MRI-derived atrophy in multiple system atrophy aligns with mitochondrial and glial gene expression patterns.

Oligodendroglial pathology is a hallmark of multiple system atrophy (MSA), yet it remains unclear whether MRI-detected atrophy reflects underlying biological mechanisms. This study investigated whether regional atrophy aligns with gene expression and neurotransmitter systems. We recruited 65 MSA patients and derived brain atrophy measures from T1-weighted MRIs. Using postmortem data from the Allen Human Brain Atlas, partial least squares (PLS) regression identified gene expression components associated with brain atrophy. Gene enrichment analyses explored biological processes, and annotation mapping identified neurotransmitter systems matching atrophy patterns. Specificity was tested against 57 patients with Parkinson's disease. Atrophy primarily affected the cerebellar white matter, pons, putamen, olive, and substantia nigra. PLS revealed two latent variables explaining 27.5% of the covariance. Atrophic regions overexpressed genes linked to mitochondrial function and oligodendrocytes, showing patterns distinct from Parkinson's disease. These regions also exhibited lower serotonin and GABA levels, and higher acetylcholine and noradrenaline receptor densities. MRI-derived atrophy in MSA is biologically grounded and may inform future therapeutic studies.