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Subtle gait changes associated with idiopathic rapid eye movement sleep behavior disorder (iRBD) could allow early detection of subjects with future synucleinopathies.The aim of this study was to create a multiclass model, using statistical learning from probability distribution of gait parameters, to distinguish between patients with iRBD, healthy control subjects (HCs), and patients with Parkinson's disease (PD).Gait parameters were collected in 21 participants with iRBD, 21 with PD, and 21 HCs, matched for age, sex, and education level. Lasso sparse linear regression explored gait features able to classify the three groups.The final model classified iRBD from HCs and from patients with PD equally well, with 95% accuracy, 100% sensitivity, and 90% specificity.Gait parameters and a pretrained statistical model can robustly distinguish participants with iRBD from HCs and patients with PD. This could be used to screen subjects with future synucleinopathies in the general population and to identify a conversion threshold to PD. © 2022 International Parkinson and Movement Disorder Society.

Wilson's disease (WD) is a rare genetic disorder that leads to copper overload, mainly in the liver then, in the brain. Patients with WD often complain about sleep disorders. We aimed to explore them.Sleep complaints and disease symptoms were compared in 40 patients with WD (20 patients with hepatic phenotype matched to 20 neurologic one) and 40 age, sex and BMI matched healthy controls.Patients with WD had more frequently (32.5 vs 10.0%, p 0.05) and more severe (10.5 ± 6.0 vs 7.6 ± 4.8, p 0.01) insomnia than controls and insomnia was more severe in neurologic than hepatic form of the disease (12.25 ± 5.89 vs 8.73 ± 5.8, p0.05). Insomnia severity was correlated with the severity of depressive symptoms (r = 0.53, p 0.001). Compared to controls, patients reported more difficulties staying asleep and more consequences of insomnia on their quality of life. REM sleep behavior disorder was more frequent in WD (20 vs 0%, p = 0.005) than controls. Patients complained more frequently of nycturia (22.8 vs 7.6%, p = 0.003) than controls. Patients did not differ from controls for sleepiness, restless legs syndrome and obstructive sleep apnea syndrome. Patients did not report cataplexia.In patients with WD, insomnia and REM sleep behavior disorder are the two main sleep complaints. Insomnia is more frequent in neurologic than hepatic form of the disease. Severity of insomnia is associated with the severity of depressive symptoms.

International audience; BACKGROUND: Insomnia is a frequent complaint of patients with Parkinson’s disease, and it negatively affects quality of life. Drugs that improve both sleep and parkinsonism would be of major benefit to patients with Parkinson’s disease-related insomnia. We aimed to test the safety and efficacy of subcutaneous night-time only apomorphine infusion in patients with Parkinson’s disease and insomnia. METHODS: We did a randomised, multicentre, double-blind, placebo-controlled, crossover trial in 11 expert centres in Parkinson’s disease and sleep centres in France. Participants aged 35-90 years with fluctuating Parkinson’s disease and moderate to severe insomnia (Insomnia Severity Index score ≥15) were randomly assigned to either first receive night-time subcutaneous apomorphine (up to 5 mg/h) or matching placebo. Randomisation was done using a computer-generated plan in blocks of four, stratified by centre. This first intervention was followed by a 14-night washout period, then crossover to the other intervention. The treatment periods consisted of a 10-night titration phase followed by a 7-night fixed-dose phase. The dose was adjusted during the titration phase on the basis of a daily telephone call assessing sleep quality and treatment tolerability. The primary efficacy endpoint was the difference in Parkinson’s disease sleep scale (PDSS) scores from the beginning to the end of each treatment period. Analysis was done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT02940912. FINDINGS: Between Jan 31, 2017, and Jan 29, 2021, 46 participants were enrolled. 25 (54%) patients were randomly assigned to receive apomorphine first and 21 (46%) patients to receive placebo first. Mean change in PDSS score was significantly greater with night-time apomorphine infusion (15·18 [SD 24·34]) compared with placebo (5·23 [21·52]; treatment effect 9·95 [95% CI 0·88-19·03]; p=0·041). Adverse events were reported in 25 (54%) participants during the apomorphine period and in 17 (37%) participants during the placebo period (p=0·16). Apomorphine was associated with more frequent dizziness than was placebo (seven [15%] vs 0; p=0·041). INTERPRETATION: Subcutaneous night-time only apomorphine infusion improved sleep disturbances according to difference on PDSS score, with an overall safety profile consistent with previous studies in Parkinson’s disease. This treatment might be useful to manage sleep disturbances in patients with advanced Parkinson’s disease and moderate to severe insomnia. FUNDING: Orkyn and Aguettant Pharma. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

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 different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention.

International audience; Objective: We aimed to identify timing distortions in production and perception of rhythmic events in patients with idiopathic REM sleep behavior disorder (iRBD) as early markers of Parkinson's disease (PD).Methods: Rhythmic skills, clinical characteristics, dysautonomia, depression, and olfaction were compared in 97 participants, including 21 participants with iRBD, 38 patients with PD, and 38 controls, matched for age, gender, and education level. Rhythmic disturbances can be easily detected with dedicated motor tasks via a tablet application. Rhythm production was tested in two conditions: to examine the ability to generate a spontaneous endogenous rhythm, tapping rate and variability in a finger tapping task without external stimulation was measured, while the ability to synchronize to an external rhythm was tested with finger tapping to external auditory cues. Rhythm perception was measured with a task, in which the participants had to detect a deviation from a regular rhythm. Participants with iRBD had dopamine transporter imaging.Results: Participants with iRBD and PD revealed impaired spontaneous rhythm production and poor rhythm perception compared to controls. Impaired rhythm production was correlated with olfaction deficits, dysautonomia, impaired non-motor aspects of daily living, and dopamine uptake measures.Conclusions: Participants with iRBD show impaired rhythm production and perception; this impairment is correlated with other early markers for PD. Testing rhythmic skills with short and inexpensive tests may be promising for screening for potential future PD in iRBD patients.

Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan–Meier survival analysis. Results: A 5′-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5′ risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3′ of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3′ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3′ of SNCA. Several 5′ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584–598.

International audience; Continuous positive airway pressure (CPAP) is efficacious in the treatment of obstructive sleep apnea syndrome (OSAS) in patients with Parkinson's disease (PD). However, this treatment is often not well tolerated in this disabled population. We explored, in a pilot study, the efficacy, observance, and usability of mandibular advancement device (MAD) for the treatment of OSAS in this peculiar population. Patients/methods: Twenty patients with PD and moderate or severe OSAS were included in the study. Ten patients had refused or not tolerated the validated treatment with CPAP so that they were treated with MAD. The patients treated with MAD were matched for sex, age and body mass index (BMI) to 10 patients with PD treated with CPAP. We explored the efficacy of MAD on sleep disorders complaints (PDSS-2) and on sleep recordings. We compared adherence, tolerance and usability with MAD and with CPAP.Results: MAD improved sleep complaints increasing PDSS-2 scores (85 [55-106] vs 106 [88-126], p < 0.005), and sleep respiratory measures reducing apnea/hypopnea index (AHI) (50.8 [30.0-76.4] vs 9.4 [5.0-45.2]

Background: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy. Objective: To examine the role of PSAP mutations in iRBD. Methods: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018). Results: Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more. Conclusion: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.

People walking side by side spontaneously synchronize their steps on some occasions but not on others, which poses a challenge to theories of perception-action based on interactive dynamic systems. How can action be spontaneously entrained by some sources of perceptual information while others are selectively ignored? The predictive processing framework suggests that saliency factors such as stimulus predictability, consistent deviation, and interactivity of the stimulus control the coupling between the motor system and perceptual information. To test this, we compared entrainment of gait cadence by two interactive auditory stimuli and two noninteractive but predictable, faster than preferred stimuli that were isochronous or statistically matched to gait. One interactive stimulus had properties that are optimal for mutual entrainment as per a mathematical model of interactive periodic processes, the Kuramoto system. In particular, the stimulus was faster than the participant but also adapted its rate to a limited degree as function of phase mismatch with the participant's steps. The second interactive stimulus fully mirrored the gait cycle hence it did not induce mutual synchronization. Furthermore, healthy participants were compared to ones with impaired gait due to Parkinson's disease, a model disorder that makes movement more dependent on external cueing. The mutually interactive condition produced the strongest entrainment, in patients and healthy participants, without differences between groups. The stimulus adapted to each participant's gait while maintaining a consistent lead in phase. Auditory-motor coupling may be enhanced by stimuli that are not only predictable but also interactive in that they align to self-generated movements. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Fil: Rascol, Olivier. Universidad de Toulouse. Hospital Universitario de Toulouse; Francia Fil: Rascol, Olivier. Centro NeuroToul COEN; Francia Fil: Rascol, Olivier. Clínica de Toulouse. Centro de Investigación. Departamentos de Neurociencias y Farmacología Clínica; Francia Fil: Cochen De Cock, Valérie. Clínica Beau Soleil. Departamento de Neurología; Francia Fil: Cochen De Cock, Valérie. Universidad de Montpellier. EuroMov Digital Health in Motion; Francia Fil: Pavy-Le Traon, Anne. Centro de referencia de atrofia multisistémica; Francia Fil: Pavy-Le Traon, Anne. Universidad de Toulouse. Hospital Universitario de Toulouse. Instituto de Enfermedades Cardiovasculares y Metabólicas. Centro de Investigación Clínica de Toulouse. Departamento de Neurociencias; Francia Fil: Foubert-Samier, Alexandra. Universidad de Toulouse. Hospital Universitario de Toulouse. Instituto de Enfermedades Cardiovasculares y Metabólicas. Departamento de Neurociencias, Centro de investigación Clínica de Toulouse; Francia Fil: Thalamas, Claire. Universidad de Toulouse. Hospital Universitario de Toulouse. Centro de Investigación Clínica de Toulouse; Francia Fil: Thalamas, Claire. Hospital Universitario de Burdeos; Francia Fil: Sommet, Agnès. Red Francesa de Infraestructura de Investigación Clínica; Francia Fil: Pérez Lloret, Santiago. Universidad Abierta Interamericana. Centro de Investigaciones Biomédicas; Argentina Fil: Pérez Lloret, Santiago. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas; Argentina Fil: Fabbri, Margherita. Red Francesa de Infraestructura de Investigación Clínica; Francia Fil: Azulay, Jean Philippe. Universidad de Aix-Marsella. Sistema de Hospitales Universitarios Públicos de Marsella; Francia Fil: Corvol, Jean-Christophe. Universidad de la Sorbona; Francia Fil: Corvol, Jean-Christophe. Hospital de la Pitié-Salpêtrière; Francia Fil: Corvol, Jean-Christophe. Red Francesa de Infraestructura de Investigación Clínica; Francia Fil: Couratier, Philippe. Red Francesa de Infraestructura de Investigación Clínica; Francia Fil: Damier, Philippe. Hospital Nord Laennec. Centro de Investigación Clínica; Francia Fil: Defebvre, Luc. Universidad en Lille; Francia Fil: Defebvre, Luc. Hospital Universitario de Marsella. Departamento de Neurología y Patología del Movimiento; Francia Fil: Durif, Franck. Centro Hospitalario Universitario, Clermont-Ferrand. Departamento de Neurología; Francia Fil: Durif, Franck. Red Francesa de Infraestructura de Investigación Clínica; Francia Fil: Geny, Christian. Universidad de Montpellier. Departamento de Neurología; Francia Fil: Houeto, Jean-Luc. Centro Hospitalario Universitario de Limoges; Francia Fil: Houeto, Jean-Luc. Centro de referencia de atrofia multisistémica. Departamento de Neurología. Centro de Expertos en Parkinson; Francia Fil: Rascol, Olivier. Centro de referencia de atrofia multisistémica; Francia Fil: Remy, Philippe. Red Francesa de Infraestructura de Investigación Clínica. Centros Expertos en Parkinson; Francia Fil: Remy, Philippe. Instituto de Investigaciones Biomédicas Mondor; Francia Fil: Tranchant, Christine. Hospital Universitario de Estrasburgo. Red Francesa de Infraestructura de Investigación Clínica. Departamento de Neurología; Francia Fil: Verin, Marc. Universidad de Rennes. Hospital Universitario de Rennes. Red Francesa de Infraestructura de Investigación Clínica. Centro de expertos en Parkinson; Francia Fil: Tison, François. Centro de referencia de atrofia multisistémica. Departamento de Neurología de Enfermedades Neurodegenerativas; Francia Fil: Meissner, Wassilios G. Instituto de Investigación del Cerebro; Nueva Zelanda Fil: Meissner, Wassilios G. Universidad de Otago. Departamento de Medicina; Nueva Zelanda Abstract: Background: There are no effective treatments for multiple system atrophy (MSA). Objective: The objective of this study was to assess the efficacy and safety of the serotonin reuptake inhibitor fluoxetine (40 mg/d) for the symptomatic treatment of MSA. Methods: This was a double-blind, parallel-group, placebo-controlled, randomized trial in patients with "probable" MSA. The primary outcome was the change from baseline to week 12 in the mean total score of the Unified MSA Rating Scale (UMSARS Parts I + II). Secondary outcomes included change from baseline to week 6 in total UMSARS, and change from baseline to week 12 in the Scales for Outcomes in Parkinson Disease-Autonomic Dysfunction, Beck Depression Inventory, and different domains of the MSA-Quality of Life Questionnaire. Exploratory outcomes included change from baseline to week 12 in the UMSARS Parts I and II separately and change from baseline to week 24 in the total UMSARS score. Results: A total of 81 patients were randomly assigned, with no significant difference in the primary outcome (-2.13 units [95% confidence interval, CI, -4.55 to 0.29]; P = 0.08). There was a greater reduction on fluoxetine in the change from baseline to 12-week in UMSARS Part II (exploratory outcome: -1.41 units [95% CI, -2.84; 0.03]; p = 0.05) and in MSA-QoL emotional/social dimension (secondary outcome: -6.99 units [95% CI, -13.40; -0.56]; p < 0.03). A total of 5 deaths occurred (3 on fluoxetine and 2 on placebo). Conclusion: The MSA-FLUO failed to demonstrate fluoxetine superiority over placebo on the total UMSARS score, whereas trends in motor and emotional secondary/exploratory outcomes deserve further investigation.

OBJECTIVES Sleep-wake disorders are common in the general population and in most neurological disorders but are often poorly recognized. With the hypothesis that neurologists do not get sufficient training during their residency, the Young European Sleep Neurologist Association (YESNA) of the European Academy of Neurology (EAN) performed a survey on postgraduate sleep education. METHODS A 16-item questionnaire was developed and distributed among neurologists and residents across European countries. Questions assessed demographic, training and learning preferences in sleep disorders, as well as a self-evaluation of knowledge based on five basic multiple-choice questions (MCQs) on sleep-wake disorders. RESULTS The questionnaire was completed by 568 participants from 20 European countries. The mean age of participants was 31.9 years (SD 7.4 years) and was composed mostly of residents (73%). Three-quarters of the participants reported undergraduate training in sleep medicine, while fewer than 60% did not receive any training on sleep disorders during their residencies. Almost half of the participants (45%) did not feel prepared to treat neurological patients with sleep problems. Only one-third of the participants correctly answered at least three MCQs. Notably, 80% of participants favoured more education on sleep-wake disorders during the neurology residency. CONCLUSIONS Education and knowledge on disorders in European neurological residents is generally insufficient, despite a strong interest in the topic. The results of our study may be useful for improving the European neurology curriculum and other postgraduate educational programmes.

International audience; Background: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD).Objective: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD.Methods: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests.Results: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls.Conclusion: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.

Objective To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated REM sleep behavior disorder (iRBD). Methods We fully sequenced 25 genes previously identified in GWASs of PD in a total of 1,039 patients with iRBD and 1,852 controls. The role of rare heterozygous variants in these genes was examined with burden tests. The contribution of biallelic variants was further tested. To examine the potential effect of rare nonsynonymous BST1 variants on the protein structure, we performed in silico structural analysis. Finally, we examined the association of common variants using logistic regression adjusted for age and sex. Results We found an association between rare heterozygous nonsynonymous variants in BST1 and iRBD (p = 0.0003 at coverage >50× and 0.0004 at >30×), driven mainly by 3 nonsynonymous variants (p.V85M, p.I101V, and p.V272M) found in 22 (1.2%) controls vs 2 (0.2%) patients. All 3 variants seem to be loss-of-function variants with a potential effect on the protein structure and stability. Rare noncoding heterozygous variants in LAMP3 were also associated with iRBD (p = 0.0006 at >30×). We found no association between rare heterozygous variants in the rest of genes and iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD. Conclusion Our results suggest that rare coding variants in BST1 and rare noncoding variants in LAMP3 are associated with iRBD. Additional studies are required to replicate these results and to examine whether loss of function of BST1 could be a therapeutic target.

This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6 ± 7.3 years, 229 males) and 243 control subjects (67.2 ± 10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P

The rapid eye movement sleep behavioural disorder (RBD) population is an ideal study population for testing disease-modifying treatments for synucleinopathies, since RBD represents an early prodromal stage of synucleinopathy when neuropathology may be more responsive to treatment. While clonazepam and melatonin are most commonly used as symptomatic treatments for RBD, clinical trials of symptomatic treatments are also needed to identify evidence-based treatments. A comprehensive framework for both disease-modifying and symptomatic treatment trials in RBD is described, including potential treatments in the pipeline, cost-effective participant recruitment and selection, study design, outcomes and dissemination of results. For disease-modifying treatment clinical trials, the recommended primary outcome is phenoconversion to an overt synucleinopathy, and stratification features should be used to select a study population at high risk of phenoconversion, to enable more rapid clinical trials. For symptomatic treatment clinical trials, objective polysomnogram-based measurement of RBD-related movements and vocalisations should be the primary outcome measure, rather than subjective scales or diaries. Mobile technology to enable objective measurement of RBD episodes in the ambulatory setting, and advances in imaging, biofluid, tissue, and neurophysiological biomarkers of synucleinopathies, will enable more efficient clinical trials but are still in development. Increasing awareness of RBD among the general public and medical community coupled with timely diagnosis of these diseases will facilitate progress in the development of therapeutics for RBD and associated neurodegenerative disorders.

We aimed to review the sleep disorders described in Wilson’s disease (WD), focusing on their mechanisms and treatments. REM sleep behavior disorder or sleepiness can be warning signs of future WD. These early symptoms may significantly reduce the time to WD diagnosis. Early anti-copper therapies (chelators or zinc salts), reducing copper accumulation in the brain and though saving brain tissue, can allow the complete disappearance of these sleep disorders and of course improve the other symptoms of WD. Insomnia, restless legs syndrome (RLS), daytime sleepiness, cataplexy, and REM sleep behavior disorder (RBD) are present in WD and should be explored with video polysomnography and multiple sleep latency test. Suggested immobilization test could be useful in the diagnosis of RLS in WD. Motor and non-motor symptoms, dysautonomic dysfunctions, drugs, and lesions of the circuits regulating wake and sleep may be involved in the mechanisms of these sleep abnormalities. Adapted treatments should be proposed.

ObjectiveTo study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration.MethodsA total of 4,147 individuals were included: 1,061 iRBD patients and 3,086 controls. GBA was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of GBA variants on the risk for iRBD, age at onset (AAO) and conversion rates.ResultsGBA variants were found in 9.5% of iRBD patients compared to 4.1% in controls (odds ratio [OR]=2.45, 95% CI=1.87–3.22, p=1×10−10). The estimated OR for mild p.N370S variant carriers was 3.69, 95% CI=1.90–7.14, p=3.5×10−5, while for severe variant carriers it was 17.55, 95% CI=2.11–145.9, p=0.0015. Carriers of severe GBA variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or non-carriers (p=0.029). Of the GBA variant carriers with available data, 52.5% had converted, compared to 35.6% in non-carriers (p=0.011), with a trend for faster conversion among severe GBA variant carriers. However, the results on AAO and conversion were based on small numbers and should be taken with caution.ConclusionsGBA variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe GBA variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of GBA variants should be studied as a potential way to identify GBA variant carriers who will develop a synucleinopathy in the future.

Background: Individuals with rapid eye movement (REM)-sleep behavior disorder (RBD) are likely to progress to synucleinopathies, mainly Parkinson's disease (PD), dementia with Lewy-bodies (DLB) and multiple system atrophy (MSA). The genetics of RBD only partially overlaps with PD and DLB, and the role of LRRK2 variants in risk for RBD is still not clear.Methods: The full coding sequence, exon-intron boundaries and 5′ and 3′ untranslated regions of LRRK2 were sequenced using targeted next-generation sequencing. A total of 350 RBD patients and 869 controls were sequenced, and regression and burden models were used to examine the association between LRRK2 variants and RBD.Results: No pathogenic mutations that are known to cause PD were identified in RBD patients. The p.N551K-p.R1398H-p.K1423K haplotype was associated with a reduced risk for RBD (OR = 0.66, 95% CI 0.44–0.98, p = 0.0055 for the tagging p.N551K substitution). A common variant, p.S1647T, was nominally associated with risk for RBD (OR = 1.28, 95% CI 1.05–1.56, p = 0.029). Burden analysis identified associations with domains and exons that were derived by the variants of the protective haplotype, and no burden of other rare variants was identified.Conclusions: Carriers of the LRRK2 p.N551K-p.R1398H-p.K1423K haplotype have a reduced risk for developing RBD, yet PD-causing mutations probably have minor or no role in RBD. Additional work is needed to confirm these results and to identify the mechanism associated with reduced risk for RBD.

International audience; Humans' ability to synchronize movement with auditory rhythms relies on motor networks, such as cortical areas, basal ganglia and the cerebellum, which also participate in rhythm perception and movement production. Current research has provided insights into the dependence of this action-perception coupling upon the entrainment of neuronal activity by external rhythms. At a physical level, advances on wearable robotics have enriched our understanding of the dynamical properties of the locomotor system showing evidences of mechanical entrainment. Here we defend the view that modelling brain and locomotor oscillatory activities as dynamical systems, at both neural and physical levels, provides a unified theoretical framework for the understanding of externally driven rhythmic entrainment of biological systems. To better understand the underlying mechanisms of this multi-level entrainment during locomotion, we review in a common framework the core questions related to the dynamic properties of biological oscillators and the neural bases of auditory-motor synchronization. Illustrations of our approach, using personalized auditory stimulation, to gait rehabilitation in Parkinson disease and to manipulation of runners' kinematics are presented.

Background Rhythmic Auditory Stimulation (RAS) is an effective technique to improve gait and reduce freezing episodes for Persons with Parkinson's Disease (PwPD). The BeatHealth system, which comprises a mobile application, gait sensors, and a website, exploits the potential of the RAS technique. This paper describes the tools used for co-designing and evaluating the system and discusses the results and conclusions. Methods Personas, interviews, use cases, and ethnographic observations were used to define the functional requirements of the system. Low fidelity prototypes were created for iterative and incremental evaluation with end-users. Field trials were also performed with the final system. The process followed a user centered design methodology defined for this project with the aim of building a useful, usable, and easy-to-use system. Results Functional requirements of the system were produced as a result of the initial exploration phase. Building upon these, mock-ups for the BeatHealth system were created. The mobile application was iterated twice, with the second version of it achieving a rating of 75 when assessed by participants through the System Usability Scale (SUS). After another iteration field trials were performed and the mobile application was rated with an average 78.6 using SUS. Participants rated two website mock-ups, one for health professionals and another for end-users, as good except from minor issues related to visual design (e.g. font size), which were resolved in the final version. Conclusion The high ratings obtained in the evaluation of the BeatHealth system demonstrate the benefit of applying a user centered design methodology which involves stakeholders from the very beginning. Other important lessons were learned through the process of design and development of the system, such as the importance of motivational aspects, the techniques which work best, and the extra care that has to be taken when evaluating non-functional mock-ups with end users. This work was supported by the BeatHealth project within the 7th Framework Programme of the European Union - Personalised health, active ageing, and independent living, contract Number FP7-610633. See also: http://www.euromov.eu/beathealth/homepage.This work has been also partially supported by the Ministry of Economy and Competitiveness of the Spanish Government and by the European Regional Development Fund (projects TIN2014-52665-C2-1-R and TIN2017-85409-P), and by the Department of Education, Universities and Research of the Basque Government under grant IT980-16.

International audience; Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson's disease and dementia with Lewy bodies. In the current study, we aimed to evaluate the role of SMPD1 variants in isolated rapid eye movement sleep behavior disorder (iRBD). SMPD1 and its untranslated regions were sequenced using targeted next-generation sequencing in 959 iRBD patients and 1287 controls from European descent. Our study reports no statistically significant association of SMPD1 variants and iRBD. It is hence unlikely that SMPD1 plays a major role in iRBD.

Objective The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications. Methods Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function. Results Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants. Interpretation Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139-153.

OBJECTIVE To determine whether patients with idiopathic and symptomatic RBD were sleepier than controls, and if sleepiness in idiopathic RBD predicted earlier conversion to Parkinson disease. METHODS The Epworth Sleepiness Scale (ESS) and its determinants were compared at the time of a video-polysomnography for an RBD diagnosis in patients with idiopathic RBD, in patients with Parkinson disease, and in controls. Whether sleepiness at time of RBD diagnosis predicted an earlier conversion to neurodegenerative diseases was retrospectively analyzed in the followed-up patients. RESULTS The 75 patients with idiopathic RBD were sleepier (ESS: 7.8 ± 4.6) at the time of RBD diagnosis than 74 age- and sex-matched controls (ESS: 5.0 ± 3.6, P < 0.0001). They reached the levels of 114 patients with Parkinson disease (ESS: 8.7 ± 4.8), whether they had (n = 78) or did not have (n = 36) concomitant RBD. The severity of sleepiness in idiopathic RBD correlated with younger age, but not with sleep measures. Among the 69 patients with idiopathic RBD who were followed up for a median 3 years (1-15 years), 16 (23.2%) developed parkinsonism (n = 6), dementia (n = 6), dementia plus parkinsonism (n = 2), and multiple system atrophy (n = 2). An ESS greater than 8 at time of RBD diagnosis predicted a shorter time to phenoconversion to parkinsonism and dementia, from RBD onset, and from RBD diagnosis (when adjusted for age and time between RBD onset and diagnosis). CONCLUSIONS Sleepiness is associated with idiopathic REM sleep behavior disorder and predicts more rapid conversion to parkinsonism and dementia, suggesting it is an early marker of neuronal loss in brainstem arousal systems.

Background: A large hexanucleotide repeat expansion in C9orf72 has been identified as the most common genetic cause in familial amyotrophic lateral sclerosis and frontotemporal dementia. Rapid Eye Movement Sleep Behavior Disorder (RBD) is a sleep disorder that has been strongly linked to synuclein-mediated neurodegeneration. The aim of this study was to evaluate the role of the C9orf72 expansions in the pathogenesis of RBD. Methods: We amplified the C9orf72 repeat expansion in 344 patients with RBD by a repeat-primed polymerase chain reaction assay. Results: We identified two RBD patients carrying the C9orf72 repeat expansion. Most interestingly, these patients have the same C9orf72 associated-risk haplotype identified in 9p21-linked amyotrophic lateral sclerosis and frontotemporal dementia families. Conclusions: Our study enlarges the phenotypic spectrum associated with the C9orf72 hexanucleotide repeat expansions and suggests that, although rare, this expansion may play a role in the pathogenesis of RBD.

International audience; The present study aimed to examine whether the APOE ε4 allele, associated with dementia with Lewy bodies (DLB), and possibly with dementia in Parkinson's disease (PD), is also associated with idiopathic rapid eye movement sleep behavior disorder (RBD). Two single nucleotide polymorphisms, rs429358 and rs7412, were genotyped in RBD patients (n = 480) and in controls (n = 823). APOE ε4 allele frequency was 0.14 among RBD patients and 0.13 among controls (OR = 1.11, 95% CI: 0.88-1.40, p = 0.41). APOE ε4 allele frequencies were similar in those who converted to DLB (0.14) and those who converted to Parkinson's disease (0.12) or multiple system atrophy (0.14, p = 1.0). The APOE ε4 allele is neither a risk factor for RBD nor it is associated with conversion from RBD to DLB or other synucleinopathies.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a fascinating parasomnia in which patients are able to enact their dreams because of a lack of muscle atonia during REM sleep. RBD represents a unique window into the dream world. Frequently associated with Parkinson's disease (PD), RBD raises various issues about dream modifications in this pathology and about aggressiveness during RBD episodes in placid patients during wakefulness. Studies on these behaviors have underlined their non-stereotyped, action-filled and violent characteristics but also their isomorphism with dream content. Complex, learnt behaviors may reflect the cortical involvement in this parasomnia but the more frequent elementary movements and the associated periodic limb movements during sleep also implicate the brainstem. Surprisingly, patients with PD have an improvement of their movements during their RBD as if they were disease-free. Also not yet understood, this improvement of movement during REM sleep raises issues about the pathways involved in RBD and about the possibility of using this pathway to improve movement in PD during the day.

Mazindol is a tricyclic, anorectic, non-amphetamine stimulant used in narcolepsy and obesity since 1970. This study aimed to evaluate the long-term benefit/risk ratio in drug-resistant hypersomniacs and cataplexy sufferers.By retrospective analysis of the patients' files in the hospitals of Paris-Salpêtrière (n=91), Montpellier (n=40) and Lyon (n=8), the benefit (Epworth Sleepiness Score (ESS), cataplexy frequency, authorization renewal) and tolerance (side-effects, vital signs, electrocardiogram and cardiac echography) of mazindol were assessed.The 139 patients (45% men) aged 36±15years (range: 9-74) suffered narcolepsy (n=94, 66% with cataplexy), idiopathic (n=37) and symptomatic hypersomnia (n=8) refractory to modafinil, methylphenidate and sodium oxybate. Under mazindol (3.4±1.3mg/day, 1-6mg) for an average of 30months, the ESS decreased from 17.7±3.5 to 12.8±5.1, with an average fall of -4.6±4.7 (p0.0001) and the frequency of cataplexy fell from 4.6±3.1 to 2±2.8 episodes per week. The cataplexy was eliminated in 14.5% of patients, improved in 27.5%, and unchanged in 29% (missing data in 29%). The treatment was maintained long term in 83 (60%) patients, and stopped because of a lack of efficacy (22%) and/or secondary effects (9%). There was no pulmonary hypertension in the 45 patients who underwent a cardiac echography. The most common adverse effects were dry mouth (13%), palpitations (10%, including one with ventricular hyperexcitability), anorexia (6%), nervousness (6%) and headaches (6%).Mazindol has a long-term, favorable benefit/risk ratio in 60% of drug-resistant hypersomniacs, including a clear benefit on cataplexy.

International audience; Autonomic failure is a key feature of multiple system atrophy (MSA). Moreover, early autonomic failure is an independent predictive factor for rapid disease progression and shorter survival. The assessment of autonomic failure is therefore important for both, the diagnosis and prognosis of MSA. Here, we evaluate autonomic dysfunction in MSA patients by the Scopa-Aut questionnaire. Potential associations between the Scopa-Aut questionnaire and established markers of disease progression - that is the Unified MSA Rating Scale (UMSARS) - were further assessed. The results confirm early and prominent autonomic failure in MSA patients. Relative scores were highest for the sexual and urinary subdomains. Surprisingly, relative scores in the cardiovascular subdomain were lowest suggesting that the Scopa-Aut questionnaire is suboptimal for the screening and evaluation of cardiovascular symptoms in MSA. A multivariate regression showed an association between total Scopa-Aut and UMSARS I scores. No significant changes in Scopa-Aut scores were observed during follow-up except for the urinary subdomain, while UMSARS I, II and IV scores significantly increased over time. In conclusion, Scopa-Aut can be used as a simple auto-questionnaire for the screening of autonomic symptoms in multiple system atrophy. It seems not useful as endpoint for disease-modification or neuroprotection trials.

Objective Supine sleep is associated with increased obstructive sleep apnea. People with Parkinson's disease (PD) complain about difficulties turning around in bed. The relationship between supine sleep and sleep-disordered breathing has never been explored in people with Parkinson's disease. Methods Fifteen consecutive people with PD with severe Obstructive Sleep Apnea Syndrome (OSAS) were compared to: (1) 15 age-matched, gender-matched, body mass index-matched and Unified Parkinson's Disease Rating Scale-III score-matched people with PD without sleep-disordered breathing; (2) 11 age-matched and gender-matched people with severe obstructive sleep apnea syndrome (OSAS) alone; and (3) 11 age-matched and gender-matched healthy controls. Outcomes were: number of position changes during the night and per hour of sleep, and the percentage of sleep time spent in supine. Results People with PD and severe OSAS spent most of their sleep time in the supine position (93 ± 11%); while people with PD without OSAS (61 ± 24%, p 0.001), people with isolated, severe OSAS (50 ± 28%, p 0.001), and the controls (40 ± 21, p 0.001) spent significantly less time on their back. People with PD and severe OSAS changed their position in bed per hour of sleep (0.4 ± 0.5) less frequently than those with PD without OSAS (1.1 ± 0.8, p = 0.002), those with isolated OSAS (1.2 ± 1.0, p = 0.006) and the controls (1.5 ± 0.5, p 0.001). Conclusion PD and severe OSAS are associated with a major reduction in the number of position changes and an increased supine sleep position during the night. For people with PD, alleviating the difficulties of turning around in bed might reduce the supine sleep position and improve sleep-disordered breathing.

Background: The purpose of this study was to determine if there was a common pattern in movements during REM sleep behavior disorder (RBD). Methods: We blindly compared video-monitored movements during RBD (n = 136 clips) and wakefulness/arousal (n = 53 clips) in patients with Parkinson's disease (n = 29) and without parkinsonism (idiopathic RBD, n = 31; narcolepsy, n = 5). Results: The scorers accurately guessed the sleep/wake stage of 94% of video clips. Compared with wake movements, RBD movements were faster and more often repeated, jerky, and pseudohallucinatory, not self-centered, never associated with tremor, and rarely involved the environment in an appropriate manner. A specific posture of the hand (limp wrist with flexed digits) during grasping movements was evidenced during RBD in 48% of patients, reminiscent of hand-babbling in babies. Conclusions: These characteristics of movements were found in the 3 conditions (Parkinson's disease, idiopathic RBD, and primary narcolepsy), delineating a common motor signature of RBD. © 2011 Movement Disorder Society

Background Narcolepsy and Parkinson’s disease (PD) are associated with hallucinations, excessive daytime sleepiness, REM sleep behavior disorder (RBD), as well as complete (narcolepsy with cataplexy) vs. partial (PD, narcolepsy without cataplexy) hypocretin-1 deficiency. Objective To compare the hallucinations associated with narcolepsy to those of PD. Methods One hundred patients with narcolepsy (with and without cataplexy) and 100 patients with PD were consecutively interviewed about their hallucinations (frequency, phenomenology, insight into unreality and association with sleep) as well as their risk factors. Results Hallucinations occurred more frequently and with more motor and multimodal aspects in narcolepsy with cataplexy (59%) than in narcolepsy without cataplexy (28%) and PD (26%). Compared to PD, the hallucinations in narcolepsy were less frequently of the passage/presence type (passage: brief visions of a person or animal passing sideways; presence: perception that a living character or an animal is behind or near the subject, without the subject actually seeing, hearing or touching it), more frequently auditory and more often associated with sleep. However, in 40% of the patients with narcolepsy and 54% of the patients with PD, the hallucinations occurred while the patients were wide awake. Patients with cataplexy had reduced immediate insight into the unreality of their hallucinations compared to patients with PD, but the delusions were exceptional (2%), transient and based on hallucinations in both groups. The risk factors for hallucinations were sleep paralysis and RBD in narcolepsy and motor disability and sleepiness in PD. Conclusions The multimodal, dreamlike aspect of hallucinations in narcolepsy with cataplexy could transiently impair the patients’ insight. The high frequency of these hallucinations (compared to those in narcolepsy without cataplexy or PD) suggests that complete (more than partial) hypocretin-1 deficiency promotes hallucinations.

The objectives of the study are to evaluate the prevalence and the associated factors of thought disorders in a large cross-sectional population of non-demented out patients with Parkinson's disease (PD). Four-hundred and nineteen consecutive non-demented PD patients were studied through the DoPaMiP cross-sectional study. Demographic and clinical variables were recorded, including motor and cognitive status, dependency, depressive and anxious symptoms, dysautonomia and sleep disorders. The presence of thought disorders over the past 15 days was assessed by the Unified Parkinson's Disease Rating Scale part I. Patients with and without thought disorders were compared using parametric tests. Logistic regression was applied to significant data. Thought disorders were present in 105 patients (25%) including vivid dreams in 83 (19.8%), benign hallucinations in 17 (4.1%), and hallucinations without insight in 5 (1.2%). No patient had delusion. Patients with thought disorders were more dependent than the others. Thought disorders were associated with longer PD duration, greater UPDRS scores and the presence of motor complications. Conversely, UPDRS tremor sub-score was lower in patients without thought disorders. Thought disorders were also associated with dysautonomia, lower MMSE score, depression and sleep disorders. Logistic regression identified PD duration, lower MMSE score, depressive and dysautonomic signs as independent risk factors. In conclusion, mild thought disorders were present in 25% of non-demented outpatients with PD, but hallucinations were present in 5% only. Thought disorders were associated with PD duration, depressive and dysautonomic symptoms and lower MMSE score.

Parkinson's disease (PD) is associated with sleep disorders and daytime sleepiness. Upper airway dysfunction in PD may promote obstructive sleep apnea. However, the frequency and clinical relevance of sleep-disordered breathing in PD remains unclear.Sleep apnea symptoms, cardiovascular events and treatment were collected in 100 patients with PD (50 unselected, consecutive patients matched for age, sex and body mass index with 50 patients referred for sleepiness) and 50 in-hospital controls. The motor and cognitive status was evaluated in patients with PD. The 150 subjects underwent a video-polysomnography.Sleep apnea (defined as an apnea-hypopnea index greater than 5) was less frequent in the PD group (27% patients, including 6% with mild, 11% with moderate and 10% with severe sleep apnea) than in the control group (40% in-hospital controls, p0.002). Sleep apnea was not associated with increased sleepiness, nocturia, depression, cognitive impairment and cardiovascular events in patients with PD. Sleep apnea was more frequent and severe in the most disabled patients. Patients with PD did not display sleep hypoventilation, stridor and abnormal central sleep apnea. In patients with REM sleep behavior disorders, snoring and obstructive sleep apnea occurred during REM sleep, although the chin muscle tone was maintained.Obstructive sleep apnea does not seem to be a clinically relevant issue in PD. Daytime sleepiness, nocturia and cognitive impairment are mostly caused by other, non-apneic mechanisms. The maintenance of chin muscle tone during REM sleep behavior disorder has no influence on the frequency of apneic events.

Altered sleep and vigilance are among the most frequent symptoms, besides parkinsonism, in movement disorders. As many as 60% of patients with Parkinson's disease (PD) experience insomnia, 15-59% show rapid eye movement (REM) sleep behavior disorders (RBDs), and 30% show excessive daytime sleepiness. Insomnia is a distressing difficulty to maintain sleep, which is exacerbated by motor disability, painful dystonia, restless legs, dysuria, anxiety and depressed mood. Improving night-time motor control by overnight treatment with levodopa, transdermal or long-acting dopamine agonists, or bilateral subthalamus stimulation, can improve sleep continuity. RBDs are violent, enacted dreams that expose the patient or their sleeping partner to night-time injuries. A striking improvement of parkinsonism is observed during these behaviors in PD. RBDs are thought to be caused by lesions in the REM sleep atonia system, and can, in association with other early markers of neurodegenerative diseases, such as olfactory, cognitive and autonomic disturbances, precede parkinsonism by several years. Daytime sleepiness, often with a narcolepsy-like phenotype, is a common occurrence in PD, owing to lesions in the arousal systems of the brain. The use of dopamine agonists increases the risk of sleep attacks, especially when driving, suggesting a drug-disease interaction.

To describe sleep characteristics and rapid eye movement (REM) sleep behavior disorder in patients with Guadeloupean atypical parkinsonism (Gd-PSP), a tauopathy resembling progressive supranuclear palsy that mainly affects the midbrain. It is possibly caused by the ingestion of sour sop (corossol), a tropical fruit containing acetogenins, which are mitochondrial poisons.Sleep interview, motor and cognitive tests, and overnight videopolysomnography.Thirty-six age-, sex-, disease-duration- and disability-matched patients with Gd-PSP (n = 9), progressive supranuclear palsy (a tauopathy, n = 9), Parkinson disease (a synucleinopathy, n = 9) and controls (n = 9).Tertiary-care academic hospital.REM sleep behavior disorder was found in 78% patients with Gd-PSP (43% of patients reported having this disorder several years before the onset of parkinsonism), 44% of patients with idiopathic Parkinson disease, 33% of patients with progressive supranuclear palsy, and no controls. The percentage of muscle activity during REM sleep was greater in patients with Gd-PSP than in controls (limb muscle activity, 8.3%+/-8.7% vs 0.1%+/- 0.2%; chin muscle activity, 24.3%+/- 23.7% vs 0.7%+/-2.0%) but similar to that of other patient groups. The latency and percentage of REM sleep were similar in patients with Gd-PSP, patients with Parkinson disease, and controls, whereas patients with progressive supranuclear palsy had delayed and shortened REM sleep.Although Gd-PSP is a tauopathy, most patients experience REM sleep behavior disorder. This suggests that the location of neuronal loss or dysfunction in the midbrain, rather than the protein comprising the histologic lesions (synuclein versus tau aggregation), is responsible for suppressing muscle atonia during REM sleep. Subjects with idiopathic REM sleep behavior disorder should avoid eating sour sop.

REM sleep behavior disorder (RBD) is included in the diagnostic criteria for dementia with Lewy bodies (DLB), and is useful for being distinguished from Alzheimer's disease. However, RBD can precede DLB for a few years and be a warning symptom when associated with visuospatial disorders and hypometabolism in occipital regions by SPECT. When RBD are associated with dangerous behaviors or increased risk of fall out of bed, they must be treated. However, RBD can be difficult to be differentiated from hallucinations related to nocturnal delirium, both symptoms being frequently associated.

Introduction: The relationship between ICD and RBD is still not yet understood and the results from the current literature are contradictory in PD. We aimed to explore the association between rapid eye movement (REM) sleep behavior disorder (RBD) and impulse control disorder in Parkinson's disease. Methods: Ninety-eight non-demented patients with Parkinson's disease underwent one night of videopolysomnography recording. The diagnosis of RBD was established according to clinical and polysomnographic criteria. Impulse control disorders were determined by a gold standard, semi-structured diagnostic interview. Results: Half of the patients (n ¼ 49) reported clinical history of RBD while polysomnographic diagnosis of RBD was confirmed in 31.6% of the patients (n ¼ 31). At least one impulse control disorder was identified in 21.4% of patients, 22.6% with RBD and 20.9% without. Logistic regression controlling for potential confounders indicated that both clinical RBD (OR ¼ 0.34, 95% CI ¼ 0.07e1.48, P ¼ 0.15) and polysomnographic confirmed RBD diagnoses (OR ¼ 0.1.28, 95% CI ¼ 0.31e5.33, P ¼ 0.34) were not associated with impulse control disorder. Conclusion: In Parkinson's disease, REM Sleep Behavior Disorder is not associated with impulse control disorder. The results of our study do not support the notion that PSG-confirmed RBD and ICD share a common pathophysiology.

International audience; Background: Excessive daytime sleepiness is a frequent complaint in Parkinson's disease (PD); however the frequency and risk factors for objective sleepiness remain mostly unknown. We investigated both the frequency and determinants of self-reported and objective daytime sleepiness in patients with Parkinson's disease (PD) using a wide range of potential predictors.Methods: One hundred and thirty four consecutive patients with PD, without selection bias for sleep complaint, underwent a semi-structured clinical interview and a one night polysomnography followed by a multiple sleep latency test (MSLT). Demographic characteristics, medical history, PD course and severity, daytime sleepiness, depressive and insomnia symptoms, treatment intake, pain, restless legs syndrome, REM sleep behaviour disorder, and nighttime sleep measures were collected. Self-reported daytime sleepiness was defined by an Epworth Sleepiness Scale (ESS) score above 10. A mean sleep latency on MSLT below 8 minutes defined objective daytime sleepiness.Results: Of 134 patients with PD, 46.3% had subjective and only 13.4% had objective sleepiness with a weak negative correlation between ESS and MSLT latency. A high body mass index (BMI) was associated with both ESS and MSLT, a pain complaint with ESS, and a higher apnea/hypopnea index with MSLT. However, no associations were found between both objective and subjective sleepiness, and measures of motor disability, disease onset, medication (type and dose), depression, insomnia, restless legs syndrome, REM sleep behaviour disorder and nighttime sleep evaluation.Conclusion: We found a high frequency of self-reported EDS in PD, a finding which is however not confirmed by the gold standard neurophysiological evaluation. Current treatment options for EDS in PD are very limited; it thus remains to be determined whether decreasing pain and BMI in association with the treatment of sleep apnea syndrome would decrease significantly daytime sleepiness in PD.

Objective: This controlled study investigated associations between comorbidity and medication in patients with polysomnographically confirmed idiopathic REM sleep behavior disorder (iRBD), using a large multicenter clinic-based cohort. Methods: Data of a self-administered questionnaire on comorbidity and medication use of 318 patients with iRBD and 318 matched controls were analyzed. Comparisons between cases and controls were made using logistic regression analysis. Results: Patients with iRBD were more likely to report depression (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.3–2.9) and concomitant antidepressant use (OR 2.2, 95% CI 1.4–3.6). Subanalysis of antidepressant agents revealed that the increased use of antidepressants in iRBD was due to selective serotoninergic reuptake inhibitors (OR 3.6, 95% CI 1.8–7.0) and not due to other antidepressant classes. Patients with iRBD reported more lifetime antidepressant use than comorbid depression (antidepressant use: OR 1.9, 95% CI 1.1–3.3; depression: OR 1.6, 95% CI 1.0–2.5). Patients with iRBD reported more ischemic heart disease (OR 1.9, 95% CI 1.1–3.1). This association did not change substantially when adjusting for cardiovascular risk factors (OR 2.3, 95% CI 1.3–3.9). The use of inhaled glucocorticoids was higher in patients with iRBD compared to controls (OR 5.3, 95% CI 1.8–15.8), likely reflecting the higher smoking rate in iRBD (smoking: OR 15.3, 95% CI 2.0–118.8; nonsmoking: OR 2.4, 95% CI 0.4–13.2) and consequent pulmonary disease. Conclusions: This large study confirms the association between comorbid depression and antidepressant use in iRBD. In addition, there was an unexpected association of iRBD with ischemic heart disease that was not explained by cardiovascular risk factors.

OBJECTIVE We report a focal morphofunctional brain impairment within the left temporopolar cortex in a patient with a posttraumatic hypersomnia. This case may contribute to better understanding the possible pathophysiological mechanism for posttraumatic hypersomnia.

Rhythmic movement disorder (RMD) is a stereotyped movement disorder of sleep characterized by rhythmic oscillations such as head banging, body rocking or head rolling [1]. RMD diagnosis relies on the clinical description of the movements, but also on video sleep recordings showing the rhythmic movements at the transition between wake and sleep. Common in childhood, RMD can persist quite long into adulthood [2,3]. The pathophysiology remains unknown. However, RMD has rarely been described in association with other sleep disorders such as sleep disordered breathing, periodic limb movements, narcolepsy and restless legs syndrome (RLS) [4,5]. RLS diagnosis is based on four clinical criteria: a desire to move the limbs, usually associated with dysaesthesias, the presence of motor restlessness, worsening of symptoms at rest with relief by activity and peaking of symptoms in the evening and/or during the night [6]. Polysomnography recordings (PSG) mostly reveal the

Diagnosis of restless leg syndrome (RLS) in Parkinson's disease (PD) is difficult because of clinical confounds. The suggested immobilization test (SIT) is validated for diagnosis of primary RLS. This study evaluated the usefulness of the SIT for diagnosis of RLS in PD. We compared SIT scores, as well as polysomnography measures in 50 patients with PD (25 with RLS, 25 without), 25 patients with primary RLS, and 25 age/sex matched controls. Mean leg discomfort score was increased in patients with PD and RLS compared to PD without RLS, and also in patients with primary RLS compared to controls. Leg discomfort was significantly higher at the end of the test in patients with RLS compared to patients without RLS. Intensity of leg discomfort was similar between patients with RLS, with or without PD. Using a mean leg discomfort cutoff of 11, we showed sensitivity of 91% and specificity of 72% for RLS diagnosis in PD during symptomatic time intervals. Periodic leg movements index during the SIT did not differ between groups. Periodic leg movements index during sleep and wakefulness was increased in patients with primary RLS compared to controls, but did not differ between patients with PD, with and without RLS. The sensory SIT is a simple test that may help diagnose RLS in patients with PD.

Dopamine replacement therapy in Parkinson's disease (PD) improves the motor symptoms. However, it has recently been shown that a small sub-group of patients suffers from motor and behavioral disturbances associated with the use of dopamine agonists (DAs). The behavioral disorders are incentive- or reward-based repetitive symptoms regrouped under the term « dopamine dysregulation syndrome » (DDS). They include pathological gambling, hypersexuality, compulsive shopping, compulsive eating, punding, and compulsive medication use. Whether these behaviors are related to the dopaminergic medications interacting with an underlying individual vulnerability or whether the primary pathological features of Parkinson's disease play a role is not entirely understood. This review is devoted to the phenomenology of the DDS and factors influencing its susceptibility. We further review the literature studies that investigated the decision-making profile using the Iowa Gambling Task in Parkinson's disease, and the recent literature devoted to these abnormal behaviors in the restless legs syndrome (RLS). Given the potential substantial impact of the DDS on personal, familial, social, and financial well-being, patients with PD or RLS should be informed that DAs use may lead to the development of impulsive and compulsive disorders, and clinicians should include the investigation of these disorders as part of routine clinical care. The refinement of clinical strategies to predict, identify and manage DDS will help the future care of motor and non-motor symptoms of Parkinson's disease.

Developmental and benign movement disorders are a group of movement disorders with onset in the neonatal period, infancy, or childhood. They are characterized by the absence of associated neurological manifestations and by their favorable outcome, although developmental abnormalities can be occasionally observed. Knowledge of the clinical, neurophysiological, and pathogenetic aspects of these disorders is poor. Based on a comprehensive review of the literature and our practical experience, this article summarizes current knowledge in this area. We pay special attention to the recognition and management of these movement disorders in children.

Restless legs syndrome (RLS) is characterized by an unpleasant sensation in the lower limbs and an urge to move, occurring during periods of rest, in the evening and during the night and improved by movement. There are two different phenotypes of RLS: an early-onset form, starting before 36 years old with mostly a familial history, being mostly severe and highly genetically determined, with a high dependence to iron brain levels; a delayed-onset form, starting after 36 years old, mostly secondary, without familial history, with a rapid evolution in two or three years, and with frequent low ferritine serum levels. The primary form of RLS is associated with a familial history in 40 to 92 % of the patients. Monozygotic twins have a 54 to 83 % concordance rate for RLS phenotype. Linkage association studies have identified eight loci involved in the familial transmission of the disease. Genetic association studies have identified allelic variants responsible for a 50 % increased risk to develop RLS in the general population. Proteins coded by some implicated genes are involved in the development of spinal motor neurons and spinal dorsal horns, and in brain iron homeostasis.

International audience; Although normal subjects do not move during REM sleep, patients with Parkinson's disease may experience REM sleep behaviour disorder (RBD). The characteristics of the abnormal REM sleep movements in RBD have, however, not been studied. We interviewed one hundred consecutive non-demented patients with Parkinson's disease and their bed partners using a structured questionnaire assessing the presence of RBD. They rated the quality of movements, voice and facial expression during RBD as being better, equal or worse than in awake ON levodopa condition. Night-time sleep and movements were video-monitored during polysomnography in 51 patients to evaluate the presence of bradykinesia, tremor and hypophonia during REM sleep. Fifty-nine patients had clinical RBD with 53/59 bed partners able to evaluate them. All 53 (100%) reported an improvement of at least one component of motor control during RBD. By history, movements were improved in 87% patients (faster, 87%; stronger, 87%; smoother, 51%), speech was better in 77% patients (more intelligible, 77%; louder, 38%; better articulated, 57%) and facial expression was normalized in 47% patients. Thirty-eight per cent of bed partners reported that movements were 'much better', even in the most disabled patients. The video-monitored purposeful movements in REM sleep were also surprisingly fast, ample, coordinated and symmetrical, without obvious sign of parkinsonism. The movements were, however, jerky, violent and often repetitive. While all patients had asymmetrical parkinsonism when awake, most of the time they used the more disabled arm, hand and leg during the RBD (P = 0.04). Movements involved six times as often the upper limbs and the face as the lower limbs (OR: 5.9, P = 0.004). The percentage of time containing tremor EMG activity decreased with sleep stages from 34.9 +/- 15.5% during wakefulness, to 3.6 +/- 5.7% during non-REM sleep stages 1-2, 1.4 +/- 3.0% during non-REM sleep stages 3-4, and 0.06 +/- 0.2% during REM sleep (in this last case, it was subclinical tremor). The restored motor control during REM sleep suggests a transient 'levodopa-like' reestablishment of the basal ganglia loop. Alternatively, parkinsonism may disappear by REM sleep-related disjunction between pyramidal and extrapyramidal systems. We suggest the following model: the movements during the RBD would be generated by the motor cortex and would follow the pyramidal tract bypassing the extrapyramidal system. These movements would eventually be transmitted to lower motor neurons because of brainstem lesions interrupting the pontomedullary pathways which mediate the REM sleep atonia.

We report a new association between interictal myoclonus and paroxysmal kinesigenic dyskinesia (PKD) in 2 patients. By definition, PKD is transient, but the overexcitability of the neuronal system that induces these attacks may be permanent. Interictal myoclonus could be a manifestation of permanent overexcitability. (c) 2006 Movement Disorder Society

Background Narcolepsy with cataplexy (NC) is a disabling sleep disorder characterized by early loss of hypocretin neurons that project to areas involved in the attention network. We characterized the executive control of attention in drug-free patients with NC to determine whether the executive deficits observed in patients with NC are specific to the disease itself or whether they reflect performance changes due to the severity of excessive daytime sleepiness. Methodology Twenty-two patients with NC compared to 22 patients with narcolepsy without cataplexy (NwC) matched for age, gender, intellectual level, objective daytime sleepiness and number of sleep onset REM periods (SOREMPs) were studied. Thirty-two matched healthy controls were included. All participants underwent a standardized interview, completed questionnaires, and neuropsychological tests. All patients underwent a polysomnography followed by multiple sleep latency tests (MSLT), with neuropsychological evaluation performed the same day between MSLT sessions. Principal Findings Irrespective of diagnosis, patients reported higher self-reported attentional complaints associated with the intensity of depressive symptoms. Patients with NC performed slower and more variably on simple reaction time tasks than patients with NwC, who did not differ from controls. Patients with NC and NwC generally performed slower, reacted more variably, and made more errors than controls on executive functioning tests. Individual profile analyses showed a clear heterogeneity of the severity of executive deficit. This severity was related to objective sleepiness, higher number of SOREMPs on the MSLT, and lower intelligence quotient. The nature and severity of the executive deficits were unrelated to NC and NwC diagnosis. Conclusions We demonstrated that drug-free patients with NC and NwC complained of attention deficit, with altered executive control of attention being explained by the severity of objective sleepiness and global intellectual level. Further studies are needed to explore whether medications that promote wakefulness can improve the executive functions in narcolepsy.

International audience; BACKGROUND: Hypocretin peptides participate in the regulation of sleep-wake cycle while deficiency in hypocretin signaling and loss of hypocretin neurons are causative for narcolepsy-cataplexy. However, the mechanism responsible for alteration of the hypocretin system in narcolepsy-cataplexy and its relevance to other central hypersomnias remain unknown. Here we studied whether central hypersomnias can be associated with autoantibodies reacting with hypocretin-1 peptide present as immune complexes. METHODOLOGY: Serum levels of free and dissociated (total) autoantibodies reacting with hypocretin-1 peptide were measured by enzyme-linked immunosorbent assay and analyzed with regard to clinical parameters in 82 subjects with narcolepsy-cataplexy, narcolepsy without cataplexy or idiopathic hypersomnia and were compared to 25 healthy controls. PRINCIPAL FINDINGS: Serum levels of total but not free IgG autoantibodies against hypocretin-1 were increased in narcolepsy-cataplexy. Increased levels of complexed IgG autoantibodies against hypocretin-1 were found in all patients groups with a further increase in narcolepsy-cataplexy. Levels of total IgM hypocretin-1 autoantibodies were also elevated in all groups of patients. Increased levels of anti-idiotypic IgM autoantibodies reacting with hypocretin-1 IgG autoantibodies affinity purified from sera of subjects with narcolepsy-cataplexy were found in all three groups of patients. Disease duration correlated negatively with serum levels of hypocretin-1 IgG and IgM autoantibodies and with anti-idiotypic IgM autoantibodies. CONCLUSION: Central hypersomnias and particularly narcolepsy-cataplexy are characterized by higher serum levels of autoantibodies directed against hypocretin-1 which are present as immune complexes most likely with anti-idiotypic autoantibodies suggesting their relevance to the mechanism of sleep-wake cycle regulation.