A Role for Epigenetic Mechanisms in the Lewy Body Dementias

Abstract Background The Lewy body diseases, Dementia with Lewy bodies (DLB), Parkinson’s disease (PD) and Parkinson’s disease dementia (PDD) are all neurodegenerative diseases classified by the accumulation of alpha‐synuclein in neurons, forming Lewy bodies (LB). We hypothesise that these LBs cause epigenetic changes within neurons and surrounding cells and that these changes can be used to distinguish the different diseases from one another. Method Bulk tissue from the cingulate gyrus and prefrontal cortex was analyzed on the Illumina Infinium Methylation EPIC array generating a quantitative measure of DNA methylation for over 850,000 CpG sites (n=∼100/disease group). Linear regression and pathway analyses were then used to identify loci that are significantly different or specific to each disease. Result Study groups have been sourced consisting of cases with PD, PDD and DLB based on LB deposition and clinical symptom staging. Age‐matched control cases have been selected that have similar levels of concomitant AD pathology to the disease groups. We have identified significant changes in methylation associated with both phenotype and neuropathology alongside the cellular pathways these changes correspond with. Conclusion We have collated a well powered study cohort to interrogate the epigenetic basis of neuropathological progression and clinical staging of LB disease, controlling for levels of concomitant AD pathology. We have completed DNA methylation analysis for two disease relevant brain regions and identified both phenotype neuropathology associated changes within these regions. Processing of samples for fluorescence activated nuclei sorting (FANS) and laser capture microdissection (LCM) has begun (n=15/group) to assess the cell type specificity of the methylation changes and the effect of Lewy bodies on neuronal methylation respectively.