Search

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.

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.

Rapid eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies. RBD also defines more severe forms of alpha-synucleinopathies. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we performed the first genome-wide association study of RBD, identifying five RBD risk loci. Expression analyses highlight SNCA-AS1 and SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Genetic risk score and other analyses provide further insights into RBD genetics, highlighting RBD as a unique subpopulation that will allow future early intervention.

PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. Since GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy, we examined the role of PSAP mutations in iRBD. 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). Two variants were stop mutations, p.Gln260Ter 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. 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.

Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) is a parasomnia, characterized by loss of muscle atonia and dream enactment occurring during REM sleep phase. Since a large subgroup of iRBD patients will convert to Parkinson’s disease, and since previous genetic studies have suggested common genes, it is likely that there is at least a partial overlap between iRBD and Parkinson’s disease genetics. To further examine this potential overlap and to identify genes specifically involved in iRBD, we fully sequenced 25 genes previously identified in genome-wide association studies of Parkinson’s disease. The genes were captured and sequenced using targeted next-generation sequencing in a total of 1,039 iRBD patients and 1,852 controls of European ancestry. The role of rare heterozygous variants in these genes was examined using burden tests and optimized sequence Kernel association tests (SKAT-O), adjusted for age and sex. The contribution of biallelic (homozygous and compound heterozygous) variants was further tested in all genes. To examine the association of common variants in the target genes, we used logistic regression adjusted for age and sex. We found a significant association between rare heterozygous nonsynonymous variants in BST1 and iRBD (p=0.0003 at coverage >50X and 0.0004 at >30X), mainly driven by three nonsynonymous variants (p.V85M, p.I101V and p.V272M) found in a total of 22 (1.2%) controls vs. two (0.2%) patients. Rare non-coding heterozygous variants in LAMP3 were also found to be associated with reduced iRBD risk (p=0.0006 at >30X). We found no statistically significant association between rare heterozygous variants in the rest of genes and risk of iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD patients vs. controls. To examine the potential impact of the rare nonsynonymous BST1 variants on the protein structure, we performed in silico structural analysis. All three variants seem to be loss-of-function variants significantly affecting the protein structure and stability. Our results suggest that rare coding variants in BST1 and rare non-coding variants in LAMP3 are associated with iRBD, and additional studies are required to replicate these results and 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

ObjectiveTo examine the role of autosomal dominant (AD) and recessive (AR) Parkinsonism genes in the risk of isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD).MethodsTen genes implicated in AD and AR Parkinsonism were fully sequenced using targeted next-generation sequencing in 1,039 iRBD patients and 1,852 controls of European ancestry. These include the AR genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7 and PLA2G6, and the AD genes LRRK2, GCH1 and VPS35. To examine the role of rare heterozygous variants in these genes, burden test and SKAT-O analyses were performed. The contribution of homozygous and compound heterozygous variants was further examined in the AR genes. Copy number variants (CNVs) in PRKN were tested in a subset of samples (n=374) using multiplex ligation-dependent probe amplification followed by analysis of all samples using ExomeDepth.ResultsWe found no association between rare heterozygous variants in the tested genes and risk for iRBD. Several homozygous and compound heterozygous carriers were identified with variants of unknown significance, yet there was no overrepresentation in iRBD patients versus controls.ConclusionOur results do not support a major role for variants in PRKN, PARK7, PINK1, VPS13C, ATP13A2, FBXO7, PLA2G6, LRRK2, GCH1 and VPS35 in the risk of iRBD.

Background: Walking regularly in Parkinson’s disease has beneficial effects on movement and quality of life. Yet, patients usually show reduced physical activity compared to healthy older adults. Using auditory stimulation, such as music, can facilitate walking but patients vary significantly in their response to the stimulus. An individualized approach adapting musical tempo to patients’ gait cadence, and capitalizing on these individual differences, is likely to provide a rewarding experience, with beneficial effects on gait in Parkinson’s disease. We aim to evaluate the observance, safety, tolerance, usability and enjoyment of a new smartphone application coupled with wearable sensors (BeatPark) delivering individualized musical stimulation for gait auto-rehabilitation at home. Methods: Forty-five patients with Parkinson’s disease underwent a one month, outdoor, gait rehabilitation program, using the BeatPark application (30 min/day, 5 days/week). The music tempo was aligned in real time to patients’ gait cadence while fostering an increase of cadence up to +20% of the patient’s preferred cadence. Evaluation was based on BeatPark use measures, questionnaires and a six-minute walk test before and after the rehabilitation program. Findings: Patients used the application 78.8 % (±28.2) of the prescribed duration and mostly enjoyed it, across the whole program. 75 % of them rated the application as easy to use. While using BeatPark, patients increased their ‘walk for exercise’ duration and frequency, reduced their fear of falling, and improved their quality of life. After the program, they improved their gait parameters in the six-minute walk test. Interpretation BeatPark is an easy to use and enjoyable musical application for individualized gait rehabilitation in Parkinson’s disease increasing ‘walk for exercise’ duration, confidence in gait and quality of life. Trial Registration: NCT02647242 Funding: This research was supported by a European grant: BeatHealth: Health and Wellness on the Beat (EU FP7-ICT contract #610633). Declaration of Interests: None to declare. Ethics Approval Statement: The study was approved by the National Ethics Committee (CPP Sud Mediterannee III, Nimes, France, ID-RCB: 2015-A00531-48). All participants gave written informed consent before participating.

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.

The aim of this article was to review the options and particularities of the treatment of restless legs syndrome (RLS) in Parkinson’s disease (PD). RLS is more frequent in PD than in the general population. Even if these two disorders share some specificity (dopa-sensitivity), they also differ in many features (iron load, genetic profile, dopaminergic cell count), resulting in different adaptations of the treatment. Only one study has specifically explored and demonstrated the efficacy of a treatment (rotigotine) in RLS with PD, constraining us to treat RLS with PD by analogy as idiopathic RLS in the other cases. However, arrangements linked to the peculiar population and pathology of PD are required. The treatment of RLS in PD consists in adaptation of dopaminergic treatment and introduction of alpha-2-delta ligands and, in refractory cases, of opioids or deep brain stimulation. Iron deficiency should probably not be compensated.

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.

Gait dysfunctions in Parkinson's disease can be partly relieved by rhythmic auditory cueing. This consists in asking patients to walk with a rhythmic auditory stimulus such as a metronome or music. The effect on gait is visible immediately in terms of increased speed and stride length. Moreover, training programs based on rhythmic cueing can have long-term benefits. The effect of rhythmic cueing, however, varies from one patient to the other. Patients' response to the stimulation may depend on rhythmic abilities, often deteriorating with the disease. Relatively spared abilities to track the beat favor a positive response to rhythmic cueing. On the other hand, most patients with poor rhythmic abilities either do not respond to the cues or experience gait worsening when walking with cues. An individualized approach to rhythmic auditory cueing with music is proposed to cope with this variability in patients' response. This approach calls for using assistive mobile technologies capable of delivering cues that adapt in real time to patients' gait kinematics, thus affording step synchronization to the beat. Individualized rhythmic cueing can provide a safe and cost-effective alternative to standard cueing that patients may want to use in their everyday lives.

BACKGROUND: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. OBJECTIVE: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. METHODS: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT-associated variants and the entire coding sequence of MAPT were analyzed. Age-, sex-, and ethnicity-adjusted analyses were performed to examine the association between MAPT, PD, and rapid eye movement sleep behavior disorder. RESULTS: MAPT-H2 variants were associated with PD (odds ratios: 0.62-0.65; P = 0.010-0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12-2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48-0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. CONCLUSIONS: Our results confirm the protective effect of the MAPT-H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus. © 2018 International Parkinson and Movement Disorder Society.

ObjectiveREM-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.MethodsFull sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n=1,076), Parkinson’s disease (PD, n=1,013), and dementia with Lewy bodies (DLB, n=415), and in control subjects (n=6,155). A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (cases n=1,782, controls n=131,250). 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.ResultsA 5’-region SNCA variant (rs10005233) was associated with iRBD (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.InterpretationThere 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, and may suggest a cognitive component to this region.

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; Parkinson’s disease (PD) is the second most common neurodegenerative diseaseafter Alzheimer’s disease. For years, PD has been traditionally defined through motor sympto-matology, but it is now recognized that the non-motor symptoms affecting neuropsychiatric,sleep, autonomic, and sensory domains occur in up to 88% of PD patients, probably resulting ina significant source of disability. In a community-based cross-sectional study, nearly two-thirdsof patients with PD presented nighttime sleeping problems and chronic insomnia was repor-ted among one-third of patients (Gjerstad et al., 2007). This rate is three times higher thanin the general population. According to the American Academy of Sleep Medicine, cognitive-behavioral therapy for insomnia (CBT-i) is the optimal recommendation for the treatment of chronic insomnia, independent of comorbities associated or non-associated with insomnia. Infact, numerous studies have documented the efficiency of CBT-i in the treatment of chronicinsomnia comorbid with a wide spectrum of psychiatric, neurological, oncological and algologi-cal problems (Geiger-Brown et al., 2015). Furthermore, it is important to emphasize that CBTis applicable and efficient in the treatment of several problems frequently associated with PD,such as anxiety, depression and impulsive-compulsive disorders. To our knowledge, there is nospecific data relating to the use of CBT in chronic insomnia comorbid with PD. In this context,the general objective of this study was to look at the efficiency of CBT-i in the treatment ofchronic insomnia comorbid with PD, in an experimental, single-case study. This efficiency wasassessed both by short interval measures (i.e. consensus sleep diary) and by longer intervalmeasures (i.e. self-assessment questionnaires). The latter concerned complaints of insomniaas well as dysfunctional thoughts and attitudes about sleep. The patient was a 62-year-old manwho was diagnosed with PD at the age of 59. Two years after diagnosis, insomnia developed. Thepatient’s predominant daily complaint concerned dissatisfaction with both sleep quantity andquality, associated with difficulty falling sleep, and difficulty staying asleep with inability to fallback to sleep. Insomnia was associated with excessive daytime sleepiness and depressive symp-toms. CBT-i treatment was carried out over six sessions in accordance with the interventionalprotocol suggested by Morin (Morin & Espie, 2003). Psychoeducation treated sleep functioningand insomnia; sleep restriction consisted in limiting the number of hours spent in bed to thenumber of real hours of sleep; stimulus control involved instructions aimed at reinforcing theassociation between sleep and temporal and contextual indices; cognitive restructuration wascentred around dysfunctional beliefs related to sleep; education on sleep hygiene included theteaching of good sleeping habits. Finally, three post-therapeutic evaluations (at two weeks,one month and three months) were carried out by an independent assessor and included thecompletion of a sleep calendar as well as different clinical evaluation scales. The results of thevisual analysis confirmed by Wilcoxon signed-rank tests, as well as the temporal series analysis show a signification reduction in the total awakening time (−72%, Z = −3.23, P = 0.001), aswell as a significant increase in sleep efficiency (+16%, Z = −3.17, P = 0.002) between the base-line and post-therapy stage. These improvements in sleep were maintained at one and threemonth follow-ups. The average efficiency of sleep increased significantly between the base-line and one-month follow-up (+19%, Z = −3.29, P = 0.001) as well as between the baseline andthree-month follow-up (+21%, Z = −3.29, P = 0.001). At the three-month follow-up the patientno longer met the diagnostic criteria of chronic insomnia (DSM-V). Improvement in sleep wasaccompanied by improvement in mood, in daytime drowsiness, in insomnia indices such as theinsomnia severity index, in dysfunctional beliefs and attitudes about sleep and in the state ofcognitive and somatic activation prior to going to bed. This single-case study demonstrates thefeasibility and potential benefit of CBT for insomnia comorbid with PD while providing importantinformation necessary to design more definitive studies in the future.; L’insomnie est une plainte très fréquente dans la maladie de Parkinson (MP). Elle est rapportée par environ 70 % des patients et son caractère est chronique dans 30 % des cas. À ce jour, l’efficacité des traitements pharmacologiques de l’insomnie associée à la MP est très modeste, et les répercussions à long terme (par exemple, tolérance, dépendance ou risque de chute) de certaines molécules n’ont jamais été vérifiées dans ce contexte. Selon l’Academy of Sleep Medicine, la thérapie comportementale et cognitive de l’insomnie (TCC-i) est une recommandation de premier niveau pour la prise en charge de l’insomnie chronique,et ce, indépendamment de comorbidités associées à l’insomnie. Plusieurs études soutiennent que les TCC sont applicables et efficaces dans la prise en charge de plusieurs problématiques associées à la MP. Il s’agit de la dépression, de l’anxiété, et plus récemment, des troubles impulsifs-compulsifs. Nous rapportons ci-dessous le cas d’un patient atteint de MP,souffrant d’une insomnie chronique, caractérisée par des pensées et attitudes dysfonctionnelles concernant le sommeil, des comportements incompatibles avec le sommeil et un contexte émotionnel négatif. Nous avons mis en place une TCC selon un protocole classiquement décrit dans le traitement de l’insomnie chronique. Les résultats obtenus montrent, d’une part, la faisabilité et l’efficacité de la TCC-i dans la prise en charge de l’insomnie chronique en cormobidité de la MP. Et, d’autre part, que l’amélioration du sommeil est elle-même associée à une amélioration de l’humeur, de la somnolence diurne et des croyances et attitudes dysfonctionnelles vis-à-vis du sommeil. Les TCC semblent constituer une voie thérapeutique prometteuse dans la prise en charge de l’insomnie chronique en comorbidité de la MP. Leur validité devra être confirmée par des études complémentaires.

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.

Objectif L’efficacite du traitement du syndrome d’apnees/hypopnees obstructives du sommeil (SAHOS) par pression positive continue nocturne (PPC) au cours de la maladie de Parkinson (MP) a ete demontree. Malheureusement ce traitement n’est en general pas bien supporte par les patients deja tres genes dans leur quotidien par leur maladie. Nous avons explore dans une etude pilote l’efficacite, la tolerance et la facilite d’utilisation de l’orthese d’avancee mandibulaire (OAM) dans cette population specifique. Methodes Vingt patients avec MP et SAHOS modere a severe ont ete etudies. Dix d’entre eux ont refuse ou mal tolere le traitement valide par PPC et ont ete traites par OAM. Nous les avons apparies en âge, sexe, IMC, severite de la maladie et index d’apnees/hypopnees a dix patients atteints de MP traites par PPC. Nous avons explore l’efficacite de l’OAM sur les plaintes de sommeil et sur les parametres respiratoires du sommeil. Nous avons compare l’observance, la tolerance et la facilite d’utilisation de l’OAM et de la PPC. Resultats L’OAM a ameliore les plaintes de sommeil augmentant le score PDSS-2 de 85 [55–106] a 106 [88–126], p Conclusion L’OAM semble etre une alternative particulierement interessante pour le traitement du SAHOS au cours de la MP.

The aim of this article was to review the different sleep disorders associated with Wilson’s disease (WD), their mechanisms and their treatments. Some of these disorders such as REM sleep behavior disorder or sleepiness can appear as a prodromal phase phenomenon in WD allowing an early treatment of the disease and sometimes a resolution of the sleep disorder. Sleep disorders in WD are frequent combining insomnia, daytime sleepiness, restless legs syndrome (RLS), cataplexy-like episodes, and REM sleep behavior disorder (RBD). Sleep recordings confirm these disorders. Mechanisms involved in these disorders are complex associating (a) lesions of the pathways regulating sleep and wake or mood but also controlling movement, (b) iatrogenic effects of the treatments, and (3) consequences of the motor or dysautonomic or metabolic disorders.

Movements and behaviors during REM sleep in RBD are very diverse. Their detailed investigation on video during polysomnography has allowed the improvement of their characterization and the development of hypotheses about the mechanisms of their generation and execution.

Introduction Parkinson's disease (PD) is characterized by rhythm disorders, which manifest across motor domains (orofacial, manual and gait), and in perceptual tasks. These disorders may result from a general dysrhythmia, linked to impaired central mechanisms supporting rhythm processing. Rhythmic auditory cueing has been used to improve motor symptoms, with a particular focus on gait, with variable effects. However, evidence is scant on the effects of training rhythmic abilities apart from gait, and their transfer to other domains. Here we report the results of a clinical trial testing the effect of rhythm training, delivered via a tapping serious game on tablet, across motor domains. Material and method Patients with PD played an at-home serious game training rhythm abilities (n = 10), a non-rhythmic video game (n = 11), or no game (n = 12, control group), for 6 weeks. We tested rhythm abilities in orofacial, manual and gait motor domains, and rhythm perception before and after the training period. Results Only patients who received the rhythm training improved their orofacial and manual performance (i.e., lowered motor variability). This beneficial effect was linked to an improvement of rhythm perception due to the rhythm training. Discussion These findings provide evidence supporting the use of technology-driven interventions aiming at alleviating rhythm-related motor deficits in PD such as hypokinetic dysarthria or gait impairment in complement to more traditional therapeutic approaches.

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.