Is Apathy a Valid and Meaningful Symptom or Syndrome in Parkinsons Disease A Critical Review Kathleen Rives Bogart Tufts University Objective To review the nearly  papers suggesting that apathy may o

Is Apathy a Valid and Meaningful Symptom or Syndrome in Parkinsons Disease A Critical Review Kathleen Rives Bogart Tufts University Objective To review the nearly papers suggesting that apathy may o - Description

Method Literature review Results The review revealed three possible explanations for the high rates of apathy found in PD First there is much interest in an endogenous explanation of apathy because the basal ganglia and dopamine are implicated in bo ID: 36013 Download Pdf

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Is Apathy a Valid and Meaningful Symptom or Syndrome in Parkinsons Disease A Critical Review Kathleen Rives Bogart Tufts University Objective To review the nearly papers suggesting that apathy may o

Method Literature review Results The review revealed three possible explanations for the high rates of apathy found in PD First there is much interest in an endogenous explanation of apathy because the basal ganglia and dopamine are implicated in bo

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Is Apathy a Valid and Meaningful Symptom or Syndrome in Parkinsons Disease A Critical Review Kathleen Rives Bogart Tufts University Objective To review the nearly papers suggesting that apathy may o

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Presentation on theme: "Is Apathy a Valid and Meaningful Symptom or Syndrome in Parkinsons Disease A Critical Review Kathleen Rives Bogart Tufts University Objective To review the nearly papers suggesting that apathy may o"— Presentation transcript:

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Is Apathy a Valid and Meaningful Symptom or Syndrome in Parkinson†s Disease? A Critical Review Kathleen Rives Bogart Tufts University Objective: To review the nearly 30 papers suggesting that apathy may occur frequently in Parkinson†s disease (PD) and that it may be a symptom or syndrome that is separate from depression. Method: Literature review. Results: The review revealed three possible explanations for the high rates of apathy found in PD. First, there is much interest in an endogenous explanation of apathy because the basal ganglia and dopamine are implicated in both PD

and apathy. Researchers have suggested links between apathy, dopamine depletion, and basal ganglia dysfunction in PD. Second, apathy in PD may be exogenous, resulting from disability and activity restriction. Third, apathy findings are inflated due to conceptual problems and methodological confounds. Indeed, apathy may be consistently confounded with symptoms of PD, including expressive masking, depression, disability, and cognitive decline. Conclusion: Because apathy has not yet been found to relate to meaningful patient outcomes, and it appears that other factors such as depression and

cognition are more strongly related to quality of life than apathy, there is not enough evidence to conclude that apathy is a clinically meaningful syndrome in PD. The role of PD in motivation is of theoretical and practical interest and deserves further research. Keywords: apathy, motivation, Parkinson†s disease, Parkinsonism Recently, researchers have suggested that apathy may be a symptom or syndrome separate from depression that occurs in neurological disorders such as Alzheimer†s disease (AD), Fronto- temporal Dementia, and Parkinson†s disease (PD; Levy et al., 1998; Marin, 1990;

Starkstein et al., 1992). In particular, many studies have reported high rates of apathy in people with PD (Aarsland et al., 2007; Isella et al., 2002; Kirsch-Darrow, Fernan- dez, Marsiske, Okun, & Bowers, 2006; Levin, 2007). However, it is difficult to conceptually define apathy, let alone separate it from other aspects of the disease. PD is a progressive neurological disorder that has widespread implications for a person†s physical and psychological experience. It may be particularly difficult to measure apathy in PD because PD is physically disabling and it reduces expressive behaviors such

as facial expression. This paper will review the conceptual definition of apathy and how it relates to PD, the research methodology used to examine apathy in PD, principal findings of studies of apathy in PD, and possible treat- ments and etiologic mechanisms for apathy in people with PD. I will explore whether the high reported rates of apathy in PD are due to endogenous or exogenous factors, or are confounded with depression, cognitive decline, and PD motor symptoms. Impor- tantly, I will explore whether apathy is valid and clinically mean- ingful for people with PD. Introduction to

Parkinson’s Disease PD is characterized by a gradual, progressive depletion of do- paminergic neurons in the substantia nigra (Birkmayer & Horny- kiewicz, 1961). The four cardinal signs for diagnosis of PD include (a) tremor at rest, (b) muscle rigidity, (c) bradykinesia or akinesia (slowness or complete lack of movement), and (d) postural insta- bility (Jankovic, 2008). The Hoehn and Yahr (1967) scale is commonly used to classify the disease progression into stages ranging from Stage I (symptoms are mild and on one side of the body only) to Stage 5 (wheelchair-bound or bedridden unless

assisted). PD becomes significantly disabling, particularly at Stage III and beyond, when it is difficult to perform daily living tasks independently (Jankovic, 2008). By the end of Stage 5, most people with PD need total assistance with activities of daily living and develop cognitive decline or dementia. Many people with PD experience a cluster of symptoms known as the expressive mask , which is characterized by reduced spon- taneity, fluidity, and intensity of facial, bodily, and vocal expres- sion (Tickle-Degnen & Lyons, 2004). With the expressive mask, the face is fixed in a rigid,

expressionless mask or freezes into fractured expressions. Speech is slow, soft, inarticulate, and mo- notonous. Limb, head, and trunk movements lose the spontaneous, fluid movement necessary for natural-appearing gestures and body language. The expressive mask is associated with poor social functioning and is a barrier to maintaining close relationships in PD (Brod, Mendelsohn, & Roberts, 1998; Ellgring et al., 1993; Karlsen, Tandberg, Arsland, & Larsen, 2000). Decades of research have shown that rehabilitation and health care practitioners unin- tentionally form inaccurate and negatively

biased impressions of the emotions and personality traits of people with PD and expres- sive masking, even though these practitioners should be aware of the physical limitations of expressive masking (Borod et al., 1990; This article was published Online First April 11, 2011. Kathleen Rives Bogart, Department of Psychology, Tufts University. I thank Linda Tickle-Degnen and Lisa Shin for their comments on earlier drafts of this paper. Correspondence concerning this article should be addressed to Kathleen Rives Bogart, Department of Psychology, Tufts University, 490 Boston Avenue, Medford, MA

02155. E-mail: Health Psychology  2011 American Psychological Association 2011, Vol. 30, No. 4, 386–400 0278-6133/11/$12.00 DOI: 10.1037/a0022851 386
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Brozgold et al., 1998; Pentland, Pitcairn, Gray, & Riddle, 1987; Pentland, Gray, Riddle, & Pitcairn, 1988; Pitcairn, Clemie, Gray, & Pentland, 1990; Tickle-Degnen & Lyons, 2004). Conceptualizing Apathy Since Marin†s (1990) assertion that apathy occurs frequently in neurological conditions such as AD, Frontotemporal Dementia, and PD, there has been interest in defining and measuring apathy. Marin

defined apathy as a lack of motivation, and he suggested that apathy could occur as a symptom secondary to a condition (e.g., a mood disorder) or as a syndrome. Marin (1991) stated that, for apathy to be considered a syndrome, it must be the primary condition, that is, the lack of motivation ‡is not attributable to intellectual impairment, emotional distress, or diminished level of consciousness” (Marin, Biedrzycki, & Firinciogullari, 1991, p. 243). Marin proposed criteria for the diagnosis of an apathy syndrome, which include reduced goal-directed behavior, reduced goal-directed cognition,

and reduced emotional engagement. See Table 1 for the proposed criteria and subsequent adaptations. Although Marin†s conception of apathy is common in the litera- ture, other definitions exist. Citing difficulties in the assessment of an internal characteristic like motivation, Stuss, Van Reekum, and Murphy (2000, p. 342) defined apathy as ‡an absence of respon- siveness to stimuli as demonstrated by a lack of self-initiated action,” which they felt allowed for more objective behavioral measurement. Marin†s (1991) diagnostic criteria were stringent in that an apathy syndrome could only be

diagnosed if it was a primary condition and the symptoms were not attributable to comorbid conditions like depression or dementia. However, Starkstein and Leentjens (2008) broadened the proposed criteria to allow apathy to be diagnosed in people with comorbid conditions such as depression or dementia. This modification also added more con- crete symptoms. Table 1 shows Starkstein and Leentjen†s (2008) modifications to Marin†s (1991) diagnostic criteria in bold. Al- though not formalized by any diagnostic or classification body, the criteria developed by Marin (1991) and Starkstein and

Leentjens (2008) are the most commonly endorsed in the literature. Based on a review of extant research, I present three possible explanations for the high rates of apathy found in PD. The first is that apathy in PD is endogenous, meaning apathy results from neurological changes resulting from disease pathology. Most re- searchers seem to be interested in finding evidence for an endog- enous etiology of PD (Aarsland, Litvan, & Larsen, 2001; Kirsch- Darrow et al., 2006; Levy et al., 1998; Starkstein et al., 1992). One reason behind studying PD, in particular, is that researchers have implicated

the basal ganglia and dopamine in apathy (Czernecki et al., 2002; Kirsch-Darrow et al., 2006; Schmidt et al., 2008). The second explanation is that apathy in PD is exogenous, meaning apathy is a reaction to being diagnosed with a progressive disease and the resulting disability. The third explanation is that apathy does not truly occur in high rates in PD and findings are due to conceptual and methodological problems. These problems may include confounding apathy with depression, disability, expressive masking, and cognitive impairment. These three explanations for apathy in PD will be

revisited throughout this paper. The Relationship Between Depression and Apathy in Parkinson’s Disease A large body of research has found increased incidence of depression in PD, ranging widely from 7–76% (Veazey, Ozlem Erden Aki, Cook, Lai, & Kunik, 2005). There are competing theories as to whether depression is exogenous or endogenous in PD. The findings that depression tends to be more prevalent shortly after diagnosis and at the end of disease progression suggests that depression is due to a combination of the subjective reaction to a receiving a diagnosis of a progressive, disabling

disease and the underlying brain dysfunctions caused by the dis- ease when it progresses to later stages (Veazey et al., 2005). Both Marin†s (1991) and Starkstein†s (2000) proposed criteria for an apathy syndrome have substantial overlap with established diagnostic criteria for depression, including the following DSM IV–TR criteria (American Psychiatric Association, 2000, p. 356): Criteria A.2, ‡markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day”; Criteria A.5, ‡psychomotor agitation or retardation nearly every day”; Table 1 Proposed

Diagnostic Criteria for the Apathy Syndrome (Starkstein et al., 2000; adapted from Marin, 1991) Criteria for the Apathy Syndrome (A) Lack of motivation relative to the patient†s previous level of functioning or the standards of his or her age and culture as indicated either by subjective account or observation by others. (B) Presence for at least 4 weeks during most of the day, of at least 1 symptom belonging to each of the following three domains: 1. Diminished goal-directed behavior 1.1 Lack of effort or energy to perform everyday activities 1.2 Dependency on prompts from others to structure

everyday activities 2. Diminished goal-directed cognition 2.1 Lack of interest in learning new things, or in new experiences 2.2 Lack of concern about one’s personal problems 3. Diminished concomitants of goal directed behavior 3.1 Unchanging or flat affect 3.2 Lack of emotional responsivity to positive or negative events (C) The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. (D) The symptoms are not due to diminished level of consciousness or the direct physiological effects of a substance. Note . Adaptations

proposed by Starkstein et al. (2000) are in bold. Reprinted with permission from the Journal of Neuropsychiatry and Clinical Neurosciences, (Copyright, 1991). American Psychiatric Association. 387 APATHY AND PARKINSON†S DISEASE
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Criteria A.6, ‡fatigue or loss of energy nearly every day”; and Criteria A.8, ‡diminished ability to think or concentrate, or inde- cisiveness, nearly every day.” In fact, only one more symptom in addition to those listed here is needed for a diagnosis of major depression. Despite the substantial conceptual overlap between depression and apathy,

researchers claim that some patients with PD have apathy in the absence of depression (Aarsland et al., 1999; Isella et al., 2002; Kirsch-Darrow et al., 2006; Levy et al., 1998; Pedersen, Larsen, Alves, & Aarsland, 2009; Sockeel et al., 2006; Starkstein et al., 1992; Zgaljardic et al., 2007). Several researchers have suggested that the high rates of depression in PD may actually be occurrences of an apathy syndrome. In fact, some have proposed removing apathy symptoms from the diagnostic criteria for depres- sion in PD so that people with ‡pure” apathy are not ‡misdiag- nosed” as having

depression (Isella et al., 2002; Kirsch-Darrow et al., 2006). I argue that depression is a valid construct with well- established diagnostic criteria and valid, reliable assessments, and the evidence for the distinctness of apathy in PD is yet unconvinc- ing, so modifying the diagnostic criteria for depression is unad- visable. Several theories predict that the disabling symptoms of PD may cause or contribute to exogenous apathy or depression. The Ac- tivity Restriction Model of Depressed Affect proposes that a major life stressor (i.e., a chronic illness) results in depression to the extent

that it restricts the person†s ability to engage in valued daily activities (Williamson & Shaffer, 2002). Similarly, this model may be a useful framework for understanding how activity restriction may result in exogenous apathy. Although the learned helplessness model is commonly used to understand depression, it is particu- larly relevant to recent conceptions of apathy (Miller & Seligman, 1975). Learned helplessness occurs when a person feels a lack of control over the outcome of a situation, which results in a feeling of helplessness and a lack of motivation. It is easy to predict that the

physical symptoms of PD may leave patients in a situation of reduced control, leading to depression or apathy. Thus, the dis- abling symptoms of PD may result in depression or apathy, and it may be difficult to distinguish them. Assessments Used in Parkinson’s Disease Apathy Research To my knowledge, six assessments have been used to measure apathy in PD. The uncertain nosological status of the definition and diagnostic criteria for apathy are fundamental problems for validating assessments for apathy (Leentjens et al., 2008). Since there is no formal definition or diagnostic criteria for

apathy, different measures tap into different conceptual and operational definitions, and apathy measures vary widely in their purported construct. Thus, study findings may vary greatly according to which measure was used. Cutoff scores on apathy scales, which sometimes vary from study to study, are used to report the prev- alence of apathy (Leentjens et al., 2008). These cutoffs are arbi- trary, since there are no diagnostic criteria to validate the choice of a certain cutoff as clinically meaningful. Apathy measures often rely on caregiver or clinician reports. In both of these cases, the

reports may be highly influenced by a patients† expressive masking. As described earlier, much research demonstrates that health care practitioners and lay people are negatively biased by expressive masking and tend to rate patients with masking as more depressed and less engaged. It is likely that caregivers are also biased by the expressive mask, and their ratings may be influenced by other factors such as caregiver distress or perceived burden and reward. Self-reports may be superior be- cause patients can describe their personal experience of symptoms of which caregivers and clinicians may

not be aware, since care- givers and clinicians must base their ratings on overt behavior. Indeed, in a study of 43 patients with PD, McKinlay et al. (2008a) found the correlation between self-reported apathy and caregivers ratings of apathy to be only .22, ns . Interestingly, patients reported more apathy than caregivers reported, which suggests that patients experience symptoms that are not overtly obvious to observers. Marin et al. (1991) developed the first apathy measure shortly after proposing criteria for an apathy syndrome. The Apathy Eval- uation Scale (AES) is a commonly used 18-item

measure of apathy for patients with many types of neurological disorders (Marin et al., 1991). There are three versions of the AES to collect informa- tion from the following sources: self-report (AES-S), clinician (AES-C), and informant (i.e., a caregiver or family member; AES-I). Each version of the form includes the same core items, but the AES-C includes the additional instructions for clinicians to base ratings on both verbal and nonverbal information, which may confound with expressive masking in PD. Interestingly, these additional instructions were not used in the validation study, so

their validity and reliability have not been established. The vali- dation study did not include people with PD; participants were left-hemisphere stroke patients and healthy elderly controls. Sev- eral questions concern social participation (e.g., ‡he or she has friends”), which may confound with reduced social participation due to expressive masking or disability in PD. Starkstein et al. (1992) published a 14-item abridged version of the AES designed specifically for use in the PD population•the Apathy Scale (AS). The questions are read by an examiner, and the patient self-reports his or her

answers based on four response choices. The fact that items are self-reported by the patient reduces the likelihood that scores will confound with expressive masking. However, some of the items could confound with disability, im- paired cognition, or downstream effects of masking such as re- duced social participation. For example, the following two ques- tions could confound with cognitive impairment or dementia: ‡Does someone have to tell you what to do each day?” and ‡Do you need a push to get started on things?” The following question may be measuring disability rather than apathy: ‡Do you

have the energy for daily activities?” The item ‡Do you have plans and goals for the future?” may be affected by the knowledge of having a terminal disease. In the validation study for this measure, 50 patients with PD completed the AS. The scores formed a bimodal distribution of apathy scores, and a cutoff score of 14 or greater was created to determine apathy because it separated the two modes. However, a subsequent study did not find a bimodal distribution in a different PD sample (Isella et al., 2002). Starkstein et al. (1992) attempted to validate the scale by having a neurologist rate 12

of the participants as apathetic or not. The method used by the neurologist to determine apathy was not described. Although the validity of using a clinician†s dichotomous ratings is question- able, the authors found a significant difference between the AS 388 BOGART
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scores of the participants rated as apathetic or not, and the scores were consistent with the recommended cutoffs. The Neuropsychiatric Inventory (NPI) is a 10-item measure that assesses the following 10 behaviors in neurological patients with dementia: delusions, hallucinations, depression, apathy, anxiety,

agitation, euphoria, disinhibition, irritability, and ab- errant motor behavior (Cummings et al., 1994). The NPI relies exclusively on caregiver reports. The interviewer asks the care- giver if there have been changes in these behaviors in the patient, to which the caregiver responds yes or no. If the caregiver reports a change in the patient†s behavior, follow-up questions about the frequency and severity of the behavior are asked. When reporting apathy rates, most researchers have used the dichotomous yes or no responses (Aarsland et al., 2007, 1999; Aarsland, Litvan, & Larsen, 2001; Levy et

al., 1998). For a poorly defined symptom such as apathy, single item measures of constructs and dichotomous response choices are ill advised because they are unlikely to capture all of the dimensions of the construct (however it is defined) or the variability between participants. The Lille Apathy Rating Scale (LARS) is a structured interview and rating scale to measure apathy specifically in PD (Sockeel et al., 2006). The clinician is instructed to rate both the speech content and the speed of the patient†s response, which creates a confound with PD symptoms such as bradykinesia and slowed

speech. Several questions concern activities of daily living and social participation that may confound with disability and expres- sive masking. Like the AS, the external criterion to judge validity was a clinician†s dichotomous rating of whether the patient was apathetic or not (Sockeel et al., 2006). The Unified Parkinson†s Disease Rating Scale (UPDRS) is commonly used to evaluate PD symptoms (Fahn, Marsden, Calne, & Goldstein, 1987), and Pedersen, Larsen, and Aarsland (2008) recently suggested the use of a single item from the UPDRS to measure apathy. For this item, a clinician rates the

patients† mo- tivation or initiative based on an interview and clinical observa- tion. In addition to the problems associated with single item measures of apathy, the item is focused on activity participation and may not capture the emotional component of apathy. Thus, it may be highly influenced by level of disability. The Frontal Systems Behavioral Scale (FSBS) is a 46-item rating scale that assesses three areas of behavioral functioning that may be linked to frontal lobe dysfunction: apathy, disinhibition, and executive functioning (Grace & Malloy, 2001). The scale is caregiver-rated and

thus may be influenced by factors such as caregiver distress or perceived burden. Several of the items pur- ported to measure apathy could confound with disability, including ‡does not finish things,” ‡neglects personal hygiene,” ‡lacks en- ergy,” and ‡is incontinent. The Movement Disorder Society organized a task force to assess the psychometric properties of the apathy measures that have been used in research on apathy in PD (Leentjens et al., 2008). They concluded that, although the reliability of most of the scales is acceptable, all are limited by the inability to test construct validity.

They recommended against the use of single-item measures of apathy like the UPDRS and NPI. The only scale that was recom- mended was the AS because it had been validated in a PD popu- lation and displayed good psychometric properties. However, this scale is still limited by a lack of construct validity, arbitrary cutoffs, and possible confounds with cognitive deficits, depression, and disability. Principal Findings of Studies of Apathy in Parkinson’s Disease A literature search revealed 27 studies that examined apathy in people with PD. Searches were conducted on Pubmed, PsycINFO, and Google

Scholar between October 2009 and August 2010, and included the keywords ‡apathy” and ‡Parkinson†s,” ‡Parkinson- ism,” or ‡Parkinsonianism.” Reference sections of relevant papers were also searched manually. Table 2 summarizes these studies. The reported rates of apathy in PD vary widely from 17% to 60% (Aarsland et al., 1999; Oguru, Tachibana, Toda, Okuda, & Oka, 2010). Several studies have compared apathy in patients with PD to healthy controls (Isella et al., 2002; Sockeel et al., 2006; Zgaljardic et al., 2007). All have found that patients with PD had significantly higher apathy than

controls. In each sample, approximately 44% of PD patients had apathy, and none of the control participants met the cutoff. The patients with PD performed significantly more poorly than controls on cognitive tasks, which has consistently been associated with apathy, and may account for the differences between the groups. It is possible that apathy is a response to chronic disability or aging, so a group of elderly people with chronic disease are a more appropriate comparison group than healthy controls. In the only study, to my knowledge, to make this comparison, Pluck and Brown (2002)

examined 45 patients with PD and 17 patients with disabling osteoarthritis. However, according to their measure of disability, ability to perform activities of daily living (ADL), the PD group was significantly more disabled than the comparison group. Statistically controlling for ADL, patients with PD were significantly more apathetic than the comparison group, and none of the participants in the comparison group met the cutoff for apathy. Since apathy has been reported to occur in many neurological conditions, it is useful to compare patients with PD to patients with these conditions. Levy

et al. (1998) compared patients with PD, AD, Frontotemporal Dementia, Huntington†s disease, and progres- sive supranuclear palsy on apathy and depression using the NPI. Apathy rates were as follows: 32% of patients with PD, 80% of patients with AD, 89% of patients with Frontotemporal Dementia, 59% of patients with Huntington†s disease, and 91% of patients with progressive supranuclear palsy. Of these groups, the PD group had the least severe apathy. Aarsland et al. (2001) compared patients with PD and progressive supranuclear palsy and found that 17% of patients with PD had apathy, and 84% of

patients with progressive supranuclear palsy had apathy. Patients with progres- sive supranuclear palsy had significantly more apathy than patients with PD. Although the authors did not control for severity of disability, they compared PD and progressive supranuclear palsy patients in the same Hoehn and Yahr stages (indicating that they had similar physical symptoms), and found that for each stage, progressive supranuclear palsy patients had higher rates of apathy than PD patients in the same stage. Kirsch-Darrow et al. (2006) examined the neuropsychiatric features of 80 patients with PD and

20 patients with idiopathic adult-onset dystonia. PD patients had significantly more apathy according to the AS compared to pa- 389 APATHY AND PARKINSON†S DISEASE
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Table 2 Summary of Studies of Apathy In PD Citation Participants Apathy measures Depression measures Other relevant measures Results Aarsland et al. (1999) 139 patients with PD from an epidemiological study of PD NPI UPDRS, MMSE, DRS, Stroop Task 16.5% of patients with PD had apathy. 4.3% had apathy without depression. 12.2% had both apathy and depression. Depression occurred in 38%. Apathy was correlated with

dementia. Two factors obtained from factor analysis: 1st was apathy and anxiety; 2nd was hallucinations, delusions, and irritability. All symptoms were more likely to occur in people living in nursing homes. Apathy was related to depression, dementia, and executive function but not age, L-Dopa dose, or disease duration. Aarsland et al. (2001) 103 patients with PD and 61 patients with PSP. All PD and 27 PSP patients were taking dopaminergic drugs NPI MMSE and Hoehn and Yahr scale 17% of patients with PD had apathy and 84% of patients with PSP had apathy. PSP patients showed significantly more

apathy and disinhibition, while PD patients had more hallucinations, dementia, and depression. Aarsland et al. (2007) 537 patients with PD and mild to moderately severe dementia NPI MMSE, UPDRS 58% had depression and 54% had apathy. Cluster analysis revealed 5 NPI clusters: a cluster with few symptoms, a mood cluster (depression, anxiety, and apathy), an apathy cluster, an agitation cluster, and a psychosis cluster. Overall NPI scores of neuropsychiatric symptoms in PD were associated with more advanced PD Hoehn and Yahr disease stages and cognitive impairment (as measured by MMSE). The

highest caregiver distress was found for patients who had symptoms of apathy, agitation, delusions, depression, and irritability. Aarsland et al. (2009) 175 patients with untreated PD and 166 controls NPI 27% of patients with PD, and 1% of controls had apathy. Chatterjee & Fahn (2002) Single-case study of patient with PD UPDRS Methylphenidate reduced apathy. Cramer et al. (2009) 70 patients with PD AES Brief Smell Identification Test and MMSE Apathetic patients with PD performed more poorly on the olfactory task than nonapathetic patients. Olfactory impairment correlated with apathy. Patients

categorized as apathetic had poorer cognition and greater disease severity. 390 BOGART
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Table 2 ( continued Citation Participants Apathy measures Depression measures Other relevant measures Results Czernecki et al. (2002) 23 nondemented, nondepressed DBS candidates with PD and 28 healthy controls AS UPDRS, Gambling Task, Stimulus- Reward Learning Task Examined PD patients on and off L-Dopa. PD patients were more apathetic than controls, and they were impaired on the Stimulus- Reward Task and the Gambling Task. AS scores were less severe during L-Dopa treatment. However, AS

scores did not correlate with performance on any of the behavioral tasks. L-Dopa did not show clear improvement effects on the behavioral tasks. Denheyer, Kiss, & Haffenden (2009) 16 male PD DBS patients FrSBe UPDRS All FrSBe scores after DBS increased relative to retrospective before DBS ratings. Drapier et al. (2006) 15 patients with PD assessed 3 and 6 months before and 3 months after subthalamic nucleus DBS AES-C and AS MADRS Apathy significantly worsened after DBS, but there were no changes in depression. Drapier et al. (2008) 17 patients with PD assessed 3 months before and 3 months

after subthalamic nucleus DBS AES-C Pictures of Facial Affect Apathy and emotion recognition ability significantly worsened after DBS, but these were not correlated with each other. Isella et al. (2002) 30 patients with PD and 25 normal controls AS GDS MRI, IADL, DRS, Executive Interview, cognitive and letter fluency tests 44% of PD sample showed apathy. No one in the control group showed apathy. 23% of patients with PD showed apathy without depression, and 13.3% showed depression without apathy. MRI showed association between apathy and temporal atrophy in PD. Apathy correlated with

impairments in executive functioning, category fluency, letter fluency, and poor IADL functioning, but not depression. Kirsch-Darrow et al. (2006) 80 patients with PD and 20 patients with idiopathic adult-onset dystonia AS BDI 51% of PD patients had apathy, compared to 20% of dystonia patients. Apathy in absence of depression was common in PD (28%) but did not occur in dystonia. Apathy scores were also significantly greater in PD than in dystonia. Levels of depression and depression combined with apathy were similar across groups. Older age in both groups was associated with more apathy. Levin

(2007) 18 patients with PD BDI apathy subscale BDI and HRSD The antidepressant Tianeptine was effective in reducing depression in patients with PD, but there was no significant change in apathy. Levy et al. (1998) 40 patients with PD who were pallidectomy candidates, 30 with AD, 28 with FTD, 22 PSP NPI MMSE Apathy rates were as follows: 32% of patients with PD, 80% of patients with AD, 89% of patients with FTD, 59% of patients with HD, and 91% of patients with PSP. Patients with PD had significantly lower apathy than the other groups. Apathy did not correlate with depression in combined

sample, but they did correlate in the PD sample. Apathy correlated with cognitive functioning in the entire sample. table continues 391 APATHY AND PARKINSON†S DISEASE
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Table 2 ( continued Citation Participants Apathy measures Depression measures Other relevant measures Results McKinlay et al. (2008a) 43 patients with PD and 43 caregivers AS, NPI, and FRSBE BDI UPDRS and FSBS This study compared reports of neuropsychiatric symptoms with self-reports of people with PD. Caregivers reported apathy in 28% of patients, while 40% of patients reported being apathetic. The level of

agreement between patient and caregiver reports was low, with 45.8% agreement on depression and 45% agreement on apathy. McKinlay et al. (2008b) 49 PD patients without dementia AS BDI MMSE, UPDRS, PDQ-39, S&E 38.8% of patients with PD had apathy. Apathy was correlated with depression, nontremor motor symptoms, and activities of daily living. Depression, but not apathy, explained a significant amount of the variance in quality of life. Mikos et al. (2009) 37 patients with PD and 21 healthy controls AES BDI BEQ-16 Participants with PD had significantly lower expressivity than controls but did

not differ in emotional intensity. No differences between informant and self-ratings of emotional expressivity. Errors of both under- and overreporting expressivity were both correlated with apathy. Oguru et al. (2010) 150 patients with PD AS BDI MMSE, UPDRS, PDQ-39 60% of patients have apathy, 17% had apathy and no depression, 43% had apathy and depression, 13% had depression with no apathy. Apathy was correlated with UPDRS scores, HY stage, and age. Both apathy and depression were negatively correlated with quality of life. Pedersen et al. (2008) 58 people with PD AS and UPDRS MADRS 17% of

patients had apathy according to AS criteria. UPDRS apathy item only moderately correlated with AS; also highly correlated with depression. Pedersen, Alves, Aarsland, & Larsen (2009) 139 patients with PD from an epidemiological study of PD. A follow-up was conducted 4 years later on 79 of these NPI At baseline, 13.9% were apathetic. After 4 years, all patients with apathy remained apathetic, and a further 39 subjects (49.4%) had apathy. (Thus, 36.7% never had apathy, 13.9% had persistent apathy, 49.9% developed apathy at follow-up.) Dementia at baseline and a more rapid decline in speech were

predictors of apathy. 392 BOGART
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Table 2 ( continued Citation Participants Apathy measures Depression measures Other relevant measures Results Pedersen, Larsen, Alves, & Aarsland (2009) 232 patients with PD UPDRS Semistructured DSM III-R interview UPDRS, MMSE 38% of patients with PD had apathy: 11% had apathy, depression, and dementia, 10% had apathy and depression but no dementia, and 9% were apathetic without depression or dementia. Apathy was significantly associated with higher depression, cognitive impairment, and motor symptoms. After excluding patients with depression,

cognitive impairment, dementia, and those using antidepressants and antipsychotics, 5% had apathy. Pluck & Brown (2002) 45 patients with PD and 17 similarly disabled patients with osteoarthritis AES-C and AES-S, but only AES-C was used in analyses HADS and BDI MMSE, CAMCOG, and several executive functioning tasks 37.8% of patients with PD had apathy, and none of the controls had apathy. Patients with PD had significantly higher apathy than the comparison group. Apathy was unrelated to disease progression. No differences in personality traits between groups were detected. The high apathy PD

group was significantly more cognitively impaired than the low apathy PD group. The high apathy group did not differ from the low apathy group in IADL functioning. Reijnders et al. (2009) 350 patients with PD UPDRS MADRS UPDRS, MMSE Cluster analysis revealed 4 subtypes of PD: rapid disease progression, young-onset, nontremor dominant, and tremor dominant. Apathy, depression, cognitive deterioration, and hallucinations clustered in the nontremor dominant subtype that is characterized by hypokinesia, rigidity, postural instability, and gait disorder. This cluster has more disability and disease

severity. Schmidt et al. (2008) 13 patients with PD who were nondemented DBS candidates, 13 patients with bilateral basal ganglia lesions and Auto Activation Deficit, and 26 matched controls AS UPDRS, MMSE, and handgrip task Patients with PD were examined both on and off their L-Dopa medicine. Both healthy controls and PD patients modulated their grip according to the magnitude of a monetary incentive offered, but there was no difference in the grip force of the AAD patients for different monetary incentives. Affective response as measured by skin conductance in patients with PD and AAD was

less strong than controls but still modulated in proportion to monetary incentives. AS scores were significantly correlated with force modulation in the incentive manipulation for all groups. Sockeel et al. (2006) 159 patients with probable PD and 58 healthy controls Lille Apathy Rating Scale, AES MADRS DRS 42.8% of PD patients had apathy: 23.3% of PD patients had apathy only, 5.6% had depression only, and 19.5% had apathy and depression. The authors did not indicate rates for the control group. Factor analysis revealed 4 factors: intellectual curiosity, self-awareness, emotion, and action

initiation. High concurrent validity with AS. table continues 393 APATHY AND PARKINSON†S DISEASE
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tients with dystonia. Apathy rates were 51% for patients with PD and 20% for patients with dystonia. Apathy without depression was common in PD (28%) but did not occur in dystonia. Levels of depression and depression combined with apathy were similar across groups. However, extent of disability was not measured, so it is difficult to conclude that the differences in apathy and depres- sion are due to difference in disease etiology and not influenced by disability. Thus, studies

have consistently reported high rates of apathy symptoms in people with PD compared to healthy controls, dis- abled comparison groups, and patients with dystonia. On the other hand, patients with PD appear to have less apathy than patients with other types of neurological conditions, including AD, Fron- totemporal Dementia, Huntington†s disease, and progressive su- pranuclear palsy. Unfortunately, none of these studies controlled for patients† degree of cognitive impairment, and only one exam- ined the role of physical symptoms (Aarsland et al., 2001), and it is likely that these play a large

role in apathy findings. Nine studies reported finding patients who had apathy in the absence of depression, meaning they met a cutoff score for apathy but did not meet diagnostic criteria or cutoff scores for depression (Aarsland et al., 1999; Isella et al., 2002; Kirsch-Darrow et al., 2006; Levy et al., 1998; Oguru et al., 2010; Pedersen et al., 2009; Sockeel et al., 2006; Starkstein et al., 1992). Caution must be used when considering these findings because they rely on arbitrary cutoffs for apathy and, sometimes, for depression. By dichotomiz- ing patients as apathetic or not at an

arbitrary cutoff point, re- searchers are missing variation in symptoms. For example, there may be patients who meet the cutoff for apathy but have moder- ately depressive symptoms that do not meet the cutoff for clini- cally significant depression. These patients would be categorized as having apathy in the absence of depression even though they also experience moderate depressive symptoms. Since dichotomizing patients on apathy and depression may reduce power and disregard information, a more sensitive way to examine whether depression and apathy are related is to examine their correlations.

Of the eight studies that reported analyzing correlations between apathy and depression in PD, seven studies have reported significant correlations, even while reporting that some patients had apathy in the absence of depression (Aarsland et al., 1999; Denheyer, Kiss, & Haffenden, 2009; Levy et al., 1998; McKinlay et al., 2008b; Oguru et al., 2010; Pedersen et al., 2009; Zgaljardic et al., 2007). Only one study reported that apathy was not correlated with depression in PD (Isella et al., 2002). Interest- ingly, in their combined sample of patients with PD, AD, Fronto- temporal Dementia, and

progressive supranuclear palsy, Levy et al. (1998) found that apathy and depression did not correlate, but when they examined the PD sample separately, there was a cor- relation. This suggests that depression and apathy may be more distinct in other neurological diseases than they are in PD. Addi- tionally, the two studies that performed cluster analyses of neuro- psychiatric symptoms in PD found that depression and apathy clustered together (Aarsland et al., 2007; Reijnders, Ehrt, Lous- berg, Aarsland, & Leentjens, 2009). Thus, it appears that there is a relatively consistent relationship

between apathy and depression in PD. Disease progression and resulting disability are all factors that could contribute to exogenous apathy or confound measurement. Six studies found that disease severity was related to apathy Table 2 ( continued Citation Participants Apathy measures Depression measures Other relevant measures Results Starkstein et al. (1992) 50 patients with mild to moderate severity PD AS PSE, HRSD, HRSA MMSE, WCST, Controlled Word Association Task, Trail Making Test 42% of patients with PD showed apathy. 12% showed apathy without depression, 30% had both apathy and

depression, and 26% had depression but no apathy. Patients with apathy showed deficits in verbal memory and timed cognitive tasks. Zgaljardic et al. (2007) 32 nondemented patients with PD and 29 matched controls FSBS BDI MMSE, MDRS, and numerous cognitive tests 43.8% of PD sample showed apathy: 15.6% had apathy without depression. 15.6 had depression and apathy. None of the control participants met the cutoff for apathy or depression. Patients with high apathy had higher depression and poorer performance on cognitive tasks. Apathy was significantly correlated with depression and executive

dysfunction. Note . LAD Alzheimer†s disease; AES Apathy Evaluation Scale; AS Apathy Scale; BDI Beck Depression Inventory; CAMCOG Cambridge Examination of Cognition in the Elderly; DBS Deep Brain Stimulation; DRS Dementia Rating Scale; FSBS Frontal Systems Behavioral Scale; FTD Frontotemporal dementia; HADS Hospital Anxiety and Depression Scale; IADL Instrumental Activities of Daily Living; GDS Geriatric Depression Scale; HRSA Hamilton Rating Scale for Anxiety; HRSD Hamilton Rating Scale for Depression; MADRS Montgomery-Asberg Depression Rating Scale; MMSE Mini Mental State Exam; NPI

Neuropsychiatric Inventory; PDQ-39 Parkinson†s Disease Questionnaire; PSE Present State Examination; PSP Progressive Supranuclear Palsy; S&E Schwab and England Activities of Daily Living; UPDRS Unified Parkinson†s Disease Rating Scale; WCST Wisconsin Card Sort Test. 394 BOGART
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(Aarsland et al., 2007; Cramer, Friedman, & Amick, 2009; McKinlay et al., 2008b; Oguru et al., 2010; Pedersen et al., 2009; Reijnders et al., 2009). Indeed, in their cluster analysis, Reijnders et al. (2009) found that the cluster that contained apathy had greater disease severity and disability.

Similarly, two studies found that the more the disease restricts the ability to perform activities of daily living (ADL), the higher the levels of apathy (Isella et al., 2002; McKinlay et al., 2008a). However, Pluck and Brown (2002) reported no difference in disability between low apathy and high apathy patient groups. The most consistent finding across apathy studies in PD is that apathy is associated with cognitive decline. All 12 studies that examined cognitive functioning found an association between poorer cognitive functioning and apathy (Aarsland et al., 2007, 1999; Cramer et al., 2009;

Denheyer et al., 2009; Isella et al., 2002; Levy et al., 1998; Oguru et al., 2010; Pedersen et al., 2009; Pluck & Brown, 2002; Reijnders et al., 2009; Starkstein et al., 1992; Zgaljardic et al., 2007). Specifically, apathy has been associated with deficits in verbal memory and timed tasks (Starkstein et al., 1992), executive function (Aarsland et al., 1999; Isella et al., 2002; Pluck & Brown, 2002; Zgaljardic et al., 2007), category fluency (Isella et al., 2002), and dementia (Aarsland et al., 1999). Indeed, Pluck and Brown (2002) reported that all of the patients that had possible dementia

were categorized as apathetic. This association may not be specific to PD because apathy correlated with cognitive decline in all four of the neurological patient populations examined by Levy et al. (1998), and was more profound in conditions that are characterized by dementia. Reijnders et al. (2009) conducted a cluster analysis of physical and neurological symptoms of 300 patients with PD and found the following four subtypes: rapid disease progression, young-onset, nontremor motor symptoms, and tremor-dominant motor symptoms. Supporting the relation- ship between apathy and cognitive

decline, they found that apathy, depression, cognitive deterioration, and hallucinations clustered together in the nontremor dominant subtype. This cluster com- prised older patients with longer disease duration, the most severe Hoehn and Yahr disease stage, and the most cognitive impairment. Thus, this study replicates the findings that apathy is associated with impaired cognition, depression, and disease severity, and adds that specific motor symptoms like hypokinesia (slowness and paucity of movement) may be related to mental slowness and paucity of motivation. In further support for the

overlap between apathy and cognitive decline, when Pedersen et al. (2009) excluded patients with cog- nitive impairment, depression, and those using antidepressants and antipsychotics, the apathy rates in their sample were reduced from 38% to 5%. These findings suggest that most apathy cases can be accounted for by cognitive decline and other factors. Even when all those patients were excluded, possible confounds such as ex- pressive masking and disability remained, and, if these were con- trolled, the apathy rates may have been reduced further. In a 4-year longitudinal study of PD, Pedersen

et al. (2009) found that 14% of patients had persistent apathy and 49% developed apathy over the course of the study. Dementia at baseline and a rapid decline in speech were the strongest predictors that a patient would later develop apathy. This consistent association raises the possibility that cognitive decline in neurological conditions, not endogenous mechanisms specific to PD, drives apathy, and that apathy may in fact be an indistinguishable aspect of cognitive decline. Interestingly, in his original proposition of the apathy syndrome, Marin (1990) stated that apathy should not be

diagnosed in people with cognitive deficits because he felt it may be an intrinsic part of dementia. On the other hand, an alternative explanation is that patients with apathy are unmotivated to perform well on cognitive tasks and thus tend to perform more poorly than nonapathetic patients. Is Apathy Associated With Meaningful Outcomes in Parkinson’s Disease? As described above, there have been nearly 30 studies of apathy in PD, and the results•that patients with PD score high on apathy assessments and that these scores are associated with depression, disease severity, disability, and

cognitive impairment•are rela- tively consistent. Until recently, few studies have attempted to look beyond these correlates of apathy and examine more mean- ingful outcomes or behavior. In a regression model, McKinlay et al. (2008b) found that the significant predictors of quality of life in patients with PD were nontremor motor symptoms, depression, anxiety, and the presence of hallucinations, but not apathy. However, Oguru et al. (2010) did the converse multiple regression, examining whether quality of life (measured by the Parkinson†s Disease Questionnaire, PDQ-39, Jenkinson, Fitzpatrick,

Peto, Greenhall, & Hyman, 1997) predicted apathy. They found that the cognitive quality of life subscale of the PDQ-39 was the strongest predictor of apathy. Oguru et al. (2010) did not include depression and apathy in the same model. When they were included as dependent variables in separate regression analyses, PDQ-39 accounted for twice the amount of variance in depression ( change .558) as in apathy ( change .282). Schmidt et al. (2008) conducted a study of behavioral response to incentives in 13 people with PD who were deep brain stimula- tion candidates, compared to 26 matched healthy

controls, and 13 patients with bilateral basal ganglia lesions who were diagnosed by the researchers as having Auto-Activation Deficit (a lack of self- initiated behavior but preserved cognition and behavior when externally motivated). Participants took part in two handgrip tasks. In the instructive task , they were instructed to modulate their handgrip to various degrees. A computer screen displayed the target force marked with a red line and showed graphical feedback of their movements. In the incentive task , they were told that the harder they squeezed the grip, the larger the percentage

of a monetary incentive they would receive. The computer feedback was similar in this task but did not have a red line marking the target force. There were no differences across groups in baseline grip force (when participants were asked to squeeze as hard as they could) or in grip force in the instructive task, but in the incentive task, PD patients varied their grip force less compared to healthy controls, and AAD patients showed little variation in force at all. Force modulation during the incentive task was significantly cor- related with AS scores when both patient samples were combined.

Thus, the AS seems to be related to self-driven initiative in people with PD and other basal ganglia lesions. Compared to healthy controls, the affective response to the incentive task•as measured by skin conductance•in patients with PD and AAD was weaker but still modulated in proportion to monetary incentives. The authors interpret these findings to suggest that basal ganglia dys- function is associated with deficits in integrating emotions into 395 APATHY AND PARKINSON†S DISEASE
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motor responses during self-motivated, but not externally moti- vated, behavior. However, it is

known that PD motor coordination is strongly facilitated by visual stimulation that guides movement, and, in fact, this phenomenon is used in therapeutic interventions for PD (e.g., Azulay et al., 1999). The instructive task, but not the incentive task, gave computer feedback with a red line denoting the target grip force, which may have served as a visual cue, facilitating movement. Thus, it is possible that the parkinsonian patients† reduced grip modulation in the incentive task was not due to a lack of self-driven motivation, as the authors concluded, but rather was due to motor

coordination problems that were tempo- rarily improved during the instructive task. Deep brain stimulation in the subthalamic nucleus is emerging as a useful treatment for people with drug-resistant PD, but there have been reports of increased apathy and emotional disturbances after DBS (Parsons, Rogers, Braaten, Woods, & Trster, 2006; Temel et al., 2006). Drapier et al. (2008) examined the hypoth- esis that apathy and emotion recognition share a common substrate in the subthalamic nucleus. They assessed 17 patients with PD using the AES-C and emotion recognition tests 3 months before

and 3 months after subthalamic nucleus deep brain stimulation. Apathy and emotion recognition ability significantly worsened after deep brain stimulation, but these were not correlated with each other. This implicates a role for the subthalamic nucleus in both apathy and emotion recognition but suggests that the emo- tional aspects of apathy are not related to emotion recognition. Mikos et al. (2009) examined whether undemented people with PD were aware of their expressive masking symptoms. They found no overall difference between self and informant ratings of the expressivity of people with

PD, suggesting that people with PD were generally aware of their expressive deficits. However, when Mikos and colleagues (2009) examined the pattern of parkinsonian participants† under- and overreporting of their expressivity, they found that both of these errors were correlated with apathy scores, such that greater under- or overreporting was associated with higher levels of apathy. Thus, apathy may be related to diminished awareness of symptoms. Studies of Treatments for Apathy It is important to examine whether apathy symptoms can be improved with treatment. Czernecki et al. (2002) studied

the effect of dopaminergic medication on apathy and behavior in PD by examining patients with PD on their dopaminergic medication -dopa) medication and after withdrawing their medication. Since dopamine function is believed to play a role in motivation and reward circuitry, it was expected that patients off their medication would be more apathetic, impaired in a stimulus-reward learning task, and less motivated to perform well in a gambling task. The stimulus-reward learning task required participants to select an image on a computer screen by touching it, and the gambling task was a

computer-based card game operated by a mouse. Overall, compared to controls, PD patients in their ‡off state” were more apathetic, as measured by the AES, and they were impaired on a stimulus-reward task and in the gambling task. Apathy scores of patients with PD improved with -dopa medication but did not improve performance on the behavioral tasks. Apathy scores were not correlated with performance on the behavioral tasks, implying that AES is not associated with these behaviors. The behavioral tasks required motor coordination to operate the computer; there- fore, the poor performance of the

PD patients could be attributed to PD motor symptoms such as tremor and bradykinesia. Dopa- minergic drugs are the standard drug that almost all patients with PD take for the treatment of the physical symptoms of PD; it could be argued that patients felt more apathetic when off their medica- tion due to the general worsening of their motor symptoms. A few small studies have reported successful treatment of apathy in patients with other neurological conditions, including traumatic brain injury and poststroke patients with the dopaminergic drugs bromocriptine and amantadine (van Reekum, Stuss, &

Ostrander, 2005). Depression and apathy are often correlated, so it is interesting to study whether antidepressants can also improve apathy. One small study examined the efficacy of the antidepressant Tianeptine in patients with PD (Levin, 2007). Tianeptine was effective in reduc- ing depression in patients with PD, but there was no significant change in apathy, as measured by the BDI apathy subscale. How- ever, there appeared to be a nonsignificant trend toward apathy reduction. Patients with various neurological conditions have been treated for apathy with some success with amphetamines,

atypical antipsychotics, and acetylcholinesterase inhibitors (Kirsch-Darrow et al., 2006). One case study reported successful treatment of apathy in a man with PD using Methylphenidate, which is an amphetamine-like drug whose actions include inhibiting dopamine reuptake (Chatterjee & Fahn, 2002). In a review of the evidence for pharmacological treatment of apathy in neurodegenerative dis- eases, Drijgers, Aalten, Winogrodzka, Verhey, and Leentjens (2009) concluded that there is yet insufficient evidence to support that pharmacological treatment improves apathy, and they called for larger

studies and randomized clinical trials. Potential Neurological Pathways for Apathy Researchers have been particularly interested in exploring en- dogenous accounts of apathy in PD because of the hypothesized role of the basal ganglia and dopamine in motivation and reward. Dopamine has an established role in motivation and reward pro- cessing in humans and monkeys (Frank, Seeberger, & O†Reilly, 2004; Pessiglione, Seymour, Flandin, Dolan, & Frith, 2006). In healthy participants, basal forebrain regions surrounding the ven- tral palladium activate bilaterally in proportion to expected re- wards

(Pessiglione et al., 2007). The findings that both apathetic and depressive symptoms appear to be particularly high in patients with PD have led some researchers to suggest that both apathy and depression might derive from a dysfunction of the dopaminergic mesocorticolimbic system, which may play a central role in the control of mood and motivation (Marin, 1991). The negative symptoms of schizophrenia are strikingly similar to the proposed symptoms of apathy in PD, and both of these patient populations share dysfunction of the dopaminergic system (Crow, 1981). In- terestingly, antipsychotics

have been shown to reduce negative symptoms in schizophrenia, and have shown preliminary support for improving apathy in a patient with a left temporal stroke (Raheja, Bharwani, & Penetrante, 1995), but they have not been tested in PD. Olfactory impairment has been reported to occur in 80–90% of patients with PD (Kranick & Duda, 2008). Olfactory impairment and apathy may be associated with overlapping brain regions. 396 BOGART
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Neuroimaging studies have indicated that hypoactivity in the an- terior cingulate gyrus and medial orbitofrontal cortex•areas that have been implicated

in olfactory processing (Doty, 2001)•are correlated with apathy in patients with AD (Marshall et al., 2007). Cramer et al. (2009) examined the relationship between olfactory impairment and apathy and found that apathetic patients with PD performed more poorly on an olfactory task than nonapathetic PD patients. Further, olfactory impairment correlated with apathy. These results may implicate a shared endogenous dysfunction that may result in apathy and olfaction. However, the poor performance of people categorized as apathetic in the olfactory task could be due to impaired cognition in those

participants. Apathy has been suggested to occur in many neurological con- ditions. Apathy has been associated with damage to the medial prefrontal, anterior cingulate, and anterior temporal paralimbic areas such as the amygdala (Starkstein, Fedoroff, Price, Leiguarda, & Robinson, 1993). In patients with AD, apathy has been corre- lated with frontotemporal hypoperfusion (Craig et al., 1996). These findings implicating widespread brain dysfunction in apathy relate to the consistent finding that apathy in PD is associated with cognitive dysfunction, and this returns us to the question, is cog-

nitive impairment distinguishable from apathy? The findings of a consistent relationship between apathy and cognitive dysfunction in PD fit well with the classical description of frontosubcortical dementias that occur in PD, progressive supranuclear palsy, and Huntington†s disease, in which apathy is described as one of the defining features (Cummings & Benson, 1988). The possibility that apathy with frontosubcortical dementia may mark a specific subtype of PD deserves further study (Pluck & Brown, 2002). Validity of Apathy in Parkinson’s Disease Now that the evidence for apathy in PD has been

reviewed, I will return to the question of whether the research supports the validity of apathy as a symptom or syndrome in PD and what further research is needed to evaluate it. I will discuss several types of validity important to diagnosis, including construct validity, external validity, content validity, predictive validity, convergent validity, and discriminant validity (Kendell, 1975). Construct validity is the extent to which the concept of apathy as a symptom or syndrome represents a true disorder that people experience (Kendell, 1975). Construct validity cannot be estab- lished until

a definition of apathy has been agreed upon. One way to evaluate construct validity is to examine possible external validators, such as behavior. There is limited evidence for the role of apathy in behavioral outcomes. As I previously discussed, Schmidt et al. (2008) found that in people with PD, AS scores were associated with less responsiveness to reward during a handgrip task, but this may have been confounded with motor symptoms such as bradykinesia. The results of Czernecki et al. (2002) con- flict with those of Schmidt and colleagues (2008), since they found that apathy was not

correlated with behavioral performance in a gambling task or reinforcement-associated learning. Content va- lidity•the extent to which the underlying characteristics of a construct are captured by the operational diagnostic criteria and assessment measures for that construct•is impossible to establish without construct validity (Kendell, 1975). A diagnosis has predictive validity when it provides useful information about a person†s future (Kendell, 1975). As the current research stands, apathy does not provide much meaningful infor- mation about the person†s prognosis. McKinlay et al. (2008b)

found that apathy was not predictive of patients† quality of life. In a longitudinal study, Pedersen, Alves, Aarsland, & Larsen (2009) found that apathy was associated with more depression at baseline, more dementia that persisted throughout the study, and more rapid disease progression and cognitive decline. Dementia, and speech and axial impairment at baseline, predicted later apathy. Essen- tially, this study demonstrates that the consistent relationship be- tween apathy, disability, and cognition persists across time. Future longitudinal studies should examine how apathy affects important

outcomes such as compliance with treatment and psychological comorbidity in PD. Until the predictive validity is known, it is difficult to know whether diagnosis of, and specific treatment for, apathy is warranted. Convergent validity occurs when different measures of the same construct yield similar results (Kendell, 1975). Several authors have tested the convergent validity of new apathy scales by as- sessing patients with several apathy scales (Sockeel et al., 2006; Starkstein et al., 1992). There has been high convergence between clinician- and caregiver-rated scales (Sockeel et al.) but

low con- vergence between patient-rated scales and other-rated scales (McKinlay et al., 2008a). This suggests that others agree on whether the person appears or seems apathetic, but this does not necessarily reflect the person†s actual experience. This is a striking parallel to findings that health care practitioners have high inter- rater reliability in their ratings of the personalities and activity preferences of people with PD, but these ratings do not correspond to the person†s self-reports; they are instead related to expressive masking (Tickle-Degnen & Lyons, 2004). Discriminant

validity describes whether a diagnosis or a mea- sure is able to distinguish between the disorder of interest and other disorders (Kendell, 1975). It is difficult to determine from extant research whether apathy is separate from depression, cog- nitive decline, and disability, since they are consistently moder- ately to highly correlated (Aarsland et al., 1999; McKinlay et al., 2008b; Pedersen et al., 2009). Cluster analyses of patient symp- toms show that depression and apathy fall in the same cluster and that patients in this cluster tend to be more disabled and cogni- tively impaired

(Aarsland et al., 2007; Reijnders et al., 2009). Striegel-Moore et al. (1998) suggested that two disorders are meaningfully different if there are measurable differences in clin- ical manifestations, natural course, treatment response, or etiology. To examine natural course and treatment response, a longitudinal study such as the one proposed above should follow PD patients with dissociated depression and apathy and examine their symp- toms, disease progression, and treatment response over time. This would be useful for understanding the sequence of the symptoms. For example, it is possible

that apathy is a prodromal phase that comes before depression. Researchers have had little success in establishing the discrim- inant validity of apathy from depression, even though some have proposed altering the diagnostic criteria for depression in PD to separate the constructs (Isella et al., 2002; Kirsch-Darrow et al., 2006). I argue that apathy in PD requires more careful study, particularly to establish the clinical utility of the concept before the well-validated construct of depression is modified. The strength of the construct of depression should be considered a boon to apathy 397

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research, and this should be used to establish discriminant validity, not be changed to suit apathy research. Conclusions Returning to the three explanations of the high reported rates of apathy I described earlier in this paper, there is a small amount of evidence for an endogenous component of apathy in PD, for example, because -dopa may decrease apathy (Czernecki et al., 2002), but it is nearly impossible to separate an endogenous etiology from other potential explanations, such as exogenous factors and confounds with depression, cognitive

dysfunction, and expressive masking. The disability resulting from a degenerative condition could be an exogenous factor contributing to apathy, and several studies found that disability severity was associated with apathy in PD (Aarsland et al., 2007; Cramer et al., 2009; Isella et al., 2002; McKinlay et al., 2008b; Pedersen et al., 2009). It is possible that all of these mechanisms are at work and that the relationship between PD and apathy is quite complex. It is important to consider whether apathy is a clinically mean- ingful concept for patients with PD. The findings are mixed as to

whether apathy is correlated with quality of life in PD, but other factors like depression and cognition are stronger predictors of quality of life (McKinlay et al., 2008b). Some researchers con- clude that behavioral studies suggest that apathy may be associated with less sensitivity to reward during a handgrip task (Schmidt et al., 2008) and that it is associated with impaired olfaction (Cramer et al., 2009). However, it is not known whether these phenomena generalize into problems in patients† daily lives. Since there is currently no substantial evidence for effective treatments for apa-

thy in PD, aside from standard dopaminergic medication that almost all patients receive anyway (Czernecki et al., 2002), diag- nosis with apathy will not change patient outcomes. Researchers have noted that patients with apathy (perhaps by definition) are not distressed or bothered by apathy, but it is significantly distressing to caregivers (McKinlay et al., 2008a). Indeed, coming to terms with a progressive illness and end-of-life is desirable, and it may bring patients a sense of peace, which may be construed by others as apathy. For example, one patient who was described as apa- thetic

described feeling a sense of tranquility (Damasio & Van Hoesen, 1983). The formalization of an apathy syndrome could further pathologize patients with PD. Could apathy serve as a way for doctors to pathologize a noncompliant patient? Given the complexity of the relationship of apathy and PD, and the lack of apparent meaningful patient outcomes associated with apathy, there is not enough evidence to conclude that a distinct apathy syndrome will add meaningful information for treatment or quality of life of patients with PD. The construct of apathy may be more meaningful if unpacked. The

correlates of apathy•cognitive decline, disability, depression, and so forth•may provide more information about the person†s experience and are easier to study and treat. Apathy may be a more meaningful construct in other neurological conditions that seem to have higher rates of apathy (Aarsland et al., 2001; Levy et al., 1998). While apathy remains theoretically interesting, particularly for understanding pathways of motivation and reward, I conclude that, given the state of research at this time, it is not a clinically useful symptom or syndrome for patients with PD. References Aarsland, D.,

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