Neuronal alpha-Synuclein Disease stage progression over five years
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Background
Neuronal alpha-Synuclein Disease (NSD) is defined by presence of an in vivo biomarker of neuronal alpha-synuclein (n-asyn) pathology, independent of presence of clinical syndrome. The NSD integrated staging system (NSD-ISS) describes progression across the disease continuum as stages 0 to 6. The objective of this analysis was to assess 5-year longitudinal change in the NSD-ISS.
Methods
Analysis included a subset of participants from the Parkinson’s Progression Markers Initiative (PPMI) enrolled before 2020 as Parkinson’s disease, prodromal, or healthy controls who met NSD criteria. Staging was defined based on biomarkers of n-asyn and dopaminergic dysfunction in early stages, clinical features (cognition, other non-motor features, and parkinsonism), and increasing degree of functional impairment in stages 3-6. Stages were examined annually for 5 years, along with the determinants of progression and effects of dopaminergic medication.
Findings
576 participants were n-asyn positive and included in the analysis. Of these, 494 were enrolled as Parkinson’s disease, 74 as prodromal and 8 as healthy controls. At baseline 56% of participants were in stage 3, 24% stage 2B, 13% stage 4, 4% stage 2A, and <1% in the other stages. At year 5, the percent of individuals in stage 2B, 3, and 4 were 11%, 50%, and 34% respectively, indicating progression through NSD stages. Median (95% CI) time to next stage increase from baseline was 1·19 (1·07-2·01) for stage 2B, 4·98 (4·07-5·35) for stage 3, and 9·77 (7·04-NA) for stage 4. Progression was driven by functional impairment in predominantly motor domain (95%) for stage 2B to 3, increasing degree of non-motor dysfunction for stage 3 to 4 (46%), and combination of motor, non-motor and cognitive domains for stage 4 to 5. Initiation of dopaminergic medications lead to stage regression in 8% participants in stage 3 and 41% in stage 4.
Interpretation
Our analysis supports the validity of the NSD-ISS in defining stages of disease progression and support the utility of the NSD-ISS as a potential tool to identify clinical trial cohorts for drug development. Further validation in interventional studies is a crucial next step.
Funding
The Michael J. Fox Foundation for Parkinson’s Research (MJFF).
