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[Preprint]. 2024 Dec 13:2024.12.12.24318917.
doi: 10.1101/2024.12.12.24318917.

Impact of dopamine deficiency and REM sleep behavior disorder on cognition in early neuronal synuclein disease with hyposmia

Daniel Weintraub  1 , Anuprita R Nair  2 , Ryan Kurth  2 , Michael C Brumm  2 , Michele K York  3 , Roseanne 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 , Todd Sherer  14 , Sohini Chowdhury  14 , Roy N Alcalay  15 , Aleksandar Videnovic  16 ; Parkinson’s Progression Markers Initiative
Affiliations

Impact of dopamine deficiency and REM sleep behavior disorder on cognition in early neuronal synuclein disease with hyposmia

Daniel Weintraub et al. medRxiv. .

Update in

Abstract

Objectives: To determine the impact of dopamine deficiency and isolated REM sleep behavior disorder (iRBD) on cognitive performance in early neuronal alpha-synuclein disease (NSD) with hyposmia.

Methods: Using Parkinson's Progression Markers Initiative baseline data, cognitive performance was assessed with a cognitive summary score (CSS) developed by applying regression-based internal norms derived from a robust healthy control (HC) group. Performance was examined for participants with hyposmia classified as NSD-Integrated Staging System (NSD-ISS) Stage 2, either Stage 2A (CSF alpha-synuclein seed amplification assay [SAA]+, SPECT 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 overall 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-value NS; effect size=0.09) and Stage 2B had a statistically worse CSS (z-score mean difference =0.23, p-value <0.05; effect size=0.40) compared with HCs. In Stage 2A participants with hyposmia alone had normal cognition, but presence of comorbid iRBD was associated with significantly worse cognition (z-score mean difference =0.33, p-value <0.05, effect size =0.50). In Stage 2B participants with hyposmia had abnormal cognition (z-score mean difference =0.18, p-value =.0078, effect size =0.29), and superimposed iRBD had a non-statistically significant additive effect.

Interpretation: Using a CSS, early NSD with hyposmia is associated with measurable cognitive deficits compared with robust HCs, particularly in presence of dopamine system impairment or comorbid iRBD, highlighting the importance of focusing on cognition in early-stage synuclein disease.

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Figures

Figure:
Figure:
Mean CSS across subgroups in Stage 2A and 2B participants
See this image and copyright information in PMC

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