Objective: To evaluate the utility of the Neuronal aSynuclein Disease Integrated Staging System (NSD-ISS) in assessing the meaningfulness of stage progression, and associations with quality of life.

Background: Existing staging systems (e.g.,H&Y) do not fully capture functional disability/patient-centred disease burden. The NSD-ISS may address this gap with Stages 3-6 reflecting increasing functional impairment. Although stage transition is associated with functional milestones, the relationship between NSD-ISS stages and health-related quality-of-life outcomes has not been evaluated[1-3].

Method: We conducted a retrospective longitudinal analysis of CPP-IPD (21 studies),all with ethics approval; the current study was approved by the University Health Network Research Ethics Board, Toronto, Canada. Three cohorts met inclusion:TRACKING-PD (n=1,998;4.5-year),STEADY-PD (n=336;3-year), and PICNICS (n=280;11.4-year). Participants with NSD-ISS stage ≥3, PDQ39/PDQ8 and >2 years follow-up were included. Functional staging used MDS-UPDRS I–II,MoCA/ACE-R, and treatment status. Associations with patient-reported outcomes (PDQ-39;PDQ-8 in TRACKING-PD) and modified milestone criteria were assessed for stage progression, responsiveness, and stability via time-to-event and mixed-effects models[4]. Minimally clinically important differences were 4.72 for PDQ-39/5.8 for PDQ-8 [5].

Results: Baseline characteristics are shown in Table1.Higher NSD-ISS stages were associated with worse patient-reported quality of life (Fig.1). Both transition from Stage 3 to 4 and from 4 to 5 doubled the odds meaningful quality-of-life worsening. Concordance between Stage progression and meaningful QoL change was low from one visit to the next. Using modified milestone criteria, walking and balance were the most common milestones met in TRACKING-PD, and PICNICS followed by either cognition or autonomic dysfunction (Table 2).Fewer new milestones were observed during transition from stage 3-4 compared with stage 4-5.

Conclusion: NSD-ISS provides a clinically meaningful framework for functional staging in PD and may support its use in clinical research and trials,although the magnitude of quality-of-life change between some stages may fall below clinically meaningful thresholds.

Table 1 Baseline staging of NSD participants

Table 2 Modified milestone criteria

PDQ39 and PDQ8 association with NSD stage

References: Acknowledgement
We would like to thank Dr Tanya Simuni for her expertize and the Michael J Fox Foundation for their funding.

1. Critical Path for Parkinson’s Integrated Parkinsons Database (CPP-IPD). https://c-path.org/tools-platforms/integrated-parkisons-database/
2. Simuni T, Gochanour C, Nair AR, Brumm MC, Coffey C, Poston KL, Chahine LM, Weintraub D, Tanner CM, Gonzalez-Latapi P, Kopil CM, Xiao Y, Chowdhury S, Dam T, Pagano G, Stephenson D, Siderowf A, Dunn B, Marek K; NSD Working Group the Parkinson’s Progression Markers Initiative. Neuronal α-Synuclein Disease Stage Progression over 5 Years. Mov Disord. 2025 Jul;40(7):1318-1330. doi: 10.1002/mds.30191.
3. Dam T, Pagano G, Brumm MC, Gochanour C, Poston KL, Weintraub D, Chahine LM, Coffey C, Tanner CM, Kopil CM, Xiao Y, Chowdhury S, Concha-Marambio L, DiBiaso P, Foroud T, Frasier M, Jennings D, Kieburtz K, Merchant K, Mollenhauer B, Montine TJ, Nudelman K, Seibyl J, Sherer T, Singleton A, Stephenson D, Stern M, Soto C, Tolosa E, Siderowf A, Dunn B, Simuni T, Marek K; Parkinson’s Progression Markers Initiative. Neuronal alpha-Synuclein Disease integrated staging system performance in PPMI, PASADENA, and SPARK baseline cohorts. NPJ Parkinsons Dis. 2024 Sep 27;10(1):178. doi: 10.1038/s41531-024-00789-w.
4. Brumm MC, Siderowf A, Simuni T, Burghardt E, Choi SH, Caspell-Garcia C, Chahine LM, Mollenhauer B, Foroud T, Galasko D, Merchant K, Arnedo V, Hutten SJ, O’Grady AN, Poston KL, Tanner CM, Weintraub D, Kieburtz K, Marek K, Coffey CS; Parkinson’s Progression Markers Initiative. Parkinson’s Progression Markers Initiative: A Milestone-Based Strategy to Monitor Parkinson’s Disease Progression. J Parkinsons Dis. 2023;13(6):899-916. doi: 10.3233/JPD-223433.
5. Luo N, Tan LC, Zhao Y, Lau PN, Au WL, Li SC. Determination of the longitudinal validity and minimally important difference of the 8-item Parkinson’s Disease Questionnaire (PDQ-8). Mov Disord. 2009 Jan 30;24(2):183-7. doi: 10.1002/mds.22240. PMID: 18972545.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuronal-asynuclein-disease-integrated-staging-system-nsd-iss-reveals-clinically-meaningful-functional-progression-and-quality-of-life-impact-in-parkinsons-disease/