Functional MRI in Multiple System Atrophy: A Promising Biomarker for Clinical Applications

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by α-synuclein pathology and pronounced clinical heterogeneity, making early diagnosis difficult. Functional magnetic resonance imaging (fMRI) has emerged as a promising tool to enhance diagnostic precision. By identifying disease- and symptom-specific network connectivity abnormalities, fMRI may reflect pathological changes in corresponding brain regions, thereby providing mechanistic insights. Recent work demonstrates that resting-state fMRI (rs-fMRI) can capture subtype-specific patterns, predominant basal ganglia-cortical disruption observed in the parkinsonian subtype of MSA (MSA-P) and cerebellar-cortical disconnection in the cerebellar subtype (MSA-C), reflecting their respective underlying pathologies of striatonigral degeneration and olivopontocerebellar atrophy. Rs-fMRI can also distinguish MSA from related parkinsonian syndromes, including Parkinson's disease (PD) and progressive supranuclear palsy (PSP), based on characteristic disruptions in cerebellar-cortical network connectivity. These patterns align with pathological features, providing important insights into disease progression. Task-based fMRI (t-fMRI), though less studied, further highlights impairments in motor network integration. Beyond diagnosis, fMRI has shown potential in evaluating treatment effects, with neuromodulatory interventions such as transcranial magnetic stimulation associated with measurable network changes. However, existing studies remain constrained by small sample sizes, single-center designs, and methodological variability. Future directions include large, multicenter trials, standardized imaging protocols, and integration with multimodal and computational approaches to establish robust fMRI-based biomarkers. Collectively, these advances position fMRI as a promising biomarker-oriented tool in MSA, supporting subtype classification, enhancing differential diagnosis from PD and PSP, elucidating symptom-specific network dysfunction, and enabling objective evaluation of therapeutic interventions in clinical and translational settings.