Objective: To assess differences between clinical and imaging phenotypes in Multiple System Atrophy (MSA) and evaluate the reliability of imaging biomarkers for subtype classification.

Background: MSA can present with distinct clinical phenotypes: parkinsonian-predominant (MSA-P) and cerebellar-predominant (MSA-C). Neuropathologically, there are distinct patterns of degeneration described as striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA). SND is characterized by marked striatal atrophy and putaminal iron accumulation, while OPCA corresponds to cerebellar and brainstem degeneration. It is assumed that the clinical presentation agrees with the pathologic pattern of degeneration. Advanced imaging techniques, including volumetric MRI and quantitative susceptibility mapping (QSM) for iron content, offer objective markers of neurodegeneration, but their agreement with clinical classifications remains uncertain.

Method: Structural and quantitative MRI data from 72 MSA patients in the ATH434-201 Phase 2 study were analyzed. Clinical classification as MSA-P or MSA-C was determined by site investigators. Automated segmentation quantified z-score-based atrophy in the brainstem (BS), lentiform nucleus (LN; putamen and globus pallidus), and cerebellum (CB) using an age-matched reference population. QSM assessed iron deposition in the LN, substantia nigra, and dentate nucleus. Imaging subtypes were classified as SND or OPCA based on atrophy and iron distribution patterns.

Results: SND was associated with LN atrophy and iron accumulation, while OPCA exhibited CB and BS atrophy with lower LN iron deposition. Clinical and imaging classifications were concordant in 64 of 72 cases, with MSA-P aligning with SND and MSA-C with OPCA. However, 4 MSA-C cases displayed an SND pattern, 3 MSA-P cases exhibited an OPCA pattern. One patient defined as OPCA had mixed and clinical and imaging features. Longitudinal data revealed that one SND-pattern patient initially classified as MSA-C later developed predominant parkinsonian symptoms, aligning with imaging findings.

Conclusion: MRI biomarkers offer an objective framework for MSA classification, potentially improving early diagnosis, refining subtype differentiation, and enhancing disease monitoring in clinical trials. Further validation is necessary to establish standardized imaging criteria.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/differences-between-clinical-and-imaging-phenotypes-in-phase-2-study-of-ath434-in-multiple-system-atrophy/