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.

Centre for Advanced Research in Sleep Medicine Hôpital du Sacré Cœur de Montréal CIUSSS NÎM Montreal Canada

Department of Medicine University of Montreal Montreal Canada

Department of Neurology and Centre of Clinical Neurosciences 1st Faculty of Medicine Charles University and General University Hospital Prague Czechia

Department of Neurology Montreal General Hospital Montreal Canada

Department of Neuroscience University of Montreal Montreal Canada

Department of Psychology Université du Québec à Montréal Montreal Canada

Department of Psychology University of Montreal Montreal Canada

Institut du Cerveau Paris Brain Institute ICM Assistance Publique Hôpitaux de Paris Sorbonne Université Paris France

Oxford Parkinson's Disease Centre and Division of Neurology Nuffield Department of Clinical Neurosciences University of Oxford Oxford UK

Research Centre Institut universitaire de gériatrie de Montréal Montreal Canada

Sherbrooke Connectivity Imaging Lab University of Sherbrooke Sherbrooke Canada

The Neuro McGill University Montreal Canada

See more in PubMed

Hogl B, Stefani A, Videnovic A. Idiopathic REM sleep behaviour disorder and neurodegeneration—an update. Nat Rev Neurol. 2018;14(1):40‐55. PubMed

Galbiati A, Verga L, Giora E, Zucconi M, Ferini‐Strambi L. The risk of neurodegeneration in REM sleep behavior disorder: a systematic review and meta‐analysis of longitudinal studies. Sleep Med Rev. 2019;43:37‐46. PubMed

Rahayel S, Tremblay C, Vo A, et al. Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression. Brain. 2022;145(9):3162‐3178. PubMed

Rahayel S, Tremblay C, Vo A, et al. Mitochondrial function‐associated genes underlie cortical atrophy in prodromal synucleinopathies. Brain. 2023;146(8):3301‐3318. PubMed PMC

Rahayel S, Postuma RB, Montplaisir J, et al. A prodromal brain‐clinical pattern of cognition in synucleinopathies. Ann Neurol. 2021;89(2):341‐357. PubMed

Rahayel S, Postuma RB, Montplaisir J, et al. Cortical and subcortical gray matter bases of cognitive deficits in REM sleep behavior disorder. Neurology. 2018;90(20):e1759‐e1770. PubMed PMC

Shin JH, Kim H, Kim YK, et al. Longitudinal evolution of cortical thickness signature reflecting Lewy body dementia in isolated REM sleep behavior disorder: a prospective cohort study. Transl Neurodegener. 2023;12(1):27. PubMed PMC

Campabadal A, Segura B, Junque C, Iranzo A. Structural and functional magnetic resonance imaging in isolated REM sleep behavior disorder: a systematic review of studies using neuroimaging software. Sleep Med Rev. 2021;59:101495. PubMed

Eisenstein T, Groenewald K, van Hillegondsberg L, et al. Cholinergic degeneration in prodromal and early Parkinson's: a link to present and future disease states. Brain. 2025. PubMed

Rahayel S, Postuma R, Baril AA, et al. (99m)Tc‐HMPAO SPECT perfusion signatures associated with clinical progression in patients with isolated rem sleep behavior disorder. Neurology. 2024;102(4):e208015. PubMed PMC

Carli G, Meles SK, Reesink FE, et al. Comparison of univariate and multivariate analyses for brain [18F]FDG PET data in alpha‐synucleinopathies. Neuroimage Clin. 2023;39:103475. PubMed PMC

Carli G, Meles SK, Janzen A, et al. Occipital hypometabolism is a risk factor for conversion to Parkinson's disease in isolated REM sleep behaviour disorder. Eur J Nucl Med Mol Imaging. 2023;50(11):3290‐3301. PubMed PMC

Kim R, Lee JY, Kim YK, et al. Longitudinal changes in isolated rapid eye movement sleep behavior disorder‐related metabolic pattern expression. Mov Disord. 2021;36(8):1889‐1898. PubMed PMC

Orso B, Mattioli P, Yoon EJ, et al. Validation of the REM behaviour disorder phenoconversion‐related pattern in an independent cohort. Neurol Sci. 2023;44(9):3161‐3168. PubMed PMC

Arnaldi D, Mattioli P, Raffa S, et al. Presynaptic dopaminergic imaging characterizes patients with REM sleep behavior disorder due to synucleinopathy. Ann Neurol. 2024;95(6):1178‐1192. PubMed PMC

Iranzo A, Stefani A, Ninerola‐Baizan A, et al. Left‐hemispheric predominance of nigrostriatal deficit in isolated REM sleep behavior disorder. Neurology. 2020;94(15):e1605‐e1613. PubMed

Chahine LM, Brumm MC, Caspell‐Garcia C, et al. Dopamine transporter imaging predicts clinically‐defined alpha‐synucleinopathy in REM sleep behavior disorder. Ann Clin Transl Neurol. 2021;8(1):201‐212. PubMed PMC

Miglis MG, Adler CH, Antelmi E, et al. Biomarkers of conversion to alpha‐synucleinopathy in isolated rapid‐eye‐movement sleep behaviour disorder. Lancet Neurol. 2021;20(8):671‐684. PubMed PMC

Pasternak O, Sochen N, Gur Y, Intrator N, Assaf Y. Free water elimination and mapping from diffusion MRI. Magn Reson Med. 2009;62(3):717‐730. PubMed

Burciu RG, Ofori E, Archer DB, et al. Progression marker of Parkinson's disease: a 4‐year multi‐site imaging study. Brain. 2017;140(8):2183‐2192. PubMed PMC

Ofori E, Pasternak O, Planetta PJ, et al. Increased free water in the substantia nigra of Parkinson's disease: a single‐site and multi‐site study. Neurobiol Aging. 2015;36(2):1097‐1104. PubMed PMC

Ofori E, Pasternak O, Planetta PJ, et al. Longitudinal changes in free‐water within the substantia nigra of Parkinson's disease. Brain. 2015;138:2322‐2331. PubMed PMC

Chen M, Wang Y, Zhang C, et al. Free water and iron content in the substantia nigra at different stages of Parkinson's disease. Eur J Radiol. 2023;167:111030. PubMed

Arribarat G, Pasternak O, De Barros A, Galitzky M, Rascol O, Peran P. Substantia nigra locations of iron‐content, free‐water and mean diffusivity abnormalities in moderate stage Parkinson's disease. Parkinsonism Relat Disord. 2019;65:146‐152. PubMed

Zhou G, Ren J, Rong D, et al. Monitoring substantia nigra degeneration using free water imaging across prodromal and clinical Parkinson's disease. Mov Disord. 2023;38(5):774‐782. PubMed

Guttuso T, Jr , Bergsland N, Hagemeier J, Lichter DG, Pasternak O, Zivadinov R. Substantia nigra free water increases longitudinally in Parkinson's Disease. AJNR Am J Neuroradiol. 2018;39(3):479‐484. PubMed PMC

Bae YJ, Kim JM, Sohn CH, et al. Imaging the substantia nigra in Parkinson disease and other parkinsonian syndromes. Radiology. 2021;300(2):260‐278. PubMed

Zhou L, Li G, Zhang Y, et al. Increased free water in the substantia nigra in idiopathic REM sleep behaviour disorder. Brain. 2021;144(5):1488‐1497. PubMed

Ofori E, Krismer F, Burciu RG, et al. Free water improves detection of changes in the substantia nigra in parkinsonism: a multisite study. Mov Disord. 2017;32(10):1457‐1464. PubMed PMC

Ray NJ, Lawson RA, Martin SL, et al. Free‐water imaging of the cholinergic basal forebrain and pedunculopontine nucleus in Parkinson's disease. Brain. 2023;146(3):1053‐1064. PubMed PMC

Zhang D, Zhou L, Lu C, Feng T, Liu J, Wu T. Free‐Water imaging of the nucleus basalis of meynert in patients with idiopathic REM sleep behavior disorder and Parkinson's Disease. Neurology. 2024;102(7):e209220. PubMed

Wang C, Wang S, Zhou C, et al. LRRK2 mutation contributes to decreased free water in the nucleus basalis of Meynert in manifest and premanifest Parkinson's disease. J Neurol. 2024;272(1):33. PubMed

Crowley SJ, Amin M, Tanner JJ, Ding M, Mareci TA, Price CC. Free water fraction predicts cognitive decline for individuals with idiopathic Parkinson's disease. Parkinsonism Relat Disord. 2022;104:72‐77. PubMed

Crowley SJ, Kanel P, Roytman S, Bohnen NI, Hampstead BM. Basal forebrain integrity, cholinergic innervation and cognition in idiopathic Parkinson's disease. Brain. 2024;147(5):1799‐1808. PubMed PMC

Schumacher J, Ray NJ, Hamilton CA, et al. Free water imaging of the cholinergic system in dementia with Lewy bodies and Alzheimer's disease. Alzheimers Dement. 2023;19(10):4549‐4563. PubMed

Tobin ER, Arpin DJ, Schauder MB, et al. Functional and free‐water imaging in rapid eye movement behaviour disorder and Parkinson's disease. Brain Commun. 2024;6(5):fcae344. PubMed PMC

Gan‐Or Z, Rao T, Leveille E, et al. The quebec parkinson network: a researcher‐patient matching platform and multimodal biorepository. J Parkinsons Dis. 2020;10(1):301‐313. PubMed PMC

Marek K, Chowdhury S, Siderowf A, et al. The Parkinson's progression markers initiative (PPMI)—establishing a PD biomarker cohort. Ann Clin Transl Neurol. 2018;5(12):1460‐1477. PubMed PMC

Medicine AAoS . The PubMed PMC

McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88‐100. PubMed PMC

Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2015;30(12):1591‐1601. PubMed

Wenning GK, Stankovic I, Vignatelli L, et al. The movement disorder society criteria for the diagnosis of multiple system atrophy. Mov Disord. 2022;37(6):1131‐1148. PubMed PMC

Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695‐699. PubMed

Goetz CG, Tilley BC, Shaftman SR, et al. Movement disorder society‐sponsored revision of the unified Parkinson's disease rating scale (MDS‐UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129‐2170. PubMed

Ayral V, Pastor‐Bernier A, Daneault V, et al. Glymphatic defect in isolated REM sleep behavior disorder is associated with phenoconversion to Parkinson's disease. Neurology. Forthcoming 2025.

Joza S, Delva A, Tremblay C, et al. Distinct brain atrophy progression subtypes underlie phenoconversion in isolated REM sleep behaviour disorder. EBioMedicine. 2025;117:105753. PubMed PMC

Theaud G, Houde JC, Bore A, Rheault F, Morency F, Descoteaux M. TractoFlow: a robust, efficient and reproducible diffusion MRI pipeline leveraging Nextflow & Singularity. Neuroimage. 2020;218:116889. PubMed

Kurtzer GM, Sochat V, Bauer MW. Singularity: scientific containers for mobility of compute. PLoS One. 2017;12(5):e0177459. PubMed PMC

Di Tommaso P, Chatzou M, Floden EW, Barja PP, Palumbo E, Notredame C. Nextflow enables reproducible computational workflows. Nat Biotechnol. 2017;35(4):316‐319. PubMed

Daducci A, Canales‐Rodriguez EJ, Zhang H, Dyrby TB, Alexander DC, Thiran JP. Accelerated microstructure imaging via convex optimization (AMICO) from diffusion MRI data. Neuroimage. 2015;105:32‐44. PubMed

Gaser C, Dahnke R, Thompson PM, Kurth F, Luders E, The Alzheimer's Disease Neuroimaging I . CAT: a computational anatomy toolbox for the analysis of structural MRI data. Gigascience. 2024;13:giae049. PubMed PMC

Fortin JP, Cullen N, Sheline YI, et al. Harmonization of cortical thickness measurements across scanners and sites. Neuroimage. 2018;167:104‐120. PubMed PMC

Orlhac F, Eertink JJ, Cottereau AS, et al. A Guide to ComBat harmonization of imaging biomarkers in multicenter studies. J Nucl Med. 2022;63(2):172‐179. PubMed PMC

Fortin JP, Parker D, Tunc B, et al. Harmonization of multi‐site diffusion tensor imaging data. Neuroimage. 2017;161:149‐170. PubMed PMC

Andica C, Kamagata K, Hatano T, et al. Free‐Water imaging in white and gray matter in Parkinson's. Disease Cells. 2019;8(8). PubMed PMC

Schulz J, Pagano G, Fernandez Bonfante JA, Wilson H, Politis M. Nucleus basalis of Meynert degeneration precedes and predicts cognitive impairment in Parkinson's disease. Brain. 2018;141(5):1501‐1516. PubMed PMC

Postuma RB, Iranzo A, Hu M, et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain. 2019;142(3):744‐759. PubMed PMC

Yang A, Li G. Nucleus basalis of Meynert predicts cognitive changes in isolated REM sleep behavior disorder. Sleep Med. 2023;109:11‐17. PubMed

Tan C, Nawaz H, Lageman SK, et al. Cholinergic nucleus 4 degeneration and cognitive impairment in isolated rapid eye movement sleep behavior disorder. Mov Disord. 2023;38(3):474‐479. PubMed PMC

Remillard‐Pelchat D, Rahayel S, Gaubert M, et al. Comprehensive analysis of brain volume in rem sleep behavior disorder with mild cognitive impairment. J Parkinsons Dis. 2022;12(1):229‐241. PubMed

Gaurav R, Pyatigorskaya N, Biondetti E, et al. Deep learning‐based neuromelanin mri changes of isolated rem sleep behavior disorder. Mov Disord. 2022;37(5):1064‐1069. PubMed PMC

Arnaldi D, Chincarini A, Hu MT, et al. Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder. Brain. 2021;144(1):278‐287. PubMed PMC

Woo KA, Kim H, Kim R, et al. Cholinergic degeneration and early cognitive signs in prodromal Lewy body dementia. Alzheimers Dement. 2025;21(2):e14584. PubMed PMC

Staer K, Iranzo A, Stokholm MG, et al. Cortical cholinergic dysfunction correlates with microglial activation in the substantia innominata in REM sleep behavior disorder. Parkinsonism Relat Disord. 2020;81:89‐93. PubMed

Staer K, Iranzo A, Terkelsen MH, et al. Progression of brain cholinergic dysfunction in patients with isolated rapid eye movement sleep behavior disorder. Eur J Neurol. 2024;31(1):e16101. PubMed PMC

Genier Marchand D, Montplaisir J, Postuma RB, Rahayel S, Gagnon JF. Detecting the cognitive prodrome of dementia with lewy bodies: a prospective study of REM sleep behavior disorder. Sleep. 2017;40(1):101093/sleep/zsw014. PubMed

Dickson DW, Heckman MG, Murray ME, et al. APOE epsilon4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology. 2018;91(12):e1182‐e95. PubMed PMC