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Butterfield, London C.
The influence of apathy and depression on cognitive functioning in Parkinson's disease
h [electronic resource] /
by London C. Butterfield.
[Tampa, Fla] :
b University of South Florida,
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Thesis (M.A.)--University of South Florida, 2008.
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ABSTRACT: Depression and apathy are two of the most common psychiatric symptoms in Parkinson's disease (PD) with prevalence estimates at higher rates than in medical populations with similar levels of disability. Several studies have provided evidence to suggest that apathy and depression are independent clinical phenomena that may differentially affect cognition. Recent research suggests that apathy may account for cognitive deficits over and above that of depression, especially in the domain of executive functioning. However, few studies have examined the independent influence of depression and apathy on cognitive abilities in patients diagnosed with PD using sensitive measures of specific cognitive domains. In addition, many have used measures of apathy and/or depression with symptom overlap, which may not adequately measure symptoms unique to the target construct.The purpose of this study was to examine the independent influences of symptoms of depression and apathy on memory and executive functioning in patients diagnosed with PD using severity scales specifically designed to provide greater discrimination between symptoms. Depression severity was assessed using items that do not overlap with apathy symptoms or with somatic symptoms of PD itself. Apathy was measured using a scale previously shown to have little overlap with depressive symptoms. Results revealed that apathy, but not depression, was significantly associated with executive functioning. In contrast, immediate memory was significantly associated with both apathy and depression. However, apathy accounted for added variance in memory scores when controlling for depression with marginal significance. When controlling for age, although less clear, these patterns remained.Differentiation of apathy and depression and understanding their independent effects on cognitive functioning have several implications both for clinical intervention and for scientific investigation. Apathy not only has a negative impact on cognitive functioning, but also on daily functioning and caregiver burden/distress. Secondly, it has been associated with increased mortality as it may interfere with medication compliance. If appropriately identified, preliminary research suggests that symptoms of apathy may be medically treated independently of depressive symptoms. Distinguishing apathy and depression has robust implications for the advancement of psychological science, patient care, and for enhancing quality of life in patients and caregivers.
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Advisor: Cynthia R. Cimino, Ph.D.
t USF Electronic Theses and Dissertations.
The Influence of Apathy and Depression on Cognitive Functioning in Parkinsons Disease by London C. Butterfield A thesis submitted in partial fulfillment of the requirements for the degree of Master of Arts Department of Psychology College of Arts and Sciences University of South Florida Major Professor: Cynthia R. Cimino, Ph.D. Jonathan Rottenberg, Ph.D. Paul Spector, Ph.D. Date of Approval: March 31, 2008 Keywords: Emotion, Mood, Motivation, Memory, Executive Copyright 2008, London C. Butterfield
i Table of Contents List of Tables iv Abstract v 1. Introduction 1 Parkinsons Disease 2 Depression in PD 6 Depression and Cognition in PD 9 Apathy in PD 12 Apathy and Depression: Indepe ndent Clinical Phenomena 15 Apathy, Depression and Cognition 18 Apathy, Depression and Cognition in PD 21 Limitations of Previous Research 23 Purpose of the Proposed Study 25 Hypotheses/Predictions 26 2. Method 28 Participants 28 Measures 28 Procedure 32 Statistical Analyses 32
ii 3. Results 34 Diagnostics 34 Descriptives 35 Frequencies of apathy and depression 37 Findings Related to Hypothesis #1 38 Correlations 39 Regressions 39 Findings Related to Hypothesis #2 40 Correlations 41 Regressions 41 Age effects 42 Ancillary Analyses 43 Exploration of the Influence of Apathy and Depression on Memory 43 Age effects 44 Use of the 21-item versus 13-item Version of the BDI-II 45 Use of Informant Ratings vers us Self-Ratings of Apathy 46 4. Discussion 47 Effects of Apathy and Depression on Memory and Executive Ability 47 Unique Effects of Apathy and Depression on Executive Function 48 Unique Effects of Apathy and Depression on Memory 50 Conclusion 51 Theoretical Implications 52
iii References 56 Appendices 70 Appendix A: Beck Depression Inventory II 71 Appendix B: Apathy Evaluation Scale Self-Rating form 73
iv List of Tables Table 1 Summary of demographic and clinical characteristics 35 Table 2 Summary of mood and cognitive scores including age-adjusted T-scores 36 Table 3 Correlations 37 Table 4 Correlations between mood and cognitive variables 39 Table 5 Simple regression analyses 40 Table 6-A Hierarchical regression analys es related to executive functioning 42 Table 6-B Hierarchical regression analys es related to executive functioning, controlling for age 42 Table 7-A Hierarchical regression anal yses related to immediate memory 44 Table 7-B Hierarchical regression anal yses related to immediate memory, controlling for age 45
v The Influence of Apathy and Depression on Cognitive Functioning in Parkinsons Disease London C. Butterfield ABSTRACT Depression and apathy are two of the mo st common psychiatric symptoms in Parkinsons disease (PD) with prevalence estimates at higher rates than in medical populations with similar levels of disabilit y. Several studies have provided evidence to suggest that apathy and depression are i ndependent clinical phenomena that may differentially affect cognition. Recent rese arch suggests that apathy may account for cognitive deficits over and above that of depression, especially in the domain of executive functioning. However, few studies ha ve examined the independent influence of depression and apathy on cognitive abilities in patients diagnosed with PD using sensitive measures of specific cognitive domains. In addition, many have used measures of apathy and/or depression with symp tom overlap, which may not adequately measure symptoms unique to the target construct. The purpose of this study was to examine the independent influences of symptoms of depression and apathy on memo ry and executive functioning in patients diagnosed with PD using severity scales specifically designed to provide greater discrimination between sympto ms. Depression severity was assessed using items that do not overlap with apathy symptoms or with somatic symptoms of PD itself. Apathy was
vi measured using a scale previously shown to have little overlap with depressive symptoms. Results revealed that apathy, but not depr ession, was significantly associated with executive functioning. In contrast, immediate memory was significantly associated with both apathy and depression. However, apathy accounted for added variance in memory scores when controlling for depression with marginal significance. When controlling for age, although less clear, th ese patterns remained. Differentiation of apathy and depressi on and understanding their independent effects on cognitive functioning have several implications both for clinical intervention and for scientific investigation. Apathy not only has a negative impact on cognitive functioning, but also on daily f unctioning and caregiver burden /distress. Secondly, it has been associated with increased mortality as it may interfere with medication compliance. If appropriately identified, prel iminary research suggests that symptoms of apathy may be medically treated independently of depres sive symptoms. Distinguishing apathy and depression has robust implications for the ad vancement of psychological science, patient care, and for enhancing quality of life in patients and caregivers.
1 1. Introduction Parkinsons Disease (PD), a chronic and degenerative neurological disorder, affects approximately one million people over the age of fifty in the United States alone. While motor dysfunction is most apparent in PD, psychiatric symptoms have been reported to occur in as many as 90% of PD patients (Starkstein, Mayberg, Leiguarda, Preziosi, and Robinson, 1992b), with depression being the most common symptom. Prevalence estimates of clinically elevated depression average at around 40% in this population (Cummings, 1992), compared to 46% of older adults in the general population (Steffens et al., 2000). Apathy, a sy mptom related to motivational and selfinitiation impairment, is also elevated in PD and other disorder s involving the basal ganglia, with an average estimated prevalence of 40.6% (van Reekum, Stuss, and Ostrander, 2005). Again, this is higher th an found in the general population, where the prevalence of clinically elevat ed apathy is estimated at 6.8% in older adults (Onyike et al., 2007). Psychiatric symptoms may negativ ely impact several patient variables, including daily functioning, cognitive f unctioning, and quality of life and may additionally impact caregiver burden and distress (Shra g, Jahanshahi, and Quinn, 2000; Chen, 2004; Keranen et al., 2003; Gote, 1999). Several studies suggest that apathy and depression are independent clinical phenomena that negatively affect memo ry, language, and executive functioning (Starkstein et al., 1992a; Pluck and Brown, 2002; Isella et al, 2002; Feil, Razani, Boone,
2 and Lesser, 2003). Recent research suggests that apathy may account for cognitive deficits over and above that of depression. Few studies have investig ated the independent influence of depression and apathy on cognitive abilities in patients diagnosed with PD. Further, the few studies that have examin ed these relationships have used simple screening measures of global cognitive ability that are insensitive to specific cognitive domains. The present study will attempt to enhan ce our understanding of the independent influences of depression and apathy on memo ry and executive functioning in patients diagnosed with PD using sensitive and more specific cognitive measures. Hierarchical regression will allow for examination of the influence of depression on cognitive performance while controlling for the independe nt influence of apat hy, and vice versa. Before providing a detailed account of the me thodological plan for the present study, an introduction to PD and a review of the lite rature that has examined the relationships between depression, apathy, and cognition in this population is provided. Parkinsons Disease First described as the shaking palsy by James Parkinson in 1817 (Parkinson, 1817), Parkinsons Disease (PD) has since beco me prevalent worldwide, occurring in an estimated 1% of people over the age of fifty, or about one million people, in the United States alone (Stern, 1993). Most cases of PD present after th e age of 50, with a mean age of onset at 55 to 60 years (Mackin, 2000; St ern, 1993). Few cases, if any, appear after the age of 80 (Mackin, 2000). Although the exac t cause of PD remains unknown, there are
3 several theorized causes of th e disorder. These include toxi c exposures (environmental, occupational, or drug induced), oxidative stre ss, and genetics. Most cases of PD are considered idiopathic or of unknown cause. PD is a chronic, progressive neurodegenerative disorder marked by slow degeneration of dopaminergic neurons primarily in the substantia nigra. The depletion of dopamine interferes largely with the nigrostriatal pathway of the basal ganglia, a system largely implicated in the production of move ment and coordinated muscle control (Gibb, 1992). PD patients have lost at least 60-70% of their dopa mine-producing cells by the time motor symptoms appear (Fearnley and Lees, 1991). Although dopamine and the nigrostriatal pathway are primarily affected, th ere is evidence of disr uption to other brain regions (e.g. locus ceoruleus, specific reticu lar nuclei) and circuits (e.g., mesolimbic pathway) as well, resulting in noradrenergic serotonergic, and c holinergic abnormalities of the basal ganglia (Lang and Lozano, 1998, Mackin, 2000). Decreased dopamine in the mesolimbic pathway, a system related to rewa rd sensitivity, may cont ribute to psychiatric symptoms of depression and apathy (Lieberman, 2006; Fibiger, 1984). The classic triad of motor signs in PD include resting tremor, rigidity, and bradykinesia/akinesia (Lang and Lozano, 1998). Resting tremor is the most common and identifiable sign of disease, being the initia l complaint in approximately 70% to 75% of cases (Stern, 1993). Tremors often occur in th e hands, fingers, forearms, foot, mouth, or chin, and take place when the limbs are at rest. When the patient voluntarily initiates movement, however, the tremor subsides. Rigidity refers to muscle stiffness that occurs, also called cogwheeling, which can result in muscle pain or discomfort during movement.
4 Bradykinesia refers to the slowness of voluntary movement, such as standing up, walking, and sitting down, that occurs because of delayed transmission signals from the brain to the muscles. Parkinsons gait, char acterized by a shortened stride, and shuffling steps, is a common feature. Other primary motor symptoms include postural instability, or poor balance, and other coordination impa irment. In later stages of the disease, akinesia (lack of voluntary movement), fe stination (more severe and abnormal gait pattern), hypophonia (voice weakness), dysarth ria (speech impairment), chewing and swallowing difficulties, as well as drooling can occur (Mackin, 2000). Symptom progression varies by individual but typically progresses over a period of 10 to 20 years (Langston, 1990). Progression ca n be divided into th ree states: early, nonfluctuating, and fluctuating (B radley, 1996). Patients in the early stage of disease may be monosymptomatic or have multiple mild symptoms that do not need medication management, with symptoms typically presenting unilaterally. In the nonfluctuating stage, symptoms become disabling and may not respond to first-line therapy. Once patients have reached the fluctuating stage of disease, continual progression of symptoms has occurred and control over symptoms fluctuates. Postural instability and gait disturbance is increased and function has beco me more impaired despite therapy. While motor dysfunction is typically th e most apparent in PD, psychiatric symptoms are also prevalent and have been re ported to occur in as many as 90% of PD patients (Starkstein et al., 1992b). Depression is the most common psychiatric symptom with apathy, anxiety, sleep dist urbance, and hallucinations oc curring at high rates as well. Hallucinations are commonly attributable to anti-Parkinsons medications and are
5 typically visual and benign in nature (M ackin, 2000). Psychiatric symptoms have a significant negative impact on da ily functioning, quality of life, cognitive functioning and caregiver burden and distress (Shrag, Jaha nshahi, and Quinn, 2000; Chen, 2004; Keranen et al., 2003). Mental decline affects up to 90% of patients (Pirozzolo, Hansch, Mortimer, Webster, and Kuskowski, 1982). In contrast, severe cognitive impairment is less frequent, affecting approximately 25% of patients, as most symptoms are subtle and do not interfere significantly with everyday activities (Mayeux et al., 1990; Stocchi and Brusa, 2000). Characteristic cognitive changes in PD include impairment in attention, abstraction and reasoning, visuospatial ab ilities, executive functions, and memory (Stocchi and Brusa, 2000). The greatest area of difficulty for PD patients involves executive functions. These mental operations are involved in adapting to novel situations, problem solving, planning, generating new concepts and elaborating cognitive and behavioral responses to environmental situations (Stocchi and Brus a, 2000). Tests commonly used to evaluate executive functions include Trail Making Te st, Stroop test, lette r fluency (e.g., FAS), Tower of London for problem solving, and Wi sconsin Card Sorting Test (WCST). Regarding memory disturbance, impair ment may be found in working memory, immediate recall, and delayed recall. Resear ch has shown that PD patients have more pronounced impairments on immediate memory tasks compared to delayed memory tasks (Sagar, Cohen, Sullivan, Corkin, and Growdon, 1988). The ability to register, store, and consolidate data appears preser ved; however, the recall deficit is due to impairment in the
6 ability to activate processes th at are associated with the f unctional use of memory stores (Stocchi and Brusa, 2000). Long-term memo ry is impaired due to a decrease in attentional resources rather than decreased storage (Pillon, Dubois, and Agid, 1996). This decreased attentional capacity interferes with organizing material to be remembered, temporal ordering, and memory retrieval strategies (Harrington, Haaland, Yeo, and Marder, 1990). Visuospatial disturbance may also be presen t in PD, but results from a decrease in processing resources rather than from a sp ecific visuospatial dys function (Brown and Marsden, 1986). Depression in PD Depression is the most common psychiat ric symptom in PD, and is found at higher rates in this populati on than in medical populations with similar levels of disability, such as rheumatoid arthritis (Brown and Jahanshahi, 1995; Cummings and Masterman, 1999; Zesiewicz a nd Hauser, 2000). Prevalence estimates of depression in PD range from 3 to 70% (Cummings, 1992; Burn, 2002), although most estimates are closer to 40%, with just over half meeti ng criteria for major de pression and just under half meeting criteria for dysthymia or minor depression (Cummings, 1992). The variability reported across studies is partially dependent upon heterogeneous samples used (e.g., hospitalized, community-based) as we ll as the research tools used to measure depression, with lower rates generally reported in studies that include diagnostic criteria and scripted interviews (e.g., Structure Clinical Interview fo r the DSM-IV, SCID)
7 compared to studies using rating scales (e.g., Beck Depression Inventory, BDI; Beck et al., 1961, 1996) (Edwards et al., 2002). Symptom overlap also contributes to th e variability in prevalence estimates. Symptoms of depression, primarily somatic [e.g., psychomotor retardation, flat affect, masked facies (reduced facial expression of emotion), anergia], often overlap with core features of PD (Edwards et al., 2002), and may lead to an over-estimation of depression in patient samples. Most prevalence studies in research centers find depression in 40% to 50% of PD patients (Edwards et al., 2002; Mayeux, Stern, Williams, Sano, and Cote, 1986; der Gotham, Brown, and Marsden, 1986), w ith half meeting criteria for major depressive disorder (MDD) and half meeting criteria for dysthymia or minor depression (Starkstein, Preziosi, Bolduc, and Robi nson, 1990b; Brown and MacCarthy, 1990). Research studies that use diagnostic crit eria in identifying levels of depression typically define major and minor depression using criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM). According to the most recent edition of the DSM (i.e., DSM-IV-TR; APA, 2000) major depression is defined by the presence of five or more of the following symptoms during the same two-week period and representing a change from prev ious functioning, with at leas t one of the symptoms being (1) or (2): (1) depressed mood (2) markedly diminished interest or pleasure in all, or almost all, activities (3) significant weight loss when not dieting or weight gain, or decrease in appetite (4) insomnia or hypersomnia (5) psychomotor agitation or retardation (6) fatigue or loss of energy (7) feelings of worthlessness or ex cessive or inappropriate guilt (8) diminished ability to think or concentrate, or indecisiveness
8 (9) recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide a ttempt or a specific plan for committing suicide As for minor depression, depres sive symptoms must be present for at least two weeks but fewer than five symptoms are required. Depression in PD differs from idiopathic depression in that PD patients experience relatively increased levels of dysphoria and pessimism about the future, irritability, sadness and suicidal ideation, while guilt, self-blame, fee lings of failure, and completed suicide are less common (Brow n, MacCarthy, Der Gotham, and Marsden, 1988; Taylor, Saint-Cyr, Lang, and Kenny, 1986). De pression in PD is an important issue to address as these patients have more ra pid disease progressio n, increased cognitive decline, increased functional disability, a nd poorer quality of life than PD patients without depression (Sano et al., 1989; Starks tein et al., 1992b; Cole et al., 1996). It remains unclear whether PD patient s have a biological vulnerability to depression, or whether depressi on is a reaction to disability. In support of the former hypothesis, Schuurman et al. (2002) found an increased incidence of PD in patients with a prior history of depression, perhaps reflecting a biological risk fact or for depression in still symptom-free, preclinical stages of PD. Other studies also support that symptoms of depression often precede motor symptoms and the diagnosis of PD (Brown and Jahanshahi, 1995; Cummings and Masterman, 1999). Hypotheses for the etiology of depression in PD tend to favor neurodegeneration as the primary source (Tandberg, Larse n, Aarsland, Laake, and Cummings, 1997; Cummings and Masterman, 1999). Evidence exis ts to suggest that dopamine, serotonin,
9 and norepinephrine play an important ro le in depression (e .g., Cummings and Masterman, 1999; Zesiewicz, Gold, Chari, and Hauser, 1999). PD patients who experience the on-off phenomenon (i.e., fluc tuations in motor symptoms that are associated with response to medication), for instance, complain of a greater level of depression during the off state, when dopami ne levels are low and motor symptoms are more severe (Menza, Sage, Marshall, Cody, and Duvoisin, 1990). Several studies have found lower levels of 5-hydroxyindoleacetic acid, the principal metabolite of serotonin, in PD patients with depression as compar ed to PD patients without depression (e.g., Sjostrom and Ross, 1973; Ashcroft et al., 1966 ). In addition, norepinephrine levels are more markedly decreased in PD patients w ith depression as compared to those without depression (Lieberman, 2006). In PD, each of these neurotransmitter systems is disrupted and may underlie the high rates of depression as well as the cognitive impairment that is experienced. Depression and Cognition in PD Prior studies of PD patients indicate th at depression has an adverse impact on cognitive functioning and may serve as a ri sk factor for cognitive decline. One epidemiologic study revealed that depression was a significant and independent predictor of incident dementia in PD (Stern, Ma rder, Tang, and Mayeax, 1993). In the first longitudinal study to investigate the influence of depression on cognitive decline in PD, Starkstein and colleagues (Starkstein, Bo lduc, Mayberg, Preziosi, and Robinson, 1990a) found that patients who were depressed at baseline showed significantly greater decline
10 in global cognitive functioning (i.e., MMSE score) at a threeto four-year follow-up as compared to PD patients who were not depressed at baseline. In a later study, Starkstein et al. (1992b) divided depr essed PD patients into two groups: (1) those meeting DSM-III criteria for major depression, and (2) those meeting DSM-III criteria for minor depression. At one year follow-up, patients with major depression at baseline evaluation showed significantly greater decline in global cognitive functioning than those with minor depression or no depression at baseline. Patients were matched for duration of illness and disability severity in order to control for the possibility that these disease factors, ra ther than depression, were accounting for the cognitive declines. In a series of studies, Trster and coll eagues built upon the literature to further investigate the relationship between depression and cognition in PD (i.e., Trster, 1995a; Trster, 1995b; Norman, Trster, Fields, a nd Brooks, 2002). First, they compared PD patients with depression (PDD) and without depression (PDN) to normal control (NC) subjects matched for age, education, gender, disease duration, age of disease onset, and disease severity to find that both PD groups (PDD and PDN) showed greater impairment on a screening measure of global cognitive abil ity (i.e., Mattis Dementia Rating Scale, DRS), with particular impairments on Con ceptualization and Init iation/Perseveration subscales, as compared to NC subjects. PDD patients performed significantly worse than PDN patients (Trster, 1995a). To follow, they used a more extensive battery of neurocognitive assessments to evaluate the qualitative difference in cognitive abilities between PDD and PDN patients (Trster, 1995b ). Results suggested that depression
11 exacerbated some memory and language impairments previously associated with PD and that depression influences the severity rather than the quality, or pattern, of cognitive impairment in PD. In a third study, these researchers (Norman et al., 2002) added a comparison group of subjects with depressi on but without PD (D) that wo uld allow them to determine whether the previously identified cognitive impairments were due to a combined effect of PD and depression or to depr ession alone. This is importa nt since the same frontal metabolic changes that may be strongly re lated to cognitive impairment are found in depressed individuals regardless of having a PD diagnosis (Dol an et al., 1994; Norman et al., 2002). Results revealed poorer overall cognitive functioning (i.e., DRS total) in both PD groups (PDD and PDN) as compared to non-PD groups (NC and D). Interestingly, both depressed groups (D and PDD) performe d more poorly on the Memory subscale as compared to PDN patients, suggesting that the memory impairment found in PDD patients may be a result of depression alone as opposed to a combined effect of depression and PD. In a similar study, Kuzis and colleag ues (1997) found that patients with depression, with or without PD, showed si gnificantly greater impairment on verbal executive (fluency) ability and auditory at tention as compared to those who were nondepressed (PDN and NC). PDD patients were si gnificantly more impaired than the other three groups on concept formation (i.e., Rave n Progressive Matrices) and set shifting (Wisconsin Card Sorting Test), a meas ure of executive func tioning. Further, no differences in cognitive performance were found between PDN patients and NC subjects.
12 In sum, the presence of depression in PD may exacerbate existing cognitive deficits on tasks such as concept formation, memory, language, and executive functioning. Apathy in PD In contrast to depression apathy and abulia (a more severe form of apathy) are not characterized by anhedonia, hopelessness, or low mood; rather, they are characterized by isolated lack of motivation and self-ini tiative (Shrag, 2004). The study of apathy as a neuropsychiatric construct in neurological disorders has only recently begun, with its initiation in 1990 (Marin, 1990; Marin, Biedryzycki, and Firinciogullari, 1990; Burns, Folstein, Brandt, and Folstein, 1990; Robinson and Starkstein, 1990). Apathy, derived from the Greek term pathos, meaning passions, is conventio nally defined as the absence or lack of emotion, feeling, interest, or concern (Mari n, 1990, 1991). Clinically, this definition of apathy is lacking and fails to address a variety of other psychological features. Individuals with frontal lobe injury, for instance, may be experiencing apathy along with some other intense emotion, such as irritability or euphoria. Similarly, a depressed individual may appear to be lacking emotion, in terest, and concern, while s/he is indeed experiencing seve re internal emotional pain. Marin provided a more clinically appropr iate definition of apathy as a primary motivational impairment that is, importantly, not seconda ry to cognitive or intellectual impairment, emotional distress, or diminished level of consciousness (drowsiness and/or diminished attention) (Marin, 1990, 1991). On e who meets this definition of apathy may
13 be regarded as having apathy syndrome Loss of motivation due to disturbance of intellect (e.g., dementia), emotion (e.g., depression), or level of consciousness (e.g., delirium) defines the symptom of apathy (Marin, 1991). Motivation it self refers to characteristics and determinants of goal-directed behavior (Marin, 1991). Stuss et al. (2000) revised the defi nition of apathy as an absence of responsiveness to stimuli as demonstrated by a lack of self-initia ted action, suggesting that this definition would allow for objectiv e behavioral measurement. They proposed that previous conceptualizations of apathy as a lack of motivation were flawed in that assessment of inner urges is problematic a nd necessitates inference based on observations of affect and behavior. Marin (1991) proposed that symptoms of apathy can be classified into three concomitants of goal-directed behavior: emotional (i.e., lack of emotional responsiveness; lack of excitement or emotional intensity; unchanging affect), cognitive (i.e., lack of interest; lack of concern about ones personal problems; diminished importance or value attributed to various goal-related domains), and (overt) behavioral (i.e., lack of effort; lack of initiative or perseverance; compliance or dependence on others to structure activity). Since apathy itself may be considered as behavioral (i.e., an observable state), Levy and Dubois (2005) refer to the third domain as an auto-activation deficit that is not primarily due to an emotional or cogni tive deficit and can be reversed by external stimulation. They proposed that the thr ee concomitants of apathy (i.e., emotionalaffective, cognitive, and auto-activation of behavior) may each be explained by
14 disruption to three underlying mechanisms and their associative basal ganglia subregions: orbital-medial, dorsal-lateral, and dorsal-me dial streams. Amotivational symptoms are reported in several cases of frontal impairme nt (i.e., stroke, dege neration, head injury) and frontal-subcortical limb ic dysfunction (i.e., PD, AD, stroke) and may underlie associated executive functioning de ficits (Isella et al., 2002). PD is a classic example of a subcortical disorder in which apathy is a wellrecognized feature (Isella et al., 2002; Pluck and Brown, 2002; Aarsland et al., 1999; Starkstein et al., 1993, 1995; Marsden and Parkes, 1977) and it is hypothesized that nigrostriatal dopamine depletion in PD may contribute (Levy and Dubois, 2005). Clinically significant apathetic symptoms ar e present in approximately 40% to 45% of PD patients (Isella et al., 2002; Starkstein et al., 1992a), compared to 6.8% in healthy older adults (Onyike et al., 2007), with apathetic syndromes (not secondary to depression, delirium, or dementia) present in about 12% of PD patients (Starkstein et al., 1992a). Apathy appears to be a result of neurologi cal disturbance rather than a result of psychosocial limitations of physical disabili ty. Pluck and Brown (2002) showed that, while PD and osteoarthritis are similarly chronic, progressive conditions that cause significant levels of disablement, significant levels of apathy were found in PD patients, but no evidence of apathy was present in osteoarthritic patients. Isella et al. (2002) showed that groups of patients with low, moderate, and high levels of apathy did not differ from each other in PD duration or severity, suggesting that apathy unlikely represents a simple reaction to disability. Th ese findings together have been provided as
15 support for the view that apathy is not a psycho logical response to phys ical disability, but rather a neurobiological feature of PD. Some hypotheses suggest that apathy a nd depression are rela ted to distinct neurological circuits, with depression be ing secondary to dysfunction of brainstem serotoninergic neurons (i.e., ra phe nuclei) that project to li mbic areas, and apathy derived from the noradrenergic deficit at the locu s coeruleus (connected with cortical and subcortical structures) (Starkstein et al., 1992a; Mayeux et al ., 1987). Marin (1990, 1991; also see Isella et al., 2002) suggested that a frontal-subcortical limbic circuit (i.e., prefrontal cortex, anterior cingulate gyrus, entorhinal co rtex, and the basal ganglia), which seems to play a cent ral role in conveying emoti onally relevant information, elaborating drive, and in pl anning and monitoring motivated behavior, may mediate the association found between apathy and executive functioning. Dysfunction of this region may result in executive deficits, amotivati on, and/or of the capacity to organize goaldirected behavior. Apathy and Depression: Independent Clinical Phenomena While certain symptoms may be shared among apathy and depression (i.e., diminished interest, psychomotor retardati on, fatigue/hypersomnia, lack of insight), several researchers have suggest ed that certain symptoms are unique to apathy (i.e., blunted affect, indifference, low social engagement, diminished initiation, poor persistence) and certain symptoms are unique to depression (i.e., dysphoria, suicidal
16 ideation, self-criticism, feelin gs of guilt, pessimism, hopelessness, sleep disturbance) (Marin et al., 1993, Marin 1990, Landes et al., 2001). Various methods have been employed to examine the discriminability of apathy and depression as independent clinical phe nomena. Depression is a syndrome in which apathy may be present, in which case it may be termed apathetic depression (Marin, 1990). In this instance, a depressed persons apathy may be described by a persons inactivity and expressed loss of interest in usual activities. However, there are several instances in which depression may exist in the absence of apathy. In the case of the depressed person who demonstrates deliberate and active avoidant be havior, or in the extreme case of suicide, clea rly apathy (which describes passivity or a lack of goaldirected behavior) is not an accurate descri ptor (Marin, 1990). Further, apathy may exist as a distinct syndrome, in which, by definiti on, there is absence of emotional distress. Weitzner, Kanfer, and Booth-Jones (2005) described four cases of pituitary disease patients who appeared to be sufferi ng from depression, but when diagnosed and treated for depression they showed little res ponse to treatment. When the patients were asked about their mood, all stated that they we re experiencing chroni c fatigue and lack of motivation, and were not feeling depressed. Wh en the diagnosis of apathy syndrome was considered and treatment with methylphenida te was implemented, the patients condition improved subjectively and on objective cogni tive tasks (i.e., verbal and nonverbal learning, several executive tasks, and psychomotor speed). One method of distinguishing apathy and de pression is to evaluate the rates and relationships between apathy a nd depression in different diagnostic groups. Marin et al.
17 ( Marin Firinciogullari and Biedrzycki, 1994) evaluated patients diagnosed with Alzheimers disease (AD), stroke, and majo r depression using the Apathy Evaluation Scale (AES; Marin Biedrzycki, and Firinciogullari 1991) and the Hamilton Depression Rating Scale (HDRS; Hamilton, 1960). Despite the fact that there was a significant correlation found between apathy and depression scores when all five diagnostic groups were included in the analysis, proportions of patients with apat hy and/or depression varied considerably among groups. Specifically, AD patient s showed high levels of apathy and low levels of depr ession, left hemisphere stroke patients and patients with major depression showed high levels of depressi on and low levels of apathy, and patients with right hemisphere stroke showed equivalent levels of apathy and depression. The authors used this evidence to suggest that apathy and depression are clinically distinct neuropsychiatric syndromes. Levy et al. (1998) evaluated whether ap athy and depression ma y be produced by different neuroanatomical or neurochemical substrates by evaluating these two symptoms in different diagnostic groups, including patients diagnosed with PD, AD, frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and Hunti ngtons disease (HD). Firstly, apathy and depression were not correlated in the combined sample. Secondly, the frequency of apathy and depr ession significantly varied across groups with a large number of AD, FTD, and PSP patients havi ng apathy without depression, and many PD and HD patients having depressi on without apathy. This dispar ity was especially notable in patients with PD and PSP. Few PD patient s presented with apat hy alone compared to those who had depression with or without apathy, and few PSP patients presented with
18 depression, but a high frequency of PSP patient s presented with apathy. These findings suggest that the relationshi p between apathy and depressi on appears to be diseasespecific. Landes et al. (2005) explored the differe ntial relationship of apathy, dysphoria, and depression with other clinical variables (i.e., stage of disease, cognitive impairment, and functional impairment) in patients dia gnosed with Alzheimers disease to provide support for the differentiation of apathy and mood disturbance. Their analyses revealed that apathy occurs more frequently than dys phoria in AD. Apathy was strongly related to disease severity, cognitive impairment, activ ities of daily living, while dysphoria was weakly related or unrelated to these variable s. Landes et al. (2005) provided these results as evidence for the importance of a syndr ome-based approach, with emphasis on the importance of distinguishing dysphoria from apathy syndrome. Apathy, Depression and Cognition Another method of dissociating apathy and de pression as distinct constructs is to evaluate their independent influences on cognitive functioning. Some studies have revealed an effect of apathy on cognitive function ing in PD that is distinct from that of depression. Starkstein and colleagues (2005) de monstrated a significa nt association of apathy and global cognitive abilities, as meas ured with the Mini Mental Status Exam (MMSE), but no significant association of de pression and global cognitive abilities. In their sample of Alzheimers disease patient s, those with apathy had significantly more severe cognitive deficits than those without apathy. Levy ( 1998) also found that apathy
19 correlated significantly with increased cognitive impairment as measured with the MMSE whereas depression did not. To investigate depression, apathy, and cogni tion in a sample of patients diagnosed with Alzheimers disease, Kusiz and collea gues (1999) classified patients into four groups: (1) depression-only (w ithout apathy); (2) apathy-only (without depression); (3) both depression and apathy; and (4) controls with neither depressi on nor apathy. Patients meeting the DSM-IV criteria for major depression or dysthymia were considered depressed, whereas patients scoring more than two standard deviations above the mean apathy scale score were considered apathe tic. Using ANOVA and post hoc t-tests to compare groups, Kusiz and colleagues found that patients with apathy only (without depression) had significantly lower scores on verbal memory and confrontational naming compared to patients without apathy (depress ion-only and control). Patients with apathy only (without depression) and patients with both apathy and depres sion had significantly lower scores on a dexterity task as comp ared to patients with neither apathy nor depression (controls) and had significantly lo wer scores on two executive measures as compared to patients without apathy (depression-only and control). Overall, their results suggest that memory and executive deficits were associated with apathy rather than depression. In a sample of non-demented older adults diagnosed with major depressive disorder (MDD), Feil and colleagues (2003) examined apathy, depression, and cognitive performance using correlations and individua l stepwise regression analyses. Results of correlational analyses revealed significant co rrelations between apathy and two cognitive
20 measures: nonverbal executive (WCST-Other Responses) and processing speed (Stroop B). Near-significant relationships were f ound between apathy and two verbal executive measures (FAS and Stroop C). Depressi on was significantly correlated with two information processing speed measures (Str oop A and Stroop B) a nd near-significant relationships were found between depression and verbal executive performance (Stroop C). Individual stepwise regression (i.e., entry of the indepe ndent variables, IVs, is determined by the statistical software base d on the magnitude of correlations with the dependent variable) was performed on the four cognitive measures that significantly correlated with apathy (i.e., Stroop B, Stroop C, FAS, and WCST) to determine whether apathy uniquely accounted for test score variance over and above that accounted for by depression, health status, age, and educa tion. Regression analyses on the four IVs revealed that apathy alone accounted for a signi ficant amount of test score variance on a nonverbal executive task (WCST; R2 = 0.13) and that apathy plus demographic variables together accounted for a signifi cant amount of variance on two verbal executive measures (FAS and Stroop C). Specifically, education was the best predictor of one verbal executive measure (FAS; R2 = 0.074), followed by apathy (R2 = 0.070). Age was the best predictor of the second verbal executive measure (Stroop C; R2 = 0.171), followed by apathy (R2 = 0.100). Apathy, depression, and age together accounted for a significant amount of variance on a proces sing speed task (total R2 = 0.308). Specifically, depression was the best predictor of processing speed (Stroop B; R2 = 0.219), followed by age (R2 = 0.046), then apathy (R2 = 0.043). Overall, both apathy and depression were associated
21 with some cognitive variables, but apathy was a greater influence on executive functioning than was de pression severity. Apathy, Depression and Cognition in PD Only four studies have investigated de pression, apathy, and cognition in a sample of patients diagnosed with PD using a more extensive battery of neurocognitive assessments (Starkstein et al., 1992a; Is ella et al., 2002; Pl uck and Brown, 2002; Aarsland et al., 1999). All four studies reveal ed a significant relati onship between apathy and cognitive impairment, particul arly in executive functioning. Starkstein and colleagues (1992a) examin ed correlates of apathy, depression, and cognition by comparing PD patients with apathy only, depression only, apathy plus comorbid depression, and neither depression nor apathy (control subjects). This research team found that the patients with apat hy (with or without depression) showed significantly more deficits on time-dependent executive tasks (speci fically, poorer verbal fluency/executive as measured by FAS and sl ower performance on Trail Making Test B), whereas depressed patients showed significantly more deficits in an untimed executive task (i.e., Wisconsin Card Sorting Task, WCST). Both apathy and depression were significantly associated with impa ired episodic verbal memory. Aarsland and colleagues (1999) found a si gnificant correlation between apathy and number of errors on the Stroop test, a measure of executive functioning. This relationship was not found between depression and cogniti on or between apathy and
22 depression, suggesting that the relationship between apathy a nd cognitive decline is not due to depression. Isella and colleagues (2002) compared PD patients with low, moderate, and high levels of apathy and found a clear associat ion between apathy and executive functioning, with the high-apathy group showing signi ficantly greater impairment in executive functioning [i.e., Executive Interview (EXIT), letter fluency and category fluency] compared to the other two groups. Depressi on was not significantly correlated with apathy or any cognitive abilities measure d. The research group did not, however, examine the independent influence of depression on cognitive abilities. Pluck and Brown (2002) found similar re sults showing that apathy, but not depression, was related to defic its in global cogni tive ability (especially on the memory and language subscales) and on three measures of executive functioning (i.e., category fluency, Stroop Color-Word test, and WCST). A series of exploratory regression analyses demonstrated that, while none of the clin ical or demographic variables (age, sex, education, duration of illness, Hoehn and Ya hr stage or Schwab and England score) predicted apathy ratings, category fluency and Stroop Interference were the best predictors of apathy scores. Overall, these studies suggest that apat hy and depression are independent clinical phenomena that negatively affect memory, language, and executive functioning. Further, they suggest that apathy may account for c ognitive deficits over and above that of depression, particularly in the cognit ive domain of executive functioning.
23 Limitations of Previous Research Although several studies have examined the relationships between apathy, depression, and cognitive functioning in patients with neurological conditions (e.g., Alzheimers disease, Frontotemporal Deme ntia, and Huntingtons disease), only four have examined specific domains of neurocognitive impairme nt in patients diagnosed with PD. The few studies have examined these relationships are limite d in several ways. First, many have used measures of ap athy and/or depression with questionable ability to measure symptoms unique to the target construct. Symptom overlap hinders discriminability among constructs. For instan ce, Starkstein et al. (1992a) used the Hamilton Depression Rating Scale (HDRS), a wide ly used measure that has been accused of being a weak index of depressive severity due to poor content validity and a multidimensional factor structure (Gibbons Clark, and Kupfer, 1993; Bagby, Ryder, Schuller, and Marshall, 2004). Aarsland et al. (1999) used the Neurops ychiatric Inventory (NPI; Cummings et al., 1994), a measure commonly used in dementia to measure dysphoria, apathy, and anxiety, among several other neuropsychiatric disturbances. Factor analysis of the NPI showed that apathy and anxiety existed together on one factor, revealing that the NPI measures shared symptoms of apathy and anxiety. Pluck and Brown (2002) measured depr essive symptoms using the Beck Depression Inventory (BDI; Beck, Ward, Mendelson, et al., 1961), which includes numerous somatic items that overlap with symp toms of PD itself. Use of such measures may artificially inflate depressive symptom severity in medical populations (Taylor, Lovibond, Nicholas, Cayley, and Wilson, 2005).
24 In the present study, the Apathy Evaluati on Scale self-ra ting form (AES-S; Marin, 1991), a scale specifically designed to discriminate apathy from depression, will be used to measure apathetic symptoms. Th e self-rating version of the AES was chosen based on the consideration that motivation is an internal state that informants may not be able to adequately assess. Further, informan ts may have difficulty distinguishing between emotional symptoms of apathy (i.e., unchangi ng affect) and masked facies, a common deficit in PD patients that refers to decr eased facial expression. A multitrait-multimethod matrix procedure was used to support the conver gent validity and disc riminant validity of the AES-S (Marin, 1991). While apathy scales, such as the AES, have been designed to discriminate between apathy and depression, no depression scales have been developed with the intent to eliminate symptoms that overlap with apathy. The present st udy will utilize select items from the Beck Depression Inventory II (BDI-II) in an attempt to assess a con tinuum of depressive symptoms that do not overlap with apathy symptoms or with somatic symptoms of PD itself. A total of 13 items will be retained from the BDI-II that assess the same content domains as identified in cognitive/affective scale of the BDI-I. Us e of the full BDI-II is not ideal for a PD population since many of these patients may experience somatic symptoms that are unrelated to depression (Taylor et al., 2005). Items co rresponding to the cognitive/affective scale of the BDI-I will be retained (e.g., sadness, pessimism, sense of failure, etc.) with the exception of the item rela ted to lack of interest due to its possible overlap with apathy. Items that correspond to the somatic/behavior scale of the Beck Depression Inventory I (BDI-I) (e.g., sleep di sturbance, appetite, tiredness/fatigability,
25 etc.) will be eliminated to protect against artificial inflation of depressive symptom severity. As mentioned above, most studies in vestigating the relationships between depression, apathy, and cognition have used measures of gl obal cognitive ability (e.g., MMSE), rather than measures assessing spec ific cognitive domains. The present study will examine verbal memory and executive f unctioning, two cognitive abilities that have shown to be associated with depression, apathy, and PD. Lastly, most of the studies described a bove have used correlational analyses and ANOVAs with post-hoc comparisons, with the exception of two (Pluck and Brown, 2002; Feil et al., 2003). While su ch designs are elegant in their ability to evaluate emotional and cognitive differences among grou ps of individuals, they do not provide information regarding the degree to which apathy or depres sion influences cognition over and above the other. In the present study, hier archical regression analyses will allow for investigation of the influence of depre ssion on cognitive performance while controlling for the independent influence of apathy, and vice versa. Purpose of the Proposed Study The purpose of this study is to examine th e independent influence of depression and apathy on cognitive functioning (specifically, memory and executive functioning) in PD patients. Depression is the most common psychiatric symptom in PD and has been shown to be associated with cognitive deficits. Apathy, a symptom related to motivational and
26 self-initiation impairment, is also prevalent in PD and has gained recent attention in this population. Several studies have demonstrated eviden ce to suggest that apathy and depression are independent clinical phenomena. Recent research suggests that apathy may account for cognitive deficits over and above that of depression. However, few studies have examined the independent influence of depression and ap athy on cognitive abilities in patients diagnosed with PD. Th e majority of these studies have used simple screening measures of global cognitive ab ility that are insensitive to sp ecific cognitive abilities, such as executive functioning and verbal memory. In addition, only two studies have examined these relationships using hierarchic al regression, only one of which was in a PD population. Hierarchical regr ession allows us to pit apathy and depression against each other in a test that provides an estimate of the degree of influence that depression has on cognitive performance while controlling for the indepe ndent influence of apathy, and vice versa Hypotheses/Predictions It is hypothesized that increased levels of depression and apathy will be associated with decreased performance on measures of executive and memory abilities. This hypothesis will be examined in two ways: magnitude of correlation coefficients and hierarchical regression. It is predicted that 1) significan t negative correlations will observed between measures of depression/ap athy and executive/memory abilities and 2)
27 depression and apathy will significantly predict level of executive and memory abilities when entered as the first variable in hierarchical regression analyses. It is hypothesized that apat hy will be more strongly associated with executive functioning than depressive symptoms. This hypothesis will also be examined in two ways: magnitude of correlation coefficien ts and hierarchical regression. Using correlational analyses and Hotellings t-test to compare correlations, it is predicted that the correlation between apathy and executive functioning will be significantly greater than the correlation between depression and executive functioning. Using hierarchical regression, it is predicted that apathy will account for a significant proportion of added variance in executive functioning scores over and above that accounted for by depression alone, but that depression will not account for a significant proportion of added variance in executive functioning scores over and a bove that accounted for by apathy alone. Examination of additional findings from regression analyses will also afford exploration of possible independent effects of apathy and depression on memory abilities although hypotheses and predictions for this variable are less clear based on prior literature.
28 2. Method Participants Sixty-eight individuals ( 44 men, 24 women) diagnosed with idiopathic, nonfluctuating PD, ages 56-82, were included in the present study. Numb er of participants required was determined by a priori power analysis using G-Power computer program (Faul and Erdfelder, 1992). Sixty-eight participants was n eeded to yield a power of 0.80 given a medium effect size of d = 0.15. All pa rticipants were recruited from Movement Disorder clinics of the University of South Florida Parkinsons Disease Center of Excellence and monthly PD support group meetings in the Tampa Bay area. Patients with atypical Parkinsons diseas e (i.e., known cause, including previous exposure to toxins or atypical presentation of symptoms), early onset PD, or current or past history of other neurologi cal disorder, cardiac arrest, psychiatric disturbance (other than depression or anxiety), or head injury with loss of consciousness were excluded from participation. In addition, patients scoring below 24 on the Mini-Mental Status Exam were excluded from participation. All pa tients were tested during the on phase, when medication is effective and motor symptoms are reduced. Measures Beck Depression Inventory II (BDI-II). The BDI-II (Beck, Steer, and Brown, 1996) is a 21-item self-report instrument intende d to assess the existe nce and severity of
29 depressive symptoms consistent with the depression criteria of the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV; 1994). BDI-II items are scored on a four-point Likert scale (0-3), w ith statements arranged to represent increasing intensity of a particular symptom of depression. For th e purposes of this study, the following 13 items of the BDI-II will be used as a measure of depressive symptom severity: Sadness, Pessimism, Past Failure, Loss of Pleasure, Guilty Feelings, Punishment Feelings, Self-dislike, Se lf-criticalness, Suicidal Thoughts or Wishes, Crying, Indecisiveness, Worthlessness, and Irritability (see Appendix A). Th is well-established measure and has excellent reliability and validity. One-week test-retest reliability was reported as r = 0.93 (Beck et al., 1996) and internal consistency acr oss studies is excellent ( = 0.89 0.94) (Dozois and Covin, 2004). Evidence for construct validity has stemmed from several factor analyses (Dozois and Covin, 2004) and convergent, discriminant, and content validity are well-supported (e.g., Beck et al, 1996; Osman et al., 1997; Dozois and Covin, 2004). Apathy Evaluation Scale Self-Rating (AES-S) and Informant-Rating (AES-I). The AES-S (Marin, 1991) is an 18-item self -rating scale that was developed to assess apathetic symptoms within behavioral, cogni tive, and emotional domains (see Appendix B). Items are scored on a four poi nt Likert scale (1 = Not at all true; 2 = Slightly true; 3 = Somewhat true; 4 = Very true) and sc oring is arranged so that higher scores represent greater apathy. This has been used in a number of clinical groups, including PD and has been found to have good construc t validity, intern al consistency ( = 0.86) and test-retest reliability ( = 0.76) (Marin et al., 1991). Multitrait-multimethod matrix
30 procedures show support for convergent and di scriminant validity (Marin, et al, 1991). The AES-I is a parallel measure completed by a relative/spouse who has regular contact with the research participant in order to provide an outside perspective. This was administered when possible in order to inve stigate informant ratings, however, the AES-S was used for analyses. Mini Mental State Exam (MMSE). The MMSE (Folstein, Folstein, and McHugh, 1975) is an 11-item examination and the most widely used cogniti ve screening test. Research provides widespread support for its validity in assessing gl obal cognitive status. Each item assesses one of the following domains: orientation to time, orientation to place, registration, attention, recall, naming, repetition, comprehension, reading, writing, and drawing. Patients scoring less than 24 will be excluded from the study to avoid confounds of significant cognitive impairment, which ma y affect patients ability to validly complete self-report measures. Wisconsin Card Sorting Test-64 (WCST-64). The WCST-64 (Kongs, Thompson, Iverson, and Heaton, 2000) is a shortened vers ion of the Wisconsin Card Sorting Test, Revised and Expanded (WCST; Heaton, Chelune Talley, Kay, and Curtiss, 1993), one of the most widely used measures of executive functioning. The test provides detailed feedback regarding specific aspects of problem-s olving abilities, such as inefficient initial conceptualization, perseveration, failure to maintain a cognitive set, and inefficient learning. In this task, subjects are required to match 64 cards to one of four target cards. Matching rules are color, shape/form, or number of symbols. Subjects infer these rules from feedback about whether the match was correct, which is provi ded by the tester
31 immediately following the match. After ten consecutive correct matches, the tester changes the rule without preannouncement. Th e Number of Categories Completed score will be selected for the present analysis as it reflects the ability to shift set from one activity to the next. Past research shows that PD patients are particularly sensitive to this type of task (eg., Cools, Barker, Sahakian, and Robbins, 2001). The WCST-64 has excellent interscorer and intrascorer re liability (0.88-0.93 and 0.91-0.96, respectively) (Paolo et al., 1996; Axelrod, Goldman, and Woodard, 1992), and has demonstrated sensitivity to executive impairment in PD, Alzheimers disease, and in individuals who have suffered frontal lobe injury (e.g., Paolo et al., 1996; Robinson, Heaton, Lehman, and Stilson, 1980). Hopkins Verbal Learning Test-Revised (HVLT-R). The HVLT-R (Benedict, Schretlen, Groninger, Brandt, 1998) is a verbal learning and memory test that consists of a list of 12 words, each belongi ng to one of three semantic categories. There are three immediate memory trials, one delayed recall trial (20-25 minutes af ter completion of the third immediate memory trial), and a recogniti on trial. The Total Recall score, which is the sum of the three immediate memory trials will be selected for the present analysis because prior research shows that PD patients have more pronounced impairments on immediate memory tasks compared to de layed memory tasks (Sagar et al., 1988). Literature supports the reliability of the HV LT-R (e.g., six-week test-retest reliability for Total Recall is 0.74 in healt hy elderly) (Benedict et al., 1998) as well as construct discriminative, and predictive validity. Shapiro and colleagues (1999) demonstrated that HVLT Total Recall was correlated with a pr ose verbal memory test (i.e., Logical
32 Memory) at r = 0.75, showed 95% sensitivity and 83% specificity, had a positive predictive value of 0.84, and a nega tive predictive value of 0.94.). Procedure Eligible participants were recruited from the Department of Neurology and Movement Disorders Clinics at the Universi ty of South Florida and from support group meetings in the Tampa Bay area. Patients were invited to participate by clinic neurologists during regular patie nt visits or by a research assistant on the present study. Diagnosis and staging of PD was determined by board-certified neurologists using the Hoehn and Yahr scale (1967), a standard stag ing scale commonly used in PD research. After giving informed consent, particip ants were screened with the MMSE to ensure that they met basic cognitive requi rements. Those with an MMSE score below 24 were excluded from further participation. Next, included participants were asked to complete a series of self-report measures to determine their affective status. Some participants completed these questionnaires after their appoi ntment and returned them by mail within one week of participation. A me mory test was then administered by the primary investigator, followed by a test of executive functioning. Statistical Analyses Two approaches were used to examine the relationship between cognitive functioning (memory and executive functioni ng) and psychological symptom severity (depression and apathy) in the present st udy: (1) correlation coefficients, and (2)
33 regression analyses. First, correlation coefficients were calculated between psychological and cognitive variables, revea ling a total of four correlation coefficients (i.e., 1. executive function and depression, 2. ex ecutive function and apathy, 3. memory and depression, 4. memory and apathy). Hierarchical regression analyses were th en conducted to compare the degree of influence that depression and apathy have on cognitive impairment. Executive function and memory served as criterion variables a nd were evaluated independently. In the two hierarchical regression analyses of executive ability, the independent effects of depression and apathy on executive functioni ng were assessed. In the fi rst hierarchical regression analysis, the selected items of the BDI-II we re entered to account for the influence of depressive symptoms. Finall y, the AES-S was entered, leav ing a final change in R2 that reflects the amount of variance in executive functioning that is accounted for by apathy above and beyond the influence of depression (i .e., while controlling for the effects of depression). In the second hier archical regression analysis of executive ability, the AES-S was entered to account for the influence of apathy symptoms Finally, the selected items of the BDI-II were entered, leaving a final change in R2 that reflects the amount of variance in executive functioning that is accounted for by depre ssion above and beyond the influence of apathy (i.e., while controlling for the eff ects of apathy). The same two hierarchical regression analyses were repeated to assess the independent influence of depression and apathy on memory The final R2 in both hierarchical regression analyses reflects th e amount of variance in memory that is accounted for by the independent infl uence of depression or apathy.
34 3. Results Diagnostics SPSS 15.0 for Windows was used to manage and analyze data. Prior to conducting analyses to investig ate the above stated hypotheses, data point distributions were examined for significant departures from normality and data was examined to ascertain that regression assumptions were met. Examination of boxplots and standardized residuals confirmed that data points of interest fell within acceptable limits (+/3 standard deviations from the m ean) for analysis. Cooks d (range: 0.000 0.218), hat values (range: 0.004 0.174), and Maha lanobis distance (range: 0-.256 11.672) values revealed that no individual case s were producing undue influence on the regression model. Examination of boxplots and descriptive sta tistics confirmed the absence of skewness and kurtosis among the variables. Scatterplots of regression standardized residuals and pred icted values verified the assu mptions of homoscedasticity and linearity. The inspection of VIF (all values 1.466) and tolerance statistics (all values 0.682), eigenvalues and variance proportions, as well as correlation coefficients between predictors (r < 0.60) revealed that the assu mption of no multicollinearity was met. Durbin-Watson statistic values (range: 1.729 2.545) fell within acceptable limits, supporting the assumption of independent errors.
35 Descriptives Data was obtained from 68 Parkinsons disease patients between the ages of 56 and 82 years (mean = 69.96, SD = 7.03). Subjects were majority male (n = 45, 66.2%) and Caucasian ( n = 63; 92.6%), Education level ranged from 12-22 years (mean = 15.74, SD = 2.62). All patients were in the mild to moderate stages of diseases (Hoehn and Yahr Stages 1-3). Depression severi ty ranged from no symptoms of depression to moderate levels and apathy severity ranged from no apathy symptoms to severe levels. Cognitive performance ranged from better than expect ed to severe impair ment. A summary of demographic, clinical, and experimental variab les from this sample is provided in Tables 1 and 2. Table 1: Summary of demographi c and clinical characteristics Range Mean (SD) Age 56 82 69.96 (7.03) Years of education 12 22 15.74 (2.62) Disease duration (yrs) <1 24 7.07 (4.96) n % Gender Male Female 45 23 66.2 % 33.8 % Ethnicity White Black Hispanic 63 1 4 92.6 % 1.5 % 5.9 %
36 Table 1 (Continued) n % Stage of disease 1 2 3 data not obtained 15 33 9 11 22.1 % 48.5 % 13.2 % 16.2 % Side of onset R L data not obtained 32 31 5 47.1 % 45.6 % 7.4 % Table 2: Summary of mood and cognitive scor es including age-adjusted T-scores Raw scores T-scores Range Mean (SD) Range Mean (SD) Depression (21-item BDI) 0-23 10.62 (5.26) 37-76 44.75 (9.16) Depression (13-item BDI) 0-14 4.10 (3.49) --Apathy (AES-S) 18-50 30.29 (7.51) 34-84 46.57 (11.73) Imm Memory (HVLT Total Recall) 8-33 21.31 (5.84) 20-70 43.34 (10.97) Executive Fx ** (WCST Categories) 0-5 2.06 (1.71) 17-64 38.75 (10.06) T-scores adjusted for age and education ** T-scores adjusted for age
37 Correlation analyses were used to evalua te the relationships between demographic and clinical variables (i.e., ag e, years of education, disease duration), and experimental variables (i.e., depression, apathy, memory, executive functioning) (see Table 3). Raw scores were used in all correlation an d regression analyses. Increasing age was significantly associated with decreases in memory and executive performance ( r = 0.279, p < 0.01 and r = -0.312, p < 0.05, respectively). Years of education and disease duration were not associated with cognitive performance. Table 3: Correlations Depression (21-item BDI) Depression (13-item BDI) Apathy (AES-S) Memory (HVLT Total Recall) Executive Fx (WCST Categories) Age .303** 0.189ns .233t -0.279* -0.312** Education 0.022ns 0.086ns 0.150ns -0.026ns 0.053ns Disease duration -0.056ns -0.096ns -0.061ns 0.111ns 0.158ns p<0.05 **p<0.01 ttrend, p<0.10 ns not significant, p>0.10 Frequencies of apathy and depression The frequency of apathy, using AES-S 38 as representative of clinically significant elevations in apathy (Pluck a nd Brown, 2002; Rabkin, Ferrando, van Gorp, et al., 2000), was 20%. This rate appears to be lower than reported frequencies of apathy in other studies using self-ratings (Kirsch-Darrow, Fernandez, Marsiske, Okun, and Bowers, 2006) and may be due to measurement differences or to the restricted range of disease severity in the present sample, as all of our participants were in the mild to moderate
38 stages of disease. When using the more commonly used BDI cut-off score of 10, the frequency of mild or greater depressive symptoms was 52%, which is similar to percentages reported in previous studie s (e.g., Brooks and Doder, 2001; Cummings, 1992). When using a cut-off score of 16/18, suggested for more accurate identification of diagnosable depression in mild to moderate PD patients (Silberman et al., 2006; Leentjens, Verhey, Luijckx, and Troost, 2000) the frequency of depression was 13.3%. The majority of patients with depression severi ty scores above this cut-off were in the mild range and fewer fell w ithin the moderate range. Based on AES and BDI cut-off scores of 38 and 18, respectively, patients in present study were assigned to four categorie s for frequency analyses (i.e., apathy-only, depression-only, apathy and depression, and no apathy or depression). The majority of patients (72.1%) were classified as neither apathetic nor depressed, whereas 14.7% of patients were classified as apathy-only, 7.4% as depressiononly, and 5.9% as apathy and depression. Findings related to Hypothesis #1 To investigate the hypothesis that increas ed levels of depression and apathy will be associated with decreased performa nce on measures of executive and memory abilities, four correlation coefficients and four simple regressions were examined.
39 Correlations Table 4 displays the results of correlation analyses. Increases in depressive symptoms were associated with decreases in memory scores ( r = -0.273, p < 0.05) but were not significantly associated with executive functioning. Increases in apathy symptoms were associated with decreases in both memory ( r = -0.331, p < 0.01) and executive functioning (r = -0.305, p < 0.05). Apathy and depressive symptoms were positively and moderately correlated ( r = 0.548, p < 0.01). Table 4: Correlations between mood and cognitive variables Variable Depression (13-item BDI) Apathy (AES-S) Memory (HVLT Total Recall) Executive Fx (WCST Categories) Depression 1.000 Apathy .548** 1.000 Memory -.273* -.331** 1.000 Executive Fx -.141ns -.305* .478** 1.000 p<0.05 **p<0.01 ns not significant, p=.251 Regressions These relationships are corr oborated by four simple regr ession analyses, in which level of depressive symptoms or apathy symp toms were entered as the sole independent variable (IV) and memory or executive f unctioning was entered as the sole dependent variable (DV) (see Table 5). First, it was found that level of depressive symptoms significantly predicted memo ry scores ( = -.273, t (66) = -2.309, p < 0.05), with 7.5% of
40 the variance explained (R2 = .075, F (1,66) = 5.331, p < 0.05). Second, level of depressive symptoms did not significantly predict ex ecutive functioning scores as evidenced by a non-significant value ( not significantly different from 0) and a non-significant F value. The third simple regression revealed that level of apathy sy mptoms significantly predicted memory scores ( = -.331, t (66) = -2.849, p < 0.01), with 10.9% of the variance explained (R2 = .109, F (1,66) = 8.115, p < 0.01). The final simple regression revealed that level of apathy significantly predicte d scores of executive functioning ( = -.305, t (66) = -2.602, p < 0.05), with 9.3% of the variance explained (R2 = .093, F (1,66) = 6.770, p < 0.05). Table 5: Simple regression analyses Criterion Predictor SB T Sig T R2F Sig F Memory Depression -.273 -2.309 .024 .075 5.331 .024* Exec. Fx Depression -.141 -1.158 .251 .020 1.341 .251 Memory Apathy -.331 -2.849 .006 ** .109 8.115 .006** Exec. Fx. Apathy -.305 -2.602 .011 .093 6.770 .011* p<0.05 **p<0.01 SB=Standardized Beta Findings related to Hypothesis #2 To investigate the hypothesis that apathy will be more strongly associated with executive functioning than depressive sy mptoms, two correlation coefficients (1. correlation between executive functioning and depression, and 2. correlation between executive functioning and apathy) and two hi erarchical regressions were examined.
41 Correlations As mentioned above (see Table 4), executive functioning was significantly correlated with apathy ( r = -.305, p < 0.05), but not with depression ( r = -.141, p = .251). Due to the non-significant correlation between executiv e functioning and apathy, the proposed Hotellings t-test to comp are correlations was not conducted. Regressions Examination of the first hierarchical regr ession analysis reveals the influence of apathy on executive functioning scores while controlling for the influence of depressive symptoms (see Table 6-A). In this analysis, de pression (IV) is entere d in the regression first and apathy (IV) is entered second to assess whether apathy contributed unique variance in accounting for ex ecutive performance above and beyond that of depressive symptoms. As noted above, depressive symp toms did not account for any significant portion variance in executive pe rformance when entered alone. However, the addition of apathy reveals that apathy accounts for 9.4% of the variance in executive performance, with a significant change in the value of the F-test with the addition of this variable (R2 = .094, p <0.05; F (1,65) = 3.372, p < 0.05).
42 Table 6-A: Hierarchical regression anal yses related to executive functioning Criterion Predictor Unstandard. beta SE SB R2 R2 F Sig F Exec. Fx (Constant) Depression Apathy 4.229 .018 -.074 .875 .069 .032 -.037 -.325 -.020 .094 -.020 .074 -1.341 5.315 -.251 .024* p<0.05 **p<0.01 SE=Standard Error; SB=Standardized Beta Age effects. Due to the fact that age was si gnificantly correlated with the DV (executive functioning) and wa s approaching significance (p = 0.056) when correlated with one of the IVs (apathy), age was entered into regression equations first in order to control for its influence on executive func tioning (see Table 6-B). Following the entry of age, apathy was entered to assess its unique influence on executive functioning while controlling for age. Depression was not entered into this model due to the nonsignificant relationship between depression and executive functioning described above, and to the potential unfavorable effect that entering th ree predictors may have on power. Analyses revealed that age accounted for 9.7% of the variance in executive performance and apathy accounted for an additi onal 5.7% of the variance in executive performance. Table 6-B: Hierarchical regr ession analyses related to ex ecutive functioning, controlling for age Criterion Predictor Unstandard. beta SE SB R2 R2 F Sig F Exec. Fx (Constant) Age Depression Apathy 8.245 -.063 .029 -.063 2.029 .029 .067 .032 --.258 .060 -.278 -.097 .104 .157 -.097 .007 .053 -7.095 .510 3.989 -.010** .478 .050* p<0.05 **p<0.01 SE=Standard Error; SB=Standardized Beta
43 Ancillary Analyses Exploration of the Influence of Apathy and Depression on Memory In order to explore the independent e ffects of apathy and depression on memory abilities, two additional hierarchical re gressions were conducted and examined. Examination of the first hierarchical regres sion analysis reveals the influence of apathy on memory scores while controlling for the influence of depressive symptoms (see Table 7-A). In this analysis, depre ssion (IV) is entered in the regr ession first and apathy (IV) is entered second to assess whether apathy contributed unique variance in accounting for memory performance above and beyond that of depressive symptoms. As noted previously, depression accounts for 7.5% of the variance in memory scores when entered first into the regression. The addition of apathy reveals th at apathy accounts for an additional 4.7% of unique varian ce in memory performance, as evidenced by a change in the value of the F-test that approaches significance with the additi on of this variable (R2 = .122; R2 change = .047, p = .067; F (1,65) = 4.499, p < .05). For exploratory purposes, a second regressi on analysis was conducted to evaluate the influence of depressive symptoms on memory performance while controlling for the influence of apathy (see Table 7-A). In this an alysis, apathy was entered in the first step and depression was entered second to assess whether depression contributed unique variance in accounting for memory perf ormance above and beyond that of apathy symptoms. As noted previously, apathy account s for 10.9% of the variance in memory scores when entered first into the regression. The addition of de pression reveals that depression does not account for any additional or unique variance in memory scores over
44 and above that of apathy, as evidenced by a non-significant value ( no t significantly different from 0) and a non-significant F value. Table 7-A: Hierarchical regression anal yses related to immediate memory Criterion Predictor Unstandard. beta SE SB R2 R2 F Sig F Memory (Constant) Depression Apathy 28.308 -.220 -.201 2.943 .232 .108 --.132 -.259 -.075 .122 -.075 .047 -5.331 3.467 -.024* .067t Memory (Constant) Apathy Depression 28.308 -.201 -.220 2.943 .108 .232 --.259 -.132 -.109 .122 -.109 .012 -3.115 .896 -.006** .347 p<0.05 **p<0.01 ttrend, p<0.10 SE=Standard Error; SB=Standardized Beta Age effects. Due to the fact that age was significantly correlated to the DV (memory) and was approaching significance ( p = 0.056) when correlated with one of the IVs (apathy), age was entered in to regression equations first in order to control for its effect on memory (see Table 7-B). Following the entry of age, depression was entered second and apathy was entered last. Analyses revealed that age accounted for 7.8% of the variance in memory performance ( p = 0.02), depression accounted for an additional 5.1% of the variance in memory performance ( p = 0.057), and apathy no longer accounted for a significant portion of additional variance in memory performance (R2 change = 3.3%, p = 0.116). Considering the p-valu e associated with the entry of apathy last (p = 0.116), it is quite possible that the reduction in power cau sed by entering a third predictor variable into the model (power = 0.75) ma y have resulted in the inabilit y to adequately identify a significant R2 change when apathy was entered as th e third variable. Interestingly, when
45 apathy was entered into the regression an alysis before depression, level of apathy symptoms significantly accounted for an a dditional 7.5% of the variance in memory performance (p = 0.02), after accounting for the influe nce of age. In this order of operations, level of depressive symptoms no longer accounted for a significant portion of additional variance in memory performance (R2 change = 0.9%, p = 0.411), consistent with the two-predictor model described previously, which did not include age in the model. Table 7-B: Hierarchical regression analyses related to immediate memory, controlling for age Criterion Predictor Unstandard. beta SE SB R2 R2 F Sig F Memory (Constant) Age Depression Apathy 39.261 -.171 -.190 -.172 6.907 .098 .229 .108 --.206 -.114 -.221 -.078 .128 .162 -.078 .051 .033 -5.573 3.767 2.534 -.021* .057t .116 Memory (Constant) Age Apathy Depression 39.261 -.171 -.172 -.190 6.907 .098 .229 .108 --.206 -.221 -.114 -.078 .153 .162 -.078 .075 .009 -5.573 5.733 .685 -.021* .020* .411 p<0.05 **p<0.01 ttrend, p<0.08 SE=Standard Error; SB=Standardized Beta Use of the 21-item versus 13item Version of the BDI-II All analyses described above included an altered version of the BDI-II (13-item BDI) as the measure of total depressive sy mptoms, which excluded somatic and apathyrelated items in order to re duce potential confounds of th ese items on the measure of depression. Comparisons were made between regression analyses that used the 13-item
46 BDI-II and the full 21-item BDI-II in order to as sess whether the decision whether or not to include somatic and apathy-related items in the measurement of depressive symptoms would result in disparate findings. Notably, when the full 21-item BDI-II was included in the regression analyses (i.e., 1. memory re gressed on apathy and depression, 2. executive functioning regressed on depres sion and apathy) in place of the 13-item version, results were comparable. In addition, there was little difference in the correlations between apathy and depression severity regardless of whether the full 21-item version or the altered 13-item version was used in the analysis ( r = 0.548 versus r = 0.563, respectively). These findings suggest that the omission of overlapping somatic and apathy-related items from the BDI for the purpose of measuring symptoms unique to depression may not be beneficial. Use of Informant-Ratings versus Self-Ratings of Apathy Comparisons were made between regression analyses that used the AES selfrating form (AES-S) and the informant-rating form (AES-I) in order to assess whether the source of this information would have an effect on the findings. In the regression analyses that included executive functioning as the DV, results were comparable regardless of whether the AES-S or AES-I was used. In the regression analyses that included memory as the DV, results were al so comparable with the use of the AES-I except that the added influence of apathy over and above that of depression reached full statistical significance (p < 0.05) as opposed to being a trend.
47 4. Discussion The purpose of the present study was to examine the independent influence of depression and apathy on immediate memory and executive functioning in PD patients using sensitive measures of cognitive perfor mance as well as rating scales that assess symptoms unique to depression and apathy. Du e to the potential c onfounds of including somatic and apathy-related items in the measurement of depression severity, only BDI-II items corresponding to the cognitive/affec tive scale were retained (e.g., sadness, pessimism, sense of failure, etc.), with the excep tion of the item related to lack of interest due to its overlap with apathy. In other words, all somatic and apathy-related items from the full BDI-II were eliminated in order to cr eate the modified version of the BDI-II used in the present study. Further, the AES was chosen to measure apathy severity due to its purported ability to discriminate between apathy and depression. Effects of Apathy and Depression on Memory and Executive Ability In the present study, two hypotheses were i nvestigated. First, it was hypothesized that increased levels of depressive sy mptoms and increased levels of apathy would be associated with decreased performance on measures of executive and memory abilities. In support of this hypothesis, apathy negativ ely correlated with memory and executive functioning in correla tion analyses and level of apathy predicted level of memory and executive functioning in regression analys es. The hypothesis was further supported in
48 that depression negatively corre lated with memory performance in correlation analyses and level of depression predicted level of memory in regression analyses. Surprisingly, however, a relationship between depression a nd executive functioning was not identified. The correlation between level of depressive symptoms and executive functioning was not significant. While it was predicted that the magnitude of the relationship between apathy and executive functioning would be significan tly larger than that of the relationship between depression and executive functioni ng, the lack of a significant correlation between depression and executive function was unexpected. Notably, the lack of association between these variables remained when the full 21-item BDI-II was included in secondary analyses, demons trating that the la ck of relationship between depression severity and executive functioning was not explained by the exclusion of somatic and apathy-related items or by the conseque nt reduction in range of scores. Unique Effects of Apathy and Depression on Executive Function Second, it was hypothesized that apathy would be more strongly associated with executive functioning than depressive symptoms as demonstrated by the magnitude of the correlation coefficients and by a significant R2 change when apathy was entered last in a hierarchical regression anal ysis. This hypothesis was supported. Increases in apathy, but not depression, were significantly associated with decreases in executive performance. Hierarchical regression analyses revealed that apathy, and not depression, accounted for a significant proportion of added variance in ex ecutive functioning. Wh en controlling for age, this finding remained.
49 It is possible that the re lationship between depression and executive function may be a small effect, and that the present st udy did not have an adequate number of participants, and hence power, to detect that relationship. While the number of participants in the present study ( n = 68) is adequate for dete cting a medium effect size with power of 0.80, this would not have been enough subjects to de tect a small effect. Alternatively, using a shortened version of the BDI-II may have restricted the range of scores on this measure of depr essive symptoms. However, this is unlikely for a couple of reasons. First, the lack of association rema ined when using the full version of the BDI-II as when using the shortened, modified version. Second, a relationship was identified between level of depressive symptoms (i.e., as measured using the shortened BDI-II) and memory, indicating that the memory analyses were not hindered by restriction of range. Regardless, the finding that the relationship between depression and executive function is not significant in the present study, but that the relationship between apathy and executive function is significant, supports the notion that apathy ha s a greater influence than depression on executive impairment in patients with Parkinsons disease. The present findings are consistent with other studies reporting similar results. Pluck and Brown (2002) found that apathy, but not depression, was associated with deficits on three measures of executive f unctioning (i.e., category fluency, Stroop ColorWord test, and WCST). Isella and colleague s (2002) found that PD patients with highapathy showed significantly greater impairmen t in executive functioning [i.e., Executive Interview (EXIT), letter flue ncy and category fluency] when compared to lowand moderate-apathy groups. Signi ficant correlations were id entified between apathy and
50 executive functioning while depression was not significantly associated with apathy or any cognitive abilities measured. Similarly, Aarsland and colleagues (1999) identified a significant association between executive functioning and apathy but not between executive functioning and depression or between apathy and depression. Unique Effects of Apathy and Depression on Memory Finally, exploratory analyses were conducted to inves tigate the possible independent effects of apathy and depressi on on immediate memory abilities. As stated above, levels of both apathy and depressive symptoms were similarly correlated with memory performance. Hierarchical regressi on analyses were used to investigate the degree of influence that apathy has on me mory performance when controlling for depression and the degree of influence that depression has on memory performance when controlling for apathy. Our findings s uggest that while depression does not predict memory scores over and above that of apat hy, apathy revealed a strong trend to predict memory over and above that of depression (i.e., p = .067). When controlling for age, the findings becam e less clear. It is important to note that by choosing to investigat e the effects of apathy and depression on memory while controlling for age, power was reduced to 0.75 due to the addition of a third independent variable (i.e., age) into the regr ession equation. A cl oser look at the p -values associated with entering either depression or apathy as the third variable (refer to Table 7-B) reveals that when age is controlled for, apathy likely remains as a significant predictor of memory scores over and above that of depression ( p = .116). In contrast, it is unlikely
51 that depression is a significan t predictor of memory scores over and above that of apathy (p = .411). A larger sample is needed to test whether this is, in fact, accurate, since there was insufficient power to investigate the infl uence of three indepe ndent variables given the sample size in this inves tigation. An alternative explanat ion for this finding is that, despite our attempts to use measures that assess non-shared aspects of apathy and nonshared aspects of depression, our measuremen t did not fully discriminate. This raises question regarding the construct validity of the scales used a nd begs further investigation into definitions and assessments of apathy. Conclusion Overall, the findings of the present study suggest that apathy and depression may exert unique effects on memory and executive function. These findings provide support for the notion of apathy and depression as discernable constructs. First, apathy and depression were differentially related to c ognitive performance, most strongly in the domain of executive functioning. Second, the fre quencies of clinical elevations of apathy and depression in the present sample also support the notion that apathy and depression can be considered as distinguishable constructs, with clinically elevated apathy symptoms existing in the absence of clinically elev ated depressive symptoms. The presence of clinically elevated apathy in the absence of depression has been even more convincingly and consistently in Alzheimers diseas e, frontotemporal dementia, progressive supranuclear palsy, and basal ganglia stroke (e.g., Levy et al., 1998; Starkstein et al., 2005).
52 While unique aspects of depression and apathy may explain their differential influence on executive functioning, shared f actors may underlie their relationship with memory. Potential shared mechanisms may include frontostriatal circuitry, reduced processing speed, anergia, avolition, and the emotional concomitants of apathy (e.g., anhedonia). While most of the apathy liter ature is consistent in defining apathy by behavioral and cognitive dimensions, opinions differ on whether definitions should include an emotion dimension (Starkstei n and Leentjens, 2007) According to a preliminary study of patients with dementia, anhedonia is rarely reported in patients who report apathy but no depression, suggesting that anhedonia may be more characteristic of depression than apathy (SE Starkstein, persona l communication; as c ited in Starkstein and Leentjens, 2007). Theoretical Implications Differentiation of apathy and depressi on and understanding their independent effects has several implications both for clinical treatment and for scie ntific pursuit. First, apathy appears to be negatively associated with cognitive functioning, daily functioning, and caregiver burden and distress (van Ree kum et al., 2005). Secondly, apathy has been associated with increased morbidity and mortality. Apathetic patients devote less attention and time to self-care, which can result in medical complications. Additionally, it may interfere with treatment response and medication compliance and has been associated with increased mo rtality and financial burden (Stephenson, 2005; van Reekum et al., 2005).
53 Further, due to the absen ce of reported or exhibited distress, patients suffering from apathy are often overlooked by the health care system. There is currently a bias in health care favoring diagnosing depression (Schulman, 2000). Cognizance of apathy in patients seeking health care services may he lp to prevent false positive diagnoses of depression and may increase efficiency in ti mely and adequate treatment of patients experiencing apathy and not depression. A dditionally, making caregivers aware of the prevalence of apathy in Parkinsons disease, among other neuropsychiatric or neurologic diseases, may help them understand that rela ted behaviors are not due to insolence or laziness but, rather, to a diseaserelated neurologic changes. Identification of apathy may be improved by the inclusion of ap athy in psychiatric classification systems. Currently, apathy is underrepresented in such classification systems. Apathy is not referenced in the ICD-10 (WHO, 1993) and is only mentioned specifically in relation to f our disorders of the DSM-IV (APA, 1994), with no inclusion of the term apathy in the DSM-IV glossar y. Discussion regarding differential diagnosis and on whether apathy should appear as a stand-alone disorder in the Diagnostic and Statistical Manual of Mental Di sorders, Fifth Edition (DSM-V) has begun (Stephenson, 2005). If not included as a stand-alone disorder, potential im provements of the status of apathy, including clarifying the definition of ap athy, adding apathy to the glossary of the DSM, or creating a reference to help direct clinicians to th e range of disorders commonly associated with apathy, are being considered by DSM-IV Editor, Michael B. First, MD (Stephenson, 2005).
54 If appropriately identified, preliminary research suggest s that symptoms of apathy may be medically or behaviorally treated independently of depressive symptoms. For example, Weitzner and colleagues (2005) desc ribed four cases of pituitary disease patients who were diagnosed and medically treated for depression but showed little response to treatment. When the diagnosis of apathy syndrome was considered and treatment with methylphenidate was impl emented, the patients condition improved subjectively and on objective cogn itive tasks. Further, Hoe hn-Saric, Lipsey, and McLeod (1990) found that apathy and indifference follo wed treatment with se lect antidepressant serotonin-reuptake-inhibitors. Notably, thes e were not randomly, controlled medication trials, which would be a great benefit to the apathy treatment literature. Behavioral treatments may also prov ide benefit to patients experiencing disruptive levels of apathy. B oyle and Malloy (2004) have su ggested that caregivers may be able to play an important role in be havioral training programs aimed at reducing apathy in patients with Alzheimers disease. By definition, apathy i nvolves the lack of motivation and initiation. Caregivers may promote behavioral activation by helping patients initiate goal-directed behaviors, increasing their involvement in pleasant activities, and providing increase d structure for activities. Future research elucidating the effectiv eness of caregiver-involved behavioral interventions, as well as randomized cont rolled medication trials, on patients with elevated levels of apathy is warranted. In addition, future studies aimed at understanding the neural underpinnings of depression and ap athy may help guide more effective choices of pharmacological and/or behavioral ma nagement of these symptoms. Further
55 investigation into the relationship between ap athy and fluctuating on/off periods in PD patients, in which levels of dopamine are ad equate or limited in the brain, may provide interesting information regarding the underlying neurotransm itter effects. Differentiation of apathy and depressi on has robust implications for the advancement of psychological science and pa tient care. The utility of investigating symptoms of apathy and depression, as opposed to solely clinical dia gnoses, is evident in that even some level of symptomatic ap athy and depression appears to influence efficiency of patients cognitive abilities. A focus on apathy symptoms in patients may optimize treatment approaches, improve patients daily functioning, increase independence, and result in an improved qua lity of life for both patients and their caregivers.
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Appendix A: Beck Depression Inventory II (Note: Items used for the 13-item modified version are highlighted) 71
73 Appendix B: Apathy Evaluation Scale Self-Rating form For each question, circle the an swer that best describes your thoughts, feelings and actions during the past 4 weeks. 1. I am interested in things. Not at All 0 items 1 Slightly 1-2 items 2 Somewhat 2-3 items 3 Very 3 or more items 4 2. I get things done during the day. Not at All 0 items 1 Slightly 1-2 items 2 Somewhat 2-3 items 3 Very 3 or more items 4 3. Getting things started on my own is important to me. Not at All Characteristic 1 Slightly Characteristic 2 Somewhat Characteristic 3 A Lot Characteristic 4 4. I am interested in having new experiences. Not at All 0 items 1 Slightly 1-2 items 2 Somewhat 2-3 items 3 Very 3 or more items 4 5. I am interested in learning new things. Not at All 0 items 1 Slightly 1-2 items 2 Somewhat 2-3 items 3 Very 3 or more items 4
74 6. I put little effort into anything. Not at All Characteristic 1 Slightly Characteristic 2 Somewhat Characteristic 3 A Lot Characteristic 4 7. I approach life with intensity. Not at All Characteristic 1 Slightly Characteristic 2 Somewhat Characteristic 3 A Lot Characteristic 4 8. Seeing a job through to the end is important to me. Not at All Characteristic 1 Slightly Characteristic 2 Somewhat Characteristic 3 A Lot Characteristic 4 9. I spend time doing things that interest me. Not at All Characteristic 1 Slightly Characteristic 2 Somewhat Characteristic 3 A Lot Characteristic 4 10. Someone has to tell me what to do each day. Not at All Characteristic 1 Slightly Characteristic 2 Somewhat Characteristic 3 A Lot Characteristic 4 11. I am less concerned about my problems than I should be. Not at All Characteristic 1 Slightly Characteristic 2 Somewhat Characteristic 3 A Lot Characteristic 4 12. I have friends. Not at All 0 items 1 Slightly 1-2 items 2 Somewhat 2-3 items 3 Very 3 or more items 4
75 13. Getting together with friends is important to me. Not at All Characteristic 1 Slightly Characteristic 2 Somewhat Characteristic 3 A Lot Characteristic 4 14. When something good happens, I get excited. Not at All Characteristic 1 Slightly Characteristic 2 Somewhat Characteristic 3 A Lot Characteristic 4 15. I have an accurate understanding of my problems. Not at All Characteristic 1 Slightly Characteristic 2 Somewhat Characteristic 3 A Lot Characteristic 4 16. Getting things done during the day is important to me. Not at All Characteristic 1 Slightly Characteristic 2 Somewhat Characteristic 3 A Lot Characteristic 4 17. I have initiative. Not at All Characteristic 1 Slightly Characteristic 2 Somewhat Characteristic 3 A Lot Characteristic 4 18. I have motivation. Not at All Characteristic 1 Slightly Characteristic 2 Somewhat Characteristic 3 A Lot Characteristic 4