OBJECTIVE: Migraine and sleep disorders share a bidirectional relationship, but little is known about the specific association between migraine and rapid eye movement (REM) sleep behaviour disorder (RBD). The aim was to assess the prevalence of RBD and associated clinical characteristics in adults with migraine.
METHODS: This analysis is part of a cross-sectional survey study conducted at the Headache Centre of the Charité-Universitätsmedizin Berlin between August 2020 and March 2023. At the end of their regular medical consultation, patients with migraine filled out (1) the validated RBD Screening Questionnaire (RBDSQ), (2) a questionnaire on REM sleep intrusions and (3) the Depression, Anxiety and Stress Scale 21. The primary endpoint was the percentage of patients with a positive RBD screening. A multivariate analysis was performed to identify characteristics independently associated with features of RBD.
RESULTS: A total of 751 patients (44.1 ± 13.2 years; 87.4% female) with complete RBDSQ were included in this analysis, of which 443 (58.9%) screened positive for RBD. In multivariate analysis, a positive screening for RBD was associated with younger age (odds ratio [OR] 0.9, 95% confidence interval [CI] 0.8-0.9 per 10-year increase; p = 0.005) and with features suggestive of REM sleep intrusions (OR 4.3, 95% CI 1.8-10.4; p = 0.001). Migraine aura remained in the model without reaching statistical significance (OR 1.3, 95% CI 0.9-1.8; p = 0.079).
CONCLUSIONS: Symptoms of RBD are frequent in adults with migraine. Further studies including polysomnography are required to confirm this association, and to explore potential common pathophysiological mechanisms.

The neurodegenerative synucleinopathies, including Parkinson\'s disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson\'s disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson\'s disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson\'s disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.

UNASSIGNED: Parkinson\'s disease (PD) is typically diagnosed when motor symptoms first occur. However, PD-related non-motor symptoms may appear several years before diagnosis. REM sleep behaviour disorder (RBD) and olfactory deficits (hyposmia) are risk factors, but they are not specific for predicting progression towards PD. Other PD-related markers, for example brain imaging markers, may help to identify preclinical PD in hyposmic RBD patients. Studies have reported abnormal structural characteristics in the corticospinal tract (CST) of PD patients, but it is unclear whether hyposmic RBD patients have similar abnormalities that may help to predict PD in these individuals. This study examined whether CST abnormalities may be a potential marker of PD risk by using diffusion tensor imaging (DTI) measures.
UNASSIGNED: Twenty hyposmic RBD patients, 31 PD patients, and 29 healthy controls (HCs) were studied. DTI data were collected on a 1.5 T MRI scanner and CST characteristics (FA, MD, AD, and RD) were evaluated using probabilistic tractography (with seed regions in the bilateral primary motor cortex and mediolateral cerebral peduncles). Olfactory function was assessed with the University of Pennsylvania Smell Identification Test (UPSIT).
UNASSIGNED: Hyposmic RBD patients showed significantly higher mean diffusivity (MD) values of the right CST compared to HCs but did not differ from PD patients. PD patients showed a trend of higher MD values compared to HCs.
UNASSIGNED: Altered diffusivity in the CST seems to be associated with RBD. The combination of RBD, hyposmia, and CST alterations may be related to later development of PD with comorbid RBD.

Parkinson\'s disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial α-synuclein aggregates originate. We have hypothesized that Parkinson\'s disease comprises two subtypes. A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type. Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups. We included 37 consecutive de novo patients with Parkinson\'s disease into this case-control PET study. Patients with Parkinson\'s disease were divided into 24 RBD-negative (PDRBD-) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients. We used 11C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity. Colon volume and transit times were assessed with CT scans and radiopaque markers. Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons. The PDRBD- and PDRBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P < 10-13, ANOVA). When compared to the PDRBD- patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P < 10-5, ANOVA) and colon 11C-donepezil standard uptake values (P = 0.008, ANOVA). The PDRBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PDRBD- (P = 0.07, t-test). In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (P < 0.001, ANOVA) and delayed colonic transit times (P = 0.01, Kruskal-Wallis). The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake. In contrast, the PDRBD- data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal. These findings support the existence of brain-first and body-first subtypes of Parkinson\'s disease.

Our objectives were to assess the prevalence of REM sleep behaviour disorder in patients with Essential Tremor, using video-polysomnography and to compare REM sleep behaviour disorder features in essential tremor with those of patients with alpha-synucleinopathies. Forty-nine patients with essential tremor were screened with the REM Sleep Behaviour Disorder Screening Questionnaire. Patients scoring positive and those with spontaneous complaints of REM sleep behaviour disorder (n = 6) underwent video-polysomnography. The clinical features of essential tremor were compared between patients with and without REM sleep behaviour disorder. Video-polysomnography data were compared between patients who had essential tremor and Parkinson\'s disease with REM sleep behaviour disorder and those with idiopathic REM sleep behaviour disorder. Fourteen patients (23.5%) screened positive for REM sleep behaviour disorder, confirmed by video-polysomnography in five (11.6%). All patients with essential tremor and REM sleep behaviour disorder had rest tremor, compared with 13 (34.2%) in the group with essential tremor but without REM sleep behaviour disorder (p = .009). In video-polysomnography, patients with essential tremor and REM sleep behaviour disorder were similar to patients with Parkinson\'s disease with REM sleep behaviour disorder and presented worse sleep dysfunction and lower severity of REM sleep behaviour disorder compared to those with idiopathic REM sleep behaviour disorder. We found a high prevalence of REM sleep behaviour disorder in patients with essential tremor, associated with a predominance of rest tremor. Polysomnography data from patients with essential tremor and REM sleep behaviour disorder were similar to those in patients with Parkinson\'s disease. This suggests a relation between this subgroup of patients with essential tremor and the alpha-synucleinopathies.

Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson\'s disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.

We report a kindred with a genetic form of REM behaviour disorder (RBD) with autosomal dominant transmission.
Clinical, polysomnography study, genetic study and brain MRI were performed to evaluate the index patients. The genetic study included exome sequencing of the index cases that detected 60,869 variants in the individuals examined.
The kindred has a RBD with autosomal dominant transmission starting in second decade of life. After filtering out the exome variants shared by two affected cases the pool of variants could be reduced to thirteen; one of them is in PVALB, a calcium-binding albumin protein present in gabaergic interneurons in the nervous system that inhibit the pyramidal cell during REM sleep.
RBD can have a genetic origin. The results of the exome study in this kindred suggest that gabaergic circuits may be altered in patients with RBD. Further studies in this family or in other pedigrees with familial RBD may clear the role of this gene in this disorder.

Pathological involvement of the noradrenergic locus coeruleus occurs early in Parkinson\'s disease, and widespread noradrenaline reductions are found at post-mortem. Rapid eye movement sleep behaviour disorder (RBD) accompanies Parkinson\'s disease and its presence predicts an unfavourable disease course with a higher propensity to cognitive impairment and orthostatic hypotension. MRI can detect neuromelanin in the locus coeruleus while 11C-MeNER PET is a marker of noradrenaline transporter availability. Here, we use both imaging modalities to study the association of RBD, cognition and autonomic dysfunction in Parkinson\'s disease with loss of noradrenergic function. Thirty non-demented Parkinson\'s disease patients [16 patients with RBD and 14 without RBD, comparable across age (66.6 ± 6.7 years), sex (22 males), and disease stage (Hoehn and Yahr, 2.3 ± 0.5)], had imaging of the locus coeruleus with neuromelanin sensitive MRI and brain noradrenaline transporter availability with 11C-MeNER PET. RBD was confirmed with polysomnography; cognitive function was assessed with a neuropsychological test battery, and blood pressure changes on tilting were documented; results were compared to 12 matched control subjects. We found that Parkinson\'s disease patients with RBD showed decreased locus coeruleus neuromelanin signal on MRI (P < 0.001) and widespread reduced binding of 11C-MeNER (P < 0.001), which correlated with amount of REM sleep without atonia. Parkinson\'s disease with RBD was also associated with a higher incidence of cognitive impairment, slowed EEG activity, and orthostatic hypotension. Reduced 11C-MeNER binding correlated with EEG slowing, cognitive performance, and orthostatic hypotension. In conclusion, reduced noradrenergic function in Parkinson\'s disease was linked to the presence of RBD and associated with cognitive deterioration and orthostatic hypotension. Noradrenergic impairment may contribute to the high prevalence of these non-motor symptoms in Parkinson\'s disease, and may be of relevance when treating these conditions in Parkinson\'s disease.