Prospective Validation of the Movement Disorder Society Prodromal Multiple System Atrophy Criteria in Pure Autonomic Failure

BACKGROUND: The Movement Disorder Society (MDS) research criteria for possible prodromal multiple system atrophy (PP-MSA) have not been prospectively validated. OBJECTIVE: To evaluate the diagnostic performance of the PP-MSA criteria in a longitudinal cohort of patients with pure autonomic failure (PAF) and to assess whether additional clinical features improve their predictive value. METHODS: Seventy-six patients with PAF enrolled across eight centers in the Natural History Study of the Synucleinopathies were followed for ≥6 years or until phenoconversion. Participants were classified according to MDS PP-MSA criteria and followed for development of MSA, Parkinson's disease, or dementia with Lewy bodies. Diagnostic performance was assessed longitudinally. Analyses were repeated using a stricter olfactory threshold (University of Pennsylvania Smell Identification Test [UPSIT]≤28) as an exclusion criterion. RESULTS: Thirty-eight participants met PP-MSA criteria, of whom 12 phenoconverted to MSA within 6 years. Sensitivity was 100% at year 1 and 92% at year 6, whereas specificity ranged from 56% to 67%. Positive predictive value (PPV) ranged from 21% to 34%. Applying a stricter olfactory threshold improved specificity (90%-97%) and PPV (53%-83%), with a modest reduction in sensitivity (to 83%). Participants who phenoconverted to MSA were younger, had more severe urinary dysfunction, and greater orthostatic heart rate responses. CONCLUSIONS: The PP-MSA criteria demonstrate high sensitivity but limited specificity in patients with PAF. A stricter olfactory threshold improves diagnostic performance and may enhance cohort enrichment for clinical trials.