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Parkinson’s disease (PD) is characterized by its main motor symptoms bradykinesia, rigidity and tremor, and additional motor and non-motor symptoms. Non-motor characteristics may include cognitive dysfunction, autonomic failure, and neuropsychiatric symptoms and disorders such as anxiety, depression, psychosis, impulse control disorders, sleep disorders, and apathy. As compared to the motor symptoms, neuropsychiatric symptoms are often reported to have a higher impact on quality of life of both patients and their caregivers. Amongst neuropsychiatric symptoms, anxiety and depression are considered major predictors of reduced quality of life, followed by cognitive dysfunction. Currently, up to 45% of PD patients experience either clinically relevant anxiety symptoms or fulfill the criteria for an anxiety disorder. Anxiety in PD can also occur in the context of response fluctuations in PD symptoms, especially related to wearing-off, i.e., the re-emergence of PD symptoms while transitioning from an ‘on’ state to an ‘off’ state, typically occurring prior to the next scheduled dose of dopaminergic medication taking effect. About 75% of patients with motor fluctuations experience fluctuations in mood and/or anxiety in parallel. Diagnosing and treating anxiety in PD is complicated, due to overlapping motor and autonomic symptoms, comorbid psychiatric symptoms, and the interplay between anxiety and motor symptoms over time. This thesis mainly focuses on understanding (part 1) and treating (part 2) anxiety symptoms in the context of motor symptoms. Chapter 1 provides a general introduction on anxiety in PD including the multiple factors that complicate diagnosis and treatment. In chapter 2 we investigated the phenomenology of anxiety in PD by performing a principal component analysis on the items of the Beck Anxiety Inventory (BAI) in a sample of 294 PD patients. To investigate the generalizability of the findings in chapter 2, chapter 3 describes the replication of the principal component analysis in 123 PD patients that were referred for neuropsychiatric evaluation to a specialized neuropsychiatric outpatient department. To investigate whether the associations between motor symptoms and anxiety differed in strength between high- versus low-anxiety PD patients, we used an explorative network analysis to study these associations in chapter 4. As symptom intensity may vary over time, we investigated the longitudinal associations between anxiety, fear of falling, and freezing of gait in 153 PD patients in chapter 5. After a description of the phenomenology of anxiety, and its cross-sectional and longitudinal associations with motor and other non-motor symptoms, part 2 of this PhD thesis focuses on the treatment of these complex symptom interactions in PD patients. In chapter 6, we describe two meta-analyses on the effects of cognitive behavioral therapy and mindfulness-based therapies on psychological distress in patients with neurodegenerative disorders. Chapters 7 and 8 present the study protocol and results of a pilot randomized controlled trial (RCT) in which we described and investigated a newly developed multidisciplinary group treatment for wearing-off related anxiety in PD named BEWARE, in which we combine elements from acceptance and commitment therapy (ACT) with physical therapy. Finally, in Chapter 9, the findings of this thesis are summarized and reflected upon. I describe the reciprocal interactions between anxiety, motor, and autonomic symptoms. I link our findings to the research field on body awareness in psychosomatic disorders, discussing the commonalities in the inaccuracy of interpretation of bodily symptoms that is seen in both PD patients with wearing-off related anxiety and patients with psychosomatic disorders. Subsequently, I provide suggestions for improving this inaccuracy. This thesis helps to understand and treat anxiety symptoms in the context of motor symptoms in PD patients.

Parkinson’s disease (PD) is characterized by its main motor symptoms bradykinesia, rigidity and tremor, and additional motor and non-motor symptoms. Non-motor characteristics may include cognitive dysfunction, autonomic failure, and neuropsychiatric symptoms and disorders such as anxiety, depression, psychosis, impulse control disorders, sleep disorders, and apathy. As compared to the motor symptoms, neuropsychiatric symptoms are often reported to have a higher impact on quality of life of both patients and their caregivers. Amongst neuropsychiatric symptoms, anxiety and depression are considered major predictors of reduced quality of life, followed by cognitive dysfunction. Currently, up to 45% of PD patients experience either clinically relevant anxiety symptoms or fulfill the criteria for an anxiety disorder. Anxiety in PD can also occur in the context of response fluctuations in PD symptoms, especially related to wearing-off, i.e., the re-emergence of PD symptoms while transitioning from an ‘on’ state to an ‘off’ state, typically occurring prior to the next scheduled dose of dopaminergic medication taking effect. About 75% of patients with motor fluctuations experience fluctuations in mood and/or anxiety in parallel. Diagnosing and treating anxiety in PD is complicated, due to overlapping motor and autonomic symptoms, comorbid psychiatric symptoms, and the interplay between anxiety and motor symptoms over time. This thesis mainly focuses on understanding (part 1) and treating (part 2) anxiety symptoms in the context of motor symptoms. Chapter 1 provides a general introduction on anxiety in PD including the multiple factors that complicate diagnosis and treatment. In chapter 2 we investigated the phenomenology of anxiety in PD by performing a principal component analysis on the items of the Beck Anxiety Inventory (BAI) in a sample of 294 PD patients. To investigate the generalizability of the findings in chapter 2, chapter 3 describes the replication of the principal component analysis in 123 PD patients that were referred for neuropsychiatric evaluation to a specialized neuropsychiatric outpatient department. To investigate whether the associations between motor symptoms and anxiety differed in strength between high- versus low-anxiety PD patients, we used an explorative network analysis to study these associations in chapter 4. As symptom intensity may vary over time, we investigated the longitudinal associations between anxiety, fear of falling, and freezing of gait in 153 PD patients in chapter 5. After a description of the phenomenology of anxiety, and its cross-sectional and longitudinal associations with motor and other non-motor symptoms, part 2 of this PhD thesis focuses on the treatment of these complex symptom interactions in PD patients. In chapter 6, we describe two meta-analyses on the effects of cognitive behavioral therapy and mindfulness-based therapies on psychological distress in patients with neurodegenerative disorders. Chapters 7 and 8 present the study protocol and results of a pilot randomized controlled trial (RCT) in which we described and investigated a newly developed multidisciplinary group treatment for wearing-off related anxiety in PD named BEWARE, in which we combine elements from acceptance and commitment therapy (ACT) with physical therapy. Finally, in Chapter 9, the findings of this thesis are summarized and reflected upon. I describe the reciprocal interactions between anxiety, motor, and autonomic symptoms. I link our findings to the research field on body awareness in psychosomatic disorders, discussing the commonalities in the inaccuracy of interpretation of bodily symptoms that is seen in both PD patients with wearing-off related anxiety and patients with psychosomatic disorders. Subsequently, I provide suggestions for improving this inaccuracy. This thesis helps to understand and treat anxiety symptoms in the context of motor symptoms in PD patients.