A prodromal brain-clinical pattern of cognition in synucleinopathies.

OBJECTIVE Isolated (or idiopathic) rapid eye movement sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Biomarkers are lacking to predict conversion to a dementia- or a motor-first phenotype. Here, we aimed at identifying a brain-clinical signature that predicts dementia in iRBD. METHODS A brain-clinical signature was identified in 48 polysomnography-confirmed iRBD using partial least squares between brain deformation and 27 clinical variables. The resulting variable was applied to 78 iRBD patients followed longitudinally to predict conversion to a synucleinopathy, specifically DLB. The deformation scores from iRBD patients were compared to 207 patients with PD, DLB or prodromal DLB to assess if scores were higher in DLB compared to PD. RESULTS One latent variable explained 31% of the brain-clinical covariance in iRBD, combining cortical and subcortical deformation and subarachnoid/ventricular expansion to cognitive and motor variables. The deformation score of this signature predicted conversion to a synucleinopathy in iRBD (p=0.036, odds ratio: 2.249; 95% CI: 1.053-4.803), specifically to DLB (odds ratio: 4.754; 95% CI: 1.283-17.618, p=0.020) and not PD (p=0.286). iRBD patients who developed dementia had scores similar to clinical and prodromal DLB patients but higher scores compared to PD patients. The deformation score also predicted cognitive performance over one, two, and four years in PD patients. INTERPRETATION We identified a brain-clinical signature that predicts conversion in iRBD to more severe/dementing forms of synucleinopathy. This pattern may serve as a new biomarker to optimize patient care, target risk reduction strategies, and administer neuroprotective trials. This article is protected by copyright. All rights reserved.