Idiopathic REM sleep behaviour disorder and neurodegeneration — an update

Key Points

  • Clinically isolated rapid eye movement (REM) sleep behavioural disorder (RBD) is considered to be an early stage of α-synucleinopathy that can provide a window into the future health of the brain

  • Elementary, minor and major body and limb jerks on surface electromyography (REM sleep without atonia) or video polysomnography are the main hallmarks of RBD

  • Accurate diagnosis of isolated RBD is critical in clinical trials and should be confirmed by polysomnography rather than implied by subjective tools such as questionnaires

  • In patients with isolated RBD, conversion to α-synucleinopathy often results in Parkinson disease dementia or dementia with Lewy bodies; the highest risk of conversion has been calculated for polysomnography-confirmed isolated RBD

  • The term 'prodromal RBD' should be used (in analogy to prodromal Parkinson disease) to define recognizable precursory disease states before the full diagnostic criteria for isolated RBD are met

  • This prodromal stage might enable the identification of individuals at risk of neurodegeneration even before the development of isolated RBD

Abstract

So-called idiopathic rapid eye movement (REM) sleep behaviour disorder (RBD), formerly seen as a rare parasomnia, is now recognized as the prodromal stage of an α-synucleinopathy. Given the very high risk that patients with idiopathic RBD have of developing α-synucleinopathies, such as Parkinson disease (PD), PD dementia, dementia with Lewy bodies or multiple system atrophy, and the outstandingly high specificity and very long interval between the onset of idiopathic RBD and the clinical manifestations of α-synucleinopathies, the prodromal phase of this disorder represents a unique opportunity for potentially disease-modifying intervention. This Review provides an update on classic and novel biomarkers of α-synuclein-related neurodegeneration in patients with idiopathic RBD, focusing on advances in imaging and neurophysiological, cognitive, autonomic, tissue-specific and other biomarkers. We discuss the strengths, potential weaknesses and suitability of these biomarkers for identifying RBD and neurodegeneration, with an emphasis on predicting progression to overt α-synucleinopathy. The role of video polysomnography in providing quantifiable and potentially treatment-responsive biomarkers of neurodegeneration is highlighted. In light of all these advances, and the now understood role of idiopathic RBD as an early manifestation of α-synuclein disease, we call for idiopathic RBD to be reconceptualized as isolated RBD.

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Figure 1: The main brain circuits responsible for REM sleep atonia, tonic and phasic motor activity in RBD.
Figure 2: The new concept of prodromal RBD.

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Acknowledgements

B.H. and A.S. acknowledge support received from the Austrian Science Fund (FWF), grant no. I2120-B27. A.V. acknowledges support received from two US NIH, National Institute of Neurological Disorders and Stroke grants: K23 NS072283 and R01 NS099055.

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Correspondence to Birgit Högl.

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B.H. declares that she has received fees for consultancy from Axovant. A.S. declares that she has received research funding from Axovant. A.V. declares no competing interests.

Supplementary information

41582_2018_BFnrneurol2017157_MOESM16_ESM.mov

Large, complex movements are characteristic of rapid eye movement (REM) sleep behaviour disorder (RBD) but account for only a very small proportion of all REM-related movements. (MOV 3061 kb)

Complex movements associated with RBD.

Large, complex movements are characteristic of rapid eye movement (REM) sleep behaviour disorder (RBD) but account for only a very small proportion of all REM-related movements. (MOV 3061 kb)

41582_2018_BFnrneurol2017157_MOESM17_ESM.mov

Simple twitches and jerks represent the vast majority of motor behaviours associated with rapid eye movement (REM) sleep behaviour disorder (RBD). (MOV 122 kb)

Simple movements associated with RBD.

Simple twitches and jerks represent the vast majority of motor behaviours associated with rapid eye movement (REM) sleep behaviour disorder (RBD). (MOV 122 kb)

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Glossary

Prodromal RBD

A stage of disease in which symptoms and signs of evolving rapid eye movement (REM) sleep behaviour disorder (RBD) are present but do not yet meet established diagnostic criteria for RBD.

REM sleep without atonia

(RWA). Defined by the American Academy of Sleep Medicine in the International Classification of Sleep Disorders, 3rd edn, as “the finding of increased EMG [electromyography] activity during REM [rapid eye movement] sleep, recorded from the mental, submental and various limb muscles”.

Prodromal PD

A stage of disease in which early symptoms or signs of Parkinson disease (PD) neurodegeneration are present, but clinical diagnosis based on fully evolved motor parkinsonism is not yet possible.

PD-related spatial covariance pattern

A highly reproducible, disease-related metabolic brain network associated with Parkinson disease (PD) that is characterized by increases in pallidothalamic, pontine and cerebellar metabolic activity and by reductions in premotor and parietal association regions.

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Högl, B., Stefani, A. & Videnovic, A. Idiopathic REM sleep behaviour disorder and neurodegeneration — an update. Nat Rev Neurol 14, 40–55 (2018). https://doi.org/10.1038/nrneurol.2017.157

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