Review
REM sleep behavior disorder: From dreams to neurodegeneration

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Abstract

REM sleep behavior disorder is a unique parasomnia characterized by dream enactment behavior during REM sleep. Unless triggered by pharmacologic agents such as antidepressants, it is generally related to damage of pontomedullary brainstem structures. Idiopathic REM sleep behavior disorder (RBD) is a well-established risk factor for neurodegenerative disease. Prospective studies have estimated that at least 40–65% of patients with idiopathic RBD will eventually develop a defined neurodegenerative phenotype, almost always a ‘synucleinopathy’ (Parkinson's disease, Lewy Body dementia or multiple system atrophy). In most cases, patients appear to develop a syndrome with overlapping features of both Parkinson's disease and Lewy body dementia. The interval between RBD onset and disease onset averages 10–15 years, suggesting a promisingly large window for intervention into preclinical disease stages. The ability of RBD to predict disease has major implications for design and development of neuroprotective therapy, and testing of other predictive markers of synuclein-mediated neurodegeneration. Recent studies in idiopathic RBD patients have demonstrated that olfaction, color vision, severity of REM atonia loss, transcranial ultrasound of the substantia nigra, and dopaminergic neuroimaging can predict development of neurodegenerative disease.

Section snippets

RBD—an introduction

REM sleep behavior disorder is characterized by loss of the normal atonia of REM sleep (Schenck and Mahowald, 2002, Schenck et al., 1986). Patients often present with dream enactment behavior, apparently moving in response to content of their dreams. Movements may occur even without recall of dream content, so failure to recognize a connection between dream content and movements does not rule out RBD (Iranzo et al., 2009). Spouses are usually the main initiator of medical consultation, as their

Pathophysiology of RBD

In 1964, Jouvert described apparent dream enactment behaviors during REM sleep after brainstem lesions in the peri-locus ceruleus area (Jouvet and Delorme, 1965). Subsequent animal studies have focused on pontine and medullary areas such as the sublaterodorsal nucleus (a REM tone flip-flop switch), and their glutaminergic projections to medullary (ventral gigantocellular reticular nucleus or magnocellular reticular formation (Luppi et al., 2011)) and/or spinal interneurons as being the crucial

What is the risk of neurodegenerative disease in idiopathic RBD?

Based on prospective studies, many (if not most) patients who present to sleep clinics with idiopathic RBD will eventually develop a neurodegenerative syndrome. In the large majority of cases, this will be either PD, LBD, or MSA. Information as to the outcome of RBD has come mainly from three studies:

In 1996 Schenck et al. reported that after a median 5-year follow-up from diagnosis, 11 of their original 29 (38%) patients with idiopathic RBD had developed a parkinsonian disorder (Schenck et

Caveats and limitations

No marker is the ideal agent, and several caveats must be noted in the considering the utility of RBD in PD prediction and in development of neuroprotective therapy.

Markers of substantia nigra dysfunction

One potential marker of subtle dopaminergic denervation is dopaminergic PET and SPECT imaging, which use radiolabelled ligands to label either pre- or post-synaptic dopaminergic terminals (Ravina et al., 2005) and therefore directly measure innervation from the SNpc. Dopaminergic PET and SPECT have very high sensitivity and specificity for parkinsonism (they will also detect MSA and LBD) (Ravina et al., 2005). Abnormalities on dopaminergic imaging have been described in patients with idiopathic

Olfaction

The large majority of PD patients have severe olfactory loss at disease onset (Hawkes, 2003). Olfactory loss may also be an important preclinical marker of Lewy body dementia (LBD) (Olichney et al., 2005). Based upon large-scale prospective studies, there have been strong suggestions that olfaction can predict PD (Ross et al., 2008). Recently, in a 5-year prospective follow-up study of 62 patients with idiopathic RBD, those with impaired olfaction at baseline had a 65% 5-year risk of developing

Visual changes

Visual changes such as loss of color vision and contrast sensitivity commonly occur in PD, often early in the course of the disease (Price et al., 1992). In a recent prospective 5-year prospective study, patients with impaired color vision at baseline, as estimated by the Farnsworth–Munsell 100-Hue test, had an estimated 74% risk of developing a defined neurodegenerative disease at 5 years follow-up, compared to a 26% risk among those with normal vision. As with olfaction, abnormalities were

Autonomic dysfunction

Staging systems of PD have described synuclein deposition of unmyelinated projection neurons of the dorsal motor nucleus of the vagus (Braak et al., 2003), and postganglionic sympathetic denervation at earliest stages of the degeneration of PD (Braak et al., 2007, Orimo et al., 2007). These abnormalities are also often seen in LBD, and cardiac denervation may even be more severe in LBD than PD (Oka et al., 2007a, Yoshita et al., 2006). Numerous studies document autonomic dysfunction in RBD, as

Sleep measures

RBD varies considerably between patients in terms of severity, presentation, and underlying etiology. In a recent clinical follow-up study, baseline sleep variables in idiopathic RBD patients were compared between those who eventually developed a defined neurodegenerative disease and those who remained disease-free. There were no differences in sleep stages between groups, except for a slight increase in Stage 1 sleep in those who developed disease, and a slight reduction in slow-wave sleep in

Other potential predictors in Idiopathic RBD

Numerous studies have described other potential markers of disease in patients with idiopathic RBD, including subtle motor dysfunction on clinical examination (Postuma et al., 2009c), motor slowing on quantitative tests of movement speed (Postuma et al., 2006, Postuma et al., 2009c), anxiety and depression symptoms, personality changes (similar to the proposed ‘Parkinson personality’) (Postuma et al., 2009c), subtle cognitive dysfunction (Ferini-Strambi et al., 2004, Massicotte-Marquez et al.,

Conclusion

RBD is a unique parasomnia related to degeneration of critical REM tonic areas in the lower brainstem. Patients with idiopathic RBD are at a high risk of developing neurodegenerative disease, a risk that continues for many years after the first symptoms develop. This has profound implications for the future development and use of neuroprotective therapy. RBD patients may be ideal candidates for neuroprotective trials in preclinical disease, and for testing other potential predictive markers of

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