Neuronal α-Synuclein Disease Stage Progression over 5 Years

Abstract

Background: Neuronal α-synuclein disease (NSD) is defined by the presence of an in vivo biomarker of neuronal alpha-synuclein (n-asyn) pathology. The NSD integrated staging system (NSD-ISS) for research describes progression across the disease continuum as stages 0 to 6.

Objective: The aim was to assess 5-year longitudinal change in NSD-ISS in early disease.

Methods: Analysis included a subset of participants from the Parkinson's Progression Markers Initiative (PPMI) enrolled before 2020 as Parkinson's disease (PD) patients, prodromal PD patients, or healthy controls (HC) who met NSD criteria. Staging was defined based on biomarkers of n-asyn and dopaminergic dysfunction in early stages, clinical features, and severity of functional impairment in stages 3 to 6. Stages were determined annually for 5 years.

Results: Of 576 NSD participants, 494 were enrolled as PD patients, 74 prodromal PD patients, and 8 HCs. At baseline, 24% of participants were stage 2B, 56% Stage 3, 13% stage 4, and less than 5% in other stages. At year 5, the respective percentages for stages 2B to 4 were 11%, 50%, and 34%, indicating progression through NSD stages. Progression was driven by functional impairment in the predominantly motor domain (95%) for stage 2B to 3, increasing degree of nonmotor dysfunction for stages 3 to 4 (46%), and a combination of domains for stages 4 to 5. Initiation of dopaminergic medications led to stage regression in 8% of participants in Stage 3 but 41% in stage 4.

Conclusions: Our analysis supports the utility of NSD-ISS in defining the stages of disease progression, at least in the early clinical and prodromal stages (2B, 3, or 4), suggesting the value of NSD-ISS as a potential research tool for drug development. Further research involving preclinical cohorts is a crucial next step. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; biological definition; dementia with Lewy bodies; neuronal α‐synuclein disease.

FIG. 1

Longitudinal staging of the PPMI (Parkinson's Progression Markers Initiative) NSD cohort. Report generated on data submitted as of February 5, 2024. NSD, neuronal α‐synuclein disease; NSD‐ISS, neuronal α‐synuclein disease integrated staging system. *After year 1, stage 2A group includes those in stage 2A or lower. **Excludes participants who were in stage 0, 1A, or 1B at baseline (n = 13) or stage 2A at baseline without follow‐up assessment of dopaminergic dysfunction (n = 8).

FIG. 2

Participant flow. (A) Participants in stage 2b at baseline. (B) Participants in Stage 3 at baseline. (2C) Participants in stage 4 at baseline. The solid bars represent the number of participants in each stage category at each annual visit (BL, 1Y, 2Y, 3Y, 4Y, 5Y). The lighter‐shaded curved bands show the “flow” between stage categories from one year to the next. Participants were included if they competed the year 5 visit and were in stages 2B, 3, or 4 at baseline. In the case of intermittent missing annual visits, stage was carried forward.

FIG. 3

Time to reaching next‐stage increase by baseline stage.