Biological Staging of the Parkinson’s Progression Markers Initiative (PPMI) Cohort Using the Research Neuronal α-synuclein Disease Integrated Staging System (NSD-ISS)
Caroline Tanner1, Tanya Simuni2, Lana Chahine3, Kathleen Poston4, Michael Brumm5, Sohini Chowdry6, Christopher Coffey5, Luis Concha-Marambio7, Tien Dam8, Peter DiBiaso6, Tatiana Foroud9, Mark Frasier6, Caroline Gochanour 5, Danna Jennings10, Karl Kieburtz11, Catherine Kopil6, Kalpana Merchant12, Brit Mollenhauer13, Thomas Montine4, Kelly Nudelman14, Gennaro Pagano15, John Seibyl16, Todd Sherer6, Andrew Singleton17, Diane Stephenson18, Matthew Stern19, Claudio Soto20, Eduardo Tolosa21, Daniel Weintraub19, Yuge Xiao 6, Andrew Siderowf19, Werner Poewe22, Kenneth Marek16
1University of California San Francisco, Weill Institute for Neurosciences, 2Northwestern University Feinberg School of Medicien, 3University of Pittsburgh, 4Stanford University, 5University of Iowa, 6The Michael J. Fox Foundation for Parkinson's Research, 7Amprion, 8Neumora Therapeutics Inc, 9Indiana University School of Medicine, 10Denali Therapeutics, 11University of Rochester Medical Center, 12Northwestern University, 13University of Goettingen, 14Indiana University, 15F. Hoffmann-La Roche Ltd, 16Institute for Neurodegenerative Disorders, 17National Institute of Aging, 18Critical Path Institute, 19University of Pennsylvania, 20University of Texas McGovern Medical School, 21Unviersity of Barcelona, 22University Hospital of Neurology
Objective:
To apply  Neuronal α-Synuclein Disease Integrated Staging System (NSD-ISS) in PPMI participants
Background:
NSD is defined by pathologic neuronal alpha-synuclein (S) and eventual dopaminergic neuronal dysfunction (D), independent of clinical features or specific syndrome. NSD-ISS integrates the biological anchors (S,D) and degree of functional impairment caused by motor, cognitive or other non-motor signs (Simuni et al, In Press).
Design/Methods:
Apply NSD-ISS staging criteria  to PPMI participants at baseline
Results:

On 6/12/23, 802 of 2307 were S+ and reported here. 695 S- are not included. For 810 S status pending, results will be added.

Among 507 sPD: 2% were NSD-ISS Stage 2A (S+,D-, subtle signs/symptoms, no functional impairment), 24% NSD-ISS Stage 2B (S+,D+, subtle signs/symptoms, no functional impairment), 64% NSD-ISS Stage 3 (S+,D+, signs/symptoms +, slight functional impairment), 10% NDS-ISS Stage 4 or 5 (S+,D+, signs/symptoms +, mild or moderate functional impairment).

Among 87 LRRK2 PD: 11% NSD-ISS Stage 2B, 61% Stage 3, 27% Stage > 4

Among 56 GBA PD: 13% NSD-ISS Stage 2B, 61% Stage 3, 26% Stage > 4

Among 9 SNCA PD: 11% NSD-ISS Stage 2B, 33% Stage 3, 55% Stage > 4

Among 63 REM Sleep Behavior Disorder: 41% NSD-ISS Stage 2A, 41% Stage 2B, 11% Stage 3, 7% Stage >4.

Among 38 hyposmics: 45% Stage 2A, 47% Stage 2B, 8% Stage 3. Among 56 GBA PD: 13% Stage 2B, 61% Stage 3, 27% Stage > 4.

Among 11 GBA NMC: 36% NSD-ISS Stage 1A (S+/D-, no signs/symptoms), 55% Stage 2A, 9% Stage 3. Among 87 LRRK2 PD: 11% Stage 2B, 61% Stage 3, 26% Stage > 4.

Among 12 LRRK2 NMC: 33% Stage 1A, 17% NSD_ISS Stage 1B (S+,D+, no signs/symptoms), 33% Stage 2A, 17% Stage 2B.


Conclusions:
We present the first data-driven application of the NSD-ISS, highlighting the heterogeneity of the biological stages in a phenotypically homogeneous cohort
10.1212/WNL.0000000000204771