Peter Geisler

Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15–25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 × 10−8). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 × 10−43) and DRB1*1301-DQB1*0603 (P < 3 × 10−7). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 × 10−14). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.

ImmunoChip Study Implicates Antigen Presentation to T Cells in Narcolepsy

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

Tinnitus and insomnia.

Sleep problems are common in individuals with tinnitus but it is not known if they can be seen as a reaction to the acoustic percept of tinnitus disturbing normal sleep, or if there are common causes. Sleep problems further impair the quality of life of individuals with tinnitus and the impairment correlates with the severity of the tinnitus. However the nature of the relationship between tinnitus and disturbed sleep in individuals with tinnitus is not clearly understood. Preliminary studies suggest that chronically disturbed sleep (insomnia) in individuals with tinnitus that is not caused by organic disorders exists unrelated to the tinnitus. We studied the relationship between tinnitus and insomnia in a retrospective sleep study of 13 hospitalized patients with insomnia and tinnitus. Patients with sleep apnea, periodic leg movements, or a severe psychiatric disorder were excluded. We collected physiologic sleep measures (EEG, EOG, EMG, and respiration) and subjective sleep information from a morning protocol during two nights. We also obtained information about performance in sustained attention tasks and the scores of self-rated depression scale and self-rated daytime-tiredness scale. Thirteen age- and sex-matched inpatients with primary insomnia who did not have tinnitus served as controls. There were no significant differences between the physiologic data obtained in patients with tinnitus and in the controls. Both groups had low sleep efficiency but the patients with both insomnia and tinnitus had longer subjective sleep latencies than insomnia patients without tinnitus (controls). No differences were found in sustained attention tasks, subjective daytime tiredness, and depression rating scores between the two groups. Similarities between the results from these two groups suggest that sleep specific psychotherapeutic methods, which are established for treating insomnia, should be further developed for the use in patients with insomnia and tinnitus.

Bilateral thalamic gray matter changes in patients with restless legs syndrome.

Restless legs syndrome (RLS) is a common neurological disorder of a primary unpleasant sensation with an urge to move the legs occurring at rest. The etiology of idiopathic RLS is unknown and structural cerebral abnormalities have so far not been detected. We studied 51 right-handed patients with an idiopathic restless legs syndrome in two independent samples (Regensburg RLS-group: n = 28, Munich RLS-group: n = 23) and compared them to 51 sex- and age-matched healthy volunteers. High-resolution T1-weighted magnetic resonance imaging (MRI) of each subject was obtained and analyzed using voxel-based morphometry (VBM) to detect regionally specific differences in gray matter between patients and controls. Conjunction analysis was used to combine results from both centers. In patients with idiopathic RLS, both study centers observed independently a bilateral gray matter increase in the pulvinar. In the conjunction analysis including all patients and controls from both study centers, a significant gray matter increase in the pulvinar bilaterally (right: x = 16, y = -21, z = 12, Z = 4.57; left: x = -16, y = -24, z = 12, Z = 4.10) was present. This is the first demonstration of structural changes in the brain of patients with idiopathic RLS. These changes in thalamic structures are either involved in the pathogenesis of RLS or may reflect a consequence of chronic increase in afferent input of behaviorally relevant information.

Hypothalamic gray matter changes in narcoleptic patients

globally activate the stress response (data not shown), although the Lewy body–like inclusions immunolabel for Hsp70 (ref. 5). As 3 μg/ml prevents dopaminergic cell loss due to α-synuclein toxicity, it is possible that only a modest change in or redistribution of molecular chaperones is sufficient for neuroprotection. Current anti-PD agents, including levodopa, dopamine receptor agonists (such as bromocriptine), and monoamine oxidase B inhibitors (such as deprenyl), are designed to relieve the symptoms of PD by restoring dopamine levels in the basal ganglia. Our studies define a potential drug class that promotes the survival of dopaminergic neurons. Although we suggest that geldanamycin is acting by upregulating or otherwise modulating molecular chaperone activity, the drug may also be modulating other pathways regulated by Hsp90. Regardless, these studies have revealed a drug that can fully protect against the toxicity of α-synuclein to dopaminergic neurons in Drosophila. Geldanamycin and its derivatives warrant further exploration as cytoprotective agents for the treatment of neurodegenerative diseases involving α-synuclein toxicity, including PD.

Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study

The aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU‐NN). We have analysed retrospective data of 1099 patients with narcolepsy diagnosed according to International Classification of Sleep Disorders‐2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin‐1 levels, and genome‐wide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women: 23.74 ± 12.43 versus 21.49 ± 11.83, P = 0.003) and longer diagnostic delay in women (men versus women: 13.82 ± 13.79 versus 15.62 ± 14.94, P = 0.044). The mean diagnostic delay was 14.63 ± 14.31 years, and longer delay was associated with higher body mass index. The best predictors of short diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep‐onset rapid eye movement periods (SOREMPs), but none of the polysomnographic variables was associated with subjective or objective measures of sleepiness. Variant rs2859998 in UBXN2B gene showed a strong association (P = 1.28E‐07) with the age at onset of excessive daytime sleepiness, and rs12425451 near the transcription factor TEAD4 (P = 1.97E‐07) with the age at onset of cataplexy. Altogether, our results indicate that the diagnostic delay remains extremely long, age and gender substantially affect symptoms, and that a genetic predisposition affects the age at onset of symptoms.

DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe

STUDY OBJECTIVE Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects. DESIGN Retrospective case-control study. SETTING A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication. PATIENTS AND PARTICIPANTS For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included. MEASUREMENTS AND RESULTS None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified. CONCLUSION An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.

Rhythmic feet movements while falling asleep.

During the wake–sleep transition and sleep, diverse motor phenomena such as hypnagogic foot tremor may occur in the lower extremities. We investigated the relevance of this phenomenon in 375 consecutive subjects examined polysomnographically in a sleep disorders center. Rhythmic feet movements while falling asleep (RFM) were found in 28 subjects (7.5%). RFM occurred mostly as single, short series with a duration of between 10 and 15 seconds. They had a high night‐to‐night variability and were detected as rhythmic, oscillating movements of the whole foot or toes. Surface electromyographic (EMG) recordings displayed series of repetitive phasic bursts with a periodicity mostly between 1 and 2 per second. Single EMG burst duration varied between 300 and 700 msec. RFM at highest intensity occurred during presleep wakefulness, and usually persisted in sleep stages 1 and 2. RFM did not have a major sleep‐disturbing effect in any of the affected subjects. Due to its high prevalence and the lack of a major sleep‐disturbing effect, short series of RFM could be considered a quasiphysiological phenomenon. However, in more severe forms of RFM with evidence of a sleep‐disturbing effect, RFM should be considered abnormal.

A review of sleep EEG patterns. Part I: A compilation of amended rules for their visual recognition according to Rechtschaffen and Kales

ZusammenfassungFragestellungAus polysomnographischen Labor- und Feldstudien leitete das DLR-Institut für Luft- und Raumfahrtmedizin Kriterien zum Schutz vor nächtlichen Fluglärm für den Flughafen Leipzig/Halle ab, der zu einem Frachtdrehkreuz ausgebaut werden soll. Mit den hier vorgestellten Analysen sollte untersucht werden, ob die prognostizierte dichte Flugabfolge in der Nacht bei Einhaltung der empfohlenen Kriterien zu gravierenden makrostrukturellen Änderungen des schlafes führt oder nicht.MethodikAls Datengrundlage diente eine Feldstudie, in der am Flughafen Köln/Bonn 64 Anwohner polysomnographisch untersucht wurden. Markov-Prozesse wurden für die Modellierung einer achtstündigen Bettzeit verwendet. Es wurde nur zwischen den beiden Zuständen Wach und Schlaf (S1-S4, REM) unterschieden. Übergangswahrscheinlichkeiten zwischen den beiden Zuständen wurden mit logistischen Regressionsmodellen in Abhängigkeit vom aktuellen Zustand, von der in diesem Zustand bereits verbrachten Dauer, von der verstrichenen Schlafzeit und vom Maximalpegel des Fluggeräusches bestimmt. 3 Flugbetriebsszenarien wurden simuliert: Ruhe, Fluglärm vorwiegend am Anfang der Nacht (Modell A) und Fluglärm vorwiegend am Ende der Nacht (Modell E).ErgebnisseBezogen auf eine Bettzeit von 8 Stunden war der Wachanteil im Vergleich zum Ruhemodell (81,1 min) im Modell A um 3,8 min (+4,7%) und im Modell E um 5,9 min (+7,3%) erhöht. Fluglärm am Ende der Nacht führte jedoch zu größeren Schlafstörungen als Fluglärm am Anfang der Nacht, weshalb empfohlen wird, Fluggeräusche in der zweiten Nachthälfte mit einem Malus von 1,4 dB zu belegen.SchlussfolgerungIm Zusammenhang mit Fluglärmwirkungen auf den Schlaf erlauben Markov-Prozesse die flexible Modellierung abhängiger Ereignisse und unterschiedlicher Betriebsszenarien. Bei einhaltung der vom DLR vorgeschlagenen Schutzkriterien ermitteln die vorgestellten Modelle nur geringfügige fluglärmbedingte Erhöhungen von Wachanteil und der Anzahl zusätzlicher erinnerbarer Aufwachreaktionen.SummaryQuestion of the studyOn the basis of polysomnographic laboratory and field studies, the DLR Institute of Aerospace Medicine has developed a concept to protect against adverse effects of nocturnal aircraft noise at Airport Leipzig/Halle, which will be extended to a freight hub. We investigated whether or not the expected high traffic densities during the night will relevantly interfere with sleep macrostructure, if the criteria suggested by DLR are met.MethodsModels were based on data sampled in a polysomnographic field study on 64 residents living in the vicinity of Airport Cologne/Bonn. Markov processes wer used to model a time in bed (TIB) of 8 h. Only two states were differentiated: wake and sleep, the latter consisting of S1-S4 and REM. Transition probabilities were estimated with logistic regression including current state (wake/sleep), duration of current state, elapsed sleep time, and maximum sound pressure level (SPL) of the aircraft noise event (ANE) as covariates. Three traffic scenarios were simulated: (i) no noise, (ii) aircraft noise at the beginning of the night (model A), and (iii) aircraft noise at the end of the night (model E).ResultsOn the basis of 8 hours TIB and compared to the scenario without aireraft noise (81.1 min), time spent awake increased by 3.8 min (+4.7%) in model A and by 5.9 min (+7.3%) in model E. However, aircraft noise at the end of the night caused more pronounced changes in sleep structure than aircraft noise at the beginning of the night. Therefore, we propose to levy a malus of 1.4 dB on aircraft noise events occurring in the second half of the night.ConclusionIn the context of noise effects on sleep, Markov processes allow for a flexible modelling of dependent events and variable traffic scenarios. If the criteria of the DLR protection concept are met, the models predict only minor noise-induced changes in time spent awake and in the number of awakenings recalled in the morning.

The effect of sleep deprivation on pain perception in healthy subjects: a meta-analysis

BACKGROUND There is strong evidence indicating an interaction between sleep and pain. However, the size of this effect, as well as the clinical relevance, is unclear. Therefore, this meta-analysis was conducted to quantify the effect of sleep deprivation on pain perception. METHODS A systematic literature search was conducted using the electronic databases PubMed, Cochrane, Psyndex, Psycinfo, and Scopus. By conducting a random-effect model, the pooled standardized mean differences (SMDs) of sleep deprivation on pain perception was calculated. Studies that investigated any kind of sleep deprivation in conjunction with a pain measurement were included. In cases of several pain measurements within a study, the average effect size of all measures was calculated. RESULTS Five eligible studies (N = 190) for the between-group analysis and ten studies (N = 266) for the within-group analysis were identified. Sleep deprivation showed a medium effect in the between-group analysis (SMD = 0.62; CI95: 0.12, 1.12; z = 2.43; p = 0.015) and a large effect in the within-group analysis (SMD = 1.49; CI95: 0.82, 2.17; z = 4.35; p <0.0001). The test for heterogeneity was not significant in the between-group analysis (Q = 5.29; df = 4; p = 0.2584), but it was significant in the within-group analysis (Q = 53.49; df = 9; p <0.0001). CONCLUSION This meta-analysis confirms a medium effect (SMD = 0.62) of sleep deprivation on pain perception. As this meta-analysis is based on experimental studies in healthy subjects, the clinical relevance should be clarified.