Evidence that the Kennedy and polyamine pathways are dysregulated in human brain in cases of dementia with Lewy bodies

Sumeyya Akyol, Ali Yilmaz, Kyung Joon Oh, Zafer Ugur, Buket Aydas, Bernadette McGuinness, Peter Passmore, Patrick G. Kehoe, Michael Maddens, Brian D. Green

Research output: Contribution to journalArticlepeer-review

Abstract

Disruptions of brain metabolism are considered integral to the pathogenesis of dementia, but thus far little is known of how dementia with Lewy bodies (DLB) impacts the brain metabolome. DLB is less well known than other neurodegenerative diseases such as Alzheimer's and Parkinson's disease which is perhaps why it is under-investigated. This exploratory study aimed to address current knowledge gaps in DLB research and search for potentially targetable biochemical pathways for therapeutics. It also aimed to better understand metabolic similarities and differences with other dementias. Combined metabolomic analyses of 1H NMR and tandem mass spectrometry of neocortical post-mortem brain tissue (Brodmann region 7) from autopsy confirmed cases of DLB (n = 15) were compared with age/gender-matched, non-cognitively impaired healthy controls (n = 30). Following correction for multiple comparisons, only 2 metabolites from a total of 219 measured compounds significantly differed. Putrescine was suppressed (55.4%) in DLB and O-phosphocholine was elevated (52.5%). We identified a panel of 5 metabolites (PC aa C38:4, O-Phosphocholine, putrescine, 4-Aminobutyrate, and SM C16:0) capable of accurately discriminating between DLB and control subjects. Deep Learning (DL) provided the best predictive model following 10-fold cross validation (AUROC (95% CI) = 0.80 (0.60–1.0)) with sensitivity and specificity equal to 0.92 and 0.88, respectively. Altered brain levels of putrescine and O-phosphocholine indicate that the Kennedy pathway and polyamine metabolism are perturbed in DLB. These are accompanied by a consistent underlying trend of lipid dysregulation. As yet it is unclear whether these are a cause or consequence of DLB onset.

Original languageEnglish
Article number146897
JournalBrain Research
Volume1743
Early online date22 May 2020
DOIs
Publication statusPublished - 15 Sep 2020

Keywords

  • H NMR
  • Brain
  • Dementia with Lewy Bodies
  • Metabolic pathways
  • Metabolomics
  • Targeted mass spectrometry

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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