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. 2025 Sep;98(3):482-491.
doi: 10.1002/ana.27263. Epub 2025 Jul 11.

Cognitive Performance in Early Neuronal Synuclein Disease with Hyposmia but without Motor Disability: Association with Dopamine Deficiency and Isolated Rapid Eye Movement Sleep Behavior Disorder

Daniel Weintraub  1 , Anuprita R Nair  2 , Ryan Kurth  2 , Michael C Brumm  2 , Christine Kohnen  2 , Michele K York  3 , Roseanne D Dobkin  4 , Kenneth Marek  5 , Caroline Tanner  6 , Tanya Simuni  7 , Andrew Siderowf  1 , Douglas Galasko  8 , Lana M Chahine  9 , Christopher Coffey  2 , Kalpana Merchant  7 , Kathleen L Poston  10 , Tatiana Foroud  11 , Brit Mollenhauer  12 , Ethan G Brown  6 , Karl Kieburtz  13 , Mark Frasier  14 , Sohini Chowdhury  14 , Roy N Alcalay  15   16 , Aleksandar Videnovic  17 ; Parkinson's Progression Markers Initiative
Affiliations

Cognitive Performance in Early Neuronal Synuclein Disease with Hyposmia but without Motor Disability: Association with Dopamine Deficiency and Isolated Rapid Eye Movement Sleep Behavior Disorder

Daniel Weintraub et al. Ann Neurol. 2025 Sep.

Abstract

Objective: To determine the impact of dopamine deficiency and isolated rapid eye movement (REM) sleep behavior disorder (iRBD) on cognitive performance in early neuronal α-synuclein disease (NSD) with hyposmia but without motor disability.

Methods: Using Parkinson's Progression Markers Initiative baseline data, cognitive performance was assessed with a cognitive summary score (CSS) derived from robust healthy control (HC) norms. Performance was examined for participants with hyposmia in early NSD-Integrated Staging System (NSD-ISS), either stage 2A (cerebrospinal fluid α-synuclein seed amplification assay [SAA]+, dopamine transporter scan [DaTscan]-) or 2B (SAA+, DaTscan+).

Results: Participants were stage 2A (n = 101), stage 2B (N = 227), and HCs (n = 158). Although stage 2 had intact Montreal Cognitive Assessment scores (mean [SD] = 27.0 [2.3]), stage 2A had a numerically worse CSS (z-score mean difference = 0.05, p = NS; effect size = 0.09) and stage 2B a statistically worse CSS (z-score mean difference = 0.23, p < 0.05; effect size = 0.40) compared with HCs. In stage 2A, hyposmia alone was associated with normal cognition, but those with comorbid iRBD had significantly worse cognition (z-score mean difference = 0.33, p < 0.05, effect size =0.50). In stage 2B, hyposmia alone had abnormal cognition (z-score mean difference = 0.18, p = 0.0078, effect size = 0.29), and superimposed iRBD had a statistically significant additive effect.

Interpretation: Using a novel CSS, we demonstrated that hyposmia is associated with cognitive deficits in prodromal NSD without motor disability, particularly when comorbid dopamine system impairment or comorbid iRBD is present. Therefore, it is critical to include and assess cognition at all stages when studying synuclein disease, even in the absence of motor disability. ANN NEUROL 2025;98:482-491.

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Conflict of interest statement

A.S. declares consultancy with GE Healthcare. K.P. was on a scientific advisory board for Amprion.

Figures

FIGURE 1
FIGURE 1
Mean cognitive summary score across subgroups in stage 2A and 2B participants. [Color figure can be viewed at www.annalsofneurology.org]
See this image and copyright information in PMC

Update of

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