Publications by authors named "Karel Sonka"

96 Publications

Idiopathic hypersomnia: a homogeneous or heterogeneous disease?

Sleep Med 2021 Jan 29;80:86-91. Epub 2021 Jan 29.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic. Electronic address:

Introduction: Idiopathic hypersomnia (IH) is a rare orphan disease characterized by excessive daytime sleepiness, frequently accompanied by prolonged nocturnal sleep and difficulties awakening, termed sleep inertia or sleep drunkenness. Severe sleepiness usually causes a greater handicap than manifestations of narcolepsy.

Methods: Forty-three IH patients (17 male, mean age 42.8 ± SD 12.2 years, range 20-67), diagnosed in the past 20 years according to ICSD-2 or ICSD-3 criteria were invited for clinical examination to evaluate the course, manifestations and severity of the disease, as well as clinical comorbidities. The patients completed a set of questionnaires scoring sleepiness, sleep inertia, fatigue, depression, anxiety, circadian preference, and quality of life.

Results: IH patients were divided according to the duration of nocturnal sleep at the time of their diagnosis into two cohorts: (1) with normal sleep duration (n = 25, 58.1%) and (2) with long sleep duration (n = 18, 41.9%). The mean duration of ad libitum sleep per 22 h in the second cohort was 732.0 ± 115.4 min (range 603-1100), and women markedly prevailed (n = 14, 77.8%). Age at disease onset was younger in the group with long sleep duration (21.2 ± 11.4 years versus 28.1 ± 13.6 years, p = 0.028), their MSLT latency was longer (7.2 ± 3.7 min versus 5.1 ± 1.7 min, p = 0.005), a history of sleep inertia prevailed (p = 0.005), and daily naps were mostly non-refreshing (p = 0.014). Additionally, questionnaires in the group with long sleep duration showed more severe sleep inertia (p = 0.007), fatigue (p = 0.004), and a tendency towards evening chronotype (p = 0.001).

Conclusions: IH patients with long sleep duration differ clinically as well as by objective measures at the time of diagnosis and in long-term follow up from IH patients without long 24-h sleep time. In our opinion they represent an independent clinical entity to be considered in the revised ICSD-3 criteria.
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http://dx.doi.org/10.1016/j.sleep.2021.01.031DOI Listing
January 2021

Novel Associations of and with Rapid Eye Movement Sleep Behavior Disorder.

Neurology 2021 Jan 4. Epub 2021 Jan 4.

Department of Human Genetics, McGill University, Montréal, QC, Canada.

Objective: To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD).

Methods: We fully sequenced 25 genes previously identified in GWASs of PD, in a total of 1,039 iRBD patients and 1,852 controls. The role of rare heterozygous variants in these genes was examined using burden tests. The contribution of biallelic variants was further tested. To examine the potential impact of rare nonsynonymous variants on the protein structure, we performed structural analysis. Finally, we examined the association of common variants using logistic regression adjusted for age and sex.

Results: We found an association between rare heterozygous nonsynonymous variants in and iRBD (=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 22 (1.2%) controls vs. two (0.2%) patients. All three variants seem to be loss-of-function variants with a potential effect on the protein structure and stability. Rare non-coding heterozygous variants in were also associated with iRBD (=0.0006 at >30X). We found no association between rare heterozygous variants in the rest of genes and iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD.

Conclusion: Our results suggest that rare coding variants in and rare non-coding variants in are associated with iRBD. Additional studies are required to replicate these results and examine whether loss-of-function of could be a therapeutic target.
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http://dx.doi.org/10.1212/WNL.0000000000011464DOI Listing
January 2021

Rare Case of Late-Onset Narcolepsy Type 1.

Case Rep Neurol 2020 Sep-Dec;12(3):428-432. Epub 2020 Nov 12.

Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia.

A 69-year-old male developed symptoms typical of the diagnosis of narcolepsy type 1 without any previous triggering events. First, daytime sleepiness occurred, soon followed by cataplexy. Nocturnal polysomnography revealed rapid eye movement (REM) sleep behavior disorder, a apnea-hypopnea index of 25.8 events/h, and no sleep-onset REM. Multiple Sleep Latency Test showed a mean sleep latency of 2.1 min and REM sleep in 3 tests. HLA DQB1*06:02 was positive and hypocretin-1 in cerebrospinal fluid unmeasurable. A treatment with 50 mg clomipramine controlled the cataplexy; excessive daytime sleepiness was sufficiently managed by repeated naps. The administration of 0.25 mg of clonazepam subjectively improved REM sleep behavior disorder. Bilevel Positive Airway Pressure improved the apnea-hypopnea index without important influence on sleepiness. Our unique case demonstrates that even elderly subjects can develop narcolepsy type 1.
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http://dx.doi.org/10.1159/000510633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747064PMC
November 2020

Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder.

Brain 2021 Feb;144(1):278-287

Clinical Neurology, Department of Neuroscience (DINOGMI), University of Genoa, Italy.

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 < 0.000001), constipation, (P < 0.000001) and age over 70 years (P = 0.0002). Combined features obtained from the generalized logistic regression achieved a hazard ratio of 5.71 (95% confidence interval 2.85-11.43). Bayesian classifier suggested that patients with higher Mini-Mental State Examination score and lower caudate SBR asymmetry were more likely to develop parkinsonism, while patients with the opposite pattern were more likely to develop dementia. This study shows that iRBD patients older than 70 with constipation and reduced nigro-putaminal dopaminergic function are at high risk of short-term phenoconversion to an overt synucleinopathy, providing an effective stratification approach for future neuroprotective trials. Moreover, we provide cut-off values for the significant predictors of phenoconversion to be used in single subjects.
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http://dx.doi.org/10.1093/brain/awaa365DOI Listing
February 2021

Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy.

Sleep 2020 Oct 14. Epub 2020 Oct 14.

Department of Neurology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.

Study Objectives: Evaluate efficacy and safety of lower-sodium oxybate (LXB), a novel oxybate medication with 92% less sodium than sodium oxybate (SXB).

Methods: Adults aged 18-70 years with narcolepsy with cataplexy were eligible. The study included a ≤30-day screening period; a 12-week, open-label, optimized treatment and titration period to transition to LXB from previous medications for the treatment of cataplexy; a 2-week stable-dose period (SDP); a 2-week, double-blind, randomized withdrawal period (DBRWP); and a 2-week safety follow-up. During DBRWP, participants were randomized 1:1 to placebo or to continue LXB treatment.

Results: Efficacy was assessed in 134 participants who received randomized treatment, and safety was assessed in all enrolled participants (N = 201). Statistically significant worsening of symptoms was observed in participants randomized to placebo, with median (first quartile [Q1], third quartile [Q3]) change in weekly number of cataplexy attacks from SDP to DBRWP (primary efficacy endpoint) in the placebo group of 2.35 (0.00, 11.61) versus 0.00 (-0.49, 1.75) in the LXB group (p < 0.0001; mean [standard deviation, SD] change: 11.46 [24.751] vs 0.12 [5.772]), and median (Q1, Q3) change in Epworth Sleepiness Scale score (key secondary efficacy endpoint) of 2.0 (0.0, 5.0) in the placebo group versus 0.0 (-1.0, 1.0) in the LXB group (p < 0.0001; mean [SD] change: 3.0 [4.68] vs 0.0 [2.90]). The most common treatment-emergent adverse events with LXB were headache (20.4%), nausea (12.9%), and dizziness (10.4%).

Conclusions: Efficacy of LXB for the treatment of cataplexy and excessive daytime sleepiness was demonstrated. The safety profile of LXB was consistent with SXB.

Clinical Trial Registration: NCT03030599.
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http://dx.doi.org/10.1093/sleep/zsaa206DOI Listing
October 2020

Comprehensive Analysis of Familial Parkinsonism Genes in Rapid-Eye-Movement Sleep Behavior Disorder.

Mov Disord 2021 01 1;36(1):235-240. Epub 2020 Oct 1.

Department of Human Genetics, McGill University, Montréal, Québec, Canada.

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.
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http://dx.doi.org/10.1002/mds.28318DOI Listing
January 2021

New 2013 incidence peak in childhood narcolepsy: more than vaccination?

Sleep 2021 Feb;44(2)

Center for Sleep Medicine, Sleep Research and Epileptology, Clinic Barmelweid AG, Barmelweid, Switzerland.

Increased incidence rates of narcolepsy type-1 (NT1) have been reported worldwide after the 2009-2010 H1N1 influenza pandemic (pH1N1). While some European countries found an association between the NT1 incidence increase and the H1N1 vaccination Pandemrix, reports from Asian countries suggested the H1N1 virus itself to be linked to the increased NT1 incidence. Using robust data-driven modeling approaches, that is, locally estimated scatterplot smoothing methods, we analyzed the number of de novo NT1 cases (n = 508) in the last two decades using the European Narcolepsy Network database. We confirmed the peak of NT1 incidence in 2010, that is, 2.54-fold (95% confidence interval [CI]: [2.11, 3.19]) increase in NT1 onset following 2009-2010 pH1N1. This peak in 2010 was found in both childhood NT1 (2.75-fold increase, 95% CI: [1.95, 4.69]) and adulthood NT1 (2.43-fold increase, 95% CI: [2.05, 2.97]). In addition, we identified a new peak in 2013 that is age-specific for children/adolescents (i.e. 2.09-fold increase, 95% CI: [1.52, 3.32]). Most of these children/adolescents were HLA DQB1*06:02 positive and showed a subacute disease onset consistent with an immune-mediated type of narcolepsy. The new 2013 incidence peak is likely not related to Pandemrix as it was not used after 2010. Our results suggest that the increased NT1 incidence after 2009-2010 pH1N1 is not unique and our study provides an opportunity to develop new hypotheses, for example, considering other (influenza) viruses or epidemiological events to further investigate the pathophysiology of immune-mediated narcolepsy.
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http://dx.doi.org/10.1093/sleep/zsaa172DOI Listing
February 2021

Instrumental analysis of finger tapping reveals a novel early biomarker of parkinsonism in idiopathic rapid eye movement sleep behaviour disorder.

Sleep Med 2020 11 18;75:45-49. Epub 2020 Jul 18.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Czech Republic.

Background: Idiopathic rapid eye movement sleep behaviour (iRBD) is considered as a risk factor for Parkinson's disease (PD) development. Evaluation of repetitive movements with finger tapping, which serves as a principal task to measure the extent of bradykinesia in PD, may undercover potential PD patients. The aim of this study was to explore whether finger tapping abnormalities, evaluated with a 3D motion capture system, are already present in RBD patients.

Methods: Finger tapping data was acquired using a contactless 3D motion capture system from 40 RBD subjects and compared to 25 de-novo PD patients and 25 healthy controls. Objective assessment of amplitude decrement, maximum opening velocity and their combination representing finger tapping decrement was performed in the sequence of the first ten tapping movements. The association between instrumental finger tapping data and semi-quantitative clinical evaluation was analyzed.

Results: While significant differences between PD and controls were found for all investigated finger tapping measures (p < 0.002), RBD differed from controls in finger tapping amplitude (p = 0.004) and velocity (p = 0.007) decrement but not in maximal opening velocity. A significant relationship between the motor score from the Movement Disorders Society - Unified Parkinson's Disease Rating Scale and finger tapping decrement was shown for both patient groups, ie RBD (r = 0.36, p = 0.02) and PD (r = 0.60, p = 0.002).

Conclusions: In our group of RBD patients we demonstrated amplitude decrement of repetitive movements, which may correspond with prodromal bradykinesia. Our findings suggest instrumental analysis of finger tapping abnormalities as a potential novel clinical marker reflecting subclinical motor disturbances in RBD.
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http://dx.doi.org/10.1016/j.sleep.2020.07.019DOI Listing
November 2020

variants in REM sleep behavior disorder: A multicenter study.

Neurology 2020 08 26;95(8):e1008-e1016. Epub 2020 Jun 26.

From the Department of Human Genetics (L.K., U.R., G.A.R., Z.G.-O.), Montreal Neurological Institute (L.K., J.A.R., U.R., E.L., F.A., R.B.P., G.A.R., Z.G.-O.), and Department of Neurology and Neurosurgery (J.A.R., F.A., R.B.P., G.A.R., Z.G.-O.), McGill University, Montréal; Oxford Parkinson's Disease Centre (M.T.M.H.) and Nuffield Department of Clinical Neurosciences (M.T.M.H.), University of Oxford, UK; Sleep Disorders Unit (I.A.), Pitié Salpêtrière Hospital, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière and Sorbonne Universities, Paris; National Reference Center for Narcolepsy, Sleep Unit (Y.D.), Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, France; Sleep Disorders Unit, Department of Neurology (B.H., A.S.), Medical University of Innsbruck, Austria; Department of Clinical Neurophysiology and Sleep Center (C.C.M.), University Lille North of France, CHU Lille; Sleep Disorder Unit (B.A.), Carémeau Hospital, University Hospital of Nîmes, France; Department of Biomedical and Neuromotor Sciences (DIBINEM) (G.P., E.A.), Alma Mater Studiorum, University of Bologna; IRCCS (G.P., E.A.), Istituto delle Scienze Neurologiche, Bologna; Department of Neurological Sciences (L.F.-S.), Università Vita-Salute San Raffaele, Milan, Italy; Department of Neurology with Institute of Translational Neurology (A.H.), University of Muenster, Germany; Department of Neurology (B.F.B.), Mayo Clinic, Rochester, MN; UC Gardner Neuroscience Institute and Gardner Family Center for Parkinson's Disease and Movement Disorders (A.J.E.), Cincinnati, OH; Sleep and Neurology Unit (V.C.D.C.), Beau Soleil Clinic, Montpellier; EuroMov (V.C.D.C.), University of Montpellier, France; Paracelsus-Elena-Klinik (B.M., F.S.-D., C.T.), Kassel; Department of Neurology (B.M., C.T.), University Medical Centre Goettingen; Department of Neurology (F.S.-D., W.O.), Philipps University, Marburg, Germany; Department of Neurology and Centre of Clinical Neuroscience (K.S., D.K.), Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic; Department of Medical Sciences and Public Health, Sleep Disorder Research Center (M.F., M.P.), University of Cagliari, Italy; Laboratory for Sleep Disorders (F.D., M.V.) and Department of Neurology (F.D., M.V.), St. Dimpna Regional Hospital, Geel, Belgium; Department of Medicine (DAME) (M.T., M.V.), University of Udine, Italy; Department of Clinical and Movement Neurosciences (M.T.), UCL Queen Square Institute of Neurology, London, UK; Clinical Neurology Unit (G.L.G., M.V.), Department of Neurosciences, University Hospital of Udine; DMIF (G.L.G.), University of Udine, Italy; Centre d'Études Avancées en Médecine du Sommeil (J.-F.G., A.D., J.Y.M., R.B.P.), Hôpital du Sacré-Cœur de Montréal; and Departments of Psychology (J.-F.G.), Neurosciences (A.D.), and Psychiatry (J.Y.M.), Université du Québec à Montréal, Canada.

Objective: To study the role of variants in the risk for isolated REM sleep behavior disorder (iRBD) and conversion to overt neurodegeneration.

Methods: A total of 4,147 individuals were included: 1,061 patients with iRBD and 3,086 controls. was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of variants on the risk of iRBD, age at onset (AAO), and conversion rates.

Results: variants were found in 9.5% of patients with iRBD compared to 4.1% of controls (odds ratio, 2.45; 95% confidence interval [CI], 1.87-3.22; = 1 × 10). The estimated OR for mild p.N370S variant carriers was 3.69 (95% CI, 1.90-7.14; = 3.5 × 10), while for severe variant carriers it was 17.55 (95% CI, 2.11-145.9; = 0.0015). Carriers of severe variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or noncarriers ( = 0.029). Of the variant carriers with available data, 52.5% had converted, compared to 35.6% of noncarriers ( = 0.011), with a trend for faster conversion among severe variant carriers. However, the results on AAO and conversion were based on small numbers and should be interpreted with caution.

Conclusions: variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of variants should be studied as a potential way to identify variant carriers who will develop a synucleinopathy in the future.
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http://dx.doi.org/10.1212/WNL.0000000000010042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668554PMC
August 2020

Subjective and polysomnographic evaluation of sleep in mitochondrial optic neuropathies.

J Sleep Res 2020 Jun 10:e13051. Epub 2020 Jun 10.

Department of Pediatrics and Adolescent Medicine, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.

Leber hereditary optic neuropathy and Dominant optic atrophy are associated with a selective loss of retinal ganglion cells (RGC). A subtype of RGC is responsible for light-dependent physiological processes. The aim of our study was to evaluate both subjective and objective sleep parameters in 36 (18 males; mean age 33.8 ± 16.7) symptomatic/asymptomatic subjects with Leber hereditary optic neuropathy and dominant optic atrophy. The Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS) and nocturnal polysomnography were used to assess sleep disturbances and sleep quality. The questionnaires indicated significantly worse sleep quality (PSQI > 5; average 7.7 ± 3.8) in 21 (70%) and excessive daytime sleepiness (ESS > 10; average 6.3 ± 5.8) in six (20%) individuals. Nocturnal polysomnography has not revealed any significant changes of sleep structure. Rapid eye movement (REM) sleep without atonia was observed in two patients with Leber hereditary optic neuropathy. Obstructive sleep apnea was noted in eight cases. No correlation between subjective and polysomnographic data and no differences between symptomatic and asymptomatic groups were observed. None of the subjects fulfilled criteria for a circadian sleep disorder. In both symptomatic and asymptomatic individuals, a subjective decrease of the quality of sleep and wakefulness was noted without any correlation on polysomnography.
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http://dx.doi.org/10.1111/jsr.13051DOI Listing
June 2020

MRI-guided voxel-based automatic semi-quantification of dopamine transporter imaging.

Phys Med 2020 May 27;75:1-10. Epub 2020 May 27.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Katerinska 32, 120 00 Prague, Czech Republic.

Purpose: Functional imaging with I-FP-CIT SPECT suffers from poor spatial resolution resulting in partial-volume effect, which affects the subsequent semi-quantification. Definition of regions of interest for semi-quantification is further subject to user's experience and inter-observer variability. The aim of this work has been to develop an automatic method for definition of volumes of interest and partial-volume correction using patient-specific MRI and providing complete contrast recovery in striatal region.

Method: The method consists of spatial pre-processing (image segmentation and multi-modality registration), partial-volume correction (performed by region-based voxel-wise technique), and calculation of uptake indices in striatal structures. Anthropomorphic striatal phantom was used to optimize the method and to assess linearity, accuracy, and reproducibility. The method was tested on 58 patient datasets and compared with clinical assessment and BasGan software.

Results: The method works automatically. The output is highly linear regarding changing striatal uptake. Complete contrast recovery is achieved using 6.5 mm FWHM. Accuracy is better than 0.15 in terms of RMSE between measured and true uptake indices. Reproducibility is better than 5% for normal uptake ratio. The method outperformed clinical assessment in all measures. With patient data, it provided results closer to BasGan (RMSE 0.9) than to clinical assessment (RMSE 1.9) and fairly correlated with both.

Conclusion: The proposed method provides complete recovery of striatal contrast under given acquisition and reconstruction conditions. It reduces intra- and inter-observer variability, accurately defines volumes of interest, and effectively suppresses partial-volume effect. It can be reproduced using publicly available software.
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http://dx.doi.org/10.1016/j.ejmp.2020.05.010DOI Listing
May 2020

SMPD1 variants do not have a major role in rapid eye movement sleep behavior disorder.

Neurobiol Aging 2020 09 18;93:142.e5-142.e7. Epub 2020 Apr 18.

Department of Human Genetics, McGill University, Montréal, Quebec, Canada; Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.005DOI Listing
September 2020

Diagnosis of central disorders of hypersomnolence: A reappraisal by European experts.

Sleep Med Rev 2020 08 23;52:101306. Epub 2020 Mar 23.

Sleep-Wake Disorders Center, National Reference Network for Narcolepsy, Department of Neurology, Gui-de-Chauliac Hospital, INSERM, U1061, University of Montpellier, CHU Montpellier, France. Electronic address:

The aim of this European initiative is to facilitate a structured discussion to improve the next edition of the International Classification of Sleep Disorders (ICSD), particularly the chapter on central disorders of hypersomnolence. The ultimate goal for a sleep disorders classification is to be based on the underlying neurobiological causes of the disorders with clear implication for treatment or, ideally, prevention and or healing. The current ICSD classification, published in 2014, inevitably has important shortcomings, largely reflecting the lack of knowledge about the precise neurobiological mechanisms underlying the majority of sleep disorders we currently delineate. Despite a clear rationale for the present structure, there remain important limitations that make it difficult to apply in routine clinical practice. Moreover, there are indications that the current structure may even prevent us from gaining relevant new knowledge to better understand certain sleep disorders and their neurobiological causes. We suggest the creation of a new consistent, complaint driven, hierarchical classification for central disorders of hypersomnolence; containing levels of certainty, and giving diagnostic tests, particularly the MSLT, a weighting based on its specificity and sensitivity in the diagnostic context. We propose and define three diagnostic categories (with levels of certainty): 1/"Narcolepsy" 2/"Idiopathic hypersomnia", 3/"Idiopathic excessive sleepiness" (with subtypes).
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http://dx.doi.org/10.1016/j.smrv.2020.101306DOI Listing
August 2020

Sleep and its disturbances in neurology.

Authors:
Karel Šonka

Cas Lek Cesk 2019 ;158(7-8):318-320

Sleep disturbances are important symptoms of neurological diseases and some so-called primary sleep disorders have a neurological nature. The development of medicine, the availability of sleep investigations and progress in the treatment of sleep disorders have caused that the care of neurological illness includes sleep-related problems. In addition, sleep disorders can be risk factors for neurological diseases (for example obstructive sleep apnea for stroke) or their prodromal stage (REM sleep behavior disorder is one of the first symptoms of synucleinopathies). The article gives a very brief overview of sleep disorders in relation to neurological diseases and vice versa.
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February 2020

Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.

Ann Neurol 2020 04 12;87(4):584-598. Epub 2020 Feb 12.

Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

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.
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http://dx.doi.org/10.1002/ana.25687DOI Listing
April 2020

Relations of non-motor symptoms and dopamine transporter binding in REM sleep behavior disorder.

Sci Rep 2019 10 29;9(1):15463. Epub 2019 Oct 29.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

The aim of this study was to evaluate associations of motor and non-motor symptoms with dopamine transporter binding in prodromal stage of synucleinopathies. We examined 74 patients with idiopathic REM sleep behavior disorder (RBD), which is a prodromal synucleinopathy, and 39 controls using Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment, University of Pennsylvania Smell Identification Test (UPSIT), Farnsworth-Munsell 100 hue test, orthostatic test, Scales for Outcomes in PD-Autonomic, Beck depression inventory-II, State-Trait Anxiety Inventory, and video-polysomnography. Electromyographic muscle activity during REM sleep was quantified according to Sleep Innsbruck-Barcelona criteria. In 65 patients, dopamine transporter single-photon emission computed tomography (DAT-SPECT) imaging was performed, putaminal binding ratio was calculated and scans were classified as normal, borderline, or abnormal. Compared to controls, RBD patients had significantly more severe scores in all examined tests. Patients with abnormal DAT-SPECT had higher MDS-UPDRS motor score (p = 0.006) and higher prevalence of orthostatic hypotension (p = 0.008). Putaminal binding ratio was positively associated with UPSIT score (p = 0.03) and negatively associated with tonic (p = 0.003) and phasic (p = 0.01) muscle activity during REM sleep. These associations likely reflect simultaneous advancement of underlying pathology in substantia nigra and susceptible brainstem and olfactory nuclei in prodromal synucleinopathy.
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http://dx.doi.org/10.1038/s41598-019-51710-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820530PMC
October 2019

Simultaneous tonic and phasic REM sleep without atonia best predicts early phenoconversion to neurodegenerative disease in idiopathic REM sleep behavior disorder.

Sleep 2019 09;42(9)

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

Study Objectives: Rapid eye movement (REM) sleep without atonia (RWA) is the main polysomnographic feature of idiopathic REM sleep behavior disorder (iRBD) and is considered to be a promising biomarker predicting conversion to manifested synucleinopathy. Besides conventionally evaluated tonic, phasic and any RWA, we took into consideration also periods, when phasic and tonic RWA appeared simultaneously and we called this activity "mixed RWA." The study aimed to evaluate different types of RWA, to reveal the most relevant biomarker to the conversion.

Methods: A total of 55 patients with confirmed iRBD were recruited with mean follow-up duration 2.3 ± 0.7 years. Scoring of RWA was based on Sleep Innsbruck Barcelona rules. Positive phenocoversion was ascertained according to standard diagnostic criteria during follow-up. Receiver operator characteristic analysis was applied to evaluate predictive performance of different RWA types.

Results: A total of nine patients (16%) developed neurodegenerative diseases. Yearly phenoconversion rate was 5.5%. Significantly higher amounts of mixed (p = 0.009), tonic (p = 0.020), and any RWA (p = 0.049) were found in converters. Optimal cutoffs differentiating the prediction were 16.4% (sensitivity 88.9; specificity 69.6) for tonic, 4.4% (sensitivity 88.9; specificity 60.9) for mixed, and 36.8% (sensitivity 77.8; specificity 65.2) for any RWA. With area under the curve (AUC) 0.778, mixed RWA has proven to be the best predictive test followed by tonic (AUC 0.749) and any (AUC 0.710).

Conclusions: Mixed, tonic and any RWA may serve as biomarkers predicting the conversion into neurodegenerative disease in iRBD. The best predictive value lies within mixed RWA, thus it should be considered as standard biomarker.
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http://dx.doi.org/10.1093/sleep/zsz132DOI Listing
September 2019

Validation of the REM sleep behavior disorder screening questionnaire in the Czech population.

BMC Neurol 2019 Jun 4;19(1):110. Epub 2019 Jun 4.

Department of Neurology and Center of Clinical Neurosciences, 1stFaculty of Medicine, Charles University, Kateřinská 30, 12000, Praha 2, Czech Republic.

Background: Idiopathic rapid eye movement sleep behavior disorder (iRBD) affects 1-2% of people over 60 years of age and presents a high risk of developing a neurodegenerative disorder from the group of synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Therefore, screening tools are needed. In 2007, the rapid eye movement sleep behavior disorder screening questionnaire (RBD-SQ) was developed and has been translated into several languages. The aim of study was to assess the validity and reliability of the Czech version of the RBD-SQ in a mixed population of sleep clinic patients, supplemented by healthy volunteers and RBD patients.

Methods: Participants included 81 iRBD patients, 205 patients with other sleep disorders (obstructive sleep apnea, insomnia, restless legs syndrome and periodic limb movement disorder, other parasomnias, or central hypersomnias including narcolepsy) and 20 healthy volunteers.

Results: The mean RBD-SQ score in the iRBD patients was 9.4 ± 2.8 points, and in the non-RBD group it was 4.5 ± 3.0 (P < 0.0001). Receiver -operator analysis yielded an area under the curve of 0.864, suggesting good diagnostic performance of the scale. When using a cut-off value for positivity of 5 points, sensitivity was 0.89 and specificity was 0.62.

Conclusions: The Czech version of the RBD-SQ is a sensitive tool for screening for iRBD patients and helps to identify subjects for complete clinical workup.
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http://dx.doi.org/10.1186/s12883-019-1340-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549323PMC
June 2019

Prospective memory impairment in idiopathic REM sleep behavior disorder.

Sleep Med 2019 07 8;59:54. Epub 2018 Dec 8.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic.

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http://dx.doi.org/10.1016/j.sleep.2018.11.015DOI Listing
July 2019

Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study.

Brain 2019 03;142(3):744-759

Department of Neurology, McGill University, Montreal General Hospital, Montreal, Canada.

Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.
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http://dx.doi.org/10.1093/brain/awz030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391615PMC
March 2019

Fragmentary myoclonus in idiopathic rapid eye movement sleep behaviour disorder.

J Sleep Res 2019 08 24;28(4):e12819. Epub 2019 Jan 24.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.

Fragmentary myoclonus is a result of muscle activity consisting of brief potentials in surface electromyography during polysomnography. Excessive fragmentary myoclonus is defined by increased intensity of the potentials. A few studies report excessive fragmentary myoclonus occurrence in neurodegenerative diseases. Because idiopathic rapid eye movement sleep behaviour disorder is considered as an early stage of neurodegeneration with involvement of the brainstem, we charted the prevalence and quantified the intensity of excessive fragmentary myoclonus in idiopathic rapid eye movement sleep behaviour disorder. Twenty-nine patients (one woman, 28 men, mean age 68 years, SD 6.2) and 29 controls (two women, 27 men, mean age 65.6 years, SD 8.6) underwent polysomnography. Fragmentary myoclonus potentials were identified and counted according to internationally used criteria. Fragmentary myoclonus intensity was quantified by the fragmentary myoclonus index. Excessive fragmentary myoclonus was diagnosed in 75.9% (22 subjects) in idiopathic rapid eye movement sleep behaviour disorder, while in 34.5% (10 subjects) among the controls (p = 0.003). Quantitative analysis showed a wide-range fragmentary myoclonus index in idiopathic rapid eye movement sleep behaviour disorder (4.0-632.4; median 60.7) and in the controls (0.8-938.1; median 34.3). The overall difference in fragmentary myoclonus index was not significant between the groups; however, patients with idiopathic rapid eye movement sleep behaviour disorder showed trends for higher fragmentary myoclonus index scores in wakefulness (p = 0.027), N1 (p = 0.032), N3 (p = 0.046) and R (p = 0.007). Fragmentary myoclonus index does not correlate with age, idiopathic rapid eye movement sleep behaviour disorder duration or R stage atonia deficiency. The prevalence of excessive fragmentary myoclonus is higher in idiopathic rapid eye movement sleep behaviour disorder compared with the controls, so fragmentary myoclonus should be taken into account in future research of rapid eye movement sleep behaviour disorder and motor control in sleep.
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http://dx.doi.org/10.1111/jsr.12819DOI Listing
August 2019

Prevalence of restless legs syndrome in functional movement disorders: a case-control study from the Czech Republic.

BMJ Open 2019 01 21;9(1):e024236. Epub 2019 Jan 21.

Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.

Objectives: The prevalence of restless legs syndrome (RLS) in functional movement disorders (FMD) is not known. Patients with FMD often present with multiple motor and sensory symptoms. Some of these symptoms might be due to comorbid RLS. Therefore, our objective was to evaluate possible association between FMD and RLS.

Design: Case-control study.

Setting: Movement Disorders Center, 1st Faculty of Medicine and General University Hospital in Prague, Czech Republic.

Participants: 96 consecutive patients with clinically established FMD (80 females, mean age (SD) 45.0 (13) years), and 76 matched controls.

Primary And Secondary Outcome Measures: The primary outcome measure was prevalence of RLS based on updated International RLS Study Group criteria. Secondary outcome measures included prevalence of periodic limb movements (PLM) using actigraphy; pain, motor and sensory symptoms in lower limbs; organic comorbidities and medication affecting RLS.

Results: RLS criteria were fulfilled in 43.8% of patients (95% CI 34 to 54) and in 7.9% of controls (95% CI 3 to 17, p<0.00001). Both RLS and PLM indices (PLMi) ≥22.5/hour were found in 21.2% of patients with FMD and 2.6% of controls. Patients with FMD with RLS had a higher mean PLMi (p<0.001) and a higher proportion of PLMi ≥22.5/hour (p<0.01) than RLS-negative patients. Patients with RLS had higher prevalence of pain and sensory symptoms in lower limbs, no difference was found in medication and prevalence of organic comorbidities in patients with FMD with and without RLS.

Conclusions: We found an increased prevalence of RLS in patients with FMD. Clinical diagnosis of RLS was supported by actigraphic measurement of clinically relevant PLM in a significant proportion of patients with FMD. Although functional motor and sensory symptoms may mimic RLS, RLS may be unrecognised in patients with FMD. This finding may have clinical implications in management of FMD, and it raises the possibility of common pathophysiological mechanisms of FMD and RLS/PLM.
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http://dx.doi.org/10.1136/bmjopen-2018-024236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347872PMC
January 2019

Anterior hippocampus volume loss in narcolepsy with cataplexy.

J Sleep Res 2019 08 13;28(4):e12785. Epub 2018 Nov 13.

Department of Anatomy, Charles University, First Faculty of Medicine, Prague, Czech Republic.

Narcolepsy with cataplexy is a lifelong disease resulting from the loss of hypocretin neurons in the hypothalamus; structural changes are not, however, limited only to the hypothalamus. We previously revealed an overall hippocampal volume loss in narcolepsy with cataplexy. The aim of this study is to describe the volume reduction of the anterior and posterior parts of the hippocampus in patients with narcolepsy with cataplexy in comparison with a control group. The anterior hippocampus is more involved in episodic memory and imagination, and the posterior hippocampus in spatial memory. Manual magnetic resonance imaging hippocampal volumetry was performed in 48 patients with narcolepsy with cataplexy and in 37 controls using the manual delineation technique in the ScanView program. All participants were examined on the same 1.5 T MR scanner; measurement was carried out as T1W 3D image with a slice thickness of 1.0/0 mm. There was a significant absolute loss of the total volume of the anterior hippocampus (sum of left and right) in patients with narcolepsy with cataplexy as compared with the controls (10.5%, p = .03 ANCOVA after correcting for total brain volume and multiple testing). We found a negative correlation between the total anterior hippocampus volume and the duration of the disease (R = -0.4036, p = .016-corrected for multiple testing).
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http://dx.doi.org/10.1111/jsr.12785DOI Listing
August 2019

Olfaction and Colour Vision: What Can They Tell Us about Parkinson's Disease?

Prague Med Rep 2018;119(2-3):85-96

Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

Parkinson's disease is a neurodegenerative disorder with the pathological accumulation of alpha synuclein in the brain and peripheral nerve tissue. Early stages of synucleinopathies, often present clinically with rapid eye movement (REM) sleep disorder (RBD). Clinical markers that indicate early progression from RBD to manifest synucleinopathies include abnormal dopamine transporter (DAT) imaging, motor and non-motor symptoms. Despite the high diagnostic strength of DAT imaging and motor abnormalities, they are not the earliest biomarkers. Non-motor signs of neurodegeneration such as colour vision and olfaction abnormalities are detectable by clinical examination as early as 20 years before disease onset. Detailed analysis of olfactory and colour vision dysfunction can provide valuable information regarding brain pathologies, further specifying clinical phenotypes, and giving clues to underlying pathophysiological mechanisms in Parkinson's disease and related disorders.
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http://dx.doi.org/10.14712/23362936.2018.8DOI Listing
April 2019

Circadian rhythms of melatonin and peripheral clock gene expression in idiopathic REM sleep behavior disorder.

Sleep Med 2018 12 9;52:1-6. Epub 2018 Aug 9.

National Institute of Mental Health, Klecany, Czech Republic; Third Faculty of Medicine, Charles University, Prague, Czech Republic. Electronic address:

Objective: To evaluate changes in the expression of clock genes and melatonin levels in patients with idiopathic REM sleep behavior disorder (RBD) as a potential early stage of synucleinopathies.

Methods: We assessed the rhythmicity of circadian clock genes using real time-quantitative polymerase chain reaction and 24-h blood melatonin profiles using radio-immunoassay in 10 RBD patients and nine age-matched controls.

Results: The RBD patients did not show circadian rhythmicity for clock genes Per2, Bmal1, and Nr1d1 but the rhythmicity of Per 1 remained, and the amplitude of Per3 was diminished. The 24-h melatonin rhythm did not differ between RBD patients and healthy control subjects. Melatonin profile in RBD patients was delayed by 2 h compared to controls, the habitual sleep phases were phase delayed by about 1 h, however no phase shift occurred in any of the clock genes studied. The control group had stable acrophases of melatonin rhythms of approximately 5 h whereas the RBD patients had a more dispersed range over 11 h.

Conclusions: Our results suggest that RBD could be associated with altered expression of clock genes and delayed melatonin secretion. Thus, we argue that circadian system dysregulation could play a role in RBD.
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http://dx.doi.org/10.1016/j.sleep.2018.07.019DOI Listing
December 2018

Eye movements in idiopathic rapid eye movement sleep behaviour disorder: High antisaccade error rate reflects prefrontal cortex dysfunction.

J Sleep Res 2019 10 25;28(5):e12742. Epub 2018 Jul 25.

Department of Neurology and Centre of Clinical Neuroscience, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.

Abnormalities of eye movements have been reported in patients with Parkinson's disease (PD). However, it is unclear if they occur in the prodromal stage of synucleinopathy represented by idiopathic rapid eye movement sleep behaviour disorder (iRBD). We thus aimed to study eye movements in subjects with iRBD and in de novo PD, to assess if their abnormalities may serve as a clinical biomarker of neurodegeneration. Fifty subjects with polysomnography-confirmed iRBD (46 male, age 40-79 years), 18 newly diagnosed, untreated PD patients (13 male, age 43-75 years) and 25 healthy controls (20 male, age 42-79 years) were prospectively enrolled. Horizontal and vertical ocular prosaccades and antisaccades were investigated with video-oculography. All patients completed the MDS-UPDRS and the Montreal Cognitive Assessment. In addition, a neuropsychological battery was performed on iRBD subjects. When compared with healthy controls, both de novo PD patients and iRBD subjects showed increased error rates in the horizontal antisaccade task (p < 0.01, p < 0.05 respectively). In the iRBD group, the error rates in horizontal and vertical antisaccades correlated with performances in the Prague Stroop Test and the Grooved Pegboard Test, as well as with motor scores of the MDS-UPDRS. De novo PD patients showed a lower gain (p < 0.01) compared with controls. In conclusion, the increased error rate in the antisaccade task of iRBD and PD patients reflects a dysfunction of the dorsolateral prefrontal cortex and is related to the impairment of executive functions and attention.
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http://dx.doi.org/10.1111/jsr.12742DOI Listing
October 2019

Exploring the clinical features of narcolepsy type 1 versus narcolepsy type 2 from European Narcolepsy Network database with machine learning.

Sci Rep 2018 Jul 13;8(1):10628. Epub 2018 Jul 13.

Center for Sleep Medicine, Sleep Research and Epileptology, Klinik Barmelweid AG, Barmelweid, Switzerland.

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 rapid-eye-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.
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http://dx.doi.org/10.1038/s41598-018-28840-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045630PMC
July 2018

Smartphone Allows Capture of Speech Abnormalities Associated With High Risk of Developing Parkinson's Disease.

IEEE Trans Neural Syst Rehabil Eng 2018 08 29;26(8):1495-1507. Epub 2018 Jun 29.

Although smartphone technology provides new opportunities for the recording of speech samples in everyday life, its ability to capture prodromal speech impairment in persons with a high risk of developing Parkinson's disease (PD) has never been investigated. Speech data were acquired through a smartphone as well as a professional microphone with a linear frequency response from 50 participants with a rapid eye movement sleep behavior disorder that are at a high risk of developing PD and related neurodegenerative disorders. Additionally, recordings of 30 newly diagnosed, untreated PD patients and 30 healthy participants were evaluated. Acoustic assessment of 11 speech dimensions representing the key aspects of hypokinetic dysarthria in the early stages of PD was performed. Smartphone allowed the detection of speech abnormalities in participants with a high risk of developing PD. Acoustic measurements related to fundamental frequency variability, duration of pause intervals, and rate of speech timing extracted from spontaneous speech were sufficiently sensitive to significantly separate groups (area under curve of 0.85 between PD and controls) and showed very strong correlation and reliability between the professional microphone and the smartphone. Speech-based biomarkers collected through smartphones may have the potential to revolutionize the diagnostic process in neurodegenerative diseases and improve stratification for future neuroprotective therapy in PD.
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http://dx.doi.org/10.1109/TNSRE.2018.2851787DOI Listing
August 2018

Modafinil Reduces Parasympathetic Activity but Does Not Influence Autonomic Reactivity to Orthostatic Load in Narcolepsy Type 1.

Clin Neuropharmacol 2018 Jul/Aug;41(4):111-115

National Institute of Mental Health, Klecany.

Introduction: Modafinil may affect autonomic functions in healthy subjects. The aim of the study was to assess the long-term modafinil administration influence on the cardiac autonomic reactivity to orthostatic load in patients with narcolepsy type 1.

Methods: In 15 patients (4 male; 11 female; median age, 47 years; range, 18-70 years) with narcolepsy type 1 treated with modafinil in daily dose of 100 to 300 mg, the short-term spectral analysis of heart rate variability (HRV) in supine-standing-supine test was performed before and after 72 hours of modafinil discontinuation.

Results: The sympathovagal reactivity to orthostatic load was not modified by modafinil treatment; nevertheless, the parasympathetic activity expressed by length of R-R interval and high-frequency component of HRV is reduced in supine position in patients taking modafinil.

Conclusions: We conclude that long-term use of modafinil does not influence the cardiac autonomic reactivity to orthostatic load expressed by the HRV changes in supine-standing-supine test in narcolepsy type 1 patients, but the parasympathetic cardiac activity may be reduced in quiet supine position in patients with narcolepsy taking modafinil.
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http://dx.doi.org/10.1097/WNF.0000000000000287DOI Listing
October 2018

Accuracy of Rating Scales and Clinical Measures for Screening of Rapid Eye Movement Sleep Behavior Disorder and for Predicting Conversion to Parkinson's Disease and Other Synucleinopathies.

Front Neurol 2018 25;9:376. Epub 2018 May 25.

Department of Neurology, Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia.

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by repeated episodes of REM sleep-related vocalizations and/or complex motor behaviors. Definite diagnosis of RBD is based on history and polysomnography, both of which are less accessible due to the lack of trained specialists and high cost. While RBD may be associated with disorders like narcolepsy, focal brain lesions, and encephalitis, idiopathic RBD (iRBD) may convert to Parkinson's disease (PD) and other synucleinopathies in more than 80% of patients and it is to date the most specific clinical prodromal marker of PD. Identification of individuals at high risk for development of PD is becoming one of the most important topics for current PD-related research as well as for future treatment trials targeting prodromal PD. Furthermore, concomitant clinical symptoms, such as subtle motor impairment, hyposmia, autonomic dysfunction, or cognitive difficulties, in subjects with iRBD may herald its phenoconversion to clinically manifest parkinsonism. The assessment of these motor and non-motor symptoms in iRBD may increase the sensitivity and specificity in identifying prodromal PD subjects. This review evaluates the diagnostic accuracy of individual rating scales and validated single items for screening of RBD and the role and accuracy of available clinical, electrophysiological, imaging, and tissue biomarkers in predicting the phenoconversion from iRBD to clinically manifest synucleinopathies.
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http://dx.doi.org/10.3389/fneur.2018.00376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980959PMC
May 2018