Ke y words Dementia Alzheimers disease Geria tric Psychiatry Apathy - PDF document

y words:Dementia, AlzheimerÕs disease, Geria-tric Psychiatry, Apathy.The prevalence,clinical correlates and treatment ofapathy in AlzheimerÕs diseaseSergio E.Starkstein,M.D., Ph.D.*Ricardo Jorge, M.D.***, M.D.***** School of Psychiatry and ClinicalNeurosciences, University of Westernustralia, and Fremantle Hospital, Westernustralia, Australia** Department of Psychiatry, The Universityof Iowa, Roy J.and Lucille A.CarverCollege of Medicine, Iowa City, USA*** PET Center for Addiction and MentalHealth, Clarke Division, Toronto, CanadaUSTRALIA, USA, CANADA ABSTRACT ÐThe aim for this article is to review the frequency,clinical correlates andtreatment of apathy in AlzheimerÕs disease. Apathy is currently defined as diminishedmotivation as expressed in poor goal-oriented behaviours and cognitions. A structuredclinical interview and a specific set of diagnostic criteria to diagnose apathy in demen-tia have been recently validated. There are several valid and reliable scales to measurethe severity of apathy in adults with neuropsychiatric disorders. Apathy is present inabout 20% of patients with mild dementia and in 60% of those with severe dementia.Among patients with AlzheimerÕs disease,apathy is significantly associated with olderage,the presence of depression,and more severe cognitive and functional deficits,andalso predicts a faster cognitive and functional decline. The mechanism of apathy in neu-ropsychiatric disorders is still unknown,but several studies suggest an important rolefor frontal lobe and basal ganglia dysfunction. There are no specific randomized con-trolled trials of psychoactive compounds to treat apathy in neuropsychiatric disorders.ulants to treat apathy in traumatic brain injury,whereas pharmacological trials forbehavioural and psychological problems in dementia suggest that anticholinesterases may have some efficacy.Received 14 October 2005Eur.J.Psychiat.Vol.20, N.¡2, (96-106) THE PREVALENCE, CLINICAL CORRELATES AND TREATMENT OF APATHY...97IntroductionDiminished motivation is one of themost frequent behavioural changes amongAmong patients with AlzheimerÕs disease(AD) the frequency of apathy has been1990,Starkstein 1992,Stark-1993,Starkstein Levy 1998). Apathy is most frequent-ly associated with depression and severedementia. AD patients with apathy aremore impaired in basic activities of dailyliving and their caregivers report signifi-cantly higher levels of distress as com-pared to AD patients without apathy (Lan-negative impact of apathy in AD,treatmentstudies for this frequent behavioural condi-tion are surprisingly few. Our group and others have also reported arelatively high frequency of apathy amongpatients with stroke lesions,traumatic braininjury,ParkinsonÕs disease,and Hunting-tonÕs disease (Burns 1990,Starkstein1992,Starkstein 1993,Starkstein1995,Levy 1998). Nevertheless,the frequency of apathy is highest amongindividuals with dementia,and the presentreview will mainly focus on the frequencyand clinical correlates of apathy in AD. Wewill briefly discuss the neurobiologicalbasis of apathy,and also review pharmaco-logical and non-pharmacological treatmentDiagnosis of ApathyMarin defined apathy as the absence orlack of feeling,emotion,interest or motiva-tion (Marin 1991). Marin and Wilkosz(Marin & Wilkosz 2005) defined dimin-ished motivation as the simultaneousdecrease in goal-related aspects of overtbehaviour,thought content and emotion inthe presence of intact level of conscious-ness,attention,language,and sensorimotorcapacity. Starkstein (Starkstein 2000) stan-dardized MarinÕs construct into a set of cri-goal-directed behaviour,diminished goal-directed cognition,and diminished con-comitants of goal-directed behaviour (TableI). These diagnostic criteria have been vali-dated for patients with AlzheimerÕs disease,ut their validity in other neuropsychiatrichow to separate apathy from depression.Both the DSM-IV and the ICD-10 allow asad mood,provided the patient reportsryÓapathy as consisting of the symptomsof apathy listed in Table I in the absence ofthe core symptoms of depression. Severalamong individuals with or without AD,although apathy and depression may alsooccur independently of each other (Stark-Several instruments are now available torate the severity of apathy. Marin andcoworkers were the first to validate theApathy Evaluation Scalepatients with stroke,ParkinsonÕs disease,or AlzheimerÕs disease (Marin can be administered as a self-rated scale,asa caregiver scale,or as a clinician adminis-tered test. Starkstein and coworkers devel-Apathy Scale(Table II),which is an abridged and slightly modified 98SERGIO E.STARKSTEIN ET AL.sion of MarinÕs instrument (Starkstein 1995). The Apathy Scale was validatedfor use in stroke,ParkinsonÕs disease,andAlzheimerÕs disease. Cummings developedNeuropsychiatric Inventorydimensional instrument administered to aninformant (Cummings 1997). This assess-ment includes a specific module to measureapathy,which consists of 8 items that areapathy module provide a measure of thefrequency and severity of apathy,as well ascaregiver distress. Roberts and coworkersApathy Inventoryformat of the Neuropsychiatric Inventory2002). The Apathy Inventorysymptoms of emotional blunting,lack ofinitiative,and loss of interest. More recent-ly,Strauss & Sperry reported on the validi-Interview and Ratingmotivation,emotional responsiveness and(Strauss & Sperry 2002). We have recentlypublished the validity and reliability of theStructured Clinical Interview for Apathy2005). This instrumentlack of motivation relative to the individ-ualÕs previous level of functioning,lack ofeffort to perform every day activities,dependency on others to structure activi-ties,lack of interest in learning new thingsor in new experiences,lack of concernabout oneÕs personal problems,unchangingor flat affect,and lack of emotionalresponse to positive or negative personalents. Based on answers to specific ques-tions,symptoms are scored as either absent,subclinical,or definitely present. This is,toour knowledge,the only standardizedtoms of apathy using a semi-structured for-Tab Lack of motivation relative to the patientÕs previous level of functioning or the standards of his or herage and culture as indicated either by subjective account or observation by others.Presence,while with lack of motivation,of at least 1 symptom belonging to each of the followingDiminished goal-directed behavior.Lack of effort.Dependency on others to structure activity.Diminished goal-directed cognitionLack of interest in learning new things,or in new experiences.Lack of concern about oneÕs personal problems.Diminished concomitants of goal-directed behavior.Unchanging affect.Lack of emotional responsivity to positive or negative events.The symptoms cause clinically significant distress or impairment in social,occupational,or otherThe symptoms are not due to diminished level of consciousness or the direct physiological effects of asubstance (e.g.,a drug of abuse,a medication). THE PREVALENCE, CLINICAL CORRELATES AND TREATMENT OF APATHY...99TabQuestionsNot at allSlightlySomeA lot 1. Are you interested in learning new things? 2.Does anything interest you? 3. Are you concerned about your condition? 4. Do you put much effort into things? 5. Are you always looking for something to do? 6. Do you have plans and goals for the future? 7. Do you have motivation? 8. Do you have the energy for daily activities? 9. Does someone have to tell you what to do each day? 10. Are you indifferent to things? 11. Are you unconcerned with many things? 12. Do you need a push to get started on things? 13. Are you neither happy nor sad,just in between?14. Would you consider yourself apathetic? Note:For questions 1-8,the scoring system is the following:not at all = 3 points; slightly = 2 points; some =1 point,a lot = 0 point.or questions 9-14:the scoring system is the following:not at all = 0 points; slightly = 1 point; some = 2In conclusion,whilst apathy is one of themost frequent behavioural changes in neu-ropsychiatric disorders,its clinical assess-for apathy have been validated forAlzheimerÕs disease only. There is a varietyof scales that are both valid and reliable torate the severity of apathy,but these instru-based on cut-off scores. This procedure mayresult in apathy groups with different syn-dromic clusters. There is also a structuredclinical interview for apathy,but its validitypatients with dementia only.Frequency of apathy inAlzheimerÕs diseasexamined the frequency of apathy in astudy that included a consecutive series of101 patients with probable AD (Starkstein 1995). Apathy was diagnosed based onratings on the motivation and initiative itemUnified ParkinsonÕs Disease Rating(Fahn & Elton 1987). Scores on thisitem are 0:normal,1:less assertive thanusual; more passive,2:loss of initiative ordisinterest in elective (non-routine) activi-ties,3:loss of initiative or disinterest in dayto day (routine) activities,and 4:withdrawn, 100SERGIO E.STARKSTEIN ET AL.complete loss of motivation. Patients withscores of 2 or higher were considered apa-thetic. Based on this diagnostic scheme,46of the 101 patients with AlzheimerÕs diseasehad apathy.In the next study we diagnosed apathyinformation was obtained from caregivers,who filled the Apathy Scale about thepatient. Briefly,apathy was diagnosedwhenever patients had 1) Poor or no motiva-tion (as rated with item 7 on the ApathyScale),2) Poor or no interests (as rated withitems 1 and 2) or effort (as rated with items4 and 9),and 3) Feelings of indifference ordiagnostic scheme,apathy was diagnosed in37% of a consecutive series of 319 patientswith AD,as compared to none of a series of36 age-comparable healthy individuals.About two thirds of the AD patients withapathy were also depressed (either major orIn a recent study we assessed the Struc-tured Clinical Interview for Apathy on anew series of 150 patients with AD. Apathylisted in Table I (Starkstein 2005). Wenostic criteria for apathy. Thirteen of these29 patients also had major depression,5patients had minor depression,and 11patients were not depressed. Taken together,our findings suggest that the frequency ofapathy in AD is lower when assessed with astructured interview and diagnosed witharbitrary cut-off points on a severity ratingAD,Landes and coworkers diagnosed apa-thy based on a cut-off score on the Demen-tia Apathy Interview and Rating (Landes 2001). They diagnosed ÒfrequentÓapa-nificant association between higher levels ofapathy and dysphoria. Using arbitrary cut-off scores on the Neuropsychiatric Invento-ry,the frequency of apathy was 27% in apopulation-based sample of 329 individualswith dementia (Lyketsos 2000),59%among 199 ambulatory patients living in the2003),69%among 162 consecutive patients admitted to1999),and76% among 435 patients with AD recruitedIn conclusion,the frequency of apathy in76%,and several methodological issuesmay account for this wide discrepancy.First,apathy has been diagnosed using ariety of rating instruments and differentstrategies. Second,the source of patientsried widely,from patients living in thedementia units. Finally,those studies thatincluded patients with relatively moresevere dementia showed a higher frequencyClinical correlates and courseof apathy in ADMost studies on apathy in AD have beencross-sectional,and all of them demonstrat-ed a significant association between moresevere apathy and more severe dementia. Inolution of apathy in a consecutive seriesof 354 patients with probable AD attending THE PREVALENCE, CLINICAL CORRELATES AND TREATMENT OF APATHY...101a memory clinic (Starkstein Apathy was assessed with the Apathy Scaleshown in Table I. At baseline,apathy wasdiagnosed in 24% of the patients. Patientswith apathy were significantly older,hadmore severe cognitive deficits and moresevere impairments in activities of daily liv-ing than patients without apathy. The fre-quency of apathy ranged from 14% in verymild AD to 61% in the stage of severe AD.Whilst apathy was significantly associatedwith depression,the latter was neither nec-essary (apathy was present in 23% ofpatients without depression) nor sufficientto produce apathy (about half of the patientsA follow-up examination was carried outyears after the baseline evaluation. Toxamine whether apathy should be consid-dementia,we first examined whether theonset of depression during the follow-upperiod was associated with increasing apa-thy. This analysis included 97 patients withneither depression nor apathy at baseline,who had major (N = 6),minor (N = 18) orno depression (N = 73) at follow-up. Theresults showed a significant overall incre-ment in apathy scores during the follow-upperiod,but there was no depression by apa-thy interaction (i.e.,the increment in apathyscores was of similar magnitude for allpatients,regardless of depression status atfollow-up). These findings suggest that apa-thy in AlzheimerÕs disease should not beconsidered as a symptom of severe depres-sion only.next examined whether apathy atbaseline may predict more severe depres-sion at follow-up. This study included non-apathy (N = 76) at baseline. We found a sig-nificantly greater increase in depressionscores during the follow-up period forpatients with apathy as compared to thosewithout apathy,suggesting that apathy is asignificant predictor of depression in AD.Finally,we also found that patients withapathy at baseline or those that developedapathy during the follow-up period had aaster cognitive and functional decline thanlow-up. This replicates recent findings byBoyle and coworkers (Boyle & Malloy2004) who found a significant correlationbetween apathy and more severe functionaldeficits.In conclusion,apathy in AlzheimerÕs dis-ease is associated with older age,more severedeficits in activities of daily living,and aaster progression of cognitive and functionalthy was found to be significantly associatedwith depression,whereas in longitudinalstudies apathy was found to be a significantpredictor of more severe depression.Mechanism of apathy in ADThe current view on the mechanism ofapathy in neurological disorders is mostlymechanistic:apathy is considered to resultÔdrive and motivationÕand that participate inthe elaboration of Ôplans for actionsÕ. In arecent review,Habib (2004) summarizedthe main clinical features of apathy (whichage,and stressed the over-representation ofimportance of parallel and segregated corti- 102SERGIO E.STARKSTEIN ET AL.originates in the anterior cingulate cortex,connects with the ventral globus pallidusand the dorsomedial thalamus,and projectsÒthe process of converting motivation intoactionÓ,and that apathy may result from thebilateral disruption at different levels of thiscircuit or from lesions in limbic areas out-side the striato-pallidal complex. Thisould explain why some patients withorbito-frontal lesions who mostly show dis-inhibited behaviours,also feature a con-comitant loss of motivation. Habib conclud-ed that ÒathymormiaÓis the result of acharacterized by deficits converting past orpresent emotional experience into action.HabibÕs proposal is certainly interestingand fits nicely with the current model ofsegregated basal ganglia-frontal lobe loopsfor the modulation of behaviour. However,HabibÕs model partially rests on the dubi-dependent on motivation. The problemwith this hypothesis is how to avoid theCartesian dilemma of psychological states(motivation and past or present emotionalIn a recent comprehensive review on themechanism of apathy (termed the Òauto-activation deficitÓ) Levy & Dubois empha-sized that apathy should not be defined asÒlack of motivationÓ(considered anobscure psychological concept),Òbut as anobservable behavioural syndrome consist-ing in a quantitative reduction of voluntary(or goal-directed) behavioursÓ(Levy &Dubois 2005). They further suggested thatapathy may result from the disruption ofprefrontal cortex-basal ganglia circuits,poseful behaviour. Levy & Dubois consid-ered that apathy may be related to thedisruption of Òemotional-affectiveÓ,Òcog-nitiveÓand Òauto-activationÓprocesses.They hypothesized that disruption of anÒemotional-affectiveÓprocess may pro-duce apathy due to the inability to associ-ate affective and emotional signals withrt behaviour; disruption of the Òcogni-tiveÓprocess may result from impairmentson cognitive functions that are Òneeded toÒauto-activation deficitÓmay result fromÒdifficulties in activating thoughts or initi-ating the motor program necessary to com-plete the behaviourÓ. It is not clear whether the behavioristmechanism for apathy suggested by Levy& Dubois may successfully avoid thetheir model. They suggest that apathy mayresult from a faulty elaboration of Òplansof actionÓand from the disruption of Òacti-ting thoughtsÓin the initiation of motorprograms,which are both psychologicalconcepts. Another limitation with Levy &age between apathy and lesions in specificbrain areas. While most studies did demon-strate a significant association betweenapathy and lesions in the lateral prefrontalcortex and/or dorsal territories of the basalganglia,these lesions are neither necessary(apathy may result from lesions elsewherein the brain) nor sufficient to produce apa-brain areas do no develop apathy). Finally,thy and cognitive impairments has beenconsistently demonstrated,it is uncertain THE PREVALENCE, CLINICAL CORRELATES AND TREATMENT OF APATHY...103whether apathy may result from deficitsrestricted to executive functions.In conclusion,current theories explainapathy as the behavioural expression of thedisruption of cognitive modules that dealwith the organization of human action,driveand motivation. These modules are consid-ered to engage independent frontal-subcor-clarify the association between apathy andlesions in specific brain areas,as well as therole of executive dysfunction in the mecha-nism of apathy.reatment of apathyThere are few randomized controlled tri-ical treatments for apathy in AD. On theother hand,there is a growing literature con-patients that were treated for apathy with ariety of psychoactive agents (see Marin &Chakravorty for a comprehensive review(Marin & Chakravorty 2005)).Politis and coworkers (Politis test the efficacy of a kit-based interventionto reduce apathy and increase quality of lifein 37 patients with dementia. The controlwith an activity therapist. The authors founda significant improvement on apathy mea-sures over the course of the study,but therewere no significant differences between thetreatment groups on any of the outcomeLee and coworkers (Lee 2003) haverecently reviewed the pharmacological treat-ic Brain Psychostimulants and dopaminergicagonists (e.g.,methylphenidate,dextroam-phetamine,pergolide and bromocriptine)may modestly improve arousal and speed ofinformation processing,reduce distractibili-ty,and improve some aspects of motivationand executive function (Plenger 2001). However,the magnitudeeffect is still controversial (Whyte 2002). A recent double blind,placebo con-trolled study evaluated the effects ofmethylphenidate on diverse cognitive func-erate to severe head injuries (Whyte 2004)Methylphenidate,at 0.3 mg/kg/dose,showed clinically significant positive effectson speed of information processing,caregiv-er ratings of attention,as well as motivationand drive to complete other cognitive2004). However,anotherrecent open study of 4 patients who devel-oped apathy after a closed head injury sug-gests that selegiline has adequate efficacy totreat apathy and is better tolerated thanmethylphenidate,but these findings requireconfirmation in appropriate controlled trials(Newburn & Newburn 2005). Amantadine,adrug with complex pharmacologic effects ondopaminergic,cholinergic and NMDAreceptors,could also have some efficacy totreat motivational deficits(Kraus & Maki1997; Meythaler 2002). Finally,there issome empirical evidence that cholinesteraseinhibitors such as donepezil may improvecognitive functioning,motivation and gener-injury (Arciniegas 1999,Freo 2002,Arciniegas 2003). In a study that included men with Parkin-sonÕs disease Ready and coworkers (Ready2004) found a significant correlationbetween low plasma levels of free testos-terone and more severe apathy. The authors 104SERGIO E.STARKSTEIN ET AL.therapy may constitute a helpful treatmentSeveral treatment studies suggested thatanticholinesterase compounds may improveapathy among patients with dementia. In arecent study,Cummings and coworkers2005) assessed the effectof rivastigmine to treat the neuropsychiatricwith moderate to severe AlzheimerÕs dis-ease. After 26 weeks of treatment there wasa significant improvement of apathy,asmeasured with the Neuropsychiatric Inven-tory. It is important to stress that the effectof rivastigmine was not specific for apathy,since improvements were also noticed onthermore,changes on the NeuropsychiatricInventory were rather small and may nothave been clinically relevant. Thus,the ben-eficial effects of cholinergic therapy in ADneeds to be replicated in larger,adequatelypowered clinical trials.ConclusionsApathy is being increasingly recognizedas one of the most frequent behaviouralatric disorders. Recent studies providedrking definitions of apathy that werecriteria. A number of valid and reliableinstruments have been developed to assessthe severity of apathy. Apathy is highlyprevalent among patients with dementia.Recent studies found that apathy inAlzheimerÕs disease is significantly associat-ed with older age,relatively more severecognitive deficits,depression,and moresevere impairments in activities of daily liv-ing. Furthermore,patients with dementiaand apathy have a significantly faster cogni-tive and functional decline than dementedindividuals without apathy. The mechanismof apathy in neuropsychiatric disordersremains unknown,but recent studies suggestglia circuits and executive dysfunction mayboth play an important role. A variety ofpsychoactive compounds were reported toimprove apathy after focal brain damage,butor small case series. Anticholinesterasedrugs may improve apathy in AlzheimerÕsdisease,although this could be an epiphe-nomenon of improvement on other behav-research are the validation of the clinicalconstruct of apathy in neuropsychiatric dis-orders,better knowledge of those brainlesions that may be associated with apathy,and finding effective treatment modalitiesAcknowledgementsThis study was partially supported withoundation,and the National Health andReferencesAalten P,de Vugt ME,Lousberg R,Korten E,Jaspers N,Senden B,et al. Behavioral problems in dementia:a factoranalysis of the neuropsychiatric inventory. Cogn Disord 2003; 15(2):99-105.Arciniegas D,Adler L,Topkoff J,Cawthra E,FilleyCM,Reite M. Attention and memory dysfunction aftertraumatic brain injury:cholinergic mechanisms,sensorygating,and a hypothesis for further investigation. Brain Inj1999 Jan; 13(1):1-13. THE PREVALENCE, CLINICAL CORRELATES AND TREATMENT OF APATHY...105Arciniegas DB. 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Effects of methylphenidate on attentiondeficits after traumatic brain injury:a multidimensional,randomized,controlled trial. Jun; 83(6):401-420.Whyte J,Vaccaro M,Grieb-Neff P,Hart T. Psychostim-ulant use in the rehabilitation of individuals with traumaticbrain injury. J Head Trauma Rehabil2002 Aug; 17(4):Zafonte RD,Lexell J,Cullen N. Possible applicationsfor dopaminergic agents following traumatic brain injury:J Head Trauma Rehabil2001 Feb; 16(1):112-116.Prof Sergio E. StarksteinEducation Building T-7,Fremantle HospitalFremantle,6959 WA,AustraliaE-mail:ses@cyllene.uwa.edu.auPhone:(61-8)-9431-2013