The clinical spectrum, pathological and proteomic features of dementia with Lewy bodies and Parkinson’s disease dementia

Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), known as Lewy body dementias, have a number of overlapping clinical and neuropathological features. At present, the one-year rule for the temporal onset of dementia and parkinsonism is used in clinical and research settings for the differentiation between DLB and PDD. Previous comparative clinical and neuropathological studies identified important differences such as more severe parkinsonism in PDD, worse cognitive deficit and more severe Alzheimer’s disease (AD) neuropathology in DLB which have contributed to the better differentiation between DLB and PDD. This thesis provides comprehensive clinical and neuropathological characteristics of DLB and PDD, and novel clinical and neuropathological differences between DLB and PDD. It also presents insights into the role of APOE genotype in Lewy body dementias and demonstrates findings from the proteomic analysis of Lewy body pathology. The findings presented in this thesis are based on a detailed analysis of more than 100 different variables which evaluated different aspects of DLB and PDD. Novel clinical and neuropathological differences include differences in clinical milestones of the disease progression and differences in the topographical distribution of cerebral amyloid angiopathy (CAA) in DLB and PDD, especially in the posterior brain areas. The neuropathological finding of CAA in DLB might have important clinical implications as it may underlie the findings on the functional imaging in the occipital lobe with higher CAA scores and represent an underlying neuropathological correlate of fluctuating cognition. APOE genotype, especially ε4 allele is a known genetic risk factor for DLB and CAA. Findings from this project demonstrated the association between amyloid-β plaques and ε4 allele in Lewy body dementias and showed that the CAA was most severe in cases with ε2/4 and ε4/4 genotype. Lewy bodies are intra-neuronal inclusions with comprising a variety of proteins. They occur in brainstem but also in neocortex as cortical Lewy bodies which represent the typical neuropathological hallmark of Lewy body dementias. This study was the first proteomic analysis of laser captured cortical Lewy bodies and Lewy neurites and aimed to identify protein constituents in Lewy bodies from cases of DLB and PDD. Proteins related to inflammatory and anti-microbial response were identified and differed in content between DLB and PDD, with the higher abundance in the PDD group. Nevertheless, this study failed to identify α-synuclein which suggested technical problems including contamination of analysed proteins. Future proteomic studies comparing PDD and DLB and aiming to validate our results will require a review of methodology to reduce potential contamination which can occur during laser capture microscopy