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

Area of Science:

• Neuroscience
• Genetics
• Radiology

Background:

• Oligodendroglial pathology is characteristic of multiple system atrophy (MSA).
• The biological basis of MRI-detected brain atrophy in MSA is not well understood.
• Investigating the link between atrophy and molecular mechanisms is crucial for understanding MSA.

Purpose of the Study:

• To determine if regional brain atrophy in MSA correlates with gene expression and neurotransmitter systems.
• To explore the biological underpinnings of MRI-derived atrophy patterns in MSA.
• To differentiate MSA-related atrophy from patterns observed in Parkinson's disease.

Main Methods:

• Recruited 65 patients with MSA and acquired T1-weighted MRI scans to measure brain atrophy.
• Utilized postmortem data from the Allen Human Brain Atlas and partial least squares (PLS) regression to link gene expression to atrophy.
• Conducted gene enrichment and neurotransmitter system analyses, with specificity testing against 57 Parkinson's disease patients.

Main Results:

• Significant atrophy was observed in the cerebellar white matter, pons, putamen, olive, and substantia nigra.
• PLS analysis identified gene expression components associated with atrophy, with overexpressed genes linked to mitochondrial function and oligodendrocytes.
• Atrophic regions showed altered neurotransmitter levels, including lower serotonin and GABA, and higher acetylcholine and noradrenaline receptor densities, distinct from Parkinson's disease.

Conclusions:

• MRI-derived brain atrophy in MSA is biologically grounded in specific molecular pathways.
• Findings highlight the role of oligodendroglial and mitochondrial dysfunction in MSA atrophy.
• This research provides a foundation for developing targeted therapeutic strategies for MSA.