DNA methylation as a biomarker for age-related cognitive impairment

PhD ThesisDue to the ageing population, the number of patients diagnosed with age-related diseases such as stroke and Parkinson’s disease are on the rise. In both post-stroke dementia (PSD) and mild cognitive impairment in Parkinson’s disease (PD-MCI), the mechanisms resulting in cognitive decline are unknown. This project aims to identify a biomarker which could predict those patients most at risk of developing cognitive decline, which would subsequently assist healthcare professionals in recommending early treatment and care. Epigenetics is an emerging field in which biomarkers have previously been useful in prognostication of cancers and prediction of cardiovascular disease. In this study, 30 patients from a PSD cohort (COGFAST) and 48 patients from a PD-MCI cohort (ICICLE) were analysed using the Illumina HumanMethylation450 BeadChip to identify differentially methylated positions which could predict patients who would later develop cognitive decline. Top hits were validated using Pyrosequencing to confirm DNA methylation differences in a replication cohort. Individual CpG sites within APOB and NGF were identified as potential blood-based biomarkers for PSD and one CpG site within CHCHD5 was highlighted as a potential blood-based biomarker for PD-MCI. In addition, methylation at one CpG site within NGF and a CpG site (cg18837178) within a non-coding RNA, were found to be associated with Braak staging (degree of brain pathology) using DNA from two brain regions. NGF deregulation has previously been associated with Alzheimer’s disease, and this finding indicates it may also have a role in the development of PSD. These novel findings represent the first steps towards the identification of blood-based biomarkers to assist with diagnosis of PSD and PD-MCI, but require further validation in a larger independent cohort. The differentially methylated genes identified may also give insight into some of the mechanisms involved in these complex diseases, potentially leading to the future development of targeted preventative treatments.Medical Research Council and Newcastle Universit

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