Neuronal alpha-Synuclein Disease Integrated Staging System performance in PPMI, PASADENA, and SPARK baseline cohorts

Area of Science:

• Neuroscience
• Neurology
• Biomarkers

Background:

• Lewy body pathology underlies various neurodegenerative disorders, including Parkinson's disease.
• Current diagnostic and staging methods for these conditions lack a unified biological and functional framework.
• The Neuronal alpha-Synuclein Disease (NSD) and its Integrated Staging System (NSD-ISS) were developed to address this gap.

Purpose of the Study:

• To develop and apply biologic and clinical data-informed definitions for the NSD-ISS.
• To stage individuals across the disease continuum, from healthy controls to those with Parkinson's disease.
• To assess the predictive value of baseline NSD-ISS stage on disease progression.

Main Methods:

• Utilized data from the PPMI, PASADENA, and SPARK studies.
• Defined and staged 1,741 participants (including Parkinson's disease, prodromal, and healthy controls) using biological, clinical, and functional anchors.
• Analyzed alpha-synuclein (SAA) data to identify individuals consistent with NSD.

Main Results:

• 59% (1,030/1,741) of participants were identified as SAA-positive, consistent with NSD.
• Among sporadic Parkinson's disease cases, 93% (683/736) met NSD criteria, with stage distribution: 2B (25%), 3 (63%), and 4 (9%).
• Median time to a clinically meaningful outcome varied significantly by baseline stage: 8.3 years (Stage 2B), 5.9 years (Stage 3), and 2.4 years (Stage 4).

Conclusions:

• The NSD-ISS provides a robust framework for staging individuals with Lewy body pathology.
• Baseline NSD-ISS stage is a significant predictor of time to disease progression.
• Further validation in longitudinal cohorts is recommended to refine the NSD-ISS anchors.