Brain Advance Access originally published online on April 5, 2007
Brain 2007 130(11):2770-2788; doi:10.1093/brain/awm056
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Review Article |
Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease
1Department of Neurology, 2Department of Psychology and Psychiatry, 3Laboratory Medicine and Pathology, 4Sleep Disorders Center and 5Neuropathology Laboratory, 6Mayo Clinic College of Medicine, Rochester, MN, 7Mayo Clinic College of Medicine, Jacksonville, FL, 8Mayo Clinic College of Medicine, Scottsdale, AZ, 9Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 10Minnesota Regional Sleep Disorders Center, University of Minnesota, Minneapolis, MN, USA and 11Institute for Clinical Neuroanatomy, J.W. Goethe University, Frankfurt/Main, Germany
Correspondence to: Bradley F. Boeve, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA E-mail: bboeve{at}mayo.edu
REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of normal skeletal muscle atonia during REM sleep with prominent motor activity accompanying dreaming. The terminology relating to RBD, and mechanisms underlying REM sleep without atonia and RBD based on data in cat and rat are presented. Neuroimaging data from the few published human cases with RBD associated with structural lesions in the brainstem are presented, in which the dorsal midbrain and pons are implicated. Pharmacological manipulations which alter RBD frequency and severity are reviewed, and the data from human neuropathological studies are presented. An anatomic framework and new schema for the pathophysiology of RBD are proposed based on recent data in rat regarding the putative flip-flop switch for REM sleep control. The structure in man analogous to the subcoeruleus region in cat and sublaterodorsal nucleus in rat is proposed as the nucleus (and its associated efferent and afferent pathways) crucial to RBD pathophysiology. The association of RBD with neurological disease (‘secondary RBD’) is presented, with emphasis on RBD associated with neurodegenerative disease, particularly the synucleinopathies. The hypothesized pathophysiology of RBD is presented in relation to the Braak staging system for Parkinson's disease, in which the topography and temporal sequence of synuclein pathology in the brain could explain the evolution of parkinsonism and/or dementia well after the onset of RBD. These data suggest that many patients with ‘idiopathic’ RBD are actually exhibiting an early clinical manifestation of an evolving neurodegenerative disorder. Such patients may be appropriate for future drug therapies that affect synuclein pathophysiology, in which the development of parkinsonism and/or dementia could be delayed or prevented. We suggest that additional clinicopathological studies be performed in patients with dementia or parkinsonism, with and without RBD, as well as in patients with idiopathic RBD, to further elucidate the pathophysiology and also characterize the clinical and pathophysiological relevance of RBD in neurodegenerative disease. Furthermore, longitudinal studies in patients with idiopathic RBD are warranted to characterize the natural history of such patients and prepare for future therapeutic trials.
Key Words: REM sleep behaviour disorder; parasomnia; dementia with Lewy bodies; Parkinson's disease; multiple system atrophy; synuclein; synucleinopathy
Abbreviations: AD, Alzheimer's disease; DLB, dementia with Lewy bodies; EEG, electroencephalographic; EMG, electromyographic; LC, locus coeruleus; LDTN, laterodorsal tegmental nucleus; LPT, lateral pontine tegmentum; MAPT, gene encoding microtubule associated protein tau; MCI, mild cognitive impairment; MCRF, magnocellular reticular formation; MSA, multiple system atrophy; PAF, pure autonomic failure; PD, Parkinson's disease; PGRN, gene encoding progranulin; PPN, pedunculopontine nucleus; PPND, pallido-ponto-nigral degeneration; PSG, polysomnography; PSP, progressive supranuclear palsy; RBD, rapid eye movement sleep behaviour disorder; REM, rapid eye movement; RN, raphe nucleus; RSWA, REM sleep without atonia; SCA-3, Spinocerebellar atrophy—type 3; SLD, sublaterodorsal nucleus; vlPAG, ventrolateral periaqueductal grey matter; VLST, ventrolateral reticulospinal tract
Received September 19, 2006. Revised February 22, 2007. Accepted February 26, 2007.
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