Search

The diagnosis of rapid eye movement (REM) sleep behavior disorder (SBD) requires videopolysomnography detection of excessive electromyographic activity during REM sleep, which is time consuming and difficult. An easier, faster, reliable, and reproducible methodology is needed for its diagnosis. The isolated form of RBD represents an early manifestation of the synucleinopathies Parkinson disease and dementia with Lewy bodies. There is a need to find neuroprotective drugs capable of preventing parkinsonism and dementia onset in isolated RBD. Clonazepam and melatonin ameliorate the RBD symptoms, but therapeutic alternatives are needed when these medications fail or show produce side effects.

Study objectives Rapid eye movement sleep behavior disorder (RBD) is frequent in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), and poses a risk of injury to patients and their bed partners. We assessed the efficacy of nelotanserin, a selective 5-HT (2A) inverse agonist, for symptomatic treatment of RBD using systematic video analysis. Methods This was a phase 2 multicenter study in DLB or PDD with video polysomnography (vPSG)-confirmed RBD. After a single-blind placebo run-in period, patients meeting eligibility criteria entered a 4-week double-blind treatment period (1:1 ratio with nelotanserin 80 mg/placebo). Whole-night vPSG was conducted during the run-in and at the end of the treatment period. Videos of all rapid eye movement (REM) sleep periods were analysed for RBD behaviors (movements and vocalizations) using the Innsbruck classification system by two of the central reviewers, and a third reviewer adjudicated ambiguous cases. Results 34 patients (N = 26 DLB, N = 8 PDD; 85.3% men; mean age 71.3 ± 6.36 years) were included in the analyses. Two (5.9%) patients were excluded due to protocol deviation in treatment compliance. Systematic video analysis demonstrated no difference between nelotanserin and placebo in RBD behaviors. Bland–Altman plot showed high interrater reliability. Conclusions Despite negative results, this is the first randomized, placebo-controlled study on symptomatic RBD treatment using objective outcome measures based on systematic video analysis. This study provides a new method for outcome research in RBD and proves that movement analysis is a feasible and meaningful outcome for studies evaluating changes in RBD severity. Clinical trial information ClinicalTrials.gov. NCT Number NCT02708186. https://clinicaltrials.gov/ct2/show/NCT02708186 .

Summary Background Isolated rapid-eye-movement (REM) sleep behaviour disorder (IRBD) can be part of the prodromal stage of the α-synucleinopathies Parkinson's disease and dementia with Lewy bodies. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has high sensitivity and specificity for the detection of misfolded α-synuclein in patients with Parkinson's disease and dementia with Lewy bodies. We investigated whether RT-QuIC could detect α-synuclein in the CSF of patients with IRBD and be used as a biomarker of prodromal α-synucleinopathy. Methods In this longitudinal observational study, CSF samples were obtained by lumbar puncture from patients with video polysomnography-confirmed IRBD recruited at a specialised sleep disorders centre in Barcelona, Spain, and from controls free of neurological disease. CSF samples were stored until analysed using RT-QuIC. After lumbar puncture, participants were assessed clinically for neurological status every 3–12 months. Rates of neurological disease-free survival were estimated using the Kaplan-Meier method. Disease-free survival rates were assessed from the date of lumbar puncture to the date of diagnosis of any neurodegenerative disease, or to the last follow-up visit for censored observations. Findings 52 patients with IRBD and 40 healthy controls matched for age (p=0·20), sex (p=0·15), and duration of follow-up (p=0·27) underwent lumbar puncture between March 23, 2008, and July 16, 2017. The CSF α-synuclein RT-QuIC assay was positive in 47 (90%) patients with IRBD and in four (10%) controls, resulting in a sensitivity of 90·4% (95% CI 79·4–95·8) and a specificity of 90·0% (95% CI 76·9–96·0). Mean follow-up from lumbar puncture until the end of the study (July 31, 2020) was 7·1 years (SD 2·8) in patients with IRBD and 7·7 years (2·9) in controls. During follow-up, 32 (62%) patients were diagnosed with Parkinson's disease or dementia with Lewy bodies a mean 3·4 years (SD 2·6) after lumbar puncture, of whom 31 (97%) were α-synuclein positive at baseline. Kaplan-Meier analysis showed that patients with IRBD who were α-synuclein negative had lower risk for developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8, and 10 years of follow-up than patients with IRBD who were α-synuclein positive (log-rank test p=0·028; hazard ratio 0·143, 95% CI 0·019–1·063). During follow-up, none of the controls developed an α-synucleinopathy. Kaplan-Meier analysis showed that participants who were α-synuclein negative (ie, five patients with IRBD plus 36 controls) had lower risk of developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8 and 10 years after lumbar puncture than participants who were α-synuclein positive (ie, 47 patients with IRBD plus four controls; log-rank test p Interpretation In patients with IRBD, RT-QuIC detects misfolded α-synuclein in the CSF with both sensitivity and specificity of 90%, and α-synuclein positivity was associated with increased risk of subsequent diagnosis of Parkinson's disease or dementia with Lewy bodies. Detection of α-synuclein in the CSF represents a potential prodromal marker of Parkinson's disease and dementia with Lewy bodies. If these findings are replicated in additional cohorts, detection of CSF α-synuclein by RT-QuIC could be used to enrich IRBD cohorts in neuroprotective trials, particularly when assessing interventions that target α-synuclein. Funding Department of Health and Social Care Policy Research Programme, the Scottish Government, and the Weston Brain Institute.

INTRODUCTION: In vivo PET studies in patients with isolated REM sleep behavior disorder (iRBD) have shown presence of neuroinflammation (microglial activation) in the substantia nigra, and reduced cortical acetylcholinesterase activity, suggestive of cholinergic dysfunction, that was more widespread in patients with poorer cognitive performances. This study aimed to explore whether reduced cortical acetylcholinesterase activity in iRBD is linked to microglial activation in the substantia innominata (SI), the major source of cholinergic input to the cortex.METHODS: We used 11C(R)-PK11195 and 11C-Donepezil PET to assess levels of activated microglia and cholinergic function, respectively, in 19 iRBD patients. 11C(R)-PK11195 binding potential (BPND) and 11C-Donepezil distribution volume ratio (DVR) values were correlated using the Pearson statistic.RESULTS: We found that a lower cortical 11C-Donepezil DVR correlated with a higher 11C(R)-PK11195 BPND in the SI (r = -0.48, p = 0.04). At a voxel level, the strongest negative correlations were found in the frontal and temporal lobes.CONCLUSION: Our results suggest that reduced cortical acetylcholinesterase activity observed in our iRBD patients could be linked to the occurrence of neuroinflammation in the SI. Early modulation of microglial activation might therefore preserve cortical cholinergic functions in these patients.

Introduction Individuals with idiopathic rapid eye movement sleep behavior disorder (iRBD) are at high risk for a clinical diagnosis of an α‐synucleinopathy (aSN). They could serve as a key population for disease‐modifying trials. Abnormal dopamine transporter (DAT) imaging is a strong candidate biomarker for risk of aSN diagnosis in iRBD. Our primary objective was to identify a quantitative measure of DAT imaging that predicts diagnosis of clinically‐defined aSN in iRBD. Methods The sample included individuals with iRBD, early Parkinson’s Disease (PD), and healthy controls (HC) enrolled in the Parkinson Progression Marker Initiative, a longitudinal, observational, international, multicenter study. The iRBD cohort was enriched with individuals with abnormal DAT binding at baseline. Motor and nonmotor measures were compared across groups. DAT specific binding ratios (SBR) were used to calculate the percent of expected DAT binding for age and sex using normative data from HCs. Receiver operative characteristic analyses identified a baseline DAT binding cutoff that distinguishes iRBD participants diagnosed with an aSN in follow‐up versus those not diagnosed. Results The sample included 38 with iRBD, 205 with PD, and 92 HC who underwent DAT‐SPECT at baseline. Over 4.7 years of mean follow‐up, 14 (36.84%) with iRBD were clinically diagnosed with aSN. Risk of aSN diagnosis was significantly elevated among those with baseline putamen SBR ≤ 48% of that expected for age and sex, relative to those above this cutoff (hazard ratio = 17.8 [95%CI: 3.79–83.3], P = 0.0003). Conclusion We demonstrate the utility of DAT SBR to identify individuals with iRBD with increased short‐term risk of an aSN diagnosis.

Neuroinflammation (microglial activation) and subclinical nigrostriatal dysfunction have been reported in subjects at risk of Parkinsonism. Eight non-manifesting carriers (NMCs) of LRRK2 G2019S mutation had 11C-PK11195 and 18F-DOPA PET to assess microglial activation and striatal dopamine system integrity, respectively. Comparisons were made with healthy controls. Five LRRK2-NMCs had subclinical reductions of putaminal 18F-DOPA uptake. Three of them had significantly raised nigral 11C-PK11195 binding bilaterally. These findings indicate that nigrostriatal dysfunction and neuroinflammation occur in LRRK2-NMCs. Studies in larger cohorts with appropriate follow-up are needed to elucidate the significance of neuroinflammation in the premotor phase of LRRK2-PD.

Video-polysomnography (v-PSG) is essential for diagnosing rapid eye movement (REM) sleep behavior disorder (RBD). Although there are current American Academy of Sleep Medicine standards to diagnose RBD, several aspects need to be addressed to achieve harmonization across sleep centers. Prodromal RBD is a stage in which symptoms and signs of evolving RBD are present, but do not yet meet established diagnostic criteria for RBD. However, the boundary between prodromal and definite RBD is still unclear. As a common effort of the Neurophysiology Working Group of the International RBD Study Group, this manuscript addresses the need for comprehensive and unambiguous v-PSG recommendations to diagnose RBD and identify prodromal RBD. These include: (1) standardized v-PSG technical settings; (2) specific considerations for REM sleep scoring; (3) harmonized methods for scoring REM sleep without atonia; (4) consistent methods to analyze video and audio recorded during v-PSGs and to classify movements and vocalizations; (5) clear v-PSG guidelines to diagnose RBD and identify prodromal RBD. Each section follows a common template: The current recommendations and methods are presented, their limitations are outlined, and new recommendations are described. Finally, future directions are presented. These v-PSG recommendations are intended for both practicing clinicians and researchers. Classification and quantification of motor events, RBD episodes, and vocalizations are however intended for research purposes only. These v-PSG guidelines will allow collection of homogeneous data, providing objective v-PSG measures and making future harmonized multicentric studies and clinical trials possible.

Background and ObjectivesAnti-IgLON5 disease is a recently described neurologic disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are underreported. We describe the frequency and types of movement disorders in a series of consecutive patients with this disease.MethodsIn this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by 3 experts in movement disorders.ResultsSeventy-two patients were included. In 41 (57%), the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least 1 movement disorder with a median of 3 per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients [72%]), chorea (24 [33%]), bradykinesia (20 [28%]), dystonia (19 [26%]), abnormal body postures or rigidity (18 [25%]), and tremor (15 [21%]). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients [32%]) including dystonia (13), myorhythmia (6), chorea (4), or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31 (43%) patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only 7 (13%) cases.DiscussionMovement disorders are a frequent and leading cause of initial neurologic consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment.

Background and purpose Cholinergic dysfunction appears to play a role in the cognitive impairment observed in Parkinson's disease and dementia with Lewy bodies. The occurrence of cholinergic dysfunction in the early stages of these conditions, however, has not been investigated. The objective of this study was to investigate cholinergic function in patients with idiopathic rapid eye movement sleep behaviour disorder (iRBD), a disorder recognized to be an early stage of both Parkinson's disease and dementia with Lewy bodies. Methods A total of 21 patients with polysomnography-confirmed iRBD with no evidence of parkinsonism and cognitive impairment and 10 controls underwent positron emission tomography (PET) to assess brain acetylcholinesterase levels (11 C-donepezil PET) and nigrostriatal dopaminergic function (18 F-DOPA PET). Clinical examination included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III, Mini Mental State Examination and Montreal Cognitive Assessment. Results The 11 C-donepezil PET was successfully performed in 17 patients with iRBD and nine controls. Compared with controls, patients with iRBD showed a mean 7.65% reduction in neocortical 11 C-donepezil levels (P = 0.005). Bilateral superior temporal cortex, occipital cortex, cingulate cortex and dorsolateral prefrontal cortex showed the most significant reductions at voxel level. Conclusion Reduced neocortical 11 C-donepezil binding in our patients indicates cholinergic denervation and suggests that the projections from the nucleus basalis of Meynert, which supplies cholinergic innervation to the neocortex, are dysfunctional in iRBD. Longitudinal studies will clarify if these changes are predictive of future cognitive impairment in these patients.

Synucleinopathies are neurodegenerative diseases with both central and peripheral immune responses. However, whether the peripheral immune changes occur early in disease and their relation to brain events is yet unclear. Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) can precede synucleinopathy-related parkinsonism and provides a prodromal phenotype to study early Parkinson's disease events. In this prospective case-control study, we describe monocytic markers in a cohort of iRBD patients that were associated with the brain-imaging markers of inflammation and neuronal dysfunction. Using (11)C-PK11195 positron emission tomography (PET), we previously showed increased immune activation in the substantia nigra of iRBD patients, while (18)F-DOPA PET detected reduced putaminal dopaminergic function. Here we describe that patients’ blood monocytic cells showed increased expression of CD11b, while HLA-DR expression was decreased compared to healthy controls. The iRBD patients had increased classical monocytes and mature natural killer cells. Remarkably, the levels of expression of Toll-like receptor 4 (TLR4) on blood monocytes in iRBD patients were positively correlated with nigral immune activation measured by (11)C-PK11195 PET and negatively correlated with putaminal (18)F-DOPA uptake; the opposite was seen for the percentage of CD163(+) myeloid cells. This suggesting a deleterious role for TLR4 and, conversely, a protective one for the CD163 expression. We show an association between peripheral blood monocytes and brain immune and dopaminergic changes in a synucleinopathy-related disorder, thus suggesting a cross-talk among periphery and brain during the disease.

The study is aimed to analyze both sleep architecture and prevalence of sleep-disordered breathing (SDB), in a group of patients with type 2 spinal muscular atrophy (SMA), considering motor dysfunction, and compare them with age-matched controls.Eighteen SMA type 2 patients (nine males median age 9.5 (4-17) years) and eighteen controls (fourteen males, median age 8,5 (1-16) years) underwent nocturnal polysomnography. SMA type 2 patients were evaluated with motor scales; Hammersmith Functional Motor Scale Expanded (HFMSE), Revised upper limb model (ULMR) and Egen Klassification Scale Version 2 (EK2). Parents/tutors completed two pediatric sleep questionnaires (respiratory subscale from Chervin Pediatric Sleep Questionnaire and Bruni's Sleep Disturbance Scale for Children).When compared with controls, SMA type 2 patients showed no significant differences in age (9.72 ± 4.2 vs 8.22 ± 3.9 (p = 0.28), gender 9 (9 men (50%) vs 14 (77,8%) (p = 0.083) and nutritional status; Body Mass Index (BMI) (16.4 (12.2-34.8) vs 17.6 (4.4-24.2) (p = 0.83). Apnea Hypopnea Index (AHI) was statistically higher in SMA type 2 patients (6.7 ± 6.2 vs 0.4 ± 0.3) (p 0.001). The SpO2 mean values in cases were (96% ± 1.4) vs (97.5% ± 1.2) (p = 0.007). TcPCO2 median value (41,5 mmHg; (range 34-47.2) in the SMA type-2 patients within normal reference values. Only one motor scale; Hammersmith Functional Motor Scale Expanded (HFMSE) showed a negative correlation with AHI (r = -0.132).Patients affected by SMA type 2 presented significantly higher apnea-hypopnea indices than controls; differences in sleep architecture identified include: decreased total sleep time, increased percentage of stage N1 of NREM sleep as well as increased sleep fragmentation seen in the SMA type 2 group, due to respiratory related arousals. We would like to point out that validated pediatric sleep questionnaires in general population, may not be useful tools when screening for SDB in these patients. This should be taken into consideration in clinical practice and in the elaboration of future clinical guidelines for these patients.

Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving alpha-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal alpha-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest alpha-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of alpha-synucleinopathy patients with isolated RBD might develop.

Isolated rapid eye movement sleep behavior disorder (iRBD) is a harbinger for developing clinical synucleinopathies. Magnetic resonance imaging (MRI) has been suggested as a tool for understanding the brain bases of iRBD and its evolution. This review systematically analyzed original full text articles on structural and functional MRI in patients with video-polysomnography-confirmed iRBD according to systematic procedures suggested by Reviews and Meta-analyses (PRISMA). The literature search was conducted via the PubMed database for articles related to structural and functional MRI in iRBD from 2000 to 2020. Investigations to date have been diverse in terms of methodology, but most agree that patients with iRBD have structural changes in deep gray matter nuclei, cortical gray matter atrophy, and disrupted functional connectivity within the basal ganglia, the cortico-striatal and cortico-cortical networks. Furthermore, there is evidence that MRI detects structural and functional brain changes associated with the motor and non-motor symptoms of iRBD. The current review highlights the need for larger multicenter and longitudinal studies, using complex approaches based on data-driven and unsupervised machine learning that will help to identify structural and functional patterns of brain degeneration. In turn, this may even allow for the prediction of subsequent phenoconversion from iRBD to the clinically defined synucleinopathies.

Isolated REM sleep behaviour disorder (RBD) is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological α-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson’s disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of α-synuclein seeding activity in CSF and olfactory mucosa of patients with α-synucleinopathies. The aim of this study was to explore RT-QuIC detection of α-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson’s disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson’s disease patients and 59 matched control subjects were analysed by α-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was α-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson’s disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson’s disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive α-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative α-synuclein RT-QuIC (P

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Background Sodium oxybate (Xyrem®), approved by the European Medicines Agency (EMA) for narcolepsy with cataplexy, is only available through risk mitigation programs due to potential adverse effects including respiratory and central nervous system depression, neuropsychiatric events, and misuse. Objective We report findings from a survey evaluating effectiveness of the European Union Xyrem® Risk Management Plan (RMP). Patients and Methods A cross-sectional, online, multiple-choice survey was distributed to randomly selected healthcare professionals (HCPs) from six European countries (April 2016–May 2018). Eligibility criteria: current/potential Xyrem® prescriber and/or sleep disorder specialist; contact information available; on the Xyrem® RMP educational materials mailing list. Primary outcome: proportion of respondents answering each question correctly (

During the prodromal period of Parkinson’s disease and other α-synucleinopathy-related parkinsonisms, neurodegeneration is thought to progressively affect deep brain nuclei, such as the locus coeruleus, caudal raphe nucleus, substantia nigra, and the forebrain nucleus basalis of Meynert. Besides their involvement in the regulation of mood, sleep, behaviour, and memory functions, these nuclei also innervate parenchymal arterioles and capillaries throughout the cortex, possibly to ensure that oxygen supplies are adjusted according to the needs of neural activity. The aim of this study was to examine whether patients with isolated REM sleep behaviour disorder, a parasomnia considered to be a prodromal phenotype of α-synucleinopathies, reveal microvascular flow disturbances consistent with disrupted central blood flow control. We applied dynamic susceptibility contrast MRI to characterize the microscopic distribution of cerebral blood flow in the cortex of 20 polysomnographic-confirmed patients with isolated REM sleep behaviour disorder (17 males, age range: 54–77 years) and 25 healthy matched controls (25 males, age range: 58–76 years). Patients and controls were cognitively tested by Montreal Cognitive Assessment and Mini Mental State Examination. Results revealed profound hypoperfusion and microvascular flow disturbances throughout the cortex in patients compared to controls. In patients, the microvascular flow disturbances were seen in cortical areas associated with language comprehension, visual processing and recognition and were associated with impaired cognitive performance. We conclude that cortical blood flow abnormalities, possibly related to impaired neurogenic control, are present in patients with isolated REM sleep behaviour disorder and associated with cognitive dysfunction. We hypothesize that pharmacological restoration of perivascular neurotransmitter levels could help maintain cognitive function in patients with this prodromal phenotype of parkinsonism.

Isolated REM sleep behaviour disorder is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological alpha-synuclein in peripheral tissues of isolated REM sleep behaviour disorder patients may identify those progressing to Parkinson’s disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-Time Quaking-Induced Conversion provided evidence of α-synuclein seeding activity in cerebrospinal fluid and olfactory mucosa of patients with α-synucleinopathies. Aim of this study was to explore Real-Time Quaking-Induced Conversion detection of α-synuclein aggregates in olfactory mucosa of large cohort of subjects with isolated REM sleep behavior disorder compared to Parkinson’s disease and controls.This prospective bicentric case-control study was performed between October 2017 and December 2018 at the Medical University of Innsbruck, Austria, and the Hospital Clinic de Barcelona, Spain. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated REM sleep behavior disorder, 31 matched Parkinson’s disease patients and 59 matched controls were analysed by α-synuclein Real-Time Quaking-Induced Conversion in a blinded fashion at the University of Verona, Italy. Median age of isolated REM sleep behavior disorder patients was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions.Olfactory mucosa was α-synuclein Real-Time Quaking-Induced Conversion positive in 44.4% isolated REM sleep behavior disorder patients, 41.9% Parkinson’s disease and 10.2% controls. While the sensitivity for isolated REM sleep behavior disorder plus Parkinson’s disease versus controls was 40.9%, specificity was high (89.8%). Among isolated REM sleep behavior disorder patients with positive α-synuclein Real-Time Quaking-Induced Conversion, 78.6% had olfactory dysfunction as compared to 21.4% with negative α-synuclein Real-Time Quaking-Induced Conversion, pReal-Time Quaking-Induced Conversion olfactory mucosa isolated REM sleep behavior disorder patients (pWe provide evidence that α-synuclein Real-Time Quaking-Induced Conversion assay enables the molecular detection of neuronal α-synuclein aggregates in olfactory mucosa of patients with isolated REM sleep behavior disorder and Parkinson’s disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as simple, non-invasive test, with a potential of use as screening test to identify subjects in the prodromal stages of α-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of α-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated REM sleep behavior disorder to overt α-synucleinopathy.

To determine if hyposmia in isolated REM sleep behavior disorder (IRBD) predicts short-term conversion to any α-synucleinopathy and declines with time. Olfaction was tested using the University of Pennsylvania Smell Identification Test (UPSIT-40) in 140 consecutive patients with polysomnography-confirmed IRBD and in 77 matched controls. Patients were followed-up during 5.6 ± 3.9 (range 0.2–13) years. Twenty-one patients underwent serial UPSIT-40 evaluations at 1–3 and 4–6 years after baseline. UPSIT-40 score was lower in patients than in controls (20.2 ± 6.5 vs. 28.6 ± 5.0; p

Study ObjectivesTo describe the characteristics of stridor during sleep (SDS) in a series of adults identified by video-polysomnography (V-PSG).MethodsRetrospective clinical, V-PSG, laryngoscopic, and therapeutic data of patients diagnosed with SDS in a tertiary referral sleep disorders center between 1997 and 2017.ResultsA total of 81 patients were identified (56.8% males, age 61.8 ± 11.2 years). Related etiologies were multiple system atrophy (MSA), amyotrophic lateral sclerosis, spinocerebellar ataxia type 1, anti-IgLON5 disease, fatal familial insomnia, brainstem structural lesions, vagus nerve stimulation, recurrent laryngeal nerve injury, the effect of radiotherapy on the vocal cords, cervical osteophytes, and others. Stridor during wakefulness coexisted in 13 (16%) patients and in MSA was only seen in the parkinsonian form. Laryngoscopy during wakefulness in 72 (88.9%) subjects documented vocal cord abductor impairment in 65 (90.3%) and extrinsic lesions narrowing the glottis in 2 (2.4%). The mean apnea–hypopnea index (AHI) was 21.4 ± 18.6 and CT90 was 11.5 ± 19.1. Obstructive AHI > 10 occurred in 52 (64.2%) patients and central apnea index >10 in 2 (2.4%). CPAP abolished SDS, obstructive apneic events and oxyhemoglobin desaturations in 58 of 60 (96.7%) titrated patients with optimal pressure of 9.0 ± 2.3 cm H20. Tracheostomy in 19 (23.4%) and cordotomy in 3 (3.7%) subjects also eliminated SDS.ConclusionsSDS in adults is linked to conditions that damage the brainstem, recurrent laryngeal nerve, and vocal cords. V-PSG frequently detects obstructive sleep apnea and laryngoscopy usually shows vocal cord abductor dysfunction. CPAP, tracheostomy, and laryngeal surgery abolish SDS.

Idiopathic hyposmia (IH) is a prodromal marker of Parkinson disease (PD). However, IH is common in the general population and only a minority will develop PD. Identification of individuals with IH at prodromal stage of PD would serve to select them to implement neuroprotective agents, when available. To identify prodromal PD in IH patients using the Movement Disorders Society (MDS) research criteria for prodromal PD. We applied the MDS research criteria for prodromal PD to 25 consecutive patients older than 50 years who were self-referred for smell loss and had IH, and to 18 controls. A number of risk and prodromal PD markers were assessed in all participants including REM sleep behavior disorder (RBD) by video-polysomnography and nigrostriatal dopaminergic dysfunction by DAT-SPECT. After follow-up of 4.7 ± 2.2 years, participants were re-assessed to look for incident PD. Prodromal PD probability was higher in patients than in controls (19.45 ± 34.9% versus 1.74 ± 4.48%; p = 0.019). Four (16%) patients met the criteria of prodromal PD surpassing 80% probability (99.8%, 99.5%, 88.3%, 86.4%). Three (12%) patients had RBD and four (16%) abnormal DAT-SPECT. At the end of follow-up, one (4%) IH patient who had RBD and baseline prodromal PD probability of 86.4% developed PD, while all controls remained disease free. Prodromal PD is infrequent among IH patients. MDS research criteria for prodromal PD are useful to identify a subgroup of IH patients at high risk of PD when RBD is assessed by video-polysomnography and nigrostriatal dopamine deficiency with DAT-SPECT.

Study Objectives Patients with isolated rapid eye movement (REM) sleep behavior disorder (IRBD) develop Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA). Magnetic resonance imaging (MRI) is abnormal in MSA showing abnormalities in the putamen, cerebellum, and brainstem. Our objective was to evaluate the usefulness of MRI to detect MRI abnormalities in IRBD and predict development of MSA and not PD and DLB. Methods In IRBD patients that eventually developed PD, DLB, and MSA, we looked for the specific structural MRI abnormalities described in manifest MSA (e.g. hot cross-bun sign, putaminal rim, and cerebellar atrophy). We compared the frequency of these MRI changes among groups of converters (PD, DLB, and MSA) and analyzed their ability to predict development of MSA. The clinical and radiological features of the IRBD patients that eventually converted to MSA are described in detail. Results A total of 61 IRBD patients who underwent MRI phenoconverted to PD (n = 30), DLB (n = 26), and MSA (n = 5) after a median follow-up of 2.4 years from neuroimaging. MRI changes typical of MSA were found in four of the five (80%) patients who converted to MSA and in three of the 56 (5.4%) patients who developed PD or DLB. MRI changes of MSA had sensitivity of 80.0%, specificity of 94.6%, positive likelihood ratio of 14.9 (95% CI 4.6–48.8), and negative likelihood ratio of 0.2 (95% CI 0.04–1.2) to predict MSA. Conclusions In IRBD, conventional brain MRI is helpful to predict conversion to MSA. The specific MRI abnormalities of manifest MSA may be detected in its premotor stage.

Increased incidence rates of narcolepsy type 1 (NT1) after the 2009-2010 H1N1 influenza pandemic (pH1N1) have been reported world-wide. While some European countries found an association between the NT1 increase and H1N1 vaccination Pandemrix, reports from Asian countries suggested the H1N1 virus rather than Pandemrix to be linked with the increase of new NT1 cases. We analyzed the number of de-novo NT1 cases in the last two decades until 2016 using the European Narcolepsy Network (EU-NN) database. Using robust data-driven modelling approaches we confirmed the peak of NT1 incidence in 2009-2010 pH1N1 and identified a new peak in 2013 that is age-specific for children/adolescents. Most of these de-novo cases showed a subacute disease onset consistent with an immune-mediated type of narcolepsy, which is most likely not related to Pandemrix vaccination that was used in 2009-2010, but may have been triggered by some new epidemiological event in Europe. Our finding of an unexpected peak in de-novo children narcolepsy in 2013 provides a unique opportunity to develop new hypotheses, such as considering other (influenza) viruses to further investigate the pathophysiology of immune-mediated narcolepsy.

Objective In right-handed patients with Parkinson's disease (PD) or isolated rapid eye movement sleep behavior disorder, dopamine transporter (DAT) [(123)I]β-carboxymethyoxy-3-β-(4-iodophenyl) tropane single photon emission computed tomography (SPECT) shows predominant nigrostriatal deficit in the left striatum. This suggests that in PD patients, the nigrostriatal system of the dominant hemisphere is more susceptible to disease-related dysfunction. To confirm this hypothesis, we investigated whether the nigrostriatal function is symmetric in healthy controls and in patients with PD. Methods In 113 right-handed healthy controls and 279 right-handed early-PD patients, we examined the striatal dopaminergic terminals function in each hemisphere using DAT-SPECT. Results In the controls, DAT-SPECT showed symmetric specific binding ratios in the putamen and caudate nucleus of each hemisphere. In patients with PD, the specific binding ratio was lower in the left than in the right putamen. Conclusions Right-handed healthy controls have symmetric nigrostriatal dopaminergic function. The left hemispheric predominance of nigrostriatal deficit seen in right-handed premotor and manifest PD represents an early pathological feature of the disease. © 2020 International Parkinson and Movement Disorder Society.

Background: The majority of patients diagnosed with idiopathic rapid eye movement sleep behaviour disorder (iRBD) progress over time to a Lewy-type α-synucleinopathy such as Parkinson's disease or dementia with Lewy bodies. This in vivo molecular imaging study aimed to investigate if extrastriatal monoaminergic systems are affected in iRBD patients and if this coincides with neuroinflammation. Methods: We studied twenty-one polysomnography-confirmed iRBD patients with 18F-DOPA and 11C-PK11195 positron emission tomography (PET) to investigate extrastriatal monoaminergic function and microglial activation. Twenty-nine healthy controls (n = 9 18F-DOPA and n = 20 11C-PK11195) were also investigated. Analyses were performed within predefined regions of interest and at voxel-level with Statistical Parametric Mapping. Results: Regions of interest analysis detected monoaminergic dysfunction in iRBD thalamus with a 15% mean reduction of 18F-DOPA Ki values compared to controls (mean difference = −0.00026, 95% confidence interval [−0.00050 to −0.00002], p-value = 0.03). No associated thalamic changes in 11C-PK11195 binding were observed. Other regions sampled showed no 18F-DOPA or 11C-PK11195 PET differences between groups. Voxel-level interrogation of 11C-PK11195 binding identified areas with significantly increased binding within the occipital lobe of iRBD patients. Conclusion: Thalamic monoaminergic dysfunction in iRBD patients may reflect terminal dysfunction of projecting neurons from the locus coeruleus and dorsal raphe nucleus, two structures that regulate REM sleep and are known to be involved in the early phase of PD. The observation of significantly raised microglial activation in the occipital lobe of these patients might suggest early local Lewy-type α-synuclein pathology and possibly an increased risk for later cognitive dysfunction.

Introduction: Glucocerebrosidase (GBA) gene variants are associated with the development of the Lewy body disorders (LBD) Parkinson disease (PD) and dementia with Lewy bodies (DLB). Idiopathic REM sleep behavior disorder (IRBD) represents prodromal LBD in most instances. We investigated whether GBA variants are overrepresented in IRBD and if their presence shortens the time to conversion to clinically defined LBD. Methods: All GBA coding exons from 69 polysomnography-confirmed IRBD patients and 84 matched controls were sequenced by the Sanger method. Results: Seven missense variants (E326K, L444P, A446T, A318G, R329C, T369M, N3705) were identified in eight (11.6%) IRBD patients and in one (1.2%) control (P = 0.026). After a mean follow-up of 8.9 3.8 years from IRBD diagnosis, five subjects with GBA variants developed LBD (3 DLB and 2 PD) and three remained disease-free. The risk of developing a LBD was similar in IRBD subjects with GBA variants than in those without variants (log rank test, p = 0.935). Conclusions: In IRBD, GBA variants are 1) more frequent when compared to controls, 2) associated with impending PD and DLB but 3) not indicative of a short-term risk for LBD after IRBD diagnosis. IRBD patients carrying GBA variants could be studied with disease-modifying interventions aiming to restore the GBA metabolic pathway. (C) 2018 Elsevier Ltd. All rights reserved.

Sleep paralysis is rare in the elderly but may occur particularly in families suffering from this phenomenon. In a minority of patients with disorders of arousal, the episodes persist until the age of 70. Zolpidem and other medications may induce sleepwalking and sleep eating-related syndrome. Most patients with idiopathic REM sleep behavior disorder (RBD) eventually develop Parkinson disease and dementia with Lewy bodies. Anti-IgLON5 disease includes abnormal behaviors in both nonrapid eye movement sleep and rapid eye movement sleep (REM) sleep. Restless legs syndrome prevalence increases with age until the sixth decade. A severe form of periodic limb movements in sleep may clinically mimic REM sleep behavior disorder (RBD).

Objective: To determine the usefulness of dopamine transporter (DAT) imaging to identify idiopathic REM sleep behavior disorder (IRBD) patients at risk for short-term development of clinically-defined synucleinopathy. Methods: Eighty-seven patients with polysomnography-confirmed IRBD underwent 123I-FP-CIT DAT-SPECT. Results were compared with 20 matched controls without RBD who underwent DAT-SPECT. In patients, FP-CIT uptake was considered abnormal when values were two standard deviations below controls' mean uptake. After DAT-SPECT, patients were followed-up during 5.7 ± 2.2 (range, 2.6-9.9) years. Results: Baseline DAT deficit was found in 51 (58.6%) patients. During follow-up 25 (28.7%) subjects developed clinically-defined synucleinopathy (Parkinson disease in 11, dementia with Lewy bodies in 13, multiple system atrophy in one) with mean latency of 3.2 ± 1.9 years from imaging. Kaplan-Meier survival analysis showed increased risk of incident synucleinopathy in patients with abnormal DAT-SPECT than with normal DAT-SPECT (20% vs. 6% at three years, 33% vs. 18% at five years; log rank test, p=0.006). Receiver operating characteristics curve revealed that reduction of FP-CIT uptake in putamen greater than 25% discriminated patients with DAT deficit who developed synucleinopathy from patients with DAT deficit that remained disease-free after three years of follow-up. At 5-year follow-up, DAT-SPECT had 75% sensitivity, 51% specificity, 44% positive predictive value, 80% negative predictive value, and like-hood ratio 1.54 to predict synucleinopathy. Interpretation: DAT-SPECT identifies IRBD patients at short-term risk for synucleinopathy. Decreased FP-CIT putamen uptake greater than 25% predicts synucleinopathy after three years follow-up. These observations may be useful to select candidates for disease-modification trials in IRBD. This article is protected by copyright. All rights reserved.

In recent years, the diagnostic approach to rapid eye movement (REM) sleep behavior disorder (RBD) has become more objective and accurate. This was achieved mainly by introduction of methods to exactly quantify electromyographic (EMG) activity in various muscles during REM sleep. The most established muscle combination for RBD diagnosis is the mentalis and upper extremity EMG. Computer-assisted systems for this analysis have been described, and an increasing number of studies looked into analysis of video events. Recently, prodromal phases of isolated RBD have been recognized.

Objective To evaluate the role of sleep cyclic alternating pattern (CAP) in patients with isolated REM sleep behavior disorder (IRBD) and ascertain whether CAP metrics might represent a marker of phenoconversion to a defined neurodegenerative condition. Methods Sixty-seven IRBD patients were included and classified into patients who phenoconverted to a neurodegenerative disease (RBD converters: converter REM sleep behavior disorder [cRBD]; n = 34) and remained disease-free (RBD non-converters: non-converter REM sleep behavior disorder [ncRBD]; n = 33) having a similar follow-up duration. Fourteen age- and gender-balanced healthy controls were included for comparisons. Results Compared to controls, CAP rate and CAP index were significantly decreased in IRBD mainly due to a decrease of A1 phase subtypes (A1 index) despite an increase in duration of both CAP A and B phases. The cRBD group had significantly lower values of CAP rate and CAP index when compared with the ncRBD group and controls. A1 index was significantly reduced in both ncRBD and cRBD groups compared to controls. When compared to the ncRBD group, A3 index was significantly decreased in the cRBD group. The Kaplan-Meier curve applied to cRBD estimated that a value of CAP rate below 32.9% was related to an average risk of conversion of 9.2 years after baseline polysomnography. Conclusion IRBD is not exclusively a rapid eye movement (REM) sleep parasomnia, as non-rapid eye movement (non-REM) sleep microstructure can also be affected by CAP changes. Further studies are necessary to confirm that a reduction of specific CAP metrics is a marker of neurodegeneration in IRBD.

Study ObjectiveTo characterize the sleep disorder of anti-IgLON5 disease.MethodsWe reviewed 27 video-polysomnographies (V-PSG), 6 multiple sleep latency tests (MSLT), 2 videsomnoscopies with dexmedetomidine, and 10 actigraphies recorded during the disease course of five patients. Due to severe sleep architecture abnormalities, we used a novel modified sleep scoring system combining conventional stages with a descriptive approach in which two additional stages were identified: undifferentiated-NREM (UN-NREM) and poorly structured N2 (P-SN2) sleep that were characterized by abnormal motor activation and absence or sparse elements of conventional NREM sleep.ResultsSleep-related vocalizations, movements, behaviors, and respiratory abnormalities were reported by bed-partners. In all patients, NREM sleep onset and sleep reentering after an awakening occurred as UN-NREM (median: 29.8% of total sleep time [TST]) and P-SN2 sleep (14.5% TST) associated with vocalizations and simple and quasi-purposeful movements. Sleep initiation was normalized in one patient with a high dose of steroids, but NREM sleep abnormalities reappeared in subsequent V-PSG. In all patients, if sleep continued uninterrupted, there was a progressive normalization with normal N2 (11.7% TST) and N3 (22.3% TST) sleep but stridor and obstructive apnea emerged. REM sleep behavior disorder (RBD) occurred in four patients. Sleep initiation was also altered in MSLT and dexmedetomidine-induced sleep. Actigraphy showed a 10-fold increase of nocturnal activity compared with controls. Sleep abnormalities remained stable during the disease.ConclusionsThe sleep disorder of anti-IgLON5 disease presents as a complex sleep pattern characterized by abnormal sleep initiation with undifferentiated NREM sleep, RBD, periods of normal NREM sleep, stridor, and obstructive apnea.

Objective: In this study we investigate cortical and subcortical gray matter structure in patients with Idiopathic REM-sleep behavior disorder (IRBD), and their relation to cognitive performance. Methods: This study includes a sample of 20 patients with polysomnography-confirmed IRBD and 27 healthy controls that underwent neuropsychological and T1-weighted MRI assessment. FreeSurfer was used to estimate cortical thickness, subcortical volumetry (version 5.1), and hippocampal subfields segmentation (version 6.0). FIRST, FSL's model-based segmentation/registration tool was used for hippocampal shape analysis. Results: Compared with healthy subjects, IRBD patients showed impairment in facial recognition, verbal memory, processing speed, attention, and verbal naming. IRBD patients had cortical thinning in left superior parietal, post-central, and fusiform regions, as well as in right superior frontal and lateral occipital regions. Volumetric and shape analyses found right hippocampal atrophy in IRBD, specifically in posterior regions. Hippocampal subfields exploratory analysis identified significant differences in the right CA1, molecular layer, granule cell layer of dentate gyrus, and CA4 of this patients. No correlations were found between cognitive performance and brain atrophy. Conclusion: This work confirms the presence of posterior based cognitive dysfunction, as well as cortical and right hippocampal atrophy in IRBD patients.

Objective The main objective of this study was to study rapid eye movement (REM) sleep behavior disorder (RBD) and other sleep disorders in dementia with Lewy bodies (DLB). Methods Consecutive patients with DLB and mild dementia severity were recruited irrespective of sleep complaints. Patients underwent clinical interview, assessment of sleep scales, and video-polysomnography (V-PSG). RBD was diagnosed with V-PSG based on electromyographic and audiovisual analysis. Results Thirty-five patients (65.7% men; mean age 77.7 ± 6.1 years) were evaluated. Poor sleep quality (54.3%), hypersomnia (37.1%), snoring (60%), and abnormal nocturnal behaviors (77.1%) were reported. Sleep–wake architecture abnormalities occurred in 75% patients and consisted of occipital slowing on awake electroencephalography (EEG; 34.4%), the absence of sleep spindles and K complexes (12.9%), slow frequency sleep spindles (12.9%), delta activity in REM sleep (19.2%), and REM sleep without atonia (44%). Three patients showed hallucinatory-like behaviors and 10 patients showed abnormal behaviors during arousals mimicking RBD. RBD was diagnosed in 50% of those patients in whom sufficient REM sleep was attained. Of these, 72.7% were not aware of displaying dream-enacting behaviors and in 63.7% RBD preceded the onset of cognitive impairment. For RBD diagnosis, the sensitivity of Mayo Sleep Questionnaire was 50%, specificity was 66.7%, positive predictive value was 83.3%, and negative predictive value was 28%. False-positive RBD cases according to clinical history had hallucinatory-like behaviors, severe obstructive sleep apnea, and prominent periodic limb movements in sleep. Occipital EEG frequency while awake and rate of electromyographic activity in REM sleep were negatively correlated, suggesting a common subcortical origin. Conclusion In DLB, RBD and sleep–wake disorders are common, heterogeneous, and complex, challenging their identification without performing V-PSG.

Neurological autoimmune diseases are characterized by an inappropriate immune response that by mistake targets the nervous system. As a result, patients experiment a number of neurological manifestations that may include insomnia, excessive daytime sleepiness, cataplexy, central hypoventilation, and REM sleep behavior disorder. Polysomnographic evaluation may reveal disorganized sleep architecture involving both NREM and REM sleep, and REM sleep intrusions into wakefulness. The study of sleep disorders in the setting of autoimmune diseases (e.g., narcolepsy, anti-IgLON5 disease, paraneoplastic neurological syndromes) shows that an abnormal immune-mediated (humoral or cellular) response target the neuronal structures (e.g., brainstem, hypothalamus) and neurotransmitters systems (e.g., hypocretin) that regulate sleep resulting in sleep impairment. It is a window to examine the link between the autoimmune system and the sleep regulation at the molecular, cellular, and anatomic level.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a combination of autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor is an additional feature for MSA diagnosis, showing a high diagnostic positive predictive value, and its early occurrence might contribute to shorten survival. A consensus definition of stridor in MSA is lacking, and disagreement persists about its diagnosis, prognosis, and treatment. An International Consensus Conference among experts with methodological support was convened in Bologna in 2017 to define stridor in MSA and to reach consensus statements for the diagnosis, prognosis, and treatment. Stridor was defined as a strained, high-pitched, harsh respiratory sound, mainly inspiratory, occurring only during sleep or during both sleep and wakefulness, and caused by laryngeal dysfunction leading to narrowing of the rima glottidis. According to the consensus, stridor may be recognized clinically by the physician if present at the time of examination, with the help of a witness, or by listening to an audio recording. Laryngoscopy is suggested to exclude mechanical lesions or functional vocal cord abnormalities related to different neurologic conditions. If the suspicion of stridor needs confirmation, drug-induced sleep endoscopy or video polysomnography may be useful. The impact of stridor on survival and quality of life remains uncertain. Continuous positive airway pressure and tracheostomy are both suggested as symptomatic treatment of stridor, but whether they improve survival is uncertain. Several research gaps emerged involving diagnosis, prognosis, and treatment. Unmet needs for research were identified.

Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-2 (NT2), but only NT1 is accepted as clearly defined entity. Both types of narcolepsies belong to the group of central hypersomnias (CH), a spectrum of poorly defined diseases with excessive daytime sleepiness as a core feature. Due to the considerable overlap of symptoms and the rarity of the diseases, it is difficult to identify distinct phenotypes of CH. Machine learning (ML) can help to identify phenotypes as it learns to recognize clinical features invisible for humans. Here we apply ML to data from the huge European Narcolepsy Network (EU-NN) that contains hundreds of mixed features of narcolepsy making it difficult to analyze with classical statistics. Stochastic gradient boosting, a supervised learning model with built-in feature selection, results in high performances in testing set. While cataplexy features are recognized as the most influential predictors, machine find additional features, e.g. mean rapideye-movement sleep latency of multiple sleep latency test contributes to classify NT1 and NT2 as confirmed by classical statistical analysis. Our results suggest ML can identify features of CH on machine scale from complex databases, thus providing 'ideas' and promising candidates for future diagnostic classifications., The EU-NN database is financed by the EU-NN. The EU-NN has received financial support from UCB Pharma Brussels for developing the EU-NN database.

Objective To evaluate the effect of continuous positive airway pressure (CPAP) on the nostrils of patients with sleep apnea–hypopnea syndrome and its impact on quality of life, and to identify predictive factors for compliance. Methods Longitudinal prospective study. Thirty-six consecutive patients evaluated before and 2 months after CPAP using the following variables: clinical (eye, nose and throat [ENT] symptoms, Epworth test, anxiety/depression scales, general and rhinoconjunctivitis-specific quality of life); anatomical (ENT examination, computed tomography); functional (auditive and Eustachian tube function, nasal flow, mucociliary transport); biological (nasal cytology); and polisomnographics. The sample was divided into partients with good adherence (≥4 h/d) and patients with bad adherence ( Results A significant improvement was observed in daytime sleepiness (P=.000), anxiety (P=.006), and depression (P=.023). Nasal dryness (P=.000), increased neutrophils in nasal cytology (P=.000), and deteriorating ciliary function were evidenced, particularly in partients with good adherence. No significant differences were observed in the other variables. Baseline sleepiness was the only factor predictive of compliance. Conclusions CPAP in patients without previous nasal pathology leads to an improvement in a series of clinical parameters and causes rhinitis and airway dryness. Some ENT variables worsened in partients with good adherence. Sleepiness was the only prognostic factor for poor tolerance.

Resumen Objetivo Evaluar el efecto de la presion positiva continua en la via aerea (CPAP) sobre las fosas nasales de pacientes con sindrome de apnea hipopnea del sueno y su impacto en la calidad de vida, e identificar factores predictivos de cumplimiento. Metodos Estudio prospectivo longitudinal. Treinta y seis pacientes consecutivos evaluados antes y 2 meses tras CPAP usando las siguientes variables clinicas (sintomas otorrinolaringologicos, test de Epworth, escala de ansiedad/depresion, calidad de vida general y especifica para rinoconjuntivitis); anatomicas (exploracion otorrinolaringologica, tomografia computarizada); funcionales (funcion auditiva y tubarica, flujo nasal, transporte mucociliar); biologicas (citologia nasal), y polisomnograficas. Se dividio la muestra entre cumplidores (≥4 h/d) y no cumplidores ( Resultados Se objetivo una mejoria significativa en la somnolencia diurna (p = 0,000), la ansiedad (p = 0,006) y la depresion (p = 0,023). Se evidencio sequedad nasal (p = 0,000), aumento de neutrofilos en la citologia nasal (p = 0,000) y deterioro de la funcion ciliar, especialmente en cumplidores. No se evidenciaron diferencias significativas en el resto de las variables. La somnolencia inicial fue el unico factor pronostico de cumplimiento. Conclusiones El tratamiento con CPAP en pacientes sin patologia nasal previa mejora una serie de parametros clinicos y provoca rinitis y sequedad en la via aerea. Algunas de las variables otorrinolaringologicas empeoran en los cumplidores. La somnolencia fue el unico factor pronostico de mala tolerancia.

Disorders of sleep are an integral part of neurodegenerative diseases and include insomnia, sleep-wake cycle disruption, excessive daytime sleepiness that may be manifested as persistent somnolence or sudden onset of sleep episodes, obstructive and central sleep apnea, rapid eye movement sleep behavior disorder, and restless legs syndrome. The origin of these sleep disorders is multifactorial including degeneration of the brain areas that modulate sleep, the symptoms of the disease, and the effect of medications. Treatment of sleep disorders in patients with neurodegenerative diseases should be individualized and includes behavioral therapy, sleep hygiene, bright light therapy, melatonin, hypnotics, waking-promoting agents, and continuous positive airway pressure.

Sleep-related movement and behaviour disorders may have an impact on sleep quality and lead to daytime symptoms. These groups of conditions include diseases such as restless legs syndrome, periodic leg movements, and REM and NREM parasomnias. The knowledge of their clinical features and management is of utmost importance for the neurologist and sleep specialist. Frequently, these patients are referred to such specialists and it is relevant to know that certain sleep disorders may be associated with other neurological conditions.

Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by unpleasant dreams, dream-enacting behaviors, loss of REM sleep atonia, lack of waking motor and cognitive complaints, and the absence of a detectable underlying condition. iRBD typically occurs in people aged 50 years or older, mainly in men, with an estimated prevalence of 0.3–1%. Content of dreams is usually of frightening situations where patients are attacked or chased, and they often have to defend themselves with aggressive behaviors. The most common RBD behaviors are limb and body jerks, but elaborated and aggressive behaviors are also typical, with consequent sleep-related injuries. Despite the ongoing motor-behavioral activity during REM sleep with RBD, it is surprising that patients usually report a good night’s sleep and feel rested upon arising in the morning. Since about 50% of patients are completely unaware of their sleep behaviors, interviews with bed partners are essential to obtain a full clinical description. Clonazepam and melatonin typically have a beneficial effect in treating both RBD nightmares and vigorous behaviors. iRBD patients show markers of neurodegeneration (hyposmia, depression, constipation, substantia nigra hyperechogenicity, abnormal executive, and visuospatial functions) and the neuropathological substrate of Parkinson disease (deposits of abnormal synuclein in the peripheral autonomous nervous system, microglial activation in substantia nigra, and decreased dopamine activity in the striatum). In the majority of cases, there is a progression from iRBD to Parkinson disease, dementia with Lewy bodies, mild cognitive impairment, and multiple system atrophy. iRBD constitutes an excellent target population to test neuroprotective agents to halt or delay the occurrence of parkinsonism and dementia.

Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia that is characterized by loss of muscle atonia during REM sleep (known as REM sleep without atonia, or RSWA) and abnormal behaviours occurring during REM sleep, often as dream enactments that can cause injury. RBD is categorized as either idiopathic RBD or symptomatic (also known as secondary) RBD; the latter is associated with antidepressant use or with neurological diseases, especially α-synucleinopathies (such as Parkinson disease, dementia with Lewy bodies and multiple system atrophy) but also narcolepsy type 1. A clinical history of dream enactment or complex motor behaviours together with the presence of muscle activity during REM sleep confirmed by video polysomnography are mandatory for a definite RBD diagnosis. Management involves clonazepam and/or melatonin and counselling and aims to suppress unpleasant dreams and behaviours and improve bedpartner quality of life. RSWA and RBD are now recognized as manifestations of an α-synucleinopathy; most older adults with idiopathic RBD will eventually develop an overt neurodegenerative syndrome. In the future, studies will likely evaluate neuroprotective therapiesinpatients with idiopathic RBD to prevent or delay α-synucleinopathy-related motorandcognitivedecline.