A new study from the PPMI cohort (Brooker et al., Movement Disorders 2026; https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.70197) looked systematically at the ~10% of sporadic PD patients who test negative on the CSF alpha-synuclein seed amplification assay (SAA). Using propensity-matched groups of SAA-negative (SAA-) and SAA-positive (SAA+) participants, the authors compared clinical features, DAT-SPECT, and MRI volumetrics at baseline and over follow-up period.
The most striking finding was diagnostic instability: roughly 1 in 7 SAA- participants received a change in diagnosis over time, compared to fewer than 1 in 100 SAA+ patients. This suggests a meaningful subset may not have a true alpha-synucleinopathy driving their parkinsonism, even though they met clinical criteria for PD and had an abnormal DAT-SPECT at enrollment. Interestingly, motor severity (MDS-UPDRS-III) and cognition (MOCA) were similar between groups at baseline, making clinical differentiation difficult. The clearest flag was olfaction: severe hyposmia was present in only 12% of SAA- patients vs. 73% of SAA+; a highly significant difference. The SAA- group also showed greater subcortical atrophy on MRI, including in the substantia nigra, which may hint at alternative pathological processes.
The implications are real for both practice and research. Clinicians should be cautious about reclassifying patients based on a negative SAA result alone. The authors recommend a watchful, longitudinal approach. For clinical trials targeting alpha-synuclein directly, excluding SAA- patients makes biological sense; but for trials focused on downstream mechanisms, blanket exclusion may be premature.
Would love to hear from physicians: have you encountered SAA- patients whose diagnosis later shifted? And how are you currently counseling patients when the SAA comes back negative?