Cognitive Performance in Prodromal Neuronal α Synuclein Disease
- 1Cleveland Clinic
Abstract
Importance: Cognitive abnormalities may emerge during prodromal neuronal a-synuclein disease (NSD), but their domain specificity and longitudinal course are uncertain. Objective: To characterize baseline cognition and longitudinal change in prodromal NSD compared with healthy controls, NSD-negative genetic carriers, and sporadic Parkinson disease (PD). Design: Longitudinal cohort study using Parkinson's Precision Medicine Initiative (PPMI) data, with first visits from July 2010 through April 2026 and up to 4 years of follow-up. Setting: Multicenter cohort. Participants: Healthy controls (HC; n=244), GBA1 or LRRK2 nonmanifesting carriers without NSD (n=323), prodromal NSD participants recruited through hyposmia or isolated rapid eye movement sleep behavior disorder cohorts (n=1640), and sporadic PD (n=824). Exposures: NSD status and clinical cohort. Main Outcomes and Measures: Cognitive summary scores for verbal memory, executive function, processing speed, language, and visuospatial function, and PPMI-defined mild cognitive impairment (MCI). Models adjusted for age, sex, education, and APOE {varepsilon}4 status. Results: Among 3031 participants (mean [SD] age, 66.6 [7.0] years; 1322 female [43.6%]), prodromal NSD participants had lower baseline verbal-memory performance than HC (adjusted difference, -0.20 SD; 95% CI, -0.34 to -0.07; adjusted P = .007); NSD-negative genetic carriers did not differ from HC. No other cognitive domain was lower than HC at baseline or longitudinally. In the primary age-adjusted analysis, verbal-memory trajectory differed from HC over 4 years (P = .009), whereas in a smaller age-matched sensitivity subset through year 3, it did not (P = .62); the baseline difference persisted (adjusted difference, -0.28 SD; 95% CI, -0.46 to -0.10; P = .003). Adjusted MCI probability increased from 10.2% to 15.1% in prodromal NSD, compared with 8.4% to 5.0% in HC and 13.4% to 17.7% in PD. The increase was greater than in HC (ratio of annual odds ratios, 1.28; 95% CI, 1.04 to 1.58; adjusted P = .04) but not PD (P = .62). Conclusions and Relevance: Prodromal NSD was associated with modestly lower verbal memory and increasing MCI probability relative to HC, without lower performance in other cognitive domains. The baseline verbal-memory difference was robust, whereas the longitudinal trajectory finding was not reproduced in the smaller age-matched sensitivity subset.
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BibTeX
@misc{anis2026cognitive,
title = {{Cognitive Performance in Prodromal Neuronal α Synuclein Disease}},
author = {S. Anis and E. Zimmerman and S. A. Sperling and J. L. Alberts and D. Weintraub and T. Simuni and A. Siderowf and H. H. Fernandez and on behalf of the Parkinson's Precision Medicine Initiative},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.05.26367361},
url = {https://www.medrxiv.org/content/10.64898/2026.11.05.26367361v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Cognitive Performance in Prodromal Neuronal α Synuclein Disease
AU - S. Anis
AU - E. Zimmerman
AU - S. A. Sperling
AU - J. L. Alberts
AU - D. Weintraub
AU - T. Simuni
AU - A. Siderowf
AU - H. H. Fernandez
AU - on behalf of the Parkinson's Precision Medicine Initiative
PY - 2026
DA - 2026/11/05
PB - medRxiv
DO - 10.64898/2026.11.05.26367361
UR - https://www.medrxiv.org/content/10.64898/2026.11.05.26367361v1
AB - Importance: Cognitive abnormalities may emerge during prodromal neuronal a-synuclein disease (NSD), but their domain specificity and longitudinal course are uncertain. Objective: To characterize baseline cognition and longitudinal change in prodromal NSD compared with healthy controls, NSD-negative genetic carriers, and sporadic Parkinson disease (PD). Design: Longitudinal cohort study using Parkinson's Precision Medicine Initiative (PPMI) data, with first visits from July 2010 through April 2026 and up to 4 years of follow-up. Setting: Multicenter cohort. Participants: Healthy controls (HC; n=244), GBA1 or LRRK2 nonmanifesting carriers without NSD (n=323), prodromal NSD participants recruited through hyposmia or isolated rapid eye movement sleep behavior disorder cohorts (n=1640), and sporadic PD (n=824). Exposures: NSD status and clinical cohort. Main Outcomes and Measures: Cognitive summary scores for verbal memory, executive function, processing speed, language, and visuospatial function, and PPMI-defined mild cognitive impairment (MCI). Models adjusted for age, sex, education, and APOE {varepsilon}4 status. Results: Among 3031 participants (mean [SD] age, 66.6 [7.0] years; 1322 female [43.6%]), prodromal NSD participants had lower baseline verbal-memory performance than HC (adjusted difference, -0.20 SD; 95% CI, -0.34 to -0.07; adjusted P = .007); NSD-negative genetic carriers did not differ from HC. No other cognitive domain was lower than HC at baseline or longitudinally. In the primary age-adjusted analysis, verbal-memory trajectory differed from HC over 4 years (P = .009), whereas in a smaller age-matched sensitivity subset through year 3, it did not (P = .62); the baseline difference persisted (adjusted difference, -0.28 SD; 95% CI, -0.46 to -0.10; P = .003). Adjusted MCI probability increased from 10.2% to 15.1% in prodromal NSD, compared with 8.4% to 5.0% in HC and 13.4% to 17.7% in PD. The increase was greater than in HC (ratio of annual odds ratios, 1.28; 95% CI, 1.04 to 1.58; adjusted P = .04) but not PD (P = .62). Conclusions and Relevance: Prodromal NSD was associated with modestly lower verbal memory and increasing MCI probability relative to HC, without lower performance in other cognitive domains. The baseline verbal-memory difference was robust, whereas the longitudinal trajectory finding was not reproduced in the smaller age-matched sensitivity subset.
ER -