Caroline Gochanour

Background: Studies reporting α‐synuclein seed amplification assay (aSyn‐SAA) results are often cross‐sectional. Objectives: In this study, we investigated the intraindividual consistency of aSyn‐SAA results (Amprion) over time from participants in the Parkinson's Precision Medicine Initiative (PPMI). Methods: A total of 1238 participants had >1 cerebrospinal fluid (CSF) aSyn‐SAA result for analysis (Parkinson's disease [PD] = 633, prodromal = 563, healthy control [HC] = 42), collected over a median (minimum, maximum) of 2.0 (0.4, 11.4) years. Emphasis was placed on evaluating consistency in aSyn‐SAA‐PD participants, aSyn‐SAA + HC participants, and conversion rates from aSyn‐SAA negative to positive results prodromal participants. Results: Of aSyn‐SAA + PD participants, 96% (474/493, 95% confidence interval [CI]: 94%–98%) remained positive in subsequent samples, and 92% (116/126, 95% CI: 86%–96%) of aSyn‐SAA‐PD participants remained negative. Ninety‐nine percent (303/307, 95% CI: 97%–99%) of aSyn‐SAA + prodromal participants remained positive, and 95% (234/247, 95% CI: 91%–97%) of aSyn‐SAA‐prodromal participants remained negative. Eighty‐nine percent (16/18, 95% CI: 67%–97%) of aSyn‐SAA + HC participants remained positive, and 87% (20/23, 95% CI: 68%–95%) of aSyn‐SAA‐HC participants remained negative. Conclusions: aSyn‐SAA testing is highly consistent over time, even in less expected scenarios. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: LRRK2-Parkinson’s disease (LRRK2-PD) is biologically heterogeneous with approximately 30% lacking aggregated alpha synuclein (αSyn) in cerebrospinal fluid by seed amplification assay (SAA). Prior work has suggested slower progression in LRRK2-PD compared to sporadic PD (sPD). Objective: We aimed to assess how LRRK2-PD with αSyn aggregates on SAA (S+ LRRK2-PD) compares to S+ sPD. Methods: Data from the Parkinson’s Progression Markers Initiative were used to compare S+ LRRK2-PD and S+ sPD cohorts propensity score-matched on age, disease duration, sex and levodopa equivalent dose (N = 79 per cohort). Baseline clinical and biological features and 4-year longitudinal features were assessed. Results: At baseline, S+ LRRK2-PD participants had lower motor scores and dopaminergic deficit. Among measures showing within group progression, longitudinal trajectories did not differ significantly between groups. Conclusions: Longitudinal clinical progression of S+ LRRK2-PD and sPD in the PPMI study is similar despite differences in baseline features.

Background and Objectives: The University of Pennsylvania Smell Identification Test (UPSIT) is a widely employed objective measure of smell function. A revised version of this test, termed the UPSIT-R, was developed in 2020 to update certain odorants and response options. The goal of this study was to establish normative age- and sex-specific data for the UPSIT-R in a large adult cohort and to compare the resultant percentiles to those of the original UPSIT. A second study was performed to compare the relative performance of these two tests in a small cohort of persons with and without Parkinson’s disease (PD). Methods: UPSIT-R percentiles were derived separately by age (60-64, 65-69, 70-74, 75-59, and ≥80 years) and sex (male, female) categories in 16,972 volunteers who were predominantly white and non-Hispanic. Percentiles were derived statistically using an empirical distribution averaging procedure. A Bland-Altman plot was employed to visualize the level of agreement between percentiles for the UPSIT-R and UPSIT. For the second study, non-parametric statistics were employed to compare the results of those with and without PD. Results: UPSIT-R performance declined with increasing age; deficits were more pronounced in men than in women. The magnitude of the difference between the original and revised test percentile scores differed by age and sex; women had up to a 3-point improvement with the UPSIT-R whereas the oldest male age had up to a 3-point decline in percentile scores. Olfactory deficits in PD were confirmed on the UPSIT-R. Discussion: This study provides normative data clinically useful for assessing the relative degree of dysfunction in persons 60 years of age and older using the UPSIT-R. Like the traditional version of the UPSIT, this version demonstrates that smell function declines with age and is generally better in women than in men, providing a solid clinical basis for physicians to accurately determine the degree of smell dysfunction in their patients. Trial Registration Information: ClinicalTrials.gov NCT05065060

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.