Methylation profiling by array for Dementia with Lewy Bodies using brain tissue

Synucleinopathies encompass Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and Parkinson’s disease dementia (PDD) and are recognized for presenting a range of cognitive, neuropsychiatric, sleep-related, motor, and autonomic symptoms. DLB manifests with early-onset dementia when Lewy bodies develop in the brainstem and cerebral cortex. We profiled the DNA methylation using the post-mortem brain tissue from the parietal cortex, specifically Brodmann area 7 and compared them with age-, and sex-matched controls. Through the integration of multi-omics approaches, we anticipate the identification of notable alterations in these well-defined samples. Additionally, our objective is to study the biochemical perturbations in the brain tissue of those individuals who died with DLB. Differentially Methylated Cytosines (DMCs) and metabolites were identified, followed by pathway enrichment analysis. Correlations between methylation changes and metabolite levels were explored. Methylation profiling revealed 3,478 significant DMCs, predominantly hypermethylated, enriched in CpG islands and gene regions related to transcription start sites. Pathway analysis identified 612 significant pathways, with notable involvement in olfactory and synaptic functions. Metabolomics profiling identified 15 significantly differentially abundant metabolites. The top perturbed pathway was Phosphatidylethanolamine (PE) Biosynthesis. Further, key correlations were found between significant DMCs and metabolites, particularly in the Phosphatidylethanolamine Biosynthesis pathway involving genes PTDSS1 and PCYT2. Further, ignsificant sex-specific epigenetic and metabolomic changes were also observed. This comprehensive analysis of DNA methylation and metabolomics in DLB highlights significant biomarkers and pathways, offering insights into disease mechanisms and potential therapeutic targets. We acquired post-mortem brain tissue from the parietal cortex, specifically Brodmann area 7 from the Brain for Dementia Research (BDR) Initiative at the Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Bristol, UK. The assessment of DLB post-mortem brains relied on available archival information and neuropathology reports, albeit limited. Control brains were selected from individuals without a clinical history of dementia, minimal neuritic plaques, a Braak tangle stage of III or lower, and no other notable neuropathological abnormalities. For DNA methylation profiling, we analyzed 15 confirmed cases of DLB and 16 healthy, aged controls, ensuring a match in sex and age within the groups. The samples were processed using Infinium MethylationEPIC Array following the manufacturer’s instructions (Illumina Infinium HD Methylation Assay Experienced User Card, Automated Protocol 15019521 v01).