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Multicenter Study
. 2025 Sep;21(9):e70570.
doi: 10.1002/alz.70570.

Free water predicts dementia with Lewy bodies in isolated REM sleep behavior disorder

Celine Haddad  1   2 , Véronique Daneault  1 , Violette Ayral  1   3 , Marie Filiatrault  1   3 , Alexandre Pastor-Bernier  1 , Christina Tremblay  1 , Arnaud Boré  4 , Maxime Descoteaux  4 , Andrew Vo  5 , Jean-François Gagnon  1   6   7 , Ronald B Postuma  1   8 , Petr Dusek  9 , Stanislav Marecek  9 , Zsoka Varga  9 , Johannes Klein  10 , Michele T Hu  10 , Stéphane Lehéricy  11 , Isabelle Arnulf  11 , Marie Vidailhet  11 , Jean-Christophe Corvol  11 ; ICEBERG Study Group  11 ; Shady Rahayel  1   12
Affiliations
Multicenter Study

Free water predicts dementia with Lewy bodies in isolated REM sleep behavior disorder

Celine Haddad et al. Alzheimers Dement. 2025 Sep.

Abstract

Introduction: Most individuals with isolated rapid eye movement sleep behavior disorder (iRBD) develop dementia with Lewy bodies (DLB) or Parkinson's disease (PD). Brain biomarkers predicting specific phenoconversion trajectories are lacking.

Methods: In this multicenter diffusion magnetic resonance imaging study (261 iRBD, 177 controls), free water (FW) was measured in the nucleus basalis of Meynert (NBM) and posterior substantia nigra (SN). Among 230 iRBD patients with follow-up, 64 converted (16 DLB, 38 PD). Time-to-event analyses were performed to assess differential phenoconversion.

Results: Phenoconverters had higher FW in the NBM and posterior SN. Only FW in the NBM predicted conversion to DLB over PD. NBM volume predicted DLB conversion, but only FW remained significant when both were modeled. FW in the NBM correlated with lower MoCA scores in iRBD.

Discussion: FW in the NBM is a sensitive biomarker of cognitive decline and DLB progression in iRBD, outperforming volume and supporting its use in early stratification.

Highlights: FW in the NBM specifically identifies conversion to DLB. Increased FW in the NBM is associated with lower global cognition in iRBD. FW in the SN in iRBD does not relate more to DLB than PD. FW in the NBM is a biomarker of differential phenoconversion in iRBD.

Keywords: Parkinson's disease; REM sleep behavior disorder; biomarker; dementia with Lewy bodies; diffusion magnetic resonance imaging; free water; prognosis.

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Conflict of interest statement

The authors declare no conflicts of interest. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Flowchart illustrating participant selection and inclusion for NBM and pSN analyses. Participants were excluded based on quality control, demographic matching, and availability of clinical measures. Time‐to‐differential‐phenoconversion analyses were only done for the NBM, as only FW in the NBM was retained as a significant predictor when used alongside the pSN. DLB, dementia with Lewy bodies; FW, free water; iRBD, isolated REM sleep behavior disorder; NBM, nucleus basalis of Meynert; PD, Parkinson's disease; pSN, posterior substantia nigra; QC, quality control.
FIGURE 2
FIGURE 2
FW levels in iRBD patients and controls. (A) Box plots and violin plots showing distribution of FW content in NBM and pSN for iRBD patients (red) and healthy controls (blue). FW content is presented after harmonization for scanner effects, with values standardized to positive values for visualization purposes. No significant differences were observed between groups in either region. (B) Box plots and violin plots showing distribution of FW content in NBM and posterior SN for iRBD converters (dark red) and non‐converters (light red). FW content in NBM and pSN was significantly increased in iRBD converters compared to non‐converters. FW, free water; iRBD, isolated REM sleep behavior disorder; NBM, nucleus basalis of Meynert; pSN, posterior substantia nigra.
FIGURE 3
FIGURE 3
Scatter plot showing relationship between FW content in NBM and MoCA scores in iRBD patients (red) and healthy controls (blue). The shaded areas represent the 95% confidence intervals for the regression lines. In iRBD, higher FW content in the NBM was significantly associated with lower MoCA scores; no significant correlation was observed in controls. FW, free water; iRBD, isolated REM sleep behavior disorder; MoCA, Montreal Cognitive Assessment; NBM, nucleus basalis of Meynert.
FIGURE 4
FIGURE 4
Kaplan–Meier survival curves showing survival probabilities (i.e., remaining disease‐free at the latest clinical follow‐up compared to receiving a diagnosis of neurodegenerative disease) over time based on FW content in (A) NBM and (B) the pSN. High FW content based on median FW level is represented in red and low FW content is represented in blue. Shaded areas indicate 95% confidence intervals for each group. FW, free water; HR, hazard ratio; iRBD, isolated REM sleep behavior disorder; KM, Kaplan‐Meier; NBM, nucleus basalis of Meynert; pSN, posterior substantia nigra.
FIGURE 5
FIGURE 5
Kaplan–Meier survival curves showing association of FW content in NBM to predict phenoconversion risk to (A) DLB and (B) PD compared to remaining disease‐free in iRBD. High FW content based on median FW level is represented in red, and low FW content is represented in blue. Shaded areas indicate 95% confidence intervals for each group. DLB, dementia with Lewy bodies; FW, free water; HR, hazard ratio; iRBD, isolated REM sleep behavior disorder; KM, Kaplan‐Meier; NBM, nucleus basalis of Meynert; PD, Parkinson's disease; pSN, posterior substantia nigra.
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