Objective: Define clinical characteristics of individuals with sporadic Parkinson’s disease (sPD) enrolled in the Parkinson’s Progression Markers Initiative (PPMI) who have a negative CSF alpha-synuclein (a-syn) seed amplification assay (SAA), and compare to SAA positive sPD participants.

Background: Alpha-synuclein pathology can be detected in the CSF in the majority of individuals with sPD, but the clinical characteristics of sPD patients with negative CSF a-syn SAA have not yet been well defined.

Method: We analyzed data from the PPMI sPD cohort, identifying participants who had a negative CSF a-syn SAA (n = 78) or positive CSF a-syn SAA (n = 872) result at baseline assessment. A comprehensive array of clinical characteristics was assessed including motor and non-motor disease scales. Given differences in median age between SAA negative and positive groups, a reduced dataset matched for age, sex, and disease duration was used for comparison of clinical characteristics.

Results: sPD SAA negative participants were median age 66.7 years (IQR 61-73.3) versus 63.9 (IQR 57.2-70) for SAA positive participants. Baseline clinical characteristics of the matched SAA negative (n = 77) versus positive (n = 231) subgroups is presented in table 1. Both groups had similar motor performance on the MDS-UPDRS part III and similar cognitive performance on the MoCA at baseline. The percentage of participants with a University of Pennsylvania Smell Identification Test (UPSIT) score less than or equal to the 15^th percentile was 24% for SAA negative versus 87% for SAA positive participants (p < 0.001). Longitudinally, the SAA negative subgroup had faster time to reach walking and balance disease milestones and 15% of SAA negative participants had a change in primary research diagnosis over time, most commonly to multiple system atrophy.

Conclusion: sPD participants in the PPMI cohort with negative a-syn SAA have similar baseline motor and cognitive clinical characteristics as those with positive a-syn SAA, but the SAA negative subgroup has a substantially lower rate of hyposmia. SAA negative participants demonstrated faster rate of development of walking and balance impairment and approximately one in seven had a change in research diagnosis over time. Further analysis to characterize a comprehensive array of fluid and imaging biomarkers in the SAA negative sPD group is underway.

Presented at AD/PD Conference April 2025

Table 1

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-characteristics-of-sporadic-parkinsons-disease-with-negative-csf-alpha-synuclein-seed-amplification-assay/