheerfulness, euphoria that is out of proportion to the circumstances often associated with a heightened emotional tone or emotional reactivity. Both depression and elated mood are commonly associated with irritability, a pervasive feeling of unease in response to a sense of threat with enhanced readiness to hostile attitudes or actions, which can be aggravated by hunger, sleepiness, and pain. Affective (or mood) lability is characterized by rapid emotional shifts, within seconds or minutes. Delusions and abnormal thought content Delusional ideas (false believes strongly held, enduring, and irrefutable) can vary widely in respect to complexity, systematization, conviction, and the extent to which patients take action in response to them. The delusions are typically less complex and organized than those observed in non-demented psychotic patients and the usual content of delusional thoughts involves suspiciousness, abandonment, and misidentification (Jeste et al., 2006). Common examples include the conviction that: people are coming into the home and hiding/stealing objects; the place in which one is residing is not one’s home; conviction that spouse is an impostor (Capgras delusion); accusation of a conspiracy to abandon or institutionalize; conviction that spouse is unfaithful; believes that other persons have acted maliciously; or with discriminatory intent (Tariot et al., 1995). When associated with severe depression, delusional thoughts can involve guilt, worthless, reference, and persecution. PERCEPTUAL DISTURBANCES Perceptual disturbances in dementia can occur in every sensorial modality. In some instances, it is somewhat difficult to ascertain Frontiers in Neurology | Dementia Behavioral and psychological symptoms of dementia whether the perceptual disturbance is an illusion or whether the patient is having a perception in the absence of sensory stimuli (hallucination). Visual hallucinations are particularly common in subjects with dementia with Lewy bodies (DLB). They are recurrent, and typically consist of well formed images of animals or persons that the patient describes in detail (McKeith et al., 2005). DISTURBANCES IN MOTOR FUNCTION Unlike the prior psychopathological domains, disturbances in motor function can be directly observed and consist in reduced or increased motor activity, not necessarily associated with specific motor abnormalities. In motor retardation the patient presents with slowed movements and speech, reduced body tone, and decreased number of spontaneous body movements, whereas motor hyperactivity is characterized by an increased energy level with more frequent movements and/or rapid speech. Agitation has been defined as “inappropriate verbal, vocal, or motor activity that is not judged by an outside observer to result directly from the needs or confusion of the agitated individual” (Cohen-Mansfield et al., 2010). This term is used interchangeably with aberrant motor behavior and encompasses a range of activities such as wandering away from home; repetitive, purposeless behaviors; social inappropriate activities including those associated with disinhibition (tendency to disregard social and cultural norms and not restrain inner feelings, such as sexual drives). According to Cohen-Mansfield (1999) four distinct categories of agitation are: (1) physically non-aggressive behavior; (2) verbally non-aggressive behavior; (3) physically aggressive behavior; and (4) verbally aggressive behavior. CIRCADIAN RHYTHMS Sleep pattern changes may occur as a consequence of normal aging, but are particularly prevalent in individuals with dementia. These include hypersomnia, insomnia, sleep-wake cycle reversal, fragmented sleep, and rapid eye movement sleep behavior disorder. Patients with dementia often show daytime napping and nighttime awakenings associated with poor quality of sleep (Rongve et al., 2010). Several factors, e.g., pain, need to urinate during the night, medications (diuretics), as well as stimulants such as coffee and bronchodilators, may contribute to this problem. APPETITE AND EATING BEHAVIOR Appetite changes can be quantitative (anorexia or hyperphagia) or qualitative (preference for particular foods associated or not to changes in taste). The preference for sweets is particularly frequent in fronto-temporal dementia. Most dementia patients lose weight which can be due to hypermetabolism and inflammatory processes, in relation with hormonal disturbances. BPSD ASSESSMENT The assessment of neuropsychiatric symptoms requires a thorough examination to collect specific and detailed information about the clinical history, patient’s subjective experiences, and objective behavior. Information from a reliable family member or caregiver is essential to obtain adequate characterization of neuropsychiatric disturbances from the patient’s own ecological context as many abnormal symptoms cannot be elicited during the clinical interview. When determining whether the disturbances require medical May 2012 | Volume 3 | Article 73 | 2 2007) whereas presence of psychosis in AD has been found to be associated with increased mortality and acceleration of cognitive decline (Emanuel et al. appear to contribute to the presence of or reported higher rates of BPSD (Sink et al. it is advisable to obtain information from different caregivers to cover behavior in different settings.. The most clinically significant symptoms are depression... hallucinations. When possible. aggression. euphoria. the most prevalent BPSD are apathy. Understanding the sources of these discrepancies is important to determine the usefulness and limitations of the information obtained from both patients and caregivers as caregiver’s emotional state can influence assessment ratings (Logsdon et al. depressive symptoms are associated with worse self-reported QoL scores (Karttunen et al. STANDARDIZED CLINICAL ASSESSMENT Several validated instruments have been developed to quantify BPSD based on data collected from clinical assessment of dementia patients and caregivers’ interviews with some scales assessing a wide range of neuropsychiatric symptoms and others focusing on specific symptoms (e. Snow et al.. BPSD also have a profound physical and psychological impact on both formal and informal caregivers. In AD patients. 2003) and subjects with dementia are likely to be affected by dysfunctional interactions with their caregivers (de Vugt et al. attention it is useful to promote early interventions instead of a crisis-based or reactionary approach. 2010. evaluating the presence and severity of 25 behavioral symptoms in 7 symptomatic categories (paranoid and delusional ideation... It is unlikely that new rating scales will completely solve the problems that are inherent in the assessment of BPSD. agitation. 1987). The first behavior rating scale for AD was the BEHAVE-AD (Reisberg et al. screaming) have been reported to be the most burdensome to caregivers (Miyamoto et al....org Behavioral and psychological symptoms of dementia time behavior disturbances. aggression and agitation).. 50% of patients have at least four neuropsychiatric symptoms simultaneously (Frisoni et al. Karlawish et al. future challenges lie in the improvement of the construction and the use of the scales with an increasing need for more standardized assessment of BPSD and for evaluation of their treatment. irritability.. comprehensive vs. Whenever possible. INTERVIEW WITH THE PATIENT Although subjects with dementia may be handicapped in their communication and social skills.. research). and disinhibition. affective symptoms. Sink et al.g. neuropsychiatric symptoms are frequent with estimated rates of 35–85% in subjects with mild cognitive impairment (MCI. specific symptom evaluation) and the setting (e.. A considerable part of caregivers’ time and distress relate directly to the manifestation of BPSD (Ballard et al. 1999. Currently. When looking at individual symptoms in dementia patients.. and anxieties and phobias).. busy clinical practice vs. more research is needed to clarify how the patient–caregiver interpersonal interactions contribute to the presence of certain neuropsychiatric symptoms. 2006).Cerejeira et al.. 2009). and more hours per week providing care assistance. activity disturbances. apathy. it is important to observe how caregivers interact with the patient and how symptoms are manifested in such interactions. increased number of BPSD correlates negatively with survival rates over a 3-year period (Tun et al. However. 2011). it is essential to have an individual assessment with them. Important factors to take into account when selecting an instrument include the purpose of the assessment (e. particularly apathy. The reported frequency of BPSD largely depends on the type of sample and setting considered. 2008).g. agitation and anxiety. depression.g. Patient’s free descriptions are least prone to be influenced by the interviewer and/or caregiver and can provide crucial information about emotional states underlying behaviors. Self-administered questionnaires are also available for caregivers. Russ et al. and anxiety. depression. apathy. and eating behavior abnormalities. 2006). THE BURDEN OF BPSD BPSD are a source of significant distress and poor quality of life (QoL) to both dementia patients and their caregivers (Ryu et al. while the rarest are euphoria. 2006). In community-dwelling subjects with dementia. Caregiver’s characteristics... such as younger age. Moreover. Nursing home placement determines a significant increase in the overall cost of dementia care in addition to other direct and indirect costs associated with BPSD (Beeri et al. It consists of a semi-structured interview retrospectively assessing 12 symptoms based on the caregiver information: delusions. Disagreements among informants should be regarded as a valuable cue to identify situational factors implicated in the genesis of symptoms. sleep disturbances. In some parts of the assessment. 2000a). May 2012 | Volume 3 | Article 73 | 3 . hallucination. neuropsychiatric symptoms are generally less frequent (56–98%) and severe than in patients recruited in hospital or long-term care facilities (91–96%). 2009).. CAREGIVER INTERVIEW The interview with caregivers is an opportunity to characterize the psychopathological features and to recognize which BPSD are of greatest concern to them as these may not necessarily coincide with the patient’s own complaints or with the clinician’s priorities. night www. Behavioral symptoms. Psychotic symptoms (e. Herrmann et al. 2002. Importantly.g. aggressiveness. 1999). Monastero et al. aberrant motor behavior. 2005. it is desirable that patients are encouraged to express their own concerns in answer to open questions before proceeding to a more systematic approach to specific symptoms. 2011) whereas mood and psychotic symptoms predict changes in the QoL 2 years later (Tatsumi et al. one of the most extensively used instruments to assess BPSD is the Neuropsychiatric Inventory (NPI) whose validity and reliability has been well established in several languages (Cummings. 2011). have a significant impact in the patient–caregiver relationship deterioration (de Vugt et al.frontiersin. less education. Rocca et al. which is a major reason for earlier institutionalization of patients (Chan et al.. Even in the early stages of cognitive impairment.g.. 1997). 2004. irritability. and providing a global rating of caregiver burden.. 2011... depressive symptoms. CLINICAL RELEVANCE OF BPSD PREVALENCE AND SEVERITY OF INDIVIDUAL SYMPTOMS There is an overall agreement that BPSD are very common regardless of the type of dementia and are present in virtually all patients during the course of their disease. Yet. and thus providing an overall picture of patient’s functioning. anxiety.. 2003).. hallucinations. disinhibition. delusions) and disruptive behaviors (e. 67% of dementia subjects with clinically significant symptoms presented at least one symptom both at baseline and at 18 months follow-up assessment. agitation. In this context.. 2007. while these symptoms have been included in different sub-syndromes by other authors (e. whereas patients with severe dementia showed fewer neuropsychiatric symptoms throughout 2 years (Aalten et al. the recognition of discrete clinical entities is important to disclose underlying causal mechanisms and to develop etiological-based therapeutic interventions. delusions and hallucinations have been consistently grouped in a “psychosis” sub-syndrome in all factor analytical studies using the NPI. frontal) (Frisoni et al. the relation between apathy (highly prevalent in dementia) and the “mood” sub-syndrome remains unclear. Fuh et al.. sleep. These discrepancies may result from the fact that individual symptoms evolve differently over the course of dementia.. Depressive symptoms in subjects with MCI have also been linked to progression to dementia (Modrego and Ferrández. and functional disability (Monastero et al. 2009). 2010). There is evidence that “psychosis. 2005. other studies were in disagreement with these findings and a systematic review found a lack of association between the severity of dementia and the prevalence of depressive symptoms or diagnosed depression (Verkaik et al. the presence of specific symptoms can aggravate cognitive decline. In the population-based Cache County Study. SYMPTOMS INTERRELATION AND EVOLUTION The unitary concept of BPSD encompassing the full range of emotional. 2007) and increased brain atrophy over 2 years (Lee et al. 2011). irritability.Cerejeira et al. Persistence rates over 16 months were highest for delusions. and eating disturbances) have not been grouped consistently across studies. disinhibition. Emanuel et al. gender. 2001. 2008.. 2008).. In MCI subjects. Overall. A less reliable factor characterized by high levels of agitation. mild extrapyramidal signs. 2010). On the other hand. Spalletta et al.. and aberrant motor behavior has emerged in several studies under various names (e.. Gabryelewicz et al. 2005a). In the Maastricht Study of Behavior in Dementia (MAASBED) patients with mild dementia at baseline showed more neuropsychiatric symptoms. However. Savva et al. 2003) presenting with heterogeneous psychopathological structure and suggesting that psychomotor features cooccur with psychotic and/or affective symptoms. 2010. 2004). certain characteristics of caregivers are known to determine the risk of burden including overload. Thus. 2012) suggesting that they may represent an early sign of a neurodegenerative disease. Yet. Studies conducted on outpatients (Aalten et al. Longitudinal studies provided further insight into the evolution of BPDS during the course of the disease (Table 3). and the size of samples. agitation. Thus. Psychotic (Scarmeas et al. 2011) were reported to predict a faster cognitive deterioration.. Several other cross-sectional studies in both community and institutionalized populations reported that greater cognitive impairment or dementia severity is associated with higher rates of some BPSD (Table 2). Aalten et al. For example. assessment tools.. 2010) and in nursing-homes (Zuidema et al. the relations between BPSD and level of cognitive impairment are non-linear with higher prevalence rates observed in the middle stages of dementia (Lövheim et al. aggression.. Aalten et al. 2007. psychosis. Dechamps et al... 1999. 2005b). 2003. patients who present with both amnestic-MCI and apathy. and levels of confidence (Campbell et al. other studies group both symptoms in the same factor (Frisoni et al. Ryu et al. 2004. depression. agitation. A distinct “mood” or “affective” cluster (depression and anxiety) has been reported by some studies (Aalten et al. 2007). 2006). 2011). level of neuroticism. it has been proposed. 1999.g. Ultimately.. Several studies have tried to identify neuropsychiatric sub-syndromes by grouping a number of individual symptoms which contingently co-occur during the course of dementia (Table 1). 2009.. Kang et al. Repeated assessments have clarified that individual symptoms have an intermittent course....... 2008... Although it appears that BPSD have a heterogeneous pattern during the course of dementia. Spalletta et al. role captivity... In the MAASBED study 65% of outpatients who had a clinically relevant NPI total score at baseline continued to experience problems during the 2-year study period..g. quality of the relationship with the patient.. Particularly. (2011) have concluded that neuropsychiatric symptoms in MCI usually persist. Huang et al. with a significant percentage of patients having at least one persistent symptom.. 2012) support that apathy and depression are distinct phenomena Frontiers in Neurology | Dementia Behavioral and psychological symptoms of dementia and belong to different neuropsychiatric syndromes. 2004). In addition to BPSD. adverse life events.. 2011). with the most persistent symptoms being apathy and aberrant motor behavior (Aalten et al. after adjustment of variables (Palmer et al. Selbæk and Engedal. one-third of patients with delusions.. and behavioral abnormalities occurring in dementia reflects the clinical heterogeneity and complexity of the symptoms and the difficulty in characterizing more specific subsyndromes or proprieties clusters co-varying during the course of the disease.. disinhibition. Although these studies differ in respect to study designs. as shown by a large cross-sectional study involving 3404 subjects. hallucinations. with elevated resolution and incidence rates throughout the time.. comorbid neuropsychiatric symptoms have been associated with worse cognitive performance. Zuidema et al. and aberrant motor behavior in a study conducted in nursing homes (Bergh et al. had an almost seven-fold risk of AD progression compared to amnestic-MCI patients without apathy. Mirakhur et al. There is limited information about the natural history and course of neuropsychiatric symptoms in MCI. Dechamps et al.. there is also a degree of concordance between the neuropsychiatric syndromes found (Table 1). but not those with depression. especially in May 2012 | Volume 3 | Article 73 | 4 . even if the precise delineation of each syndrome remains elusive.. 2007. Hollingworth et al. 2011). BPSD tend to be present chronically and most patients with baseline symptoms continue to show at least one symptom at subsequent assessments. These symptoms were more severe at baseline (Ryu et al. and agitation were symptom-free in the following 4 months (Bergh et al.” and “agitation/aggression” factors remain stable across a 31-month period (Selbæk and Engedal. with delusions and depression being the most persistent (Steinberg et al.. 2008. 2012). 2008). 2011) and depressive symptoms (Chan et al. The debate about the definition of the several psychiatric and behavioral symptoms in dementia continues as a number of symptoms (apathy. psychological. 2010... hyperactivity. while apathy increases linearly with cognitive decline.” “affective. PCA turbance Psychosis: delusions. hallucinations NPI. appetite (community + nursing homes) Psychosis: delusions. (2007) 2354/2808 AD patients Hyperactivity : agitation. elation/euphoria Schreinzer et al. anxiety Harwood et al. disinhibition. (1992) 106 AD patients (outpatient Disinhibition clinic) BSSD Apathy-indifference Dependency motor agitation Self-destructive behaviors Hope et al. euphoria. other delusions Depression: tearfulness. appetite NPI. physical aggression. aberrant clinic) motor activity NPI. aimless walking. depressed mood Activity disturbance: wandering. other anxiety clinic) Psychosis: delusions of theft. (2001) 320 AD + 212 VaD patients Mood and psychosis (outpatient clinic) Psychomotor regulation NPI. physical treats/violence. hallucinations) Aalten et al. PCA Altered circadian rhythms 140 AD patients (outpatient Psychosis: delusions. anxiety. (2006) 1120 AD patients Behavioral dyscontrol: euphoria. anxiety of upcoming events. PCA Aggression: verbal aggression. hallucinations Hypomania: disinhibition. LCA Affective disturbance (depression. FA Mood : apathy. (2001) Lyketsos et al. aberrant motor behavior. PCA Mood: depression. PCA Affective symptoms: depression. verbal aggression and hos- PBE. disinhibition. night time behavior disturbance NPI. aggression Aalten et al. disinhibition.org May 2012 | Volume 3 | Article 73 | 5 . appetite/eating dis- NPI. hallucinations. (2004) 199 dementia patients Hyperactivity : agitation. irritability. (2005) Matsui et al. irritability. fear of being left alone. appetite/eating abnormalities (Continued) www. anxiety euphoria) Psychotic disturbance (delusions. (1998) 151 AD patients (outpatient Agitation/anxiety : agitation. Reference Sample/methods Clusters Devanand et al. agitation. visual hallucinations BEHAVE-AD. (2003) Mirakhur et al. delusion one’s house is not one’s home Frisoni et al. persecutory ideas. trailing or checking (community) Aggressive behavior : aggressive resistance.frontiersin. irritability.Cerejeira et al. FA Social engagement 198 AD patients (community) Minimally symptomatic NPI. suspiciousness/paranoia. irritability. anxiety. PCA tility Psychosis: hallucinations. hallucinations. apathy. anxiety. depression/euphoria Euphoria: euphoria Hollingworth et al. anxiety Apathy : apathy. euphoria. (1999) 162 AD patients (hospital) Mood syndrome NPI. (1997) 97 AD or VaD patients Overactivity : walking more. Behavioral and psychological symptoms of dementia Table 1 | Neuropsychiatric sub-syndromes reported in patients with dementia. PCA Psychosis syndrome Frontal syndrome Fuh et al. sleep. apathy Agitation: irritability. hallucinations. sleep. disinhibition. (2006) 133 dementia patients Agitation (chronic care hospital) Affective disturbance BEHAVE-AD. aberrant motor behavior (outpatient clinic) Mood/apathy : depression. PCA Psychosis: delusions. (2008) (outpatient clinic) chosis: delusions. anxiety 435 AD patients (outpatient Affect : depression/dysphoria. aberrant motor behavior. irritability. sleep disturbance. aberrant motor behavior Psy- Aalten et al. agitation/aggression clinic) Physical behavior : apathy. depression. hallucinations NPI. (2010b) 491 AD patients (outpatient Psychotic: hallucinations. delusions Factor 4: Appetite and eating Garre-Olmo et al. present behavioral examination. agitation NPI. anxiety. irritability. apathy and wandering GMS. sleep disorder. and eating change NPI. Behavioral and psychological symptoms of dementia Table 1 | Continued Reference Sample/methods Clusters Zuidema et al. eating disorders GDS 7: Factor 1: agitation. euphoria. aberrant motor behavior Factor 5: night-time behavior. anxiety (nursing homes) Factor 2: sleep disorder. depression Maniac: euphoria. apathy NPI. appetite AD. night-time (nursing homes) behavior NPI. eating disorders Factor 4: euphoria GDS 6 Factor 1: agitation. agitation Factor 4: elated mood. hallucinations Factor 4: aberrant motor behavior. latent class analysis. apathy. disinhibition Apathetic: apathy Selbæk and Engedal (2012) 895 dementia patients Agitation: agitation. FA Factor 2: anxiety and depression Factor 3: irritability. disinhibition. (2010) 319 dementia patients Factor 1: disinhibition. (2007) 1437 dementia patients GDS 4/5: (nursing homes) Factor 1: agitation. (2009) 587 AD patients (community) Factor 1: psychosis. disinhibition Factor 3: depression. disinhibition and irritability (nursing homes) Affective: depression. PCA Affective: anxiety. aberrant motor behavior. apathy and aberrant motor behavior Hallucinations: hallucination and sleeping disturbances Savva et al. PCA. night-time behavior Factor 5: apathy. VaD. FA Factor 2: depression. agitation and wandering Kang et al. aberrant motor behavior. disinhibition. GMS. Frontiers in Neurology | Dementia May 2012 | Volume 3 | Article 73 | 6 . delusions clinic) Affective: depression. appetite Prado-Jean et al. agitation. sleep. FA (exploratory and Affect : depression. (2010) 778 AD patients (hospital) Hyperactivity : agitation/aggression. hallucinations Apathy/vegetative symptoms: apathy. PCA Factor 3: Euphoria. euphoria. anxiety. irritability. principal component analysis. PBE. eating disorders Dechamps et al. neuropsychiatric inventory. irritability. anxiety Apathy/appetite: apathy. irritability.Cerejeira et al. aberrant motor behavior confirmatory) Spalletta et al. irritability. geriatric mental state. disinhibition. FA (exploratory and Behavior : euphoria. hallucinations. anxiety Factor 4: apathy. (2008) 109 dementia patients Hyperactivity : agitation. hallucinations. hallucinations. neuropsychiatric inventory-nursing home version. NPI-NH. irritability. (2010) 1015 AD patients (outpatient Psychomotor: agitation. NPI. irritability NPI. clinic) Psychosis: delusions. PCA Psychosis: delusions. aberrant motor behavior. anxiety. behavioral syndromes scale for dementia. persecution. PCA Psychosis/affective: delusions. irritability Factor 2: delusions. Alzheimer disease. delusions. euphoria Factor 2: depression. LCA. hallucinations. hallucinations. delusions NPI. vascular dementia. disinhibition. BSSD. disinhibition. anxiety confirmatory) Psychosis: delusions. anxiety Factor 3: delusions. aberrant motor behavior. night time behavior Factor 3: apathy. 17% in moderate. 37 AD + 28 VaD patients Behavioral changes without correlation with severity of dementia in AD. to AD). Severity of delusions. 344 AD + 91 MCI + 50 All behavioral disorders increased with cognitive impairment. psychotic symptoms. (2010) Thompson et al. Matsui et al. (2010) 320 AD + 212 VaD patients Delusions. and 19% in severe dementia). and hallucinations exhibited the most rapid disappearance over time. (2009) (long-term care) AD patients aggressiveness. (2005) García-Alberca et al. (2010) 1015 AD patients (outpatient Poor association between cognitive deficits and severity of BPSD clinic) symptoms. care centers Passiveness increased linearly with the severity of cognitive impairment. aberrant motor behavior. outpatient sleep and appetite disorders. hallucination. outpatient clinic) (amnestic-MCI to multidomain-MCI. irritability.Cerejeira et al. Reference Sample Findings Aalten et al. 24% in moderate dementia. elation/euphoria. 1155 AD patients Psychiatric symptoms. Cheng et al. (2005) 435 AD patients (hospital) Depression/dysphoria and apathy /indifference more frequent in less severe dementia. and aberrant motor behavior more frequent in severe dementia. (2008) Lyketsos et al.org May 2012 | Volume 3 | Article 73 | 7 . 329 dementia patients Severity of dementia associated with increased prevalence of (community) agitation/aggression (13% in mild dementia. Apathy was the most persistent symptom. more frequent in more controls Lopez et al. (2000) 3040 residents in geriatric Higher prevalence rates of BPSD in the middle stages of dementia. clinic) Fuh et al.frontiersin. (2006) 140 AD patients (outpatient Psychosis and agitated behaviors co-occurred with dementia progression. 125 AD patients (outpatient No predictive value for MMSE in BPSD. clinic) Geda et al. activity disturbances. except major depression. except for controls (hospital. multidomain-MCI + 58 Fernández Martínez et al. hallucinations. night-time behavior and appetite changes correlated to cognitive decline in VaD. but was not statistically significant. Behavioral and psychological symptoms of dementia Table 2 | BPSD and dementia severity: cross-sectional studies. (2010) 119 AD + 68 Apathy more prevalent with increasing severity of cognitive syndromes amnestic-MCI + 107 controls increased from amnestic-MCI to multidomain-MCI. Lövheim et al. but not with dementia. Craig et al. Depression prevalence No association with night-time disturbances. (2008a) (hospital. hallucinations. (2008) 2808 AD patients (outpatient Psychosis and hyperactivity co-occurred more often in more severe stages clinic) of dementia. clinic) Spalletta et al. (2008b) Fernandez-Martinez et al. delusions. (2004) 87 AD + 54 MCI + 514 Total NPI scores significantly different among the 3 groups. Di Iulio et al. hallucinations. aggression. and 29% in severe dementia) and aberrant motor behavior (9% in mild. Fernández Martínez et al. (2003) severe stages of the dementia. (2010) 81 AD + 14 VaD + 10 Prevalence of neuropsychiatric symptoms increased with dementia PLBD + 3FTD (community) severity. and aberrant motor activities more common in (hospital. diurnal rhythm disturbance and behavioral problems significantly associated with severity of dementia. 377 AD + 74 VaD patients Association between severity of BPSD and severity of dementia (outpatient clinic) (Continued) www. 138 (outpatient clinic) +173 Severity of delusion/paranoid ideation. outpatient clinic) later stages in both AD and subcortical VaD. (nursing homes) with higher prevalence in more severe stages of dementia.. FRONTO-TEMPORAL LOBAR DEGENERATION Fronto-temporal lobar degeneration (FTLD) is the prototype of a neurodegenerative disorder where changes in behavior. 2005). 2010).. Chiu et al. A number of associations. TMT.3%). albeit not consistently replicated. behavior and psychological symptoms of dementia. 2002). mild cognitive impairment. mini mental state examination.. Frequencies of all neuropsychiatric syndromes significantly different in relation to the severity of disease. PLBD.. Stavitsky et al. except loss of enjoyment and social withdrawal (more frequent in mild stages).. are the presenting feature and dominate the clinical picture throughout the disease course. BPSD occur in a psychopathological pattern partially resembling primary psychiatric disorders. The clinical spectrum of FTLD encompasses three distinct syndromes. Some behavioral features. MMSE. DEMENTIA WITH LEWY BODIES Studies comparing the clinical profile of autopsy-confirmed cases of DLB and AD have consistently found a higher prevalence of Frontiers in Neurology | Dementia delusions (misidentification. aberrant motor behavior. ALZHEIMER’S DISEASE VS. rather than in cognitive function. RAVLT. ALZHEIMER DISEASE VS. Early changes in language function are observed in semantic dementia and primary progressive non-fluent aphasia (Neary et al.. 2006. different profiles of neuropsychiatric symptoms could emerge in each sub-type of dementia. Rey auditory verbal learning test. MCI. 2010c). a higher prevalence of hallucinations and sleep disorders has been reported in non-amnestic-MCI. AD. Chiu et al.. food cramming. the type of underlying vascular disease seems to determine a different clinical profile in VaD as apathy. 2008) and supporting a personalized approach to each patient.Cerejeira et al. 2001). VaD. Inertia showed the highest frequency in mild stages. ALZHEIMER DISEASE VS. These symptoms occur in up to 80 and 60% of patients respectively and tend to be more persistent over the course of the disease compared with AD patients (Ballard et al. although a substantial overlap can exist between the two dementia syndromes (Table 4).. Behavioral and psychological symptoms of dementia Table 2 | Continued Reference Sample Findings Youn et al. vascular dementia. pacing a fixed route. Alzheimer disease...2%) whereas subjects with fronto-temporal dementia had higher levels of activity disturbances (92. other factors such as demographic variables and the use of medication have not been extensively explored. appetite changes. trail-making test. that distinct groups of patients can be identified based on progressive changes in the frequency and severity of their BPSD (Garre-Olmo et al. ethnicity. Stereotypic behavior. instead of being independent phenomena. except for vegetative symptom. VASCULAR DEMENTIA The most consistent finding from the studies comparing vascular dementia (VaD) with AD is a higher prevalence and severity of depression and anxiety. (2011) 216 AD patients (hospital. 2006). provide diagnostic specificity as they are only rarely seen in other sub-types of dementia (Bathgate et al. 2003). and loss of social awareness are characteristic of FTLD with complex ritualized behaviors occurring more frequently in patients with fronto-temporal and semantic dementia than in AD (Bozeat et al.. and hallucinations have been associated with small-vessel VaD. 2001. the co-occurrence of sub-syndromes is common reflecting the complex and multi-level interaction between each BPSD (Dechamps et al. and impaired insight. (2001) features that best discriminate FTLD from other dementias consist in loss of basic emotions. 2008). although not so common. ALZHEIMER DISEASE VS. OTHER FACTORS ASSOCIATED WITH BPSD Besides the influence of dementia stage and subtype on the emergence of BPSD. seem to be equally common across the three groups (Nyatsanza et al. However. the psychopathological profile of each sub-syndrome is highly variable across patients (Savva et al. supporting a syndrome approach to their study and management. BPSD. NPI. In contrast. Neuropsychiatric symptoms more frequent in moderate-to-severe stages outpatient clinic) of AD. May 2012 | Volume 3 | Article 73 | 8 . Zuidema et al. in comparison to amnestic-MCI (Rozzini et al.. and degree of cognitive impairment (Rockwell et al. (2006) found that AD outpatients presented with an increased incidence of anxiety and phobias (61. theft) and hallucinations (usually visual) in DLB patients independently of gender. 2000). OTHER DEMENTIA TYPES Although the manifestations of BPSD may be influenced by a variety of factors. whereas euphoria and agitation/aggression were more severe among patients with large-vessel VaD (Staekenborg et al. such as echolalia. similar rates of psychotic symptoms. AD. and less severe aberrant motor behavior among subjects with VaD. neuropsychiatric inventory. However. studies comparing the profile of BPSD in AD and nonAlzheimer dementia have not yielded entirely uniform results (Tables 4 and 5). It would be reasonable to assume that. Parkinson–Lewy body dementia. According to Bathgate et al. even at early stages. as with the clinical and neuropsychological features. Thus. simpler verbal stereotypes/perseveration or stimulus bound behavior.. they are primarily the result of the ongoing pathophysiological brain changes. Similarly.. Using the BEHAVE-AD scale. such as lack of pain awareness. (2010) 1289 dementia patients Dementia severity predicted physically aggressive behavior and apathy. Also. The most common fronto-temporal dementia (also known as behavioral variant of fronto-temporal dementia) presents with a dramatic change in personal and social behavior. Ikeda et al. 2000. preserved capacity of locating objects. 2009). more likely to progress to non-AD dementia. In conclusion. and apathy and appetite disorder. apathy. (2005a) 2 years (each 6 No significant changes over time in the three sub-syndromes or in the NPI total score. (2004) 18 months Delusions and depression were the most persistent. Zuidema et al. delusions (56%). and disinhibition (agitation). 2011). (2011) 3. disinhibition (37. Garre-Olmo et al.. Apathy increased from the second visit (after six months). depression.8%) and depression 4 months) (31. 2009. 2009). In other studies. Tschanz et al. irritability. (2009) psychosis at follow-up.6%). Wetzels et al. Conversely. (2009) 2 years Presence of apathy. (2010c) 24-months Increase of psychotic and behavioral symptoms (18–26% and 63–72%. irritability. (2011) 16 months (each Highest cumulative incidence for irritability (42. persistent and severe with disease progression.. although individual symptoms often showed an intermittent course with higher resolution for depression (58%). 2010.frontiersin. Rate of change in NPS was Drop-out: 29% weakly correlated with rate of change in cognition or function.. and elation did not tend to persist.5%). agitation. whereas the reverse was observed with severe dementia. and wandering behavior at baseline were strong indicators for their presence at follow-up. Bergh et al. 2009. Delusions and irritability/lability increased significantly.8 years Increasing occurrence. In one study. (2005b) Mild dementia at baseline predicted increasing prevalence of NPS with time. age and gender did not influence the likelihood of BPSD manifestation in AD or VaD (Savva et al. High persistence for Delusions. delusions and hallucinations (psychosis). Di Iulio et al. irritability and aberrant motor behavior. while disinhibition was the least. 2010. No significant change in the severity of the NPS during the follow-up period. Hyperactivity predicted the development of psychosis but not vice-versa. May 2012 | Volume 3 | Article 73 | 9 . Anxiety..org been associated with depressive/anxious symptoms and verbally agitated help-seeking behavior (Lövheim et al. Selbæk and Engedal (2012) 31 months The most stable co-occurring symptoms in one and the same factor were depression and anxiety (affective). Serra et al. and patient-related or environmental factors. Selbaek et al.. Reference Follow-up Findings Aalten et al. Behavioral and psychological symptoms of dementia Table 3 | BPSD evolution: longitudinal studies. Steinberg et al. Affective symptoms decreased. Karttunen et al.Cerejeira et al. depression. respectively). 2 years Greater global cognitive impairment was present at base line in subjects who developed Wancata et al. anxiety.7% suffered from any marked or severe non-cognitive symptoms. and agitation/aggression (47%). have been described between neuropsychiatric symptoms. PATIENT-RELATED FACTORS Demographic factors Aggressiveness or aberrant motor behavior has been more frequently reported in men with dementia whereas female gender has www. disinhibition. (2003) Weamer et al. months) Depression became less common. and overall severity of NPS over time. Agitation and aberrant motor behavior were the most persistent symptoms. depression. agitation/aggression. 2010). 33. rate. female elderly with VaD had more neuropsychiatric symptoms than male elderly (Hsieh et al. Symptoms of psychosis were more persistent. Affective symptoms remained stable over the follow-up. elated mood or confabulation at follow-up was not significantly linked to their presence at baseline. Staekenborg et al. Savva et al.. Presence of NPI symptoms at baseline predicted the subsequent development of symptoms (especially mood/apathy). 6 months While. and anxiety remained substantially the same at follow-up. at T1. (2010b) 12 months Frequency and severity of dysphoria/depression. Aalten et al. showing low persistence over time.. 11. and persisted during the more advanced stages of dementia. and aberrant motor behavior were the most prevalent over the 2 years.6% Drop-out: 26. apathy tended to increase. (2008) 12-month Symptoms were chronically present. Psychosis (delusions) was most common in the moderate stages. agitation. (2010) 2 years Agitation.9% remitted from these symptoms within 6 months. Kim et al. Aberrant motor Fernández Martínez et al. (2006) 17 FTD + 85 AD + 32 VaD Higher incidence of activity disturbances in FTD. depression. (2008b) 3 FTD + 81 AD + 14 VaD Higher aberrant motor activity prevalence in FTD. fronto-temporal lobar degeneration. Ikeda et al. (2003) 99 AD + 36 VaD Depression and anxiety significantly more severe in VaD than in AD. ischemic white matter subcortical changes and lacunar infarctions. fronto-temporal lobar degeneration. aberrant motor behavior. Ballard et al. (2001) 30 FTD + 75 AD + 34 VaD Loss of basic emotions. Table 5 | BPSD: Alzheimer’s disease vs. (2002) 23 FTD + 25 SD + 43 AD Changes in eating behaviors more common in both FTLD groups compared with AD. RMBPCL. Behavioral and psychological symptoms of dementia Table 4 | BPSD: Alzheimer’s disease vs. Disinhibition. VaD. Fuh et al. Complex ritualized behaviors were significantly more frequent in patients with fvFTD and semantic dementia than in AD. VaD-WSI. and an absence of insightfulness differentiated FTD from other dementias. FTLD. activity more common in subcortical VaD. behavior problems check list. an absence of difficulty in locating objects. (2002) 258 AD + 104 non-AD Similar prevalence in AD and non-AD dementia. Patients with FTD more disinhibited. Thompson et al. SD. and mixed VaD. Chiu et al. Fernández Martínez et al. Frontiers in Neurology | Dementia May 2012 | Volume 3 | Article 73 | 10 . Fernández Martínez et al. (2005) 44 AD + 31 VaD Similar symptom profile in AD and in VaD. (2009) common in VaD and in AD. and agitation in AD and VaD behavior in AD. (2004) 21 AD + 28 VaD Delusions and aberrant motor behavior more likely in AD. AD. Bozeat et al. and appetite/eating disturbances could reliably differentiate AD and VaD from FTLD. cortical VaD. (2006) 85 AD + 32 VaD VaD with higher incidence of paranoid and delusional ideation and affective disturbance. (2008b) 81 AD + 14 VaD Similar prevalence of BPSD in AD and VaD. (2003) Srikanth et al. Alzheimer disease. higher prevalence of Ikeda et al. Lyketsos et al. except for more frequent aberrant motor Srikanth et al. revised memory and behavior problems check list. (2005) 320 AD + 212 VaD Similar prevalence in AD. (2000a) 92 AD + 92 VaD Depression and anxiety more common in VaD than in AD. Hsieh et al. fronto-temporal dementia. Alzheimer disease. hallucinations. FTD. vascular dementia. apathy. food cramming. AD. (2000) 214 AD + 62 VaD Delusions more likely in AD and depression more frequent in VaD. (2000) 30 AD + 30 VaD Aggression. Lyketsos et al. BPCL. (2000) 13 FTD + 20 SD + 37 AD Stereotypic and eating behavior and loss of social awareness more common in the FTD group.Cerejeira et al. Psychotic symptoms similarly Chiu et al. disturbance in cortical VaD than in AD. semantic dementia. vascular dementia. Reference Sample Findings Bathgate et al. aberrant motor behavior. and euphoria in patients with FTD compared with AD. (2008a) 37 AD + 28 VaD Sleep disturbances and appetite changes more prevalent in AD than in VaD. (1996) 22 FTD + 30 AD Nyatsanza et al. (2005) 18 FTD + 13 SD + 28 AD 23 FTLD + 44 AD + 31 VaD Higher scores for disinhibition. (2010) 377 AD + 74 VaD No significant difference in AD and VaD patients on the BPCL or on the RMBPCL. pacing a fixed route. Similar prevalence of delusions. Levy et al. sub-cortical VaD. More severe sleep 77 AD + 77 VaD Higher prevalence of night-time behavior (sleep disturbance) in AD. Reference Sample Findings Aharon-Peretz et al. depression in VaD. anxiety and apathy significantly more severe in VaD-WSI than in AD. Mental rigidity and depression more frequent in SD than in FTD. Two studies found an association of psychosis with increased severity of beta-amyloid senile plaques (SP) in the presubiculum (Zubenko et al... Psychopathological symptoms Depression affects up to 43% of patients with dementia and it predicts an increased number of neuropsychiatric symptoms. 2010) and in verbal learning tasks (Starr and Lonie.. duration. 1991) and across cortical regions (Mukaetova-Ladinska et al. personality traits.. no significant differences were found between AD patients with (n = 24) and without (n = 24) psychosis in respect to SP and NFT densities in the study by Sweet et al. PATHOPHYSIOLOGY AND NEUROBIOLOGY OF BPSD The behavioral or psychological disturbances occurring in dementia can be understood as ineffective attempts of the patient to cope with environmental or physiological stress factors. to trace back these symptoms to premorbid psychosocial functioning which is determined by constitutional factors (e. 2010).. (1994) reported changes in neuronal counts in the CA1 hippocampus and parahippocampal gyrus. patients being restrained. Consistently with the neocortical role underlying psychotic symptomatology. frontal. PSYCHOSIS Not many studies have examined the neuropathological correlates of psychosis in AD. AD subjects with psychosis demonstrated significant elevations of glycerophosphoethanolamine and significant reductions of N -acetyl-l-aspartate in temporal. 2010). However. executive function.. and aberrant motor behavior although this was not confirmed by a recent study (Garre-Olmo et al.. 2009). The presence of specific neurocognitive deficits. and irritability (Prado-Jean et al. Considering that most studies included white population from northern European descent it’s difficult to make assumptions about whether different symptom profile may arise according to ethnicity as reported by a few studies (Chen et al. such as crowded www. or behavioral symptoms in general (Vogel et al. 2006). Anatomically. Lack of insight occurs in the majority of AD patients even in early stages and appears to be an important predictive factor for the occurrence of increased levels of neuropsychiatric symptoms including apathy. 2007). frontal. was reported to predict greater BPSD symptom severity in patients with MCI. age of onset and duration of dementia did not show any significant correlation with BPSD in patients with AD or VaD. these changes partially coincide with cholinergic and dopaminergic pathways supporting. particularly of depression and anxiety (Rosenberg et al. Neuropsychological deficits The presence of alterations in specific cognitive domains may have a predictive value for the occurrence of BPSD. 2010a). Similarly.5% of Swedish 85 years-old people (Ostling et al. (2007) found conversely that early onset AD patients showed fewer BPSD than their late onset counterparts. cognitive styles. However. 2010). (2000). Toyota et al.. Farber et al. magnitude. particularly delusions. therefore. such as executive dysfunction.. hallucinations. no similar relation was observed in non-neocortical areas or with SP burden. 2011).5% for irritability and 2. timing. and modifiability of internal conditions and/or observable behaviors are expected to emerge beyond the limits of normal variability as the ongoing neuropathological changes of dementia undermine the individual’s usual psychological capacities to adequately respond to everyday demands.. while Zubenko et al. BPSD are also common in non-demented older adults with rates of 5. irritability. impairments in memory (episodic and semantic). Chow et al.. 2008).g. Aalten et al. Förstl et al. attitudes of care staff toward challenging behaviors and/or the size of the units in which patients reside throughout the day (Zuidema et al.. Psychotic symptoms in AD patients have been found to correlate with impairments in verbal fluency (Tsai et al.The same holds true for antipsychotics which have been found to have little effect on the sub-syndrome factor structure of BPSD (Aalten et al.. particularly agitation. ENVIRONMENTAL FACTORS Presence of neuropsychiatric symptoms may arise from the characteristics of psychosocial/physical environment. 2007). Abnormalities in the intensity. In a cross-sectional study. Psychotropic medication Aggressiveness and psychotic symptoms in outpatients with dementia have been found to increase the likelihood of receiving psychotropic medications by at least two-fold and this was coupled with a higher caregiver burden (Chiu et al. On the other hand. In the study by Kim et al. Premorbid IQ has been proposed to mediate the relationship between BPSDs and cognition in AD as it significantly correlated with mood. Although this finding could derive from a therapeutic effect the available evidence suggests a modest impact of these drugs on neuropsychiatric symptoms (Rodda et al. 2011). cerebral blood flow. together with neurochemical and May 2012 | Volume 3 | Article 73 | 11 . and emotional reactivity). Furthermore..3-fold greater density of neocortical NFTs than AD subjects devoid of psychotic symptomatology.. Neuroimaging studies have similarly confirmed severe abnormalities in grey matter volume. 1995). and psychotic factors (Starr and Lonie. It is important. disinhibition.6% for anxiety. agitation. 2000) while psychotic symptoms are present in up to 10.org Behavioral and psychological symptoms of dementia housing conditions leading to sensory overstimulation (for which patients with dementia are more susceptible). 2009).frontiersin.. (2000) reported that AD patients with psychosis had a 2. anxiety. and verbal fluency all correlated with the severity of neuropsychiatric symptoms (García-Alberca et al. 2010). especially wandering and aggression (Kunik et al. and metabolism in the above cortical regions of AD subjects with psychotic symptoms (reviewed in Casanova et al. (2008) reported that the use of cholinesterase inhibitors (ChEI) influenced the structure of the apathy factor... Defining these neuroanatomical and neurochemical correlates of BPSD has been an area of active research with a hope that clarification of the underlying neurobiology will lead to more effective treatments (Tables 6–8). 2000.. (1991) described increased density of neurofibrillary tangles (NFT) in the middle frontal cortex. may also contribute to a range of BPSD symptoms. 4. (2003). 2002). or subjected to multiple moves and procedures.8% for agitation/aggression (Lyketsos et al.. Indeed. psychosis. and parietal cortices (Sweet et al. past experiences and level of education. agitation. conclusions regarding the effects of medication on the natural course of BPSD are unclear as most studies don’t have available data concerning the usual treatment of patients or don’t include sub-analysis regarding this variable. 2002).Cerejeira et al. 2010). depression with cognitive impairment (DCI). magnetic resonance imaging. (2008) 31 mild AD patients Massimo et al. Symptoms Findings References Sample Depression Hypoperfusion and hypometabolism in some areas of Hirono et al. (2009) 149 MCI +131 DA + 127 DCI patients Decreased perfusion and hypometabolism in anterior Lanctôt et al. (2009) 40 FTLD patients Delusions Decreased GM volume in frontal. (2010) 37 AD patients atrophy Anxiety. (1995) 21 AD patients Aggressive behavior Hypoperfusion in the temporal cortex (right middle and left Lanctôt et al. (2007b) 51 AD patients Benoit et al.Cerejeira et al. Alzheimer disease. (2010a) 54 AD patients Massimo et al. Behavioral and psychological symptoms of dementia Table 6 | BPSD and structural changes in neuroimaging exams. orbitofrontal. and frontosubcortical areas Psychosis Hypometabolism in frontal lobe Sultzer et al. gray matter. MRI. (2011) 111 AD patients atrophy Bruen et al. (1994) 56 AD patients Computerized tomography Magnetic resonance imaging Depression Decreased gray matter volume in right hippocampus and amygdala Egger et al. WMH. (2007) 41 AD patients Craig et al. orbitofrontal. (1999) 63 AD patients Marshall et al. and parietal lobes Staffen et al. (2000) 45 AD patients temporal. Symptoms Findings Delusional misidentification Right frontal and temporal atrophy References Sample Förstl et al. and limbic regions Visual hallucinations Lesions on visual cortex and association areas detected in MRI Holroyd et al. fronto-temporal dementia. (1995) 21 AD patients Hallucinations Hypoperfusion in parietal lobe Kotrla et al. Table 7 | BPSD and functional changes in neuroimaging exams (PET and SPECT studies). mild cognitive impairment. (2008) 31 mild AD patients Aggressive behavior Amygdala atrophy Poulin et al. FTLD. (2009) 40 FTLD patients Berlow et al. (2009) 40 FTLD patients Bruen et al. temporal. (2004) 49 AD patients anterior) Hirono et al. Increased WMH volume and aberrant motor behavior AD. fronto-temporal lobar degeneration. (2008) 31 mild AD patients Massimo et al. (2011) 264 AD patients Disinhibition Cingulate frontal cortex atrophy and medial orbital frontal cortex Serra et al. right Staff et al. (1995) 30 AD patients Delusions Hypometabolism of prefrontal. frontal. and parietal cortex Sultzer et al. Alzheimer disease. white matter hyperintensities. (1998) 53 AD patients temporal. MCI. (2003) 25 AD patients Increased metabolism in the inferior temporal gyrus and Hirono et al. (1996) 31 AD patients Apathy cingulated gyrus. DCI. anterior cingulate. FTLD. and frontosubcortical areas Tunnard et al. sleep disorders. (2000) 10 dementia patients AD. Frontiers in Neurology | Dementia May 2012 | Volume 3 | Article 73 | 12 . (2008) 14 AD patients Apathy Anterior cingulated gyrus. (2000) 14 AD patients Agitation Anterior cingulated cortex and left insula atrophy Bruen et al. (1998) 65 AD patients decreased metabolism in the occipital lobe Agitation Changes in metabolism in frontal and temporal cortices Sultzer et al. GM. increased sleep DRD1 G Higher irritability (p = 0... DAO. with a significant May 2012 | Volume 3 | Article 73 | 13 .54 for disinhibition and euphoria...25 and 0. 5-HT2A receptor polymorphism (102T)] while others may be“protective”(5-HTTLPR. and 1. However.Cerejeira et al. in other post-mortem studies in AD subjects with depressive symptoms were not related to the level of pathology (Wilson et al.05 Lower risk for “frontal” endophenotype (ORs = 0. thus providing a rationale for the therapeutic use of cholinergic drugs to treat these symptoms. Cholinergic deficits have been described for hallucinations and delusions in both AD (Tsang et al.frontiersin. 2011). DRD4. 1998. So. DRD1.007) Increased agitation (p = 0. dopamine transporter gene. Depressed non-demented patients present with chronic elevation of inflammatory mediators. lower aberrant motor behavior DRD3 Bal I C abnormalities (p = 0. such as those involving the neurotransmitter systems. Moreover. 2006) or presenting with concurrent depression (Rapp et al.032) (p = 0.80 for delusions. Behavioral and psychological symptoms of dementia Table 8 | Associations between BPSD and genes..003) increased aberrant motor behavior (p = 0. (2009) 5-HT2A receptor No correlation with any endophenotype 80 AD patients Serotonin Delusions associated with T allele (p < 0. 2002.. serotonin transporter gene polymorphism STin2. in addition to being merely an emotional reaction to early memory deficits depression can be a prodromal symptom of dementia. It has been hypothesized that chronic depression may accelerate neurodegenerative changes of AD as a result of the neurotoxic effects of elevated cortisol levels in the hippocampus (Korczyn and Halperin. and 0. Other genes have also been associated with higher risk of psychosis [(COMT. DEPRESSION Several lines of evidence suggest that depression shares complex pathophysiological routes with dementia. dopamine receptor 4. 2011). 2. References Gene Sample Pathway Clinical correlates Borroni et al.41. 2008) and DLB (Ballard et al. Teaktong et al. Indeed. 2011). P < 0. the observation that the late-life depressive disorders are commonly associated with increased number of white matter hyperdensities in subcortical areas supported the so-called “vascular hypothesis” www.023) Lower depression (p = 0. frontal. In DLB. (2012) DAT 10R Serotonin Dopamine Less “psychosis” (p = 0. SERT STin2 12R. as well as in thalamus and lentiform nucleus of depressed compared to non-depressed AD patients (Hirono et al.009) DRD4 2R Increased “moods” levels (p = 0.32. 2011). hallucinations. G72 gene (locus DAO). Reversely. The only prospective study assessing brain tissue from dementia-free subjects (n = 153) did not find increased AD or cerebrovascular pathology in those with late-life depression (Tsopelas et al. apolipoprotein E. 2009). known to play a central role in AD pathogenesis.. 2004). A strong hereditability has been reported for psychosis in AD.. 2005). SERT STin2. Staffen et al.. respectively) APOE4 Angelucci et al.. APOE. and sleep disturbance symptoms. D-amino acid oxidase. neurodegenerative and vascular changes may act as a risk factor for depression.025) and less apathy (p = 0. Psychosis has also been associated with the relative preservation of norepinephrine in the substantia nigra and a significant serotonin reduction in the presubiculum (Ismail et al. 2009) and with less severe density of neocortical tangles (Ballard et al.05. dopamine receptor 1. suggesting that depression per se may be linked to additional. 2000b. suggesting an important role for APOE4 (Ismail et al. 2010). dopamine receptor 3 Ball polymorphism. respectively) p < 0. serotonin 2A receptor. 5-HT2A.. pharmacological evidence.01).004). DRD3. serotonin gene-linked polymorphic region. catechol-O-methyl transferase. respectively). (2006) COMT 232 AD patients Dopamine Higher risk for “psychosis” (ORs = 3. a disturbed serotoninergic system has been associated with depressive symptoms in AD as several areas of the brain exhibit decreased serotonin concentration.. Sweet et al. DAT.25 for disinhibition and euphoria. 2009). 2008). 2005).007) COMT..38..05) SERT STin2 12R 1008 AD patients polymorphism (102T/C) Di Maria et al. more subtle neuropathological and/or neurobiochemical changes.. Tsuang et al. a risk factor for neurodegeneration or co-occur with cognitive impairment. and parietal cortex. Functional imaging studies revealed decreased perfusion and hypometabolism in the temporal. together with altered serotonin metabolism and reduced neurotrophic activity (Caraci et al. 0. 5-HTTLPR..05) G72 gene (locus DAO) 185 AD patients Glutamate Delusions and hallucination (p < 0. 2003. the role of acetylcholine and dopamine imbalance in the pathogenesis of AD psychosis (reviewed in Pinto et al. Table 8).05 5-HTTLPR Serotonin Lower risk for “psychosis” (ORs = 0. Post-mortem studies in AD subjects found higher burden of neuropathological lesions in those with a lifetime history of depression (Rapp et al. (2009) Proitsi et al. 2004). visual hallucinations have been linked to higher Lewy Body density in the temporal cortex and amygdala (Harding et al..org of depression (Alexopoulos. Benoit et al. 2003). Gauthier et al. APATHY Post-mortem and in vivo studies suggest that AD is associated with a dysfunctional dopaminergic system. Similarly. benzodiazepines. 2007b. 2009). 2008.Cerejeira et al. PHARMACOLOGICAL INTERVENTIONS A variety of medications have been used to treat BPSD including typical and atypical antipsychotics. 2011). tardive dyskinesia. while aggressive behaviors have been associated with neuronal loss in locus ceruleus (Matthews et al. Marshall et al. 2001). psychosis. thus. despite efforts in investigating these interventions. or overstimulation... 2010). 2005).... validation therapy). apathy. sedation. 2010.. particularly music therapy (Choi et al. hypoperfusion and hypometabolism (Craig et al... 2005). 2007) in the anterior cingulated gyrus and orbitofrontal areas (Tables 6. OTHER SYMPTOMS Increased burden of NFT in the orbitofrontal cortex has been linked to agitation (Tekin et al.. has increased over time (Briesacher et al. 2006).. which increase significantly the risk of both medical complications and drug interactions. Salzman et al. 1996. However the evidence regarding other BPSD symptoms is not convincing (Ballard et al. 2011).... This suggests that dysfunction in the frontosubcortical cingulate pathways is implicated in apathy regardless of the sub-type of dementia. They include the features of trained staffing. and agitation (Ballard et al. 2006). 2008. it is important to carefully analyze the causes for the disruptive behavior: such causes may include pain. 2011). They have shown efficacy in treating specific symptoms. loneliness.. and family involvement (Lai et al. 2011).. right dorso-lateral prefrontal cortex (Massimo et al. particularly since the introduction of atypical antipsychotics. 2009). 2007a). recent studies support the effectiveness of home-based exercise programs for people with dementia and their caregivers to reduce depressive symptoms (Prick et al. fatigue. a modified physical environment. and before opting for any intervention. antidepressants. including extrapyramidal symptoms. aromatherapy. These drugs have variable efficacy and effectiveness in treating BPSD. and aggressive behaviors (Lanctôt et al.. anticonvulsant mood stabilizers.. Deterioration of brainstem regions and in the suprachiasmatic nucleus of the hypothalamus has been reported in patients with sleep disorders (Yesavage et al. 7). 2007. 2009). Association between genetic factors and depression are summarized in Table 8. aromatherapy (Ballard et al. The pharmacological treatment of BPSD should consider the presence of additional comorbidities and associated medications. simulated presence Frontiers in Neurology | Dementia Behavioral and psychological symptoms of dementia therapy. and adjacent medial frontal cortex (Rosen et al. massage/touch. and other drugs.. Azermai et al. Recently animal-assisted activities were suggested to be associated with a decrease in anxiety and sadness and an increase in positive emotions and motor activity (Mossello et al. understimulation. Specific therapeutic interventions for different symptoms of BPSD have also been investigated.. anticholinergic side effects. It is also possible that dysfunction in these areas underlies the reported relation between increased frontal white matter changes and apathy (Starkstein et al. cerebrovascular events. 2009).. Strategies reported to be useful to reduce agitation include sensory interventions. with an increased risk of psychotropic medication misuse. have been described in discrete brain regions coinciding with the mesocorticolimbic pathway (Mitchell et al. and (iv) other psychosocial interventions such as animal-assisted therapy and exercise. consistent evidence about the efficacy of the various psychosocial therapies is lacking (Kong et al. 2011): (i) cognitive/emotionoriented interventions (reminiscence therapy. gait disturbances. antipsychotic are May 2012 | Volume 3 | Article 73 | 14 . 1999. and social and environmental stressors (Iwata et al. Current guidelines recommend non-pharmacological interventions as first-line treatment followed by the least harmful medication for the shortest time possible (Gauthier et al. such as memantine. and. Antipsychotics The use of antipsychotics. medical illness. Unfortunately. In relation to agitation and aggressive behavior.. Despite serious side effects. falls. transcutaneous electrical nerve stimulation). 2011). and environmental modification (Weitzel et al. apathy has been associated with atrophy in the anterior cingulated cortex. represents an important challenge for clinicians. Special care units have been developed since the 1980s and are commonly situated in nursing homes..... neuroimaging studies in AD have been consistently showing a significant association between apathy and changes in the brain reward system including atrophy (Apostolova et al... 2009). Lanctôt et al. since reduced levels of dopamine (DA) and homovanilic acid. especially when delivered individually (Livingston et al. (ii) sensory stimulation interventions (acupuncture. In FTD subjects. reduction in 5-HT1 and 5-HT2 receptors throughout the cerebral cortex (Lanari et al. music therapy... light therapy. 2008)... 2005). 2010). Bruen et al. depending on the target symptom and class of medication. and increased mortality. as well as altered DA receptor density. 2011). Current guidelines recommend careful consideration of both benefits and limitations of each drug class with the use of the least harmful medication for the shortest time possible (Gauthier et al. 2002). On the other hand.. MANAGEMENT OF BPSD Management of BPSD is a key component of a comprehensive approach to the treatment of dementia requiring the judicious combination of pharmacological and non-pharmacological interventions. 2009) together with disruption of deep white matter afferents and efferents to the basal ganglia and/or by decrement of metabolic activity in frontal subcortical regions. NON-PHARMACOLOGICAL INTERVENTIONS Non-pharmacological interventions have been classified into the following categories (O’Neil et al. Regarding depression. ChEI. Tunnard et al. Benefits from psycho-educational interventions for caregivers were documented to be long-lasting... Changes of GABAergic plasma levels observed in final stages of AD have also been associated with depression. Snoezelen multisensory stimulation. loss of noradrenergic cells in consequence of degeneration of the locus coeruleus is also seen in individuals with dementia who manifest depressive symptoms (Lanari et al. 2008). such as aggression. depression. 1993.. Treatment of these symptoms remains problematical. (iii) behavior management techniques. Antidepressants Antidepressants can be an effective and well-tolerated alternative to antipsychotics in vulnerable elderly individuals for treatment of BPSD (Henry et al. an NMDA receptor antagonist. infection. so they are not recommended for routine use.. ACKNOWLEDGMENTS We are grateful to Miss Maxine Berwick and Mrs. lamotrigine. The mortality risk with haloperidol was highest during the first 30 days and decreased significantly over time (Kales et al. In particular sodium valproate has been shown to be ineffective in the treatment of agitation in AD. when all other methods have failed to alleviate the most distressing symptoms of dementia. or rivastigmine have all shown a modest effect on the broad spectrum of neuropsychiatric symptoms in AD (Rodda et al. Cholinergic inhibitors Current guidelines support the use of ChEI for BPSD although different recommendations exist to each specific drug (Gauthier et al. CONCLUSION Neuropsychiatric symptoms are frequent in dementia and contribute significantly for burden caregiver and illness costs. 2009). However. 2012). The latest report on combined memantine and ChEIs (donepezil) treatment did not show any major advantages on cognitive and behavioral changes in subjects with moderate-to-severe AD. The pathogenesis of these symptoms is not well understood. and aberrant motor behavior (Cummings. In the UK.. May 2012 | Volume 3 | Article 73 | 15 . risperidone is licensed for up to 6 weeks treatment of persistent aggression in subjects with moderate-to-severe AD. The use of memantine appears to improve specific behaviors. combination of non-pharmacological and appropriate pharmacological strategies represents the best treatment of BPSD. 2011). Carla Alves for secretarial support.. including falls.. Citalopram was effective in treating disinhibition.frontiersin.. Anticonvulsants may allow dose reduction of antipsychotics. and well-tolerated pharmacological therapies. This class of drugs has been used primarily for depression. can also have beneficial effects on behavior. 2010). Some authors found that citalopram and sertraline could improve symptoms of agitation and psychosis in subjects with dementia with similar efficacy. Donepezil.. It is necessary to encourage application of novel non-pharmacological interventions. olanzapine. safe. The behavioral symptoms most likely to improve with ChEIs treatment appear to be apathy. and tolerability of these drugs has produced mixed results.. Memantine Memantine. Development and use of new specific investigation techniques may be helpful to better understand the underlying etiological mechanisms of various neuropsychiatric symptoms.. compared to risperidone.. than haloperidol and risperidone (Gauthier et al. and psychotic symptoms should be timelimited and a careful individual evaluation is recommended due to increased risk of stroke and mortality.Cerejeira et al. However. 2011). galantamine. with only negligible improvement on the NPI scores in the subjects treated with the combination of the two antidementia drugs (Howard et al. Benzodiazepines Benzodiazepines may be used at short-term for acute agitation or agitation associated with anxiety (Azermai et al.. 2004. such as agitation and irritability. there is no consistent evidence about specific strategies for individual symptoms. 2011). more symptom targeted. 2008). 2011). gabapentin. however. which are safer than pharmacological therapies. and specific interventions that will improve significantly the management of BPSD symptoms in subjects with dementia.. Risperidone. and the recommendations are to be used as a last resort for aggression. 2010). depression. as well as on cognition and function. This will help to devise novel.. It is prudent to initiate with a low dose and regularly review the prescription in function of the patient’s response and presence of adverse events.. Correct identification and evaluation of these symptoms is a crucial part of the clinical approach to dementia.5-fold increase in mortality associated with the use of haloperidol. and the current knowledge supports multifactorial causes. and only when it is in the best interests of the person (https://www. Gauthier et al. A recent study on dementia patients reported a 1. compared to those treated with either memantine or donepezil. irritability and depression and also behaviors specific to FTD (Herrmann et al. topiramate are widely used in clinical practice. the evidence so far does not support the use of these medications for BPSD other than depression (Azermai et al.. The use of an antipsychotic for severe symptoms such as agitation. and haloperidol appear to be more effective for managing BPSD (Azermai et al.org Behavioral and psychological symptoms of dementia those affected by ChEIs (mood symptoms... 2010). 2011). They should be initiated prior to the use of other psychotropic agents since ChEIs reduce behavioral changes and improve or delay cognitive and functional decline (Gauthier et al. investigation regarding benefits.alzheimers. Seitz et al. Holmes et al. Feldman et al. At present. but better tolerability and safety. 2011).org. 2005). Treatment regimens with anticonvulsant mood stabilizers have shown promising results and seem to be beneficial for some dementia patients (Konovalov et al. and has been associated with increased adverse effects. with efficacy especially for the selective serotonin reuptake inhibitors (SSRIs. and aberrant motor behavior). 2010. Anticonvulsants Anticonvulsant mood stabilizers such as carbamazepine.. which differ from www. apathy. safety. 2011). 2009). 2004. Combination therapy may have advantages in patients with multiple BPSD (Gauthier et al. 2012)..uk/antipsychotics). aggression. Further investigation is similarly needed to find more effective. Despite the tentative efforts to group different symptoms into clusters (to facilitate clinical/diagnostic investigations). still widely used off-label (Azermai et al. valproic acid. 2011). there is not yet an established model.. however there is insufficient evidence to recommend its use (Azermai et al. olanzapine or quetiapine. 2010). and gastrointestinal disorders (Lonergan and Luxenberg. Washington. G. The course of neuropsychiatric symptoms in patients with dementia in Norwegian nursing homes. Am.... (2008). R. K. Cogn. Tsolaki. L. J. J. Jaspers. J. P. Arch. J. 58. (2002).. Delusion symptoms and response to antipsychotic treatment Frontiers in Neurology | Dementia Behavioral and psychological symptoms of dementia are associated with the 5-HT2A receptor polymorphism (102T/C) in Alzheimer’s disease: a 3-year followup longitudinal study. F. 367–378. Disord. T... Psychogeriatr. Int... 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