Objective: To analyze long term progression in Neuronal Synuclein Disease (NSD) participants who were originally enrolled in the sporadic Parkinson Disease (sPD) cohort in PPMI

Background: NSD-Integrated Staging System (NSD-ISS) represents a staging system anchored in biological characterization and functional impairment [1]. PPMI has been ongoing >10 years, which presents the opportunity to report on long term outcomes in a deeply characterized cohort of NSD individuals with sPD.

Method: We analyzed longitudinal data from individuals enrolled in sPD cohort in PPMI who met NSD criteria and were recruited before 2020. NSD staging anchors are presented in [Table 1]. Participants were assessed with comprehensive motor/non-motor scales, DAT imaging, and biofluid biomarkers. Time to milestone  analyses were performed as described in Brumm et al [2].

Results: N=357 NSD sPD participants were included in the analysis. At baseline, the distribution of NSD staging in the cohort was: 2b=87; 3=234; 4=36. Baseline demographic and key clinical characteristics by stage are presented in Table 2. Mean striatal, caudate, and putamen DAT binding was significantly lower in NSD Stage 4 individuals at baseline.  CSF A-beta was proportionally lower (<683 pg/mL cut off) among NSD Stage 4 at baseline. There were no other significant biofluid differences among NSD stages. Time to event analysis demonstrated that participants in NSD Stage 4 reached all disease milestones earlier, compared to those in NSD Stage 2b and Stage 3 [Figure 1] [Figure 2]. N=35 (10%) participants died. Retention was 79% at 5 years and 47% at 10 years and inversely correlated with the baseline stage.

Conclusion: We describe the largest cohort of biologically characterized sPD participants with >10 year follow up. There was significant baseline NSD stage heterogeneity in the cohort despite all being recruited as de novo PD. Thus, NSD-ISS based recruitment allows for reduced heterogeneity of participants. Baseline NSD-ISS predicted disease progression, long term survival and retention. Biological underpinnings of stage heterogeneity and the role of co-pathology need to be further explored, and the NSD-ISS provides the framework to do so. These results have significant implications on selection of participants and study designs testing disease modifying interventions.

Table 1

Table 2

Figure 1

Figure 2

References: 1. Simuni T, Chahine LM, Poston K, et al. A biological definition of neuronal alpha-synuclein disease: towards an integrated staging system for research. Lancet Neurol. 2024 Feb;23(2):178-90.
2. Brumm MC, Siderowf A, Simuni T, et al. Parkinson’s Progression Markers Initiative: A Milestone-Based Strategy to Monitor Parkinson’s Disease Progression. J Parkinsons Dis. 2023;13(6):899-916.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/baseline-nsd-iss-stage-predicts-long-term-progression-and-survival-in-sporadic-pd-10-year-ppmi-data-analysis/