Cholinergic Nucleus 4 Degeneration in Isolated Rapid Eye Movement Sleep Behavior Disorder: One Piece of the Puzzle

We read with interest the article by Tan et al.1 that describes how patients with isolated REM sleep behavior disorder (iRBD) have reduced gray matter density in the cholinergic nucleus 4 (Ch4) compared with healthy individuals. This atrophy was linked to a lower performance in working memory, which agrees with a previous study from our group that found that only patients with iRBD with concomitant mild cognitive impairment (MCI) had left Ch4 atrophy compared with healthy individuals,2 although no correlation was found between Ch4 atrophy and cognitive functions. Most patients with iRBD will develop a manifest synucleinopathy, with approximately half being diagnosed first with Parkinson's disease and the other half being diagnosed first with dementia with Lewy bodies (DLB).3 MCI affects more than a third of patients with iRBD and is related to a higher risk of developing DLB in this population.3, 4 The heterogeneous clinical presentation and progression of symptoms in patients with iRBD suggest that different neurodegenerative pathways are involved. In their article, Tan et al.1 mention that the reduced Ch4 gray matter density could be part of a larger regional atrophy, citing a study from 2012 that reported decreased volume of the cerebellum, pons, and left parahippocampal gyrus in iRBD.5 However, over the past decade, there has been a significant increase in our knowledge of atrophy and its importance in iRBD. Our team and others have demonstrated that structural alterations in iRBD take various forms, including gray matter volume reduction, cortical thinning, abnormal tissue deformation, subcortical surface contraction, and increased cortical surface area.2-4 ,6-8 These alterations correlated with cognitive features in iRBD and involved large areas outside Ch4, especially the frontal and temporal lobes.2-4 ,6-8 Notably, atrophy was a particularly noticeable feature in iRBD with concomitant MCI.2, 3, 6 Given that 48.6% of patients in Tan et al.'s study1 had MCI, it is possible that the atrophy found in Ch4 was indeed associated with MCI. However, there was no comparison between patients with and without MCI. Controlling for the interaction between atrophy and cognitive phenotype is crucial, because research in iRBD has shown that atrophy forms a brain-clinical signature that can predict the development of DLB in iRBD and may be used as a marker for personalized prognosis.6 This supports the idea that most of the structural alterations in iRBD are features of prodromal DLB. Hence initiatives with expert centers in iRBD have been undertaken to understand the underlying mechanisms of this prodromal atrophy. In a study of 182 patients and 261 controls from five different cohorts, the authors found that the pattern of atrophy in iRBD is constrained by the brain's structural connectivity architecture and the spatial distribution of gene expression.7 Specifically, the pattern of atrophy in iRBD appears to target regions with higher expression of genes involved in mitochondrial function and macroautophagy.8 These findings suggest that the atrophy in iRBD is not an isolated event but is interconnected with specific genes and connectivity patterns. In conclusion, the changes in Ch4 are part of a larger pattern of structural brain modifications that may link a subgroup of patients with iRBD to an increased risk of DLB. S.R. reports a scholarship from the Canadian Institutes of Health Research. J.-F.G. holds a Canada Research Chair in Cognitive Decline in Pathological Aging. Shady Rahayel, Ronald B. Postuma, and Jean-François Gagnon were all involved in the design, execution, writing, and editing of the final version of this work. Jean-François Gagnon reports grants from the Fonds de recherche du Québec–Santé, the Canadian Institutes of Health Research, the W. Garfield Weston Foundation, The Michael J. Fox Foundation for Parkinson's Research, and the National Institutes of Health/National Institute on Aging outside the submitted work. Ronald B. Postuma reports grants and personal fees from the Fonds de recherche du Québec–Santé, the Canadian Institutes of Health Research, The Parkinson Society of Canada, W. Garfield Weston Foundation, The Michael J. Fox Foundation, Webster Foundation, National Institutes of Health/National Institute on Aging, grants and personal fees from Roche, personal fees from Takeda, Teva Neurosciences, Biogen, Boehringer Ingelheim, Theranexus, GE HealthCare, Jazz Pharmaceuticals, AbbVie, Jannsen, Otsuko, Phytopharmics, Inception Sciences, and Paladin outside the submitted work. Not applicable.