Multiparametric MRI and imaging transcriptomics reveal molecular and cellular correlates of neurodegeneration in experimental multiple system atrophy
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Multiple system atrophy (MSA) is a rapidly progressive α-synucleinopathy characterized by parkinsonism, cerebellar ataxia, and autonomic dysfunction associated with widespread oligodendroglial α-synuclein inclusions, gliosis, and neurodegeneration. Although magnetic resonance imaging (MRI) has revealed characteristic patterns of brain atrophy and microstructural alterations in MSA, the molecular and cellular mechanisms underlying these imaging abnormalities remain poorly understood. The proteolipid protein–human α-synuclein (PLP-αSyn) transgenic mouse model reproduces key pathological and behavioral features of MSA and provides a valuable platform to dissect the biological substrates of MRI-detected changes and their relevance to disease mechanisms.
Methods
We performed the first whole-brain MRI characterization of the PLP-αSyn model using ex vivo structural and diffusion tensor imaging (DTI). To elucidate the molecular mechanisms associated with imaging alterations, we applied an imaging transcriptomics framework integrating MRI-derived phenotypes with more than 4,000 spatial gene expression maps from the Allen Brain Atlas. Gene ontology and cell-type enrichment analyses identified biological processes and cellular contributors linked to MRI changes, and imaging-correlated genes were compared with differentially expressed genes from cerebellar RNA sequencing (RNAseq) to assess molecular concordance.
Results
PLP-αSyn mice exhibited widespread brain atrophy involving the brainstem, cerebellum, thalamus, and white matter tracts, closely mirroring neuroimaging findings in patients with MSA. DTI revealed decreased fractional anisotropy in major white matter tracts and increased mean diffusivity in the brainstem and cerebellum, reflecting distinct microstructural pathologies. Imaging transcriptomics linked these alterations to genes regulating myelination, gliogenesis, and neuroinflammation, strongly enriched for oligodendrocyte and astrocyte markers, while diffusivity changes were associated with neuronal connectivity and energy metabolism. Imaging-correlated gene signatures showed significant overlap with RNAseq–derived molecular profiles, reinforcing the biological validity of the imaging-derived mechanisms.
Conclusions
MRI sensitively detects MSA-like neurodegeneration in the PLP-αSyn mouse, providing a translationally relevant platform to investigate the biological basis of imaging biomarkers. Integrating MRI with spatial transcriptomics reveals distinct molecular and cellular mechanisms underlying MRI-detected alterations, advancing mechanistic understanding of MRI changes in MSA and establishing imaging transcriptomics as a powerful approach to bridge neuroimaging with molecular pathology in α-synucleinopathies.
