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Spinocerebellar ataxia 38 (SCA 38) is an autosomal dominant disorder caused by conventional mutations in the ELOVL5 gene which encodes an enzyme involved in the synthesis of very long fatty acids, with a specific expression in cerebellar Purkinje cells. Three Italian families carrying the mutation, one of which is of Sardinian descent, have been identified and characterized. One session of cerebellar intermittent theta burst stimulation (iTBS) was applied to 6 affected members of the Sardinian family to probe motor cortex excitability measured by motor-evoked potentials (MEPs). Afterwards, patients were exposed to ten sessions of cerebellar real and sham iTBS in a cross-over study and clinical symptoms were evaluated before and after treatment by Modified International Cooperative Ataxia Rating Scale (MICARS). Moreover, serum BDNF levels were evaluated before and after real and sham cerebellar iTBS and the role of BDNF Val66Met polymorphism in influencing iTBS effect was explored. Present data show that one session of cerebellar iTBS was able to increase MEPs in all tested patients, suggesting an enhancement of the cerebello-thalamo-cortical pathway in SCA 38. MICARS scores were reduced after ten sessions of real cerebellar iTBS showing an improvement in clinical symptoms. Finally, although serum BDNF levels were not affected by cerebellar iTBS when considering all samples, segregating for genotype a difference was found between Val66Val and Val66Met carriers. These preliminary data suggest a potential therapeutic use of cerebellar iTBS in improving motor symptoms of SCA38.

Rapid eye movement sleep behavior disorder (RBD) is highly comorbid with Parkinson’s disease (PD). Emerging evidence suggests that dopamine-replacement therapies (DRTs) for PD may modify the course of RBD, yet the nature of the association between DRTs and RBD remains unclear. To begin addressing this issue, we conducted a preliminary retrospective study to document whether DRTs are associated with the occurrence of RBD symptoms in PD patients. The study included 250 PD patients who were screened for probable RBD via the RBD Screening Questionnaire (RBDSQ). For each patient, disease severity data were collected, in addition to their therapy and the associated levodopa equivalent daily dose (LEDD). The association between DRTs and RBDSQ scores was analyzed using logistic regression and correlation models. RBD scores were found to be associated with the LEDD of levodopa alone, but not of dopaminergic agonists (mainly D2/D3 receptor agonists) or their combination with levodopa. This association was not accounted for patient age or Hoehn and Yahr (H&Y) severity scores. Our study detected a significant association between doses of levodopa and RBD symptoms in PD patients. Future longitudinal studies are needed to establish what causal nexus may link these variables.

Background and purpose Several studies have indicated that altered serotonergic neurotransmission may contribute to non-motor features commonly associated with Parkinson's disease (PD) such as apathy and depression. 5-hydroxytryptophan (5-HTP) is the intermediate metabolite of L-tryptophan in the production of serotonin. To date, there has been inconsistent research on the use of 5-HTP in PD. The purpose of this study was to compare the effects of 5-HTP with those of placebo on apathy and depressive symptoms in patients with PD. Methods A single-center, randomized, double-blind placebo-controlled cross-over trial was employed; 25 individuals were subsequently enrolled into the study. Patients received placebo and 50 mg of 5-HTP daily over a period of 4 weeks. For the assessment of efficacy on depressive and apathy symptoms the Beck Depression Inventory-II (BDI-II), Hamilton Depression Rating Scale (HDRS) and Apathy Scale (AS) were respectively administered at screening, baseline and weeks 4, 8, 12 and 16. Primary efficacy outcomes were the comparison of 5-HTP to placebo in mean change from baseline to weeks 4, 8, 12 and 16 in total score on the AS, BDI-II and HDRS. Results Repeated-measures analysis revealed a significant improvement of depressive symptoms during the 50-mg 5-HTP treatment compared with placebo as assessed by the HDRS. No effect of 5-HTP was seen on apathy symptoms assessed by the AS. Conclusions This study provides preliminary evidence of clinical benefit of 5-HTP for treating depressive symptoms in PD. Larger studies with a longer treatment duration are needed to corroborate these early findings.

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.

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.

Impulse control disorders (ICDs) in Parkinson's disease (PD) are defined as a failure to resist an "urge" to behave in a way that may be debilitating for oneself or others. The suggested immobilization test (SIT) has been developed to assess the "urge" to move and support the diagnosis of restless legs syndrome (RLS) in the general population and in PD. A clinical association between RLS and ICDs has been shown in PD and in the general population. We hypothesized that there could be a semiological overlap between RLS and ICDs, and conducted SIT in PD patients with and without ICDs. Fifty PD patients with (n = 17) and without (n = 33) current ICDs were included. SIT, videopolysomnography, demographical treatment, and motor, psycho-behavioural and sleep characteristics, including RLS, were recorded. PD patients with ICDs reported increased subjective discomfort during SIT (SD-SIT) compared to those without ICDs (p = .024). Multivariable analysis confirmed ICDs as an independent factor associated with increased SD-SIT in PD, regardless of the presence of RLS, PD severity and dopamine agonist treatment dose. The discomfort measured by SIT might not only reflect the "urge" to move in RLS but also the ICDs in PD, suggesting that ICDs and RLS in PD could share a common phenomenology.

Summary Over the last two decades, our understanding of clinical and pathophysiological aspects of sleep‐related epileptic and non‐epileptic paroxysmal behaviours has improved considerably, although it is far from complete. Indeed, even if many core characteristics of sleep‐related hypermotor epilepsy and non‐rapid eye movement parasomnias have been clarified, some crucial points remain controversial, and the overlap of the behavioural patterns between these disorders represents a diagnostic challenge. In this work, we focused on segments of multichannel sleep electroencephalogram free from clinical episodes, from two groups of subjects affected by sleep‐related hypermotor epilepsy (N = 15) and non‐rapid eye movement parasomnias (N = 16), respectively. We examined sleep stages N2 and N3 of the first part of the night (cycles 1 and 2), and assessed the existence of differences in the periodic and aperiodic components of the electroencephalogram power spectra between the two groups, using the Fitting Oscillations & One Over f (FOOOF) toolbox. A significant difference in the gamma frequency band was found, with an increased relative power in sleep‐related hypermotor epilepsy subjects, during both N2 (p

Purpose Altered serotonergic neurotransmission may contribute to the non-motor features commonly associated with Parkinson’s disease (PD) such as sleep disorders. The 5-hydroxytryptophan (5-HTP) is the intermediate metabolite of l-tryptophan in the production of serotonin and melatonin. The purpose of this study was to compare the effects of 5-HTP to placebo on REM sleep behavior disorder (RBD) status in patients with PD. Methods A single-center, randomized, double-blind placebo-controlled crossover trial was performed in a selected population of 18 patients with PD and RBD. The patients received a placebo and 50 mg of 5-HTP daily in a crossover design over a period of 4 weeks. Results 5-HTP produced an increase in the total percentage of stage REM sleep without a related increase of RBD episodes, as well as a marginal, non-significant reduction in both arousal index and wake after sleep onset. The self-reported RBD frequency and clinical global impression (CGI) were improved during 5-HTP and placebo treatment in comparison to baseline. 5-HTP significantly improved our patients’ motor experiences of daily living as rated by the Unified Parkinson’s Disease Rating Scale (UPDRS) part II. Conclusions This study provides evidence that 5-HTP is safe and effective in improving sleep stability in PD, contributing to ameliorate patients’ global sleep quality. Larger studies with higher doses and longer treatment duration are needed to corroborate these preliminary findings.

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.

Traumatic brain injury (TBI) is an important cause of death and disability at all ages in the world. Complete functional recovery is not always complete, and, often, persistent symptoms may last for a long time. Sleep disorders and sleep-wake alterations are among the most common complications both in the acute and chronic phases after the trauma, and they may have a negative impact on daily activities and on quality of life of these patients. Sleep and sleep-wake cycle are not always carefully assessed in patients after TBI, they are overlooked, and often patients have a persistent excessive daytime sleepiness, even for years after the TBI, without receiving a proper diagnosis and treatment. Moreover, scientific evidence has been provided for the role of sleep in neuroprotection and recovery after brain injury; hence, promoting an optimal sleep function and early diagnosing and treating sleep disorders may be helpful for rehabilitation and functional recovery of patients after TBI.

Sleep-related movements comprise a broad spectrum of simple and usually stereotyped movements that are sometimes associated with sleep disturbance (insomnia, sleep fragmentation, and non-restorative sleep). They may represent a physiological variant or a sleep disorder, depending on their intensity, frequency, and associated sleep disruption degree. Sleep-related movements involve usually the lower limbs; they can be idiopathic or associated with other sleep disorders, neurological disease, and medical condition or occur as a consequence of drug use. Several pathophysiological hypotheses have been proposed, but for the majority of these disorders, the neurobiological mechanism is far from being completely understood. Further studies are needed to elucidate the pathophysiology of sleep-related movements in order to better appreciate their clinical significance. This chapter describes the neurobiology of sleep-related movements, namely, periodic limb movements, alternating leg muscle activation, hypnagogic foot tremor, high-frequency myoclonus, excessive fragmentary myoclonus, propriospinal myoclonus at sleep onset, neck myoclonus during sleep, sleep bruxism, sleep-related rhythmic movement disorder, sleep-related leg cramps, and sleep starts. We also present a mechanistic model of the potential role of the spinal central pattern generator for locomotion in generating the leg movements.

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.

Study Objectives To ascertain whether current diagnostic criteria for REM sleep behavior disorder (RBD) are appropriate in patients with Parkinson’s disease (PD) consulting a movement disorder center, to evaluate the accuracy of REM sleep without atonia (RSWA) thresholds and determine the value of screening questionnaires to discriminate PD patients with RBD. Methods One hundred twenty-eight consecutive PD patients (M = 80; mean age: 65.6 ± 8.3 years) underwent screening questionnaires, followed by a sleep-focused interview and a full-night video-polysomnography (vPSG). Without a gold standard, latent class models (LCMs) were applied to create an unobserved (“latent”) variable. Sensitivity analysis was performed using RSWA cutoff derived from two visual scoring methods. Finally, we assessed the respective diagnostic performance of each diagnostic criterion for RBD and of the screening questionnaires. Results According to the best LCM-derived model, patients having either “history” or “video” with RSWA or alternatively showing both “history” and “video” without RSWA were classified as having RBD. Using both SINBAR and Montreal scoring methods, RSWA criterion showed the highest sensitivity while concomitant history of RBD and vPSG-documented behaviors, regardless to presence of RSWA, displayed the highest specificity. Currently recommended diagnostic threshold of RSWA was found to be optimal in our large cohort of PD patients. Both the RBD screening questionnaire (RBDSQ) and the RBD single question (RBD1Q) showed poor sensitivity and specificity. Conclusions Results of the best LCM for diagnosis of RBD in PD were consistent with the current diagnostic criteria. Moreover, RBD might be considered in those PD patients with both history and vPSG-documented dream enactment behaviors, but with RSWA values within the normal range.

REM sleep without atonia (RSWA) is the polysomnographic (PSG) hallmark of rapid eye movement (REM) sleep behavior disorder (RBD), a feature essential for the diagnosis of this condition. Several additional neurophysiological aspects of this complex disorder have also recently been investigated in depth, which constitute the focus of this narrative review, together with RSWA. First, we describe the complex neural network underlying REM sleep and its muscle atonia, focusing on the disordered mechanisms leading to RSWA. RSWA is then described in terms of its polysomnographic features, and the methods (visual and automatic) currently available for its scoring and quantification are exposed and discussed. Subsequently, more recent and advanced neurophysiological features of RBD are described, such as electroencephalography during wakefulness and sleep, transcranial magnetic stimulation, and vestibular evoked myogenic potentials. The role of the assessment of neurophysiological features in the study of RBD is then carefully discussed, highlighting their usefulness and sensitivity in detecting neurodegeneration in the early or prodromal stages of RBD, as well as their relationship with other proposed biomarkers for the diagnosis, prognosis, and monitoring of this condition. Finally, a future research agenda is proposed to help clarify the many still unclear aspects of RBD.

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.

Rapid eye movement (REM) Sleep Behavior Disorder (RBD) in Parkinson's disease (PD) may be associated with a malignant phenotype. Despite its prognostic value, little is known about the time course of RBD in PD. In this study, we aimed to ascertain whether or not RBD is a stable feature in PD. In this study, we prospectively evaluated clinical and neurophysiological features of RBD, including REM Sleep Without Atonia (RSWA), in PD patients with RBD at baseline and after three years then assessed whether the changes in measures of RSWA parallel the progression of PD.In sum, 22 (17M, mean age 64.0 ± 6.9 years) moderate-to-advanced PD patients (mean PD duration at baseline:7.6±4.8 years) with RBD, underwent a video-polysomnography (vPSG) recording and clinical and neuropsychological assessment at baseline and after three years.At follow-up, the self-assessed frequency of RBD symptoms increased in six patients, decreased in six and remained stable in 10, while RSWA measures significantly increased in all subjects. At follow-up, patients showed worse HY stage (p = 0.02), higher dopaminergic doses (p = 0.05) and they performed significantly worse in phonetic and semantic fluency tests (p = 0.02; p = 0.04). Changes in RSWA correlated significantly with the severity in levodopa-induced dyskinesia (r = 0.61,p = 0.05) and motor fluctuation (r = 0.54,p = 0.03) scores, and with the worsening of executive functions (r = 0.78,p = 0.001) and visuo-spatial perception (r = -0.57,p = 0.04).Despite the subjective improvement of RBD symptoms in one-fourth of PD patients, all RSWA measures increased significantly at follow-up, and their changes correlated with the clinical evolution of motor and non-motor symptoms. RBD is a long-lasting feature in PD and RSWA is a marker of the disease's progression.

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.

Study ObjectivesThe neurophysiological hallmark of REM sleep behavior disorder (RBD) is loss of atonia during REM sleep. Indeed, signs and symptoms of neurodegeneration can occur after years, even decades, from its beginning. This study aimed to measure neurophysiological alterations of the brainstem that potentially correlate with the severity of atonia loss, and determining whether a prodromal neurodegenerative disorder underlines this condition when it occurs as an isolated condition (iRBD).MethodsSubjects with iRBD and matched healthy controls were recruited. The study included the recording of one-night polysomnography, vestibular-evoked myogenic potentials (VEMPs), and a [123I]-FP-CIT dopamine transporter (DAT) scan. The quantification of REM sleep without atonia (RSWA) was made according to two previously published manual methods and one automated method.ResultsThe rate of alteration of VEMPs and VEMP score were significantly higher in iRBD patients than controls. Moreover, VEMP score was negatively correlated with the automated REM atonia index; a marginal statistical significance was also reached for the positive correlation with the visual tonic electromyographic parameter, while the other correlations, including that with DAT-scan score were not statistically significant.ConclusionsBrainstem neurophysiology in iRBD can be assessed by VEMPs and their alterations may possibly indicate an early expression of the neurodegenerative process underlying this disorder at the brainstem level, which awaits future longitudinal confirmation. The correlation between RSWA and VEMP alteration might also represent a prodromal aspect anticipating the possible evolution from iRBD to neurodegeneration, whereas DAT-scan abnormalities might represent a later step in this evolution.

Ischaemic stroke is accompanied by important alterations of cardiac autonomic control, which have an impact on stroke outcome. In sleep, cardiac autonomic control oscillates with a predominant sympathetic modulation during REM sleep. We aimed to assess cardiac autonomic control in different sleep stages in patients with ischaemic stroke. Forty-five patients enrolled in the prospective, multicentre SAS-CARE study but without significant sleep-disordered breathing (apnea-hypopnea index < 15/hr) and without atrial fibrillation were included in this analysis. The mean age was 56 years, 68% were male, 76% had a stroke (n = 34, mean National Institutes of Health Stroke Scale [NIHSS] score of 5, 11 involving the insula) and 24% (n = 11) had a transitory ischaemic attack. Cardiac autonomic control was evaluated using three different tools (spectral, symbolic and entropy analysis) according to sleep stages on short segments of 250 beats in all patients. Polysomnographic studies were performed within 7 days and 3 months after the ischaemic event. No significant differences in cardiac autonomic control between sleep stages were observed in the acute phase and after 3 months. Predominant vagal modulation and decreased sympathetic modulation were observed across all sleep stages in ischaemic stroke involving the insula. Patients with ischaemic stroke and transitory ischaemic attack present a loss of cardiac autonomic dynamics during sleep in the first 3 months after the ischaemic event. This change could represent an adaptive phenomenon, protecting the cardiovascular system from the instabilities of autonomic control, or a risk factor for stroke, which precedes the ischaemic event.

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.

Objectives: To investigate brainstem function in idiopathic REM sleep Behavior Disorder (iRBD), a condition occurring as a result of a derangement of connections within brainstem structures, with a battery of Vestibular Evoked Myogenic Potentials (VEMPs), neurophysiological tools suited for the functional investigation of the brainstem. Neurophysiological data were correlated with clinical characteristics of patients.Methods: Twenty patients with iRBD and 22 healthy controls underwent cervical (cVEMP), masseter (mVEMP) and ocular (oVEMP) VEMP recording. Patients were assessed clinically according to presence of motor as well as non-motor symptoms such as constipation, depression, and hyposmia. Also, they were screened for postural instability through the Berg Balance Scale (BBS). VEMPs were categorized as for increasing degrees of abnormalities, namely latency delay, amplitude reduction and absence; a VEMP score was built accordingly.Results: Compared with controls, iRBD had higher rates of abnormalities both in the VEMP battery (iRBD 75%, Controls 23%; p < 0.01) as well as in each single VEMP (cVEMP: 45 vs. 5%; mVEMP: 65 vs. 13.6%; oVEMP: 50 vs. 5%; p < 0.01), which exhibited significantly lower amplitudes (cVEMP and oVEMP: p < 0.0001; mVEMP: p = 0.001) in iRBD. Within altered reflexes, absence was predominant in oVEMP (81%), amplitude reduction in mVEMP (50%) and cVEMP (70%). Severity of VEMP alterations was significantly higher in iRBD compared with controls (p < 0.05 for all VEMPs), as indicated by the larger VEMP scores in the former. The oVEMP score correlated inversely with poor performances on the BBS.Conclusion: VEMPs unveil consistent and extensive brainstem abnormalities in iRBD patients. Further studies are warranted for testing the potential of VEMPs in the monitoring of the evolution of iRBD over time.

This paper aims to explore the relationship between impulse-control disorders (ICDs) and sleep problems in patients with Parkinson’s disease (PD) among scientific literature. Previously published results are controversial and sometimes inconclusive. ICDs and sleep disruption represent important non-motor features of Parkinson’s disease, responsible for reducing quality of life and increasing burden of disease. The relationship between sleep problems and ICDs is complex and bidirectional. Indeed, sleep disturbances and fragmentation may play a crucial role in increasing susceptibility to impulsive behavior and may represent a risk factor for developing ICDs in PD patients. Moreover, REM sleep behavior disorder (RBD) and restless legs syndrome (RLS) have been indicated as independent risk factors for ICDs in PD patients. On the other hand, also ICDs may lead to sleep restriction and fragmentation, suggesting a bidirectional relationship. The association between sleep problems and ICDs in PD is far from being completely understood. Further studies are needed to confirm the nature of this relationship and its pathophysiology.

IntroductionBecause the association between rapid eye movement sleep behaviour disorder (RBD) and impulse control disorders (ICDs) in Parkinson’s disease (PD) has been debated, we assessed the sleep characteristics and the frequency of RBD using video-polysomnography (v-PSG) in patients with PD with versus without ICDs.MethodsEighty non-demented patients with PD consecutively identified during routine evaluation at three movement disorders centres were enrolled in a case–control study. Forty patients (22 men; mean age: 62.6±9.7 years, Hoehn & Yahr: 2.1±0.6) with one or more current ICDs were age-matched and sex-matched with 40 patients with no history of ICDs (22 men, mean age: 64.9±7.8 years, Hoehn & Yahr: 2.2±0.6). They underwent a detailed sleep interview followed by a full-night in-lab v-PSG. Sleep was scored blindly to ICDs condition and RBD diagnosis included a clinical complaint of enacted dreams and/or documented behaviour during rapid eye movement (REM) sleep, with the presence of quantified REM sleep without atonia (RSWA).ResultsPatients with ICDs had a higher arousal index and higher RSWA than those without ICDs (51.9%±28.2%vs 32.2±27.1%, p=0.004). In addition, RBD was more frequent in the ICD group (85%vs53%, p=0.0001). RBD was still associated with ICDs in a multivariate regression analysis including age of onset, PD duration and severity, treatment duration, levodopa-equivalent and dopamine agonist-equivalent daily doses and antidepressant use (OR: 4.9 (95% CI 1.3 to 18.5), p=0.02).ConclusionsThis large, controlled series of patients with PD with ICDs assessed by v-PSG confirms the association between ICDs and RBD. Increased surveillance of symptoms of ICDs should be recommended in patients with PD with RBD.

There is great interest in the study of sleep in healthy and cognitively impaired elderly. Sleep disorders have been related to quality of aging. Sleep-related movements are a frequent cause of disordered sleep and daytime sleepiness. Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is often unrecognized in the elderly. This review explores RLS/WED in the elderly population. The elderly population may be subdivided into 3 groups: healthy, dependent, and frail. The RLS/WED could be a predictor for lower physical function; its burden on quality of life and health care-related costs, in the elderly, should be an important clinical and public health concern.

Study objectives To compare three different methods, two visual and one automatic, for the quantification of rapid eye movement (REM) sleep without atonia (RSWA) in the diagnosis of REM sleep behavior disorder (RBD) in Parkinson's disease (PD) patients. Methods Sixty-two consecutive patients with idiopathic PD underwent video-polysomnographic recording and showed more than 5 minutes of REM sleep. The electromyogram during REM sleep was analyzed by means of two visual methods (Montreal and SINBAR) and one automatic analysis (REM Atonia Index or RAI). RBD was diagnosed according to standard criteria and a series of diagnostic accuracy measures were calculated for each method, as well as the agreement between them. Results RBD was diagnosed in 59.7% of patients. The accuracy (85.5%), receiver operating characteristic (ROC) area (0.833) and Cohen's K coefficient (0.688) obtained with RAI were similar to those of the visual parameters. Visual tonic parameters, alone or in combination with phasic activity, showed high values of accuracy (93.5-95.2%), ROC area (0.92-0.94), and Cohen's K (0.862-0.933). Similarly, the agreement between the two visual methods was very high, and the agreement between each visual methods and RAI was substantial. Visual phasic measures alone performed worse than all the other measures. Conclusion The diagnostic accuracy of RSWA obtained with both visual and automatic methods was high and there was a general agreement between methods. RAI may be used as the first line method to detect RSWA in the diagnosis of RBD in PD, together with the visual inspection of video-recorded behaviors, while the visual analysis of RSWA might be used in doubtful cases.

Restless legs syndrome, also known as Willis-Ekbom disease (RLS/WED), is a frequent condition, though its pathophysiology is not completely understood. The diagnosis of RLS/WED relies on clinical criteria, and the only instrumental tool, the suggested immobilization test, may lead to equivocal results. Recently, neurophysiological parameters related to F-wave duration have been proposed as a diagnostic aid. The aim of this study is to assess and compare the diagnostic values of these parameters in diagnosis of RLS/WED.Fifteen women affected by primary RLS/WED and 17 age- and sex- matched healthy subjects. A complete electroneurographic evaluation, including nerve conduction studies (NCS), cutaneous silent period (CSP), and F-wave parameters, namely amplitude, F-wave duration (FWD), and the ratio between FWD and duration of the corresponding compound muscle action potential (FWD/CMAPD).No subject showed alterations of the NCS. However, FWD and FWD/CMAPD of both upper and lower limbs were significantly longer in patients than controls. Tibial FWD/CMAPD best discriminated RLS/WED patients from controls. A cutoff of 2.06 yielded a sensitivity of 69.2%, a specificity of 94.1%, a positive predictive power of 90%, and a negative predictive power of 80% (area under the curve = 0.817; 95% confidence interval = 0.674-0.959). The combination of ulnar or tibial FWD/CMAPD increases the sensitivity (85.7%) while slightly decreasing the specificity (87.5%, positive predictive value: 85.7%, negative predictive value: 87.5%).Lower limb FWD/CMAPD ratio may represent a supportive diagnostic tool, especially in cases of evening lower leg discomfort of unclear interpretation.

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Nocturnal frontal lobe epilepsy (NFLE) is a syndrome characterized by the occurrence of sleep related seizures of variable complexity and duration. Hypermotor seizures (HMS) represent a classic manifestation of this syndrome, associated with a perturbation of the ventromesial frontal cortex and anterior cingulate gyrus regions. Nevertheless, in recent years, reports have showed that the seizure onset zone (SOZ) need not be of frontal origin to generate HMS. Here we report an unusual case of a patient presenting with a seven-year history of drug-resistant sleep related HMS arising from the mesial parietal region. The presence of an infrequent feeling of levitation before the HMS was key to suspecting a subtle focal cortical dysplasia in the right precuneus region. A stereo-EEG investigation confirmed the extra-frontal seizure onset of the HMS and highlighted the interrelationship between unstable sleep and seizure precipitation.

s for the 6th World Congress on Sleep Medicine, 23 March to 25 March 2015 Altered sleep architecture in autosomal dominant spinocerebellar ataxias: A polysomnographic based study S. Donilparthi 1, R. Yadav 1, A. Sasidharan 2, P. Pal 1, S. Jain 3, B. Kutty 2 1 Department of Neurology, NIMHANS, Bangalore, India 2 Department of Neurophysiology, NIMHANS, Bangalore, India 3 Molecular Genetics Laboratory, NIMHANS, Bangalore, India Introduction: Spinocerebellar ataxias (SCAs), are tri nucleotide repeat length progressive neurodegenerative disorders in which the cerebellum slowly degenerates, often accompanied by degenerative changes in the brainstem. Sleep disturbances have been reported in few studies. Materials and methods: Objective: To identify and to characterize the sleep disturbances in patients with genetically positive spinocerebellar ataxias (SCA 1, 2, 3). Methods: Patients with progressive ataxia were identified and assessed clinically. All the patients were interviewed with sleep questionnaire. Disease severity was measured with International Ataxia Rating Scale (ICARS) scale. Sleep quality was assessed with Pittsburgh Sleep Quality Index (PSQI), Mayo Sleep Questionnaire (MSQ), Epworth Sleepiness Scale (ESS). Genetically confirmed cases (20 patients) underwent overnight polysomnography (PSG) using 40 channel Galileo Mizar-40 Polysomnography sytem (EB Neuro, Italy). The sleep scoring was carried out according to AASM-2012 using POLYMAN v1.15 (Marco Roessen and Bob Kemp) and sleep variables were analysed across sleep cycles using custom scripts written in MATLAB 2012b (Mathworks, USA). Results: Patients of SCA1, 2, 3 (n = 20; 11 males) were recruited. SCA1 = 8; SCA2 = 7; SCA3 = 5; Mean age = 35.49 ± 7.75; Mean ICARS = 35.15 ± 18.75; Mean PSQI =3.8 ± 3.6, Mean ESS =2.1 ± 1.7. All patients (8/8) of SCA1 reported no sleep distrubances; 3/7 patients of SCA 2 reported delayed sleep onset; 3/5 patients of SCA3 reported delayed sleep onset and intermittent awakening. And none of them gave a history suggestive of REM sleep behaviour disorder (RBD), rest less leg syndrome (RLS), excessive day time somnolence (EDS). Polysomnographic analysis showed significant alteration of sleep architecture predominantly affecting REM sleep states. Average Sleep Efficiency = 75.6 ± 17.6; N1% = 17.6 ± 12; N2% = 52 ± 14.6; N3% = 24.5 ± 12.5; REM% = 5.6 ± 6.8. Absent REM sleep states in 70% of SCA2 patients, 60% of SCA3 patients, present in all patients in SCA1 but with significant reduction. There is negative correlation between disease severity (ICARS) and REM percentage (p = 0.028). Conclusion: In SCAs as the degeneration progresses brain stem structures are involved apart from the cerebellum. The more severe affection of REM sleep States in SCA2 patients and SCA3 supports early affection of brain stem structures. This needs further exploration by neuroimaging and pathology studies. Acknowledgements: Department of Neurology, NIMHANS, Department of Neurophysiology, NIMHANS. http://dx.doi.org/10.1016/j.sleep.2015.02.003 Diagnosing REM sleep behaviour disorder in patients with Parkinson’s disease: The role of screening questionnaires and of measures of REM sleep without atonia M. Figorilli 1, R. Ferri 2, B. Pereira 3, P. Beudin 4, F. Marrosu 5, M. Puliggheddu 5, F. Durif 6, M. Fantini 6 1 Sleep Disorder Center, Department of Public Health & Clinical and Molecular Medicine, University of Cagliari, Italy 2 Department of Neurology I.C., Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Italy 3 Biostatistics Unit (DRCI) Clermont-Ferrand, France 4 Neurology Department, Chu Clermont-Ferrand, France 5 Sleep Disorder Center, Department of Public Health & Clinical and Molecular Medicine, Italy 6 EA 7980, UFR Medicine, University of Clermont, Clermont-Ferrand

Introduction Restless legs syndrome (RLS) is a frequent pathology, yet underrated and underestimated, affecting inasmuch as 5–10% of the population as a whole. However the pathophysiology has not been completely understood. The dopaminergic system has certainly a primary role, and some studies have highlighted a condition of spinal hyper-excitability. The aim of our study is to explore this hypothesis throughout the electrophysiological evaluation of the spinal and peripheral nervous system in primitives RLS patients. Materials and methods Among the patients affected by primitive RLS admitted to our Sleep Centerlab, we selected 15 women, and compared them with 17 control subjects of the same sex and age. All subjects had undergone ENG evaluation to exclude any secondary causes of lower limb paresthesia and to evaluate spinal excitability. According to a previous study, we considered two parameters which can be easily extracted from the routine tests normally carried out in the neurophysiopathology labs, the duration of F waves (FWD) of the Internal Popliteal (IPN) and ulnar nerves, and the relationship between FWD and the duration of the corresponding CMAP (CMAPD). Results None of the subjects (RLS and controls) included in our study presented alterations in the nerve conduction velocity. Compared to the control group, significantly higher values were found in the RLS patients for the FWD/CMAPD ratio average (p 0.001 test Mann–Whitney) and for the FWD average for both nerves ulnar (p 0.05 unpaired t-test) and IPN (p 0.01 unpaired t-test). Conclusion The results of our study confirm the absence of peripheral involvement in primitive RLS, while they indicate a spinal motorneuronal hyper-excitability, which seems widespread, as both IPN and ulnar nerve stimulation indicators are altered. Such condition could be due mainly to an alteration of the modulation in the interneuronal system. Presently, RLS diagnosis is based exclusively on clinical criteria. The FWD/CMAPD ratio can help to shed light on the pathogenesis of RLS, and can be used as an instrumental diagnostic indicator, easily obtainable and useful especially in cases of lower leg discomfort at night of unclear interpretation. Acknowledgements The authors would like to thank Prof. F. Marrosu and Dr. M. Fraschini, University of Cagliari, Italy, and Prof. L. Parrino, University of Parma, Italy, for their important contribution.