APATHY, NEUROCOGNITIVE FUNCTIONING, AND PARKINSON‘S DISEASE

By LINDSEY KIRSCH-DARROW

A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2010

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© 2010 Lindsey Kirsch-Darrow

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ACKNOWLEDGMENTS I would like to thank my mentor, Dawn Bowers, for her generous time, encouragement, and constant support. I would like to thank Michael Marsiske for his ready support, and assistance from the beginning to the end of this project. I would also like to thank Michael Okun and his colleagues at the Movement Disorders Center for access to patients and for insightful comments on the study. I thank Russell Bauer, Jay Rosenbek, and the students from the Bowers‘ lab, especially Laura Zahodne, Utaka Springer, and Ania Mikos for their insightful comments on the study. I thank my husband, Adam Darrow, for his unwavering devotion, love, patience, and support for all of my endeavors. Finally, I would like to express appreciation and respect for all of the PD patients who participated in this study, and whose lives have been altered by mood disorders.

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TABLE OF CONTENTS page LIST OF TABLES ...........................................................................................................................6 LIST OF FIGURES .........................................................................................................................8 ABSTRACT .....................................................................................................................................9 CHAPTER 1

STATEMENT OF THE PROBLEM ......................................................................................11

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BACKGROUND ....................................................................................................................14 Motor Symptoms in Parkinson Disease ..................................................................................14 Depression in PD ....................................................................................................................15 Defining Apathy .....................................................................................................................16 Lack of Accepted Diagnostic Criteria for Apathy ...........................................................18 Apathy Rating Scales in PD ............................................................................................19 Phenomenology of Apathy: Clinical Correlates and Course ...........................................23 Separating Apathy and Depression in PD ..............................................................................26 Confirmatory Factor Analysis: Rationale for Selection of Factors ........................................27 Prior Exploratory Factor Analysis of BDI-II and AS ......................................................29 Potential Contribution of Confirmatory Factory Analysis ..............................................30 Potential Implications ......................................................................................................31 Apathy and Cognitive Impairment .........................................................................................33 Overview of Cognitive Impairment in PD ......................................................................33 Executive Functions: Definition and Review of Findings in PD ....................................35 Cognitive Impairment: Association with Demographic and Disease Variables .............39 Mood Disorders in PD: Effect on Cognition. ..................................................................40

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SPECIFIC AIMS OF THE PRESENT STUDY .....................................................................51

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PARTICIPANTS AND METHODS ......................................................................................53 Participants .............................................................................................................................53 Procedure ................................................................................................................................55 Overview of Design .........................................................................................................55 Study 1: Examining Apathy and Depression Factors ......................................................55 Analytic Approach...........................................................................................................57 Study 2: Apathy and Cognitive Impairment ....................................................................59 Analytic Approach...........................................................................................................60

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RESULTS ...............................................................................................................................66 Aim 1: Relationship Between Apathy and Depression ..........................................................66

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Frequency of Apathy and Depression Symptoms ...........................................................66 Differences Between Apathy-Depression Groups on Demographics, Disease Variables, and Medication Usage ................................................................................66 Differences Between Apathy-Depression Groups on State and Trait Anxiety ...............69 Factor Structure of Apathy and Depression: Confirmatory Factor Analysis ..................70 Aim 2: Relationship between Apathy and Cognition ............................................................74 Cognitive Domain Regression Analyses .........................................................................75 Summary of Regression Results ......................................................................................79 Apathy‘s Relationship to Individual Executive Functioning ..........................................79 Subsample‘s Performance: Wisconsin Card Sort Test ...................................................81 Summary of Hierarchical Regression Results ..........................................................82 6

DISCUSSION .......................................................................................................................112 Prevalence of Apathy and Depression ..................................................................................113 Factor Structure of Apathy and Depression in PD ...............................................................114 Apathy and Cognition ...........................................................................................................119 Apathy‘s Relationship to Cognitive Domains ...............................................................119 Apathy and Stroop color word performance: Relationship to anterior cingulate cortex ..................................................................................................................120 Apathy and speeded verbal fluency .......................................................................123 Apathy-Depression Group Findings ..............................................................................125 Comparison to the Current Literature............................................................................127 Relationship Between Apathy and Anxiety ..........................................................................128 Limitations ............................................................................................................................129 Conclusions and Directions for Future Research .................................................................131

LIST OF REFERENCES .............................................................................................................134 BIOGRAPHICAL SKETCH .......................................................................................................145

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LIST OF TABLES Table

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Marin‘s proposed criteria for the syndrome of apathy.......................................................48

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Proposed consensus criteria for a syndrome of apathy from the European Psychiatric Association .........................................................................................................................49

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Summary of PD studies examining cognition in apathetic versus nonapathetic groups ...50

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Patient characteristics.........................................................................................................62

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Proposed loadings of each item. ........................................................................................63

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Tests categorized into rationally derived cognitive domains. DV = dependent variable. ..............................................................................................................................64

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Demographic, disease variable, and medication average scores, standard deviations, and ranges between no symptom, pure apathy, pure depression, and mixed apathydepression groups...............................................................................................................85

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STAI State and Trait average scores, standard deviations, and ranges between no symptom, pure apathy, pure depression, and mixed apathy-depression groups ................86

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Confirmatory factor analysis loadings and uniquenesses ..................................................90

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Factor correlations .............................................................................................................91

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Goodness-of-fit statistics for confirmatory factor analysis of full four factor model and alternative nested models ............................................................................................91

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Descriptive statistics for individual cognitive tests ...........................................................92

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Descriptive statistics for cognitive domains used in hierarchical regressions (z score metric) ................................................................................................................................92

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Correlations among cognitive domains (Pearson correlations). ........................................93

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Multicollinearity statistics for hierarchical multiple regressions .......................................94

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Hierarchical multiple regression results, showing the relationship between predictors and Executive functioning .................................................................................................96

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Hierarchical multiple regression results, showing the relationship between predictors and Processing speed .........................................................................................................98

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Hierarchical multiple regression results, showing the relationship between predictors and Verbal episodic memory ...........................................................................................100 6

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Hierarchical multiple regression results, showing the relationship between predictors and Working Memory ......................................................................................................102

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Hierarchical multiple regression results, showing the relationship between predictors and Language Functioning ...............................................................................................104

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Hierarchical multiple regression results, showing the relationship between predictors and Wisconsin Card Sorting Test, raw number of categories achieved ..........................106

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Hierarchical multiple regression results, showing the relationship between predictors and Wisconsin Card Sorting Test, raw number of perseverative errors ..........................108

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Demographic, disease variable differences between apathetic and nonapathetic groups. ..............................................................................................................................110

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Mood and anxiety differences between apathetic and nonapathetic groups. ...................111

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LIST OF FIGURES Figure

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Overlap between apathy and depression, apathy alone, and depression alone between groups. ................................................................................................................................47

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Prevalence of apathy and depression in 161 Parkinson patients........................................84

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Mean State Anxiety Scores across Apathy-Depression subgroups. ..................................87

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Mean Trait Anxiety scores across Apathy-Depression subgroups ....................................88

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Percentages of patients with clinically elevated trait anxiety across ApathyDepression subgroups. .......................................................................................................89

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Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy APATHY, NEUROCOGNITIVE FUNCTIONING, AND PARKINSON‘S DISEASE By Lindsey Kirsch-Darrow August 2010 Chair: Dawn Bowers Major: Psychology Apathy is a common neuropsychological feature of Parkinson‘s disease (PD). The aims of the present study were twofold: 1) to test the hypothesis that apathy and depression are separate syndromes in PD, and 2) to determine the effect of apathy on neurocognitive performance in PD patients after controlling for important comorbidities such as dementia, depression, and disease variables. One-hundred sixty-one non-demented PD patients (age = 64.1, ± 8.4 yrs; UPDRS motor severity = 25.13 ± 8.6) were administered neuropsychological tests and completed the Apathy Scale and Beck Depression Inventory-II. Items were proposed to load onto four factors: 1) an apathy factor representing loss of motivation, 2) dysphoric mood factor representing sadness and negativity, 3) loss of interest and pleasure factor, and 4) somatic factor representing bodily complaints. CFA was used to examine the fit of the items to the factors. Hierarchical regression was used to quantify whether apathy uniquely explained variance in specific cognitive domains (e.g. Executive functioning, Processing speed, Verbal episodic memory, Working memory, and Language domains).

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There was a good fit for the overall CFA model, χ2 (128, N = 146) = 194.9, p