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Aging and disease
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Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Diseases: An Update
Feng Zhang1,2, Long Niu1,2, Xinyao Liu1,2, Yufei Liu1,2, Song Li1,2, Huan Yu3, Weidong Le1,2,*
1Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, China.
2Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, China.
3Sleep and Wake Disorders Center and Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
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Rapid eye movement sleep behavior disorder (RBD) is a sleep behavior disorder characterized by abnormal behaviors and loss of muscle atonia during rapid eye movement (REM) sleep. RBD is generally considered to be associated with synucleinopathies, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), and usually precedes years before the first symptom of these diseases. It is believed that RBD predicts the neurodegeneration in synucleinopathy. However, increasing evidences have shown that RBD is also found in non-synucleinopathy neurodegenerative diseases, including Alzheimer’s disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), etc. Sleep disturbance such as RBD may be an early sign of neurodegeneration in these diseases, and also serve as an assessment of cognitive impairments. In this review, we updated the clinical characteristics, diagnosis, and possible mechanisms of RBD in neurogenerative diseases. A better understanding of RBD in these neurogenerative diseases will provide biomarkers and novel therapeutics for the early diagnosis and treatment of the diseases.

Keywords rapid eye movement sleep behavior disorder      synucleinopathy      dementia      neurodegeneration     
Corresponding Authors: Weidong Le   
Just Accepted Date: 29 August 2019  
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Feng Zhang
Long Niu
Xinyao Liu
Yufei Liu
Song Li
Huan Yu
Weidong Le
Cite this article:   
Feng Zhang,Long Niu,Xinyao Liu, et al. Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Diseases: An Update[J]. Aging and disease, 10.14336/AD.2019.0324
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Figure 1.  The potential mechanisms of RBD and related pathological pathways associated with neurodegenerative diseases. During rapid eye movement (REM) sleep, the γ-aminobutyric acid (GABA)-ergic neurons located in the lateral hypothalamus and other nuclei inactivate REM-inhibiting monoaminergic neurons in the tuberomammillary nucleus, locus coeruleus (LC), and dorsal raphe and GABA-ergic neurons in the ventrolateral periaqueductal grey (vlPAG) to induce REM sleep. Sublaterodorsal nucleus (SLD) glutamatergic/GABA-ergic neurons stimulate inhibitory spinal interneurons or glycinergic and GABA-ergic premotor neurons in the ventromedial medulla (VMM) resulting in skeletal muscle atonia. SLD neurons may be activated by the cholinergic laterodorsal tegmental nucleus and pedunculopontine tegmental nucleus (LDTN/PPN) neurons. The cortical activation during REM sleep leads to the activation of spinal motor neurons. Blocking glycine and GABA receptors or the degeneration of glycinergic and GABA-ergic neurons in the SLD and VMM removes the inhibition of spinal motor neurons and prevents the induction of muscle atonia. This could be the possible mechanism of RBD. In neurodegenerative diseases, pathological changes affecting the REM sleep regulating nuclei and circuits may contribute to the pathogenesis of RBD in these specific diseases.
Figure 2.  The possible mechanisms of RBD associated with synucleinopathies or non-synucleinopathies. Lesions in caudal brainstem are thought to eliminate atonia during REM sleep and the brainstem is the same structure where α-syn pathology might begin in synucleinopathies. In non-synucleinopatheis, the pathological changes may affect pedunculopontine pathways, locus coeruleus (LC), corticothalamic circuits or cholinergic system and finally affect the REM sleep regulating systems to induce RBD.
DiseasePrevalenceGender differencePossible mechanisms of pathogenesis of RBD
PD42.3%[50]Male>female [51]α-syn pathology affects the circuit that regulates REM sleep, associated with GBA [39], SCARB2 [40], MAPT [40], USP25[40], PINK1 [41], LRRK2 [2] mutations
MSA88%[33]Female>male [59]α-syn pathology affects the circuit that regulates REM sleep, depletion of cholinergic neurons in the PPN/LDTN complex, periaqueductal grey matter, and LC [33]
PSP13%[13]-Loss of cholinergic neurons in the pedunculopontine tegmentum [13]
CBDCase reports[38, 68]2 female patients [38, 68]Degenerative process in cortical and subcortical structures and in the nuclei of the brain stem and pedunculopontine pathways [38].
AD4.8-26.7%[12, 71]Male>female [12]An imbalance of neurotransmitter acetylcholine [12], neuronal loss in LC [12]
DLB46.7-83%[81-83]Male>female [82]α-syn pathology affects the circuit that regulates REM sleep [4]
FTDRare (only case report)[90]1 male patient [90]Associated with C9ORF72 repeat expansion [89]
VaD25.6%-72.6%[81, 93]-Hypoperfusion or hemodynamic abnormalities affect the brain areas that regulate REM sleep [4]
HD12% or lower[14, 96]Female>male [14]Associated with mutant huntingtin [14]
ALS4.9%[15]2 male patients [15]Neurodegeneration of nuclei in REM-associated pathways in the brainstem and the dysfunction of dopaminergic system in substantia nigra striatum may be the main pathophysiological culprit in the development of RBD [15], associated with C9ORF72 repeat expansion [91, 100]
CJD7.1%[101]2 male patients [101]Associated with corticothalamic degeneration [102]
Table 1  Summarized prevalence, gender difference and underlying mechanisms of RBD in neurodegenerative diseases.
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