Multiple system atrophy: integrating clinical phenotypes and multimodal biomarkers for early diagnosis

Multiple system atrophy is a rare and rapidly progressive synucleinopathy characterized by parkinsonism, cerebellar ataxia, and prominent autonomic dysfunction. Neuropathological findings include misfolded α-synuclein accumulation in oligodendrocytes and neuronal loss leading to multisystem neurodegeneration. As a definite diagnosis still requires postmortem confirmation, there is a critical need for reliable in vivo diagnostic and prognostic biomarkers, particularly for early and prodromal disease stages in the context of upcoming disease-modifying therapies. This review provides a comprehensive overview of current concepts in the diagnosis of MSA with a particular focus on established and emerging biomarkers. It summarizes the clinical diagnostic framework and functional testing that support differential diagnosis in routine practice. Furthermore, it discusses the role of imaging biomarkers, ranging from conventional MRI to advanced multimodal MRI-techniques and molecular imaging approaches such as PET markers of neuroinflammation and α-synuclein pathology. In addition, it reviews the current state of fluid biomarkers such as seed amplification assays and neurofilament light chain and addresses biomarker-based strategies for disease monitoring and patient stratification in clinical trials. Overall, this review aims to integrate literature of clinical, imaging, and fluid biomarkers into a multimodal framework to improve early diagnosis, support biological classification, and facilitate therapeutic development in MSA.