
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.02.14.24302818
preprint
2
Article
Neuronal alpha-Synuclein Disease Integrated Staging System performance in PPMI, PASADENA, and SPARK baseline cohorts
Dam Tien http://orcid.org/0000-0002-7786-5825

Pagano Gennaro http://orcid.org/0000-0002-6247-8988

Brumm Michael C http://orcid.org/0000-0002-3173-9989

Gochanour Caroline http://orcid.org/0009-0009-3263-8344

Poston Kathleen L http://orcid.org/0000-0003-3424-7143

Weintraub Daniel http://orcid.org/0000-0003-0633-7168

Chahine Lana M. http://orcid.org/0000-0003-2521-7196

Coffey Christopher
Tanner Caroline M. http://orcid.org/0000-0002-3775-5082

Kopil Catherine M. http://orcid.org/0000-0001-8678-7550

Xiao Yuge http://orcid.org/0009-0003-0382-8014

Chowdhury Sohini http://orcid.org/0009-0009-8321-0081

Concha-Marambio Luis http://orcid.org/0000-0002-9454-8389

DiBiaso Peter
Foroud Tatiana http://orcid.org/0000-0002-5549-2212

Frasier Mark http://orcid.org/0000-0002-1730-0603

Jennings Danna http://orcid.org/0000-0003-0753-6281

Kieburtz Karl http://orcid.org/0000-0002-1645-6921

Merchant Kalpana http://orcid.org/0000-0003-1118-9403

Mollenhauer Brit http://orcid.org/0000-0001-8437-3645

Montine Thomas J http://orcid.org/0000-0002-1346-2728

Nudelman Kelly http://orcid.org/0000-0003-4040-1717

Seibyl John http://orcid.org/0000-0002-4917-5413

Sherer Todd http://orcid.org/0000-0001-9667-6600

Singleton Andrew http://orcid.org/0000-0001-5606-700X

Stephenson Diane
Stern Matthew
Soto Claudio http://orcid.org/0000-0002-3412-0524

Tolosa Eduardo http://orcid.org/0000-0002-3781-0854

Siderowf Andrew http://orcid.org/0000-0002-1750-7698

Dunn Billy
Simuni Tanya http://orcid.org/0000-0002-2361-6604

Marek Kenneth http://orcid.org/0000-0002-4197-5627

the Parkinson’s Progression Markers Initiative
10 9 2024
2024.02.14.24302818https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
http://medrxiv.org/lookup/doi/10.1101/2024.02.14.24302818
nihpp-2024.02.14.24302818.pdf
ABSTRACT

The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinson’s disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline. Across the three studies 1,741 participants had SAA data and of these 1,030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD, and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Median (95% CI) time to developing a clinically meaningful outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for baseline stage 2B, 3, and 4, respectively.

We propose pilot biologic and clinical anchors for NSD-ISS. Our results highlight the baseline heterogeneity of individuals currently defined as early PD. Baseline stage predicts time to progression to clinically meaningful milestones. Further research on validation of the anchors in longitudinal cohorts is necessary.
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