Mitochondrial genomic variation in dementia with Lewy bodies: association with disease risk and neuropathological measures

Rebecca R. Valentino, Chloe Ramnarine, Michael G. Heckman, Patrick W. Johnson, Alexandra I. Soto-Beasley, Ronald L. Walton, Shunsuke Koga, Koji Kasanuki, Melissa E. Murray, Ryan J. Uitti, Julie A. Fields, Hugo Botha, Vijay K. Ramanan, Kejal Kantarci, Val J. Lowe, Clifford R. Jack, Nilufer Ertekin-Taner, Rodolfo Savica, Jonathan Graff-Radford, Ronald C. PetersenJoseph E. Parisi, R. Ross Reichard, Neill R. Graff-Radford, Tanis J. Ferman, Bradley F. Boeve, Zbigniew K. Wszolek, Dennis W. Dickson, Owen A. Ross

Research output: Contribution to journalArticlepeer-review

Abstract

Dementia with Lewy bodies (DLB) is clinically diagnosed when patients develop dementia less than a year after parkinsonism onset. Age is the primary risk factor for DLB and mitochondrial health influences ageing through effective oxidative phosphorylation (OXPHOS). Patterns of stable polymorphisms in the mitochondrial genome (mtDNA) alter OXPHOS efficiency and define individuals to specific mtDNA haplogroups. This study investigates if mtDNA haplogroup background affects clinical DLB risk and neuropathological disease severity. 360 clinical DLB cases, 446 neuropathologically confirmed Lewy body disease (LBD) cases with a high likelihood of having DLB (LBD-hDLB), and 910 neurologically normal controls had European mtDNA haplogroups defined using Agena Biosciences MassARRAY iPlex technology. 39 unique mtDNA variants were genotyped and mtDNA haplogroups were assigned to mitochondrial phylogeny. Striatal dopaminergic degeneration, neuronal loss, and Lewy body counts were also assessed in different brain regions in LBD-hDLB cases. Logistic regression models adjusted for age and sex were used to assess associations between mtDNA haplogroups and risk of DLB or LBD-hDLB versus controls in a case-control analysis. Additional appropriate regression models, adjusted for age at death and sex, assessed associations of haplogroups with each different neuropathological outcome measure. No mtDNA haplogroups were significantly associated with DLB or LBD-hDLB risk after Bonferroni correction.Haplogroup H suggests a nominally significant reduced risk of DLB (OR=0.61, P=0.006) but no association of LBD-hDLB (OR=0.87, P=0.34). The haplogroup H observation in DLB was consistent after additionally adjusting for the number of APOE ε4 alleles (OR=0.59, P=0.004). Haplogroup H also showed a suggestive association with reduced ventrolateral substantia nigra neuronal loss (OR=0.44, P=0.033). Mitochondrial haplogroup H may be protective against DLB risk and neuronal loss in substantia nigra regions in LBD-hDLB cases but further validation is warranted.

Original languageEnglish (US)
Article number103
JournalActa Neuropathologica Communications
Volume10
Issue number1
DOIs
StatePublished - Dec 2022

Keywords

  • Dementia with Lewy-bodies
  • Lewy body disease
  • Mitochondrial DNA
  • Mitochondrial haplogroups
  • Neuropathology

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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