Epigenetic and metabolic landscape of Dementia with Lewy Bodies

Sangeetha Vishweswaraiah*, Ali Yilmaz, Juozas Gordevicius, Milda Milčiūtė, Karolis Krinickis, Ieva Kerseviciute, Bernadette McGuinness, Peter Passmore, Patrick G. Kehoe, Brian D. Green, Uppala Radhakrishna, Stewart F. Graham*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Lewy body diseases, including dementia with Lewy bodies (DLB), are characterized by α-synuclein accumulation, leading to dementia. Previous studies suggest distinct epigenetic and metabolomic profiles in DLB. Objective: This study aims to identify diagnostic biomarkers by analyzing the methylome and metabolome in the Brodmann area 7 of postmortem brain tissues from DLB patients and control subjects using multiomics approaches. 

Methods: Methylation analysis was performed using the Illumina EPIC array, and metabolomics profiling was conducted via 1H nuclear magnetic resonance (NMR) and direct injection/liquid chromatography coupled with mass spectrometry. Differential methylation and metabolite analysis were conducted, followed by pathway enrichment to explore biological relevance. 

Results: We identified 3478 significantly differentially methylated cytosines, mostly hypermethylated, enriched in CpG islands near transcription start sites. Pathway enrichment analysis showed significant pathways, primarily linked to olfactory and synaptic functions. Metabolomics profiling identified 15 significantly altered metabolites, with Phosphatidylethanolamine (PE) Biosynthesis being the most affected pathway. Key correlations between differentially methylated cytosines and metabolites, particularly in the PE Biosynthesis pathway involving PTDSS1 and PCYT2 genes, were observed. 

Conclusions: Notably, sex-specific differences were found, with females exhibiting more epigenetic and metabolomic changes than males. Increased hypermethylation, linked to transcriptional silencing, and disruptions in PE biosynthesis suggest a role in synaptic dysfunction and olfactory deficits. In addition, α-aminoadipic acid was strongly associated with vascular functions, hinting at a possible overlap between vascular health and DLB. This study provides new insights into DLB mechanisms and potential therapeutic targets.

Original languageEnglish
JournalMovement Disorders
Early online date30 Dec 2024
DOIs
Publication statusEarly online date - 30 Dec 2024

Bibliographical note

Publisher Copyright:
© 2024 International Parkinson and Movement Disorder Society.

Keywords

  • dementia
  • dementia with Lewy bodies
  • DNA methylation
  • epigenetics
  • metabolomics
  • multiomics

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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