Idiopathic Parkinson’s disease (IPD) is the second most common neurodegenerative disease, yet effective disease modifying treatments are still lacking. Neurodegeneration involves multiple interacting pathological pathways. The extent to which neurovascular mechanisms are involved in IPD is not well defined. Indeed within the umbrella term of IPD great heterogeneity of motor (and non-motor) features exists, suggesting that different phenotypes may have differing underlying pathophysiologies. We aimed to determine whether novel magnetic resonance imaging (MRI) techniques can reveal changes in structural or physiological neurovascular measures, herein also referred to as ‘altered neurovascular status (NVS)’, in IPD.Based on preliminary data from our initial exploratory study in a small IPD cohort, phenotypic differences in structural and physiological MRI measures of NVS were investigated in a larger study. The 3 Tesla (3T) MRI protocol included T2-weighted fluid-attenuated inversion recovery (FLAIR) imaging to assess white matter lesion (WML) burden, arterial spin labelling (ASL) measurements of cerebral blood flow (CBF) and arterial arrival time (AAT) and dynamic contrast enhanced (DCE) measures of blood-brain barrier (BBB) integrity. Analysis was undertaken of IPD clinical phenotypes, by comparison with two control groups. In total, fifty-one patients with IPD (mean age 69.0 ± 7.7 years) (21 tremor dominant [TD], 24 postural instability and gait disorder [PIGD] and 6 intermediates) were compared with 2 control groups, the first comprising 18 control positive (CP) subjects with a history of clinical cerebrovascular disease (CVD) (mean age 70.1 ± 8.0 years) and the second comprising 34 control negative (CN) subjects without a history of clinical CVD (mean age 67.4 ± 7.6 years). IPD patients showed diffuse regions of significantly prolonged AAT and lower CBF by comparison with CN subjects, and a few regions of prolonged AAT by comparison with CP subjects, despite significantly fewer vascular risk factors. TD patients showed regions of significantly prolonged AAT and lower WML volume by comparison with PIGD patients. IPD patients also showed increased leakiness of the BBB in basal ganglia regions compared to the CN group, with a similar pattern in both IPD phenotypes. These data provide evidence of altered NVS in IPD, with IPD phenotype specific differences.

Introduction: Idiopathic Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder that is characterised by motor symptoms. However, there is increasing awareness that a range of neuropsychiatric and cognitive problems also accompanys PD. The objective of this thesis was to examine the profile of neuropsychiatric and cognitive problems for patients with PD without dementia. Parkinson's disease patients who could be identified at the time of this study were invited to participate. Each patient was individually matched to a healthy control in terms of age, premorbid intelligence, and years of education. Results: Neuropsychiatric symptoms were common for this patient group, over 40% self reported symptoms consistent with depression, 40% with physical fatigue, 38% with mental fatigue, 38% with apathy and 32% with sleep problems. More than 77% of patients with PD reported symptoms associated with at least one problem and over 46% with 3 or more problems. Increased symptoms consistent with depression and anxiety and the presence of hallucinations also predicted poorer quality of life after controlling for motor symptoms. However, the of level agreement between patient report and that of a person who know them well was low: 40.9% for apathy, 28% for hallucinations, 39% for depression, 25% for sleep problems and only 7.7% agreement for the presence of anxiety. To obtain an accurate profile of cognitive impairments patients were assessed on measures of higher order language ability and a broad range of commonly used cognitive tests. Overall, PD patients were impaired on aspects of higher-order language. However, results indicated that these deficits were not a primary effect of PD, but could be explained in terms of deficits in speed of information processing associated with the disease. Compared to healthy controls, PD patients also showed deficits on measures of executive function, working memory, problem solving, and visuospatial skills. However, they were unimpaired on measures of planning, attention and memory/learning. Deficits in problem solving were only evident for tasks with a high visuospatial content and were no longer significant when visuospatial skills were controlled for. Further investigation indicated that planning in PD patients was not impaired in general and was dependent on the sensitivity of tests used. To further examine cognitive deficits, patients were divided into groups according to their cognitive performance. Three sub-groups of patients were identified that formed a continuum of cognitive impairment from none/mild to severe. Compared to controls, one subgroup showed no or minimal impairment (PD-NCI), a second group showed a more variable pattern of severe and mild impairments (PD-UCI), and a third group had evidence of severe impairment across most of the cognitive domains tested. This latter group was labelled PD-Mild Cognitive Impairment (PD-MCI). The PD-UCI and PD-MCI groups were also significantly different from their controls with respect to their ability to carry out functional activities of everyday living. The PD-MCI group had evidence of global cognitive decline, possibly reflecting a stage of pre-clinical dementia. The severity of cognitive deficits was not associated with other clinical and demographic characteristics such as motor impairments, age or disease duration. These results were confirmed when patients were retested one year later. Conclusions: Comorbid neuropsychiatric and cognitive problems are common for patients with PD prior to any overt signs of dementia. However, PD patients are heterogeneous with regard to their presentation and different subgroups of patients are identifiable based on cognitive performance. This information has both theoretical and clinical relevance.