| dc.description.abstract | Lewy body dementia is an umbrella term encompassing multiple neurodegenerative conditions that share primary symptoms of cognitive, motor, sleep and neuropsychiatric disorder linked to the abnormal accumulation of the alpha-synuclein protein in the brain, termed Lewy bodies. These conditions include Dementia with Lewy bodies, wherein cognitive and neuropsychiatric symptoms manifest early in disease and Parkinson’s disease dementia where cognitive decline occurs secondarily to longer standing Parkinson’s disease. Together, these dementias constitute the second most common form of neurodegenerative dementia, carrying greater burden on both patients and carers than the most common cause of dementia, Alzheimer’s disease. Nevertheless Lewy body dementia has been historically under-researched, with the genetic contribution to disease development only recently being robustly studied. Limited exploration has been undertaken into epigenetics, which are molecular processes that alter the expression of genes and potentially hold important molecular insights into the significant variability observed in Lewy body dementia.
This thesis aimed to expand the Lewy body dementia research field by investigating epigenetic contributions to the disease, principally through DNA methylation. This included a large scale epigenome-wide association study into the development of Lewy body pathology in the brain and the differential presentation of Dementia with Lewy bodies and Parkinson’s disease dementia, nominating a number of associated sites with evidence of altered DNA methylation. The contribution of DNA methylation to clinical heterogeneity in Parkinson’s disease was further assessed, finding evidence of altered DNA methylation linked to specific cell types of the midbrain associated with the development of neuropsychiatric symptoms. Protocols for the isolation of Lewy body affected neurons were tested and the most established DNA methylation profiling method was benchmarked for feasibility in future research into pathology-specific epigenetic changes. Finally, machine learning based methods were tested for their utility in predicting the progression of cognitive decline in Parkinson’s disease and the inclusion of blood based epigenetic measures were assessed for their contribution to the accuracy of a multi-modal classifier of future outcome prediction. In summary, the studies within this thesis represent a comprehensive assessment of DNA methylation in Lewy body dementia, highlighting targets with evidence of epigenetic association to both pathological development and clinical heterogeneity, for future study. | en_GB |
