Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects.
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SUBMITTER: Krohn L
PROVIDER: S-EPMC9722930 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
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Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects.
Krohn Lynne L Heilbron Karl K Blauwendraat Cornelis C Reynolds Regina H RH Yu Eric E Senkevich Konstantin K Rudakou Uladzislau U Estiar Mehrdad A MA Gustavsson Emil K EK Brolin Kajsa K Ruskey Jennifer A JA Freeman Kathryn K Asayesh Farnaz F Chia Ruth R Arnulf Isabelle I Hu Michele T M MTM Montplaisir Jacques Y JY Gagnon Jean-François JF Desautels Alex A Dauvilliers Yves Y Gigli Gian Luigi GL Valente Mariarosaria M Janes Francesco F Bernardini Andrea A Högl Birgit B Stefani Ambra A Ibrahim Abubaker A Šonka Karel K Kemlink David D Oertel Wolfgang W Janzen Annette A Plazzi Giuseppe G Biscarini Francesco F Antelmi Elena E Figorilli Michela M Puligheddu Monica M Mollenhauer Brit B Trenkwalder Claudia C Sixel-Döring Friederike F Cochen De Cock Valérie V Monaca Christelle Charley CC Heidbreder Anna A Ferini-Strambi Luigi L Dijkstra Femke F Viaene Mineke M Abril Beatriz B Boeve Bradley F BF Scholz Sonja W SW Ryten Mina M Bandres-Ciga Sara S Noyce Alastair A Cannon Paul P Pihlstrøm Lasse L Nalls Mike A MA Singleton Andrew B AB Rouleau Guy A GA Postuma Ronald B RB Gan-Or Ziv Z
Nature communications 20221205 1
Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in differen ...[more]
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| S-EPMC5238706 | biostudies-literature
Project description:Isolated REM sleep behavior disorder (iRBD) is an early stage of synucleinopathy with most patients progressing to Parkinson's disease (PD) or related conditions. Quantitative susceptibility mapping (QSM) in PD has identified pathological iron accumulation in the substantia nigra (SN) and variably also in basal ganglia and cortex. Analyzing whole-brain QSM across iRBD, PD, and healthy controls (HC) may help to ascertain the extent of neurodegeneration in prodromal synucleinopathy. 70 de novo PD patients, 70 iRBD patients, and 60 HCs underwent 3 T MRI. T1 and susceptibility-weighted images were acquired and processed to space standardized QSM. Voxel-based analyses of grey matter magnetic susceptibility differences comparing all groups were performed on the whole brain and upper brainstem levels with the statistical threshold set at family-wise error-corrected p-values <.05. Whole-brain analysis showed increased susceptibility in the bilateral fronto-parietal cortex of iRBD patients compared to both PD and HC. This was not associated with cortical thinning according to the cortical thickness analysis. Compared to iRBD, PD patients had increased susceptibility in the left amygdala and hippocampal region. Upper brainstem analysis revealed increased susceptibility within the bilateral SN for both PD and iRBD compared to HC; changes were located predominantly in nigrosome 1 in the former and nigrosome 2 in the latter group. In the iRBD group, abnormal dopamine transporter SPECT was associated with increased susceptibility in nigrosome 1. iRBD patients display greater fronto-parietal cortex involvement than incidental early-stage PD cohort indicating more widespread subclinical neuropathology. Dopaminergic degeneration in the substantia nigra is paralleled by susceptibility increase, mainly in nigrosome 1.
| S-EPMC11002348 | biostudies-literature
Project description:ObjectiveNightmare disorder consists of the appearance of unpleasant and vivid, repeated dreams, with a situation of discomfort and anguish on awakening. Its prevalence is 3%-4% in adults. They do not associate muscle mobilization during this phase. REM sleep behavior disorder (RSBD) is a rare parasomnia (0.5% of people older than 60 years of age), characterized by the presence of unpleasant dreams, with violent content, and vigorous movements of limbs (kicks and punches), reflecting a loss of muscle atony typical of the REM phase of sleep. Language (screams and words) can also be emitted. The same clinical manifestations of RSBD can appear in other sleep disorders. The diagnosis requires the performance of a polysomnography.MethodsWe present the case of a 41-year-old man referred for vivid and unpleasant dreams, beginning in the last year, related to work stress.ResultsThe polysomnography showed the loss of atony in the REM phase and emission of a prolonged howl after which the patient continues in the REM phase.DiscussionProlonged howling is a very rare symptom in sleep disorders, and very atypical in RSBD, so polysomnography is essential to confirm the diagnosis and rule out other parasomnias.
| S-EPMC9987201 | biostudies-literature
Project description:BackgroundAbnormal sleep behavior has been reported in 5 dogs during recovery from tetanus.HypothesisREM sleep behavior disorder (RBD) is a more common consequence of tetanus than previously reported in veterinary literature and easily confused for epileptic seizures.AnimalsSixty-one client-owned dogs diagnosed with tetanus at 2 UK referral centers.MethodsA retrospective review of medical records was combined with a questionnaire sent to owners of surviving dogs, to identify cases that developed clinically probable RBD and determine its clinical progression and effect on quality of life of affected dogs and their owners. Descriptive statistical evaluation was performed.ResultsEleven dogs (18%) died or were euthanized before discharge. At least 46% surviving dogs developed abnormal "dream enactment" clinically consistent with RBD. Twitching, running, and vocalization were new sleep behaviors in 53, 80, and 60% of affected dogs. Clinically probable RBD was described as violent or "nightmare"-like in 36% affected dogs, and like an epileptic seizure in 40% affected dogs. When trialed, antiepileptic medications were ineffective. Onset occurred before discharge in 25% cases. For dogs that developed clinically probable RBD postdischarge, onset occurred within 2 weeks of discharge in 77% dogs. Clinically probable RBD did not worsen in severity or frequency in any dog, and spontaneously resolved within 6 months in 43% cases.Conclusions and clinical importanceClinically probable RBD is a common sequel to canine tetanus with many clinical similarities to epileptic seizure activity. Owners should be made aware of its potential development and care taken to avoid misdiagnosis with epileptic seizure activity.
| S-EPMC6272037 | biostudies-literature
Project description:ImportancePrevious studies conducted among patients with Parkinson disease (PD) reported that parasomnias other than rapid eye movement (REM) sleep behavior disorder (RBD), particularly sleepwalking (SW), are associated with PD severity. However, it remains unclear whether the presence of SW is associated with altered odds of having PD in a population-based study.ObjectiveTo evaluate whether probable SW, either alone or co-occurring with probable RBD, is associated with higher odds of PD in men.Design, setting, and participantsThis cross-sectional study included 25 694 men from the Health Professionals Follow-up Study, a population-based cohort of male health professionals in the US with information on probable SW and probable RBD. Data collection took place between January 2012 and June 2018, and data analysis took place from July 2020 to October 2020.ExposuresProbable SW and probable RBD were measured by questions adapted from the Mayo Sleep Questionnaire in 2012.Main outcomes and measuresPD, confirmed after review of medical records by a movement disorder specialist.ResultsOf the 25 694 studied men (mean [SD] age, 75.6 [7.4] years), 223 (0.9%) had probable SW, 2720 (10.6%) had probable RBD, and 257 (1.0%) had PD. After adjusting for potential confounders (eg, age, smoking, caffeine intake, chronic disease status, and other sleep disorders), compared with individuals without probable SW and probable RBD, participants with probable SW, probable RBD, and both probable SW and probable RBD had higher odds of PD, (probable SW: odds ratio [OR], 4.80; 95% CI, 1.61-14.26; probable RBD: OR, 6.36; 95% CI, 4.83-8.37; both probable SW and probable RBD: OR, 8.44; 95% CI, 3.90-18.27).Conclusions and relevanceIn this cross-sectional study of a male population, probable sleep parasomnias, including both SW and RBD, were associated with higher odds of having PD. PD-related neurodegeneration may impair arousal regulation during sleep.
| S-EPMC8044732 | biostudies-literature
Project description:Study objectivesREM sleep behavior disorder (RBD) is associated with antidepressant treatment, especially in younger patients; but quantitative REM sleep without atonia (RSWA) analyses of psychiatric RBD patients remain limited. We analyzed RSWA in adults receiving antidepressants, with and without RBD.DesignWe comparatively analyzed visual, manual, and automated RSWA between RBD and control groups. RSWA metrics were compared between groups, and regression was used to explore associations with clinical variables.SettingTertiary-care sleep center.ParticipantsParticipants included traditional RBD without antidepressant treatment (n = 30, 15 Parkinson disease [PD-RBD] and 15 idiopathic); psychiatric RBD receiving antidepressants (n = 30); and adults without RBD, including antidepressant-treated psychiatric (n = 30), untreated psychiatric (n = 15), and OSA (n = 60) controls.InterventionsN/A.Measurements and resultsRSWA was highest in traditional and psychiatric RBD, intermediate in treated psychiatric controls, and lowest in untreated psychiatric and OSA controls (P < 0.01). RSWA distribution and type also differed between antidepressant-treated patients having higher values in anterior tibialis, and PD-RBD with higher submentalis and tonic RSWA. Psychiatric RBD had significantly younger age at onset than traditional RBD patients (P < 0.01).ConclusionsAntidepressant treatment was associated with elevated REM sleep without atonia (RSWA) even without REM sleep behavior disorder (RBD), suggesting that antidepressants, not depression, promote RSWA. Differences in RSWA distribution and type were also seen, with higher anterior tibialis RSWA in antidepressant-treated patients and higher tonic RSWA in Parkinson disease-RBD patients, which could aid distinction between RBD subtypes. These findings suggest that antidepressants may mediate different RSWA mechanisms or, alternatively, that RSWA type and distribution evolve during progressive neurodegeneration. Further prospective RSWA analyses are necessary to clarify the relationships between antidepressant treatment, psychiatric disease, and RBD.
| S-EPMC4434557 | biostudies-literature
Project description:Despite decades of research, there is a persistent debate regarding the localization of GABA/glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical (or REM) sleep (PS), resulting in the loss of muscle tone during this sleep state. Combining complementary neuroanatomical approaches in rats, we first show that these inhibitory neurons are localized within the ventromedial medulla (vmM) rather than within the spinal cord. We then demonstrate their functional role in PS expression through local injections of adeno-associated virus carrying specific short-hairpin RNA in order to chronically impair inhibitory neurotransmission from vmM. After such selective genetic inactivation, rats display PS without atonia associated with abnormal and violent motor activity, concomitant with a small reduction of daily PS quantity. These symptoms closely mimic human REM sleep behavior disorder (RBD), a prodromal parasomnia of synucleinopathies. Our findings demonstrate the crucial role of GABA/glycine inhibitory vmM neurons in muscle atonia during PS and highlight a candidate brain region that can be susceptible to α-synuclein-dependent degeneration in RBD patients.
| S-EPMC5799338 | biostudies-literature
Project description:Synucleinopathies are neurodegenerative diseases with both central and peripheral immune responses. However, whether the peripheral immune changes occur early in disease and their relation to brain events is yet unclear. Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) can precede synucleinopathy-related parkinsonism and provides a prodromal phenotype to study early Parkinson's disease events. In this prospective case-control study, we describe monocytic markers in a cohort of iRBD patients that were associated with the brain-imaging markers of inflammation and neuronal dysfunction. Using 11C-PK11195 positron emission tomography (PET), we previously showed increased immune activation in the substantia nigra of iRBD patients, while 18F-DOPA PET detected reduced putaminal dopaminergic function. Here we describe that patients' blood monocytic cells showed increased expression of CD11b, while HLA-DR expression was decreased compared to healthy controls. The iRBD patients had increased classical monocytes and mature natural killer cells. Remarkably, the levels of expression of Toll-like receptor 4 (TLR4) on blood monocytes in iRBD patients were positively correlated with nigral immune activation measured by 11C-PK11195 PET and negatively correlated with putaminal 18F-DOPA uptake; the opposite was seen for the percentage of CD163+ myeloid cells. This suggesting a deleterious role for TLR4 and, conversely, a protective one for the CD163 expression. We show an association between peripheral blood monocytes and brain immune and dopaminergic changes in a synucleinopathy-related disorder, thus suggesting a cross-talk among periphery and brain during the disease.
| S-EPMC7958435 | biostudies-literature
Project description:ObjectiveWe aimed to investigate relationships between sleep disturbances and phenoconversion to neurodegenerative diseases in patients with REM sleep behavior disorder (RBD).MethodUsing a comprehensive sleep database in a university-affiliated hospital between December 2014 and March 2021, we reviewed the data of 226 patients with RBD (182 patients with idiopathic RBD (iRBD) and 44 patients with symptomatic RBD (sRBD) with a neurodegenerative disease).ResultsAmong 226 patients with RBD (male, 61.5%), the mean age at RBD onset and mean disease duration were 59.4 ± 10.5 and 5.9 ± 5.6 years, respectively. Further, 111 (49.1%) patients had periodic limb movements during sleep (PLMS, PLM index ≥ 15/h), while 110 patients (48.7%) had comorbid obstructive sleep apnea (OSA, respiratory disturbance index ≥ 15/h). There was a positive correlation between age at RBD onset and the apnea-hypopnea index and Pittsburgh Sleep Quality Index. Compared to patients with iRBD, patients with sRBD showed a lower N3 sleep (3.3 ± 5.0 vs. 1.6 ± 3.1%, p = 0.004) and higher periodic limb movement index (36.3 ± 31.8 vs. 56.9 ± 47.5/h, p = 0.021) at the baseline. Among the 186 patients with iRBD, 18 (8.0%) developed neurodegenerative diseases (converters, mean follow-up duration: 2.5 ± 1.6 years) and 164 did not (non-converters, mean follow-up 2.4 ± 2.2 years). There was no significant between-group difference in the demographics and baseline clinical features. Continuous positive airway pressure (CPAP) therapy was prescribed in 101 patients with OSA; among them, 71 (70%) patients agreed to use it. CPAP improved dream enactment behaviors.ConclusionIn our study, 8.0% of patients with iRBD showed phenoconversion within a mean follow-up duration of 2.5 years. Polysomnographic parameters could not predict phenoconversion to neurodegenerative disease. However, approximately half of the patients with RBD presented with significant sleep disorders, including OSA or PLMS. CPAP therapy may alleviate RBD symptoms in patients with RBD-OSA.
| S-EPMC8536960 | biostudies-literature
Project description:ObjectivesRapid eye movement sleep behavior disorder (RBD) patients have a high risk of developing a Parkinsonian disorder, offering an opportunity for neuroprotective intervention. Predicting near-term conversion, however, remains a challenge. Dopamine transporter imaging, while informative, is expensive and not widely available. Here, we investigate the utility of susceptibility-weighted MRI (SWI) to detect abnormalities of the substantia nigra in RBD, and explore their association with striatal dopaminergic deficits.MethodsSWI of the substantia nigra was performed in 46 RBD patients, 27 Parkinson's patients, and 32 control subjects. Dorsal nigral hyperintensity (DNH) was scored by two blinded raters, and separately quantified using a semiautomated process. Forty-two RBD patients were also imaged with 123 I-ioflupane single-photon emission computed tomography (DaT SPECT/CT).ResultsConsensus visual DNH classification was possible in 87% of participants. 27.5% of RBD patients had lost DNH, compared with 7.7% of control subjects and 96% of Parkinson's patients. RBD patients lacking DNH had significantly lower putamen dopaminergic SPECT/CT activity compared to RBD patients with DNH present (specific uptake ratios 1.89 vs. 2.33, P = 0.002). The mean quantified DNH signal intensity declined in a stepwise pattern, with RBD patients having lower intensity than controls (0.837 vs. 0.877, P = 0.01) but higher than PD patients (0.837 vs. 0.765, P < 0.001).InterpretationOver one quarter of RBD patients have abnormal substantia nigra SWI reminiscent of Parkinson's, which is associated with a greater dopaminergic deficit. This modality may help enrich neuroprotective trials with early converters.
| S-EPMC6952317 | biostudies-literature