Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease

Abstract

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.

Impaired GABA and Glycine Transmission Triggers Cardinal Features of Rapid Eye Movement Sleep Behavior Disorder in Mice

“…First, glycine-and GABA-mediated inhibition of skeletal motoneurons is partly responsible for suppression of muscle activity during normal REM sleep (Morrison et al, 2003;Chase and Morales, 2005;Brooks and Peever, 2008b). Second, strokes and lesions that affect brainstem regions containing glycine and GABA neurons trigger motor activation during REM sleep (Schenkel and Siegel, 1989;Lu et al, 2006;Boeve et al, 2007). Third, patients with impaired glycine and GABA transmission often experience heightened motor activity during sleep (de Groen and Kamphuisen, 1978;Martinelli et al, 1996).…”

Wilson?s disease presenting as rapid eye movement sleep behavior disorder: a possible window to early treatment

“…We present four cases of early neurological WD with RBD; three of them developed RBD as their initial manifestation of WD. All four cases show TCS hyperintensities of midbrain tegmentum, the location considered crucial for the genesis of idiopathic RBD 5,6,7 and of RBD in Parkinson's disease (PD) 8 . The relationship between WD and PD has been an issue of special interest in research on extrapyramidal syndromes, since S. A. Kinnier Wilson stressed already in his seminal first description of WD the considerable parallels between these diseases, both in clinical symptoms and in localization of brain lesions 9 .…”

Treatment of sleep disturbances in posttraumatic stress disorder: A review

“…RBD is more common in older adults, with a mean age of onset from 50 to 65 years, and can be associated with and may precede neurodegenerative disorders, such as Parkinson disease, dementia with Lewy bodies, and multiple system atrophy (Boeve et al [25]). However, in almost 50 percent of RBD cases, no brain lesion is observed (Olson et al [26]).…”