NSD-ISS and SynNeurGe definitions

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Simuni, Chahine, Poston, Brumm, Marek and colleagues, 35 authors in all (NSD-ISS; funders listed include the Michael J. Fox Foundation, the US National Institute on Aging, Parkinson's UK, Cure Parkinson's, the Lewy Body Dementia Association and Parkinson Canada); Höglinger, Adler, Berg, Klein, Outeiro, Poewe, Postuma, Stoessl and Lang (SynNeurGe, nine authors).

What happened

Both appeared in Lancet Neurology in February 2024 as expert proposals, not trial results.

• NSD-ISS defines "neuronal alpha-synuclein disease" by two biological anchors: S (a positive alpha-synuclein seed test) and D (dopamine-system dysfunction on imaging). Stages run from 0 (a fully penetrant SNCA variant) through 1A (S+ without symptoms), 1B (S+ and D+), 2 (subtle signs) to 3–6 (increasing impairment). A clinical diagnosis is neither necessary nor sufficient.
• SynNeurGe classifies by alpha-synuclein (S), neurodegeneration on imaging (N), genetics (G) and a clinical component.

Both are research-only frameworks. See landmark 9 for the test itself; this entry is about the controversy and trial design.

Why it moved us toward a cure

They let trials enrol people by biology, and before symptoms, reducing heterogeneity. That is the practical precondition for prevention and early slowing trials.

Outcome

Open: debated, but adopted in research design.

• Controversy: at launch, Lang argued that biomarkers can sort trial participants without creating a new disease (Alzforum). Critics (Okubadejo, Okun and Jankovic in JAMA Neurology, 2024, DOI 10.1001/jamaneurol.2024.2054) warned the assays need subjective interpretation and more validation, tests are costly and often unavailable, and dropping the name Parkinson's has wide consequences. Others raised the effect of a biological diagnosis on people with no symptoms. Both proposals leave out some people, such as LRRK2 or parkin carriers who test negative for the seed (in PPMI only 67.5% of LRRK2 Parkinson's was seed-positive, landmark 9). In 2025 Espay, Lees and colleagues published a rebuttal of the NSD-ISS staging in Movement Disorders (DOI 10.1002/mds.30269), and Simuni's group replied (DOI 10.1002/mds.30272). An independent check of the staging in 1,741 people with seed data from three studies (Dam et al., npj Parkinson's Disease 2024) found 59% seed-positive and that baseline stage predicted time to a clinically meaningful milestone: median 8.3 years from stage 2B, 5.9 from stage 3 and 2.4 from stage 4 (DOI 10.1038/s41531-024-00789-w).
• Consequences: the FDA's 2024 letter of support for the seed test acknowledges NSD-ISS. MJFF's "Path to Prevention" platform trial in PPMI targets stage 2B: a randomised Phase 2 with 125 per arm, at least 24 months, aiming at 85% power to detect a 40% slowing. In September 2024 the first drugs had not been chosen. On 27 January 2026 ABLi Therapeutics announced an agreement with the Foundation to include its c-Abl inhibitor risvodetinib, saying the trial would launch "in the coming months" (company release; no start date given). The Foundation's trial page (Oct 2026) lists three regimens but no enrolment start, and I found no registry record.

Sources

• Simuni et al., Lancet Neurol 2024;23:178–190, DOI 10.1016/S1474-4422(23)00405-2 · MJFF full-text PDF
• Höglinger et al., Lancet Neurol 2024;23:191–204, DOI 10.1016/S1474-4422(23)00404-0. PubMed lists an erratum for this paper (Lancet Neurol 2024;23(3):e7, DOI 10.1016/S1474-4422(24)00048-6); its content was not read.
• Alzforum, 9 Feb 2024
• MJFF Path to Prevention page · ABLi release, 27 Jan 2026 (reprint)
• MDedge, 12 Jul 2024
• NeurologyLive on Path to Prevention, 28 Sep 2024
• Not yet verified: what the SynNeurGe erratum corrects; the full text of the critics' and rebuttal papers (abstracts and citations only); whether P2P has enrolled anyone.