Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Mitochondrial dysfunction has been implicated in the pathobiology of Parkinson's disease (PD), yet the spatial relationship between regional energetic demand and patterns of neurodegeneration remains poorly understood, limiting mechanistic insight and development of disease-modifying therapies. OBJECTIVES: This study tested whether regional mitochondrial density aligns with patterns of brain atrophy in PD, how this alignment differs across genetic groups, and whether the mitochondrial-atrophy axis associates with motor and cognitive features. METHODS: Structural magnetic resonance imaging data were analyzed from 849 individuals (210 healthy controls, 639 patients with PD). Principal component analysis (PCA) identified dominant atrophy axes and tested their association with regional mitochondrial density and complex I activity. Transcriptomic validation used Allen Human Brain Atlas gene expression data restricted to 924 MitoCarta-annotated genes across 31 cortical regions. RESULTS: Participants with PD exhibited higher volumetric loss in limbic and subcortical regions than controls. PCA showed a posterior cortical axis of atrophy (PC3) that correlated positively with regional mitochondrial density and was more strongly expressed in LRRK2-PD than in sporadic PD. This axis was selectively associated with visuospatial dysfunction. Transcriptomic validation confirmed that regions of greater atrophy preferentially expressed mitochondrial genes, with mitoribosome assembly, mitochondrial DNA maintenance, and coenzyme Q biosynthesis emerging as the strongest pathway-level predictors. CONCLUSION: These findings link the brain's regional mitochondrial landscape to spatially patterned neurodegeneration in PD, with amplification in LRRK2 mutation carriers. This mitochondrial atrophy axis may provide a biologically informed marker aiding patient stratification and mitochondrial-targeted therapeutic development. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Source: Movement Disorders
DOI: 10.1002/mds.70561
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
Funders: U.S. Department of Defense, Michael J. Fox Foundation for Parkinson's Research, Bristol-Myers Squibb, Eli Lilly and Company, Sanofi, Regeneron Pharmaceuticals, Voyager Therapeutics, Weston Family Foundation, Australian Rotary Health, H. Lundbeck A/S, Genentech, National Health and Medical Research Council
Awards: Predicting, diagnosing and treating synucleinopathies, From dreams to delirium and dementia: Cognitive fluctuations as a window into novel biomarkers and therapeutic targets for neurodegeneration, Cell type and organelle specific identification of molecular mechanisms initiating and propagating neurodegenerative diseases
OpenAlex ID: W7225347655