Multiparametric MRI and imaging transcriptomics reveal molecular and cellular correlates of neurodegeneration in experimental Parkinsonism.

Multiple system atrophy (MSA) is an atypical Parkinsonian disorder marked by oligodendroglial α-synucleinopathy and selective neurodegeneration. Although MRI can capture regional atrophy and microstructural alterations in the MSA brain, the molecular substrates underlying these phenotypes remain poorly defined. Imaging transcriptomics provides a computational framework to relate spatial imaging patterns to brain-wide gene expression. While this approach has been applied to human MSA, interpretation is constrained by limited experimental control and a lack of disease-matched molecular validation. Here, we apply imaging transcriptomics in a controlled preclinical setting by integrating high-resolution ex vivo multimodal MRI with transcriptomic mapping in the PLP-αSyn mouse model of MSA. Structural and diffusion MRI revealed distinct patterns of regional atrophy and microstructural abnormalities. Atlas-based analyses associated imaging phenotypes with gene programs related to oligodendrocyte biology, energy metabolism, and neuroinflammation, with modality-specific signatures. These associations were supported by independent RNA-sequencing and showed convergence with human MSA findings. Our work benchmarks MRI-transcriptomic relationships in MSA and provides a translational framework for interpreting imaging biomarkers in synucleinopathies.