Yves Dauvilliers - Academia.edu (original) (raw)
Papers by Yves Dauvilliers
Journal of Clinical Investigation, 2010
Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscl... more Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataplexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder. Authorship note: Vesna Cvetkovic-Lopes and Laurence Bayer, as well as Michel Mühlethaler and Mehdi Tafti, contributed equally to this work.
Scientific Reports
The pathophysiology of rapid eye movement sleep behavior disorder (RBD) associated with narcoleps... more The pathophysiology of rapid eye movement sleep behavior disorder (RBD) associated with narcolepsy type 1 (NT1) is still poorly understood, potentially distinct from idiopathic RBD (iRBD), but may share affected common pathways. We investigated whether MIBG cardiac uptake differs between iRBD and NT1 comorbid with RBD. Thirty-four patients with NT1-RBD and 15 patients with iRBD underwent MIBG cardiac scintigraphy. MIBG uptake was measured by calculating the early and delayed heart to mediastinum (H/M) ratios. A delayed H/M ratio lower than 1.46 was considered abnormal based on a population of 78 subjects without neurological or cardiac diseases. Patients with iRBD were older, had an older RBD onset age and higher REM sleep phasic and tonic muscular activities than NT1-RBD. Lower delayed and early H/M ratios were associated with iRBD, but not with NT1-RBD, in crude and adjusted associations. The delayed H/M ratio differed between iRBD and controls, after adjustment, but not between patients with NT1-RBD and controls. In conclusion, the MIBG cardiac uptake difference between NT1-RBD and iRBD supports the hypothesis of different processes involved in RBD pathogenesis, providing for the first time a cardiac biomarker to differentiate those disorders. Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by repeated and often violent episodes of dream-enacting behaviors that may cause injury or sleep disruption 1,2. Preclinical and clinical evidences indicate that RBD results from the breakdown of the brainstem signaling network underlying REM sleep atonia, with an excess of muscle activity during REM sleep 3,4. RBD can be idiopathic (iRBD) or secondary. Secondary RBD can be associated with neurodegenerative disorders, especially synucleinopathies, narcolepsy, but also brainstem lesions, Guillain-Barré syndrome, intake of some drugs, and alcohol withdrawal 2. Conversely, iRBD is not associated with other neurological diseases, but often precedes the development of synucleinopathies. The presence of RBD is frequently associated with autonomic dysfunction in both idiopathic and secondary form associated with Parkinson's disease (PD). Cardiac 123 I-labeled meta-iodobenzylguanidine (MIBG, a physiological norepinephrine analogue) scintigraphy is used to assess the function of postganglionic presynaptic cardiac sympathetic nerve endings. MIBG cardiac uptake is markedly decreased in patients with iRBD in the same range as in PD and dementia with Lewy bodies, and could be used as an early biomarker of iRBD 5,6. However, it is unclear whether and to which extent MIBG cardiac accumulation is impaired in the presence of secondary RBD outside the context of neurodegenerative diseases. Narcolepsy type 1 (NT1) is a rare disease caused by the selective and irreversible loss of hypocretin neurons 7. It is characterized by excessive daytime sleepiness (EDS), cataplexy, clinical manifestations related to REM sleep dysregulation (RBD, sleep paralysis and hypnagogic hallucinations) and frequent autonomic dysfunction 7,8. RBD is observed in up to 60% of patients with NT1, and may be the first symptom even in children 9,10. Differently from
Nature Communications
Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently ... more Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently requires visual inspection of polysomnography records by trained scoring technicians. Here, we used neural networks in approximately 3,000 normal and abnormal sleep recordings to automate sleep stage scoring, producing a hypnodensity graph-a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated in 70 subjects assessed by six scorers. The best model performed better than any individual scorer (87% versus consensus). It also reliably scores sleep down to 5 s instead of 30 s scoring epochs. A T1N marker based on unusual sleep stage overlaps achieved a specificity of 96% and a sensitivity of 91%, validated in independent datasets. Addition of HLA-DQB1*06:02 typing increased specificity to 99%. Our method can reduce time spent in sleep clinics and automates T1N diagnosis. It also opens the possibility of diagnosing T1N using home sleep studies.
Annals of Neurology
Objective: To determine whether brain amyloid burden in elderly patients with narcolepsy type 1 (... more Objective: To determine whether brain amyloid burden in elderly patients with narcolepsy type 1 (NT1) is lower than in controls, and to assess in patients with NT1 the relationships between amyloid burden, cerebral spinal fluid (CSF) markers of Alzheimer's disease (AD), CSF orexin-A, and cognitive profile. Methods: Cognitive and 18 F-florbetapir-positron emission tomography (PET) data were compared in patients with NT1 aged ≥65 years (n=23) and in age-and sex-matched controls free of clinical dementia selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n=69) and the Multidomain Intervention Alzheimer's Prevention Trial (MAPT-AV45; n=23) cohorts. The standardized uptake values (SUV) of the cortical retention index for six regions of interest were computed and averaged to create a mean SUV ratio normalized to three subcortical reference regions (cerebellum, pons and a composite region). A cortical/cerebellum SUV ratio ≥1.17 defined positive PET amyloid. Results: Lower cortical amyloid burden was observed in the NT1 than in the ADNI and MAPT-AV45 groups (mean cortical/cerebellum SUV ratios: 0.95±0.15, 1.11±0.18 (p<0.0001), and 1.14 ±0.17 (p=0.0005), respectively). Similar results were obtained with all subcortical reference regions and for all cortical regions of interest, except cingulum. Only one patient with NT1 (4.4%) had positive PETamyloid compared with 27.5% in the ADNI and 30.4% in the MAPT group. In the NT1 group, cortical or regional amyloid load was not associated with CSF orexin-A, CSF AD biomarkers or neuropsychological profile. Interpretation: Lower brain amyloid burden, assessed by 18 F-florbetapir-PET, in patients with NT1 suggests delayed appearance of amyloid plaques.
Scientific reports, Jan 13, 2018
Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-... more 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 additio...
The international journal of neuropsychopharmacology, Jan 15, 2018
Modafinil, a nonamphetaminic wake-promoting compound, is prescribed as first line therapy in narc... more Modafinil, a nonamphetaminic wake-promoting compound, is prescribed as first line therapy in narcolepsy, an invalidating disorder characterized by excessive daytime sleepiness and cataplexy. Although its mode of action remains incompletely known, recent studies indicated that modafinil modulates astroglial connexin-based gap junctional communication as administration of a low dose of flecainide, an astroglial connexin inhibitor, enhanced the wake-promoting and procognitive activity of modafinil in rodents and healthy volunteers. The aim of this study is to investigate changes in glucose cerebral metabolism in rodents, induced by the combination of modafinil+flecainide low dose (called THN102). The impact of THN102 on brain glucose metabolism was noninvasively investigated using 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography imaging in Sprague-Dawley male rats. Animals were injected with vehicle, flecainide, modafinil, or THN102 and further injected with 18F-2-fluoro-2-d...
Sleep, 2017
To assess the test-retest reliability of the polysomnography-multiple sleep latency test (PSG-MSL... more To assess the test-retest reliability of the polysomnography-multiple sleep latency test (PSG-MSLT) diagnostic classification and measures and to study the determinants of its variability in patients with narcolepsy type 1 (NT1) or with noncataplectic central disorders of hypersomnolence (NCHS): type 2 (NT2), idiopathic hypersomnia (IH), and unspecified hypersomnolence (unspecified excessive daytime sleepiness [UnsEDS]). PSG-MSLT in drug-free conditions was administered twice (median interval of 1.9 years) in 22 patients with NT1 (10 males, median age 31.2 years) and 75 patients with NCHS (32 males, median age 25.7 years). At the first PSG-MSLT, patients with NCHS were classified as having NT2 (22.7%), IH (26.7%), or UnsEDS (50.6%). A positive PSG-MSLT was confirmed in 72.7% of NT1. The classification consistency at retesting was significantly lower for the NT2 (47.1%), IH (25.0%), and UnsEDS (42.1%) categories than NT1 (81.3%). The between-test mean sleep latency (MSL) variability ...
![Research paper thumbnail of [18F]Fludeoxyglucose-Positron Emission Tomography Evidence for Cerebral Hypermetabolism in the Awake State in Narcolepsy and Idiopathic Hypersomnia](https://attachments.academia-assets.com/79229804/thumbnails/1.jpg)
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Brain
The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocr... more The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocretin (orexin) neurons, leading to the hypothesis that the condition is caused by an immune or autoimmune mechanism. All genetic variants associated with narcolepsy are immune-related. Among these are single nucleotide polymorphisms in the P2RY11-EIF3G locus. It is unknown how these genetic variants affect narcolepsy pathogenesis and whether the effect is directly related to P2Y 11 signalling or EIF3G function. Exome sequencing in 18 families with at least two affected narcolepsy with cataplexy subjects revealed non-synonymous mutations in the second exon of P2RY11 in two families, and P2RY11 re-sequencing in 250 non-familial cases and 135 healthy control subjects revealed further six different non-synonymous mutations in the second exon of P2RY11 in seven patients. No mutations were found in healthy controls. Six of the eight narcolepsy-associated P2Y 11 mutations resulted in significant functional deficits in P2Y 11 signalling through both Ca 2 + and cAMP signalling pathways. In conclusion, our data show that decreased P2Y 11 signalling plays an important role in the development of narcolepsy with cataplexy.
Scientific Reports, 2016
I 125 radioimmunoassay (RIA) is currently the standard technique for quantifying cerebrospinal fl... more I 125 radioimmunoassay (RIA) is currently the standard technique for quantifying cerebrospinal fluid (CSF) orexin-A/hypocretin-1, a biomarker used to diagnose narcolepsy type 1. However, orexin-A RIA is liable to undergo cross-reactions with matrix constituents generating interference, high variability between batches, low precision and accuracy, and requires special radioactivity precautions. Here we developed the first quantitative mass spectrometry assay of orexin-A based on a multiple reaction monitoring (MRM) approach. This method was tested in keeping with the Clinical and Laboratory Standards Institute (CLSI) guidelines and its clinical relevance was confirmed by comparing patients with narcolepsy type 1 versus patients with other neurological conditions. The results obtained using MRM and RIA methods were highly correlated, and Bland-Altman analysis established their interchangeability. However, the MRM values had a wider distribution and were 2.5 time lower than the RIA findings. In conclusion, this method of assay provides a useful alternative to RIA to quantify orexin-A, and may well replace it not only in narcolepsy type 1, but also in the increasing number of pathologies in which the quantification of this analyte is relevant. The hypocretins (Hcrt), which are also known as orexins, consist of two neuropeptides, orexin-A/hypocretin-1 (Orex-A/Hcrt-1) and orexin-B/hypocretin-2 (Orex-B/Hcrt-2). They originated from the same precursor gene (preprohypocretin) present in a few thousand neurons localized in the perifornical area of the lateral hypothalamus 1,2. The longer peptide of the two, Orex-A/Hcrt-1, contains 33 amino acids, and the shorter one, Orex-B/ Hcrt-2, 28 amino acids 3. After being released, these peptides bind to two 7-transmembrane G-coupled receptors, Hcrt receptor 1 (Hcrt-1R) and 2 (Hcrt-2R) 3. Hcrt-1R is abundantly expressed in the locus coeruleus and the dorsal raphe nucleus, and has a preferential binding affinity for hypocretin-1, whereas Hcrt-2R is expressed in several brain regions and binds to both forms of Hcrt with a similar affinity 4-6. Hcrt-containing neurons project widely in the brain to target sites involved in sleep/wake regulation and arousal processes, reward-motivated behavior, endocrine homeostasis, and stress states 7-9. More than a decade ago, a dramatic decrease (85-95%) in the number of Hcrt neurons was identified as the cause of human narcolepsy with cataplexy 10,11. Narcolepsy was further divided in the third revised International Classification of Sleep Disorders into narcolepsy type 1 (NT1), which is also known as hypocretin deficiency syndrome, and narcolepsy type 2 (narcolepsy with normal hcrt levels) rather than being classified as previously as narcolepsy with and without cataplexy 12. Highly specific and sensitive methods of measuring patients' CSF hcrt-1 levels are therefore required for diagnosing NT1 1. Recent studies have also suggested that these levels are
Sleep, Jan 6, 2015
Basic experiments support the impact of hypocretin on hyperarousal and motivated state required f... more Basic experiments support the impact of hypocretin on hyperarousal and motivated state required for increasing drug craving. Our aim was to assess the frequencies of smoking, alcohol and drug use, abuse and dependence in narcolepsy type 1 (NT1, hypocretin-deficient), narcolepsy type 2 (NT2), idiopathic hypersomnia (IH) (non-hypocretin-deficient conditions), in comparison to controls. We hypothesized that NT1 patients would be less vulnerable to drug abuse and addiction compared to other hypersomniac patients and controls from general population. We performed a cross-sectional study in French reference centres for rare hypersomnia diseases and included 450 adult patients (median age 35 years; 41.3% men) with NT1 (n = 243), NT2 (n = 116), IH (n = 91), and 710 adult controls. All participants were evaluated for alcohol consumption, smoking habits, and substance (alcohol and illicit drug) abuse and dependence diagnosis during the past year using the Mini International Neuropsychiatric I...
Sleep medicine reviews, Jan 27, 2014
Sleep and sleep disorders are complex and highly variable phenotypes regulated by many genes and ... more Sleep and sleep disorders are complex and highly variable phenotypes regulated by many genes and environment. The catechol-O-methyltransferase (COMT) gene is an interesting candidate, being one of the major mammalian enzymes involved in the catabolism of catecholamines. The activity of COMT enzyme is genetically polymorphic due to a guanine-to-adenine transition at codon 158, resulting in a valine (Val) to methionine (Met) substitution. Individuals homozygous for the Val allele show higher COMT activity, and lower dopaminergic signaling in prefrontal cortex (PFC) than subjects homozygous for the Met allele. Since COMT has a crucial role in metabolising dopamine, it was suggested that the common functional polymorphism in the COMT gene impacts on cognitive function related to PFC, sleep-wake regulation, and potentially on sleep pathologies. The COMT Val158Met polymorphism may predict inter-individual differences in brain electroencephalography (EEG) alpha oscillations and recovery pr...
Sleep medicine, 2015
Despite published treatment recommendations and the availability of approved and off-label pharma... more Despite published treatment recommendations and the availability of approved and off-label pharmacologic therapies for narcolepsy, the clinical management of this incurable, chronic neurologic disorder remains challenging. While treatment is generally symptomatically driven, decisions regarding which drug(s) to use need to take into account a variety of factors that may affect adherence, efficacy, and tolerability. Type 1 narcolepsy (predominantly excessive daytime sleepiness with cataplexy) or type 2 narcolepsy (excessive daytime sleepiness without cataplexy) may drive treatment decisions, with consideration given either to a single drug that targets multiple symptoms or to multiple drugs that each treat a specific symptom. Other drug-related characteristics that affect drug choice are dosing regimens, tolerability, and potential drug-drug interactions. Additionally, the patient should be an active participant in treatment decisions, and the main symptomatic complaints, treatment g...
Frontiers in aging neuroscience, 2014
To examine relationships between cerebrospinal fluid (CSF) Alzheimer' disease (AD) biomarkers... more To examine relationships between cerebrospinal fluid (CSF) Alzheimer' disease (AD) biomarkers and hypocretin-1 levels in patients with cognitive abnormalities and hypocretin-deficient narcolepsy-cataplexy (NC), estimate diagnostic accuracy, and determine correlations with sleep disturbances. Sleep disturbances are frequent in AD. Interactions between brain β-amyloid (Aβ) aggregation and a wake-related neurotransmitter hypocretin have been reported in a mouse model of AD. Ninety-one cognitive patients (37 AD, 16 mild cognitive impairment-MCI that converts to AD, 38 other dementias) and 15 elderly patients with NC were recruited. Patients were diagnosed blind to CSF results. CSF Aβ42, total tau, ptau181, and hypocretin-1 were measured. Sleep disturbances were assessed with questionnaires in 32 cognitive patients. Lower CSF Aβ42 but higher tau and P-tau levels were found in AD and MCI compared to other dementias. CSF hypocretin-1 levels were higher in patients with MCI due to AD co...
To assess the presence of polysomnographic characteristics of REM sleep behavior disorder (RBD) i... more To assess the presence of polysomnographic characteristics of REM sleep behavior disorder (RBD) in narcolepsy; and to quantify REM sleep parameters in patients with narcolepsy, in patients with "idiopathic" RBD, and in normal controls. Design: Sleep laboratory study Participants: Sixteen patients with narcolepsy and cataplexy matched for age and sex with 16 patients with "idiopathic" RBD and with 16 normal controls were studied. Measurements and Results: Higher percentages of REM sleep without atonia, phasic electromyographic (EMG) activity, and REM density were found in patients with narcolepsy than normal controls. In contrast, RBD patients had a higher percentage of REM sleep without atonia but a lower REM density than patients with narcolepsy and normal controls. Based on a threshold of 80% for percentage of REM sleep with atonia, 50% of narcoleptics and 87.5% of RBD patients had abnormal REM sleep muscle activity. No significant behavioral manifestation in REM sleep was noted in either narcoleptics or controls. We also found a higher frequency of periodic leg movements during wake (PLMW) and during sleep (PLMS) in narcoleptic patients compared to controls. Conclusions: The present study demonstrates abnormalities in REM sleep motor regulation with an increased frequency of REM sleep without atonia, phasic EMG events and PLMS in narcoleptic patients when compared to controls. These abnormalities were seen more prominently in patients with RBD than in narcoleptics, with the exception of the PLMS index. We proposed that dysfunctions in hypocretin/dopaminergic system may lead to motor dyscontrol in REM sleep that results in dissociated sleep/wake states.
Archives of general psychiatry, 2012
Excessive sleepiness (ES) is poorly defined in epidemiologic studies, although its adverse implic... more Excessive sleepiness (ES) is poorly defined in epidemiologic studies, although its adverse implications for safety, health, and optimal social and vocational functioning have been extensively reported. To determine the importance of ES definition, measurement, and prevalence in the general population, together with its coexisting conditions. Cross-sectional telephone study. A total of 15 929 individuals representative of the adult general population of 15 states in the United States. Interviews were carried out using Sleep-EVAL, a knowledge-based expert system for use in epidemiologic studies, focusing on sleep, as well as physical and mental disorders, according to classification in DSM-IV and the second edition of the International Classification of Sleep Disorders. The interviews elicited information on ES, naps, frequency, duration, impairment, and distress associated with ES symptoms. Excessive sleepiness was reported by 27.8% (95% CI, 27.1%-28.5%) of the sample. Excessive slee...
SLEEP, 2014
Narcolepsy without Cataplexy-Baumann et al. 1. INTRODUCTION Narcolepsy with Cataplexy is usually ... more Narcolepsy without Cataplexy-Baumann et al. 1. INTRODUCTION Narcolepsy with Cataplexy is usually easy to diagnose as cataplexy is often distinctive and occurs in almost no other conditions. In contrast, Narcolepsy without Cataplexy is often a challenging diagnosis, even for highly experienced clinicians. This uncertainty arises from the nonspecific nature of the symptoms, the limitations of our current diagnostic tests, and the lack of useful biomarkers. The problem is further compounded by the fact that in some patients, narcolepsy may evolve over time; for example, patients in whom daytime sleepiness is the sole initial manifestation may develop cataplexy many years later. To advance understanding of Narcolepsy without Cataplexy, a group of clinician scientists experienced in narcolepsy convened in June 2012 to discuss these diagnostic challenges. The participants have all published extensively on narcolepsy, and the meeting (but not the writing of this paper) was funded by Jazz Pharmaceuticals. This meeting helped clarify aspects of this disorder and inspired us to write this manuscript. The goals of this paper are to review briefly what is known about Narcolepsy without Cataplexy, to discuss the usefulness
PLoS ONE, 2012
Background: Patients with narcolepsy-cataplexy (NC) mostly exhibit undetectable hypocretin levels... more Background: Patients with narcolepsy-cataplexy (NC) mostly exhibit undetectable hypocretin levels. Hypocretin system is one of the key players in the complex interaction between sleep and the cardiovascular system. We tested the hypothesis that hypocretin deficiency affects cardiovascular risk factors by measuring nighttime and daytime ambulatory blood pressure (BP) and the night-today BP ratio as well as endothelial dysfunction by the digital pulse amplitude response in drug-free patients with NC compared to controls. Methodology: Sleep, clinical and biological cardiovascular risk factors, fingertip peripheral arterial tonometry, and 24-hour ambulatory BP monitoring were recorded in 50 drug-free patients with NC and 42 healthy control subjects, except for BP monitoring available in all controls but in 36 patients with NC.
Journal of Clinical Investigation, 2010
Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscl... more Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataplexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder. Authorship note: Vesna Cvetkovic-Lopes and Laurence Bayer, as well as Michel Mühlethaler and Mehdi Tafti, contributed equally to this work.
Scientific Reports
The pathophysiology of rapid eye movement sleep behavior disorder (RBD) associated with narcoleps... more The pathophysiology of rapid eye movement sleep behavior disorder (RBD) associated with narcolepsy type 1 (NT1) is still poorly understood, potentially distinct from idiopathic RBD (iRBD), but may share affected common pathways. We investigated whether MIBG cardiac uptake differs between iRBD and NT1 comorbid with RBD. Thirty-four patients with NT1-RBD and 15 patients with iRBD underwent MIBG cardiac scintigraphy. MIBG uptake was measured by calculating the early and delayed heart to mediastinum (H/M) ratios. A delayed H/M ratio lower than 1.46 was considered abnormal based on a population of 78 subjects without neurological or cardiac diseases. Patients with iRBD were older, had an older RBD onset age and higher REM sleep phasic and tonic muscular activities than NT1-RBD. Lower delayed and early H/M ratios were associated with iRBD, but not with NT1-RBD, in crude and adjusted associations. The delayed H/M ratio differed between iRBD and controls, after adjustment, but not between patients with NT1-RBD and controls. In conclusion, the MIBG cardiac uptake difference between NT1-RBD and iRBD supports the hypothesis of different processes involved in RBD pathogenesis, providing for the first time a cardiac biomarker to differentiate those disorders. Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by repeated and often violent episodes of dream-enacting behaviors that may cause injury or sleep disruption 1,2. Preclinical and clinical evidences indicate that RBD results from the breakdown of the brainstem signaling network underlying REM sleep atonia, with an excess of muscle activity during REM sleep 3,4. RBD can be idiopathic (iRBD) or secondary. Secondary RBD can be associated with neurodegenerative disorders, especially synucleinopathies, narcolepsy, but also brainstem lesions, Guillain-Barré syndrome, intake of some drugs, and alcohol withdrawal 2. Conversely, iRBD is not associated with other neurological diseases, but often precedes the development of synucleinopathies. The presence of RBD is frequently associated with autonomic dysfunction in both idiopathic and secondary form associated with Parkinson's disease (PD). Cardiac 123 I-labeled meta-iodobenzylguanidine (MIBG, a physiological norepinephrine analogue) scintigraphy is used to assess the function of postganglionic presynaptic cardiac sympathetic nerve endings. MIBG cardiac uptake is markedly decreased in patients with iRBD in the same range as in PD and dementia with Lewy bodies, and could be used as an early biomarker of iRBD 5,6. However, it is unclear whether and to which extent MIBG cardiac accumulation is impaired in the presence of secondary RBD outside the context of neurodegenerative diseases. Narcolepsy type 1 (NT1) is a rare disease caused by the selective and irreversible loss of hypocretin neurons 7. It is characterized by excessive daytime sleepiness (EDS), cataplexy, clinical manifestations related to REM sleep dysregulation (RBD, sleep paralysis and hypnagogic hallucinations) and frequent autonomic dysfunction 7,8. RBD is observed in up to 60% of patients with NT1, and may be the first symptom even in children 9,10. Differently from
Nature Communications
Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently ... more Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently requires visual inspection of polysomnography records by trained scoring technicians. Here, we used neural networks in approximately 3,000 normal and abnormal sleep recordings to automate sleep stage scoring, producing a hypnodensity graph-a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated in 70 subjects assessed by six scorers. The best model performed better than any individual scorer (87% versus consensus). It also reliably scores sleep down to 5 s instead of 30 s scoring epochs. A T1N marker based on unusual sleep stage overlaps achieved a specificity of 96% and a sensitivity of 91%, validated in independent datasets. Addition of HLA-DQB1*06:02 typing increased specificity to 99%. Our method can reduce time spent in sleep clinics and automates T1N diagnosis. It also opens the possibility of diagnosing T1N using home sleep studies.
Annals of Neurology
Objective: To determine whether brain amyloid burden in elderly patients with narcolepsy type 1 (... more Objective: To determine whether brain amyloid burden in elderly patients with narcolepsy type 1 (NT1) is lower than in controls, and to assess in patients with NT1 the relationships between amyloid burden, cerebral spinal fluid (CSF) markers of Alzheimer's disease (AD), CSF orexin-A, and cognitive profile. Methods: Cognitive and 18 F-florbetapir-positron emission tomography (PET) data were compared in patients with NT1 aged ≥65 years (n=23) and in age-and sex-matched controls free of clinical dementia selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n=69) and the Multidomain Intervention Alzheimer's Prevention Trial (MAPT-AV45; n=23) cohorts. The standardized uptake values (SUV) of the cortical retention index for six regions of interest were computed and averaged to create a mean SUV ratio normalized to three subcortical reference regions (cerebellum, pons and a composite region). A cortical/cerebellum SUV ratio ≥1.17 defined positive PET amyloid. Results: Lower cortical amyloid burden was observed in the NT1 than in the ADNI and MAPT-AV45 groups (mean cortical/cerebellum SUV ratios: 0.95±0.15, 1.11±0.18 (p<0.0001), and 1.14 ±0.17 (p=0.0005), respectively). Similar results were obtained with all subcortical reference regions and for all cortical regions of interest, except cingulum. Only one patient with NT1 (4.4%) had positive PETamyloid compared with 27.5% in the ADNI and 30.4% in the MAPT group. In the NT1 group, cortical or regional amyloid load was not associated with CSF orexin-A, CSF AD biomarkers or neuropsychological profile. Interpretation: Lower brain amyloid burden, assessed by 18 F-florbetapir-PET, in patients with NT1 suggests delayed appearance of amyloid plaques.
Scientific reports, Jan 13, 2018
Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-... more 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 additio...
The international journal of neuropsychopharmacology, Jan 15, 2018
Modafinil, a nonamphetaminic wake-promoting compound, is prescribed as first line therapy in narc... more Modafinil, a nonamphetaminic wake-promoting compound, is prescribed as first line therapy in narcolepsy, an invalidating disorder characterized by excessive daytime sleepiness and cataplexy. Although its mode of action remains incompletely known, recent studies indicated that modafinil modulates astroglial connexin-based gap junctional communication as administration of a low dose of flecainide, an astroglial connexin inhibitor, enhanced the wake-promoting and procognitive activity of modafinil in rodents and healthy volunteers. The aim of this study is to investigate changes in glucose cerebral metabolism in rodents, induced by the combination of modafinil+flecainide low dose (called THN102). The impact of THN102 on brain glucose metabolism was noninvasively investigated using 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography imaging in Sprague-Dawley male rats. Animals were injected with vehicle, flecainide, modafinil, or THN102 and further injected with 18F-2-fluoro-2-d...
Sleep, 2017
To assess the test-retest reliability of the polysomnography-multiple sleep latency test (PSG-MSL... more To assess the test-retest reliability of the polysomnography-multiple sleep latency test (PSG-MSLT) diagnostic classification and measures and to study the determinants of its variability in patients with narcolepsy type 1 (NT1) or with noncataplectic central disorders of hypersomnolence (NCHS): type 2 (NT2), idiopathic hypersomnia (IH), and unspecified hypersomnolence (unspecified excessive daytime sleepiness [UnsEDS]). PSG-MSLT in drug-free conditions was administered twice (median interval of 1.9 years) in 22 patients with NT1 (10 males, median age 31.2 years) and 75 patients with NCHS (32 males, median age 25.7 years). At the first PSG-MSLT, patients with NCHS were classified as having NT2 (22.7%), IH (26.7%), or UnsEDS (50.6%). A positive PSG-MSLT was confirmed in 72.7% of NT1. The classification consistency at retesting was significantly lower for the NT2 (47.1%), IH (25.0%), and UnsEDS (42.1%) categories than NT1 (81.3%). The between-test mean sleep latency (MSL) variability ...
Brain
The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocr... more The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocretin (orexin) neurons, leading to the hypothesis that the condition is caused by an immune or autoimmune mechanism. All genetic variants associated with narcolepsy are immune-related. Among these are single nucleotide polymorphisms in the P2RY11-EIF3G locus. It is unknown how these genetic variants affect narcolepsy pathogenesis and whether the effect is directly related to P2Y 11 signalling or EIF3G function. Exome sequencing in 18 families with at least two affected narcolepsy with cataplexy subjects revealed non-synonymous mutations in the second exon of P2RY11 in two families, and P2RY11 re-sequencing in 250 non-familial cases and 135 healthy control subjects revealed further six different non-synonymous mutations in the second exon of P2RY11 in seven patients. No mutations were found in healthy controls. Six of the eight narcolepsy-associated P2Y 11 mutations resulted in significant functional deficits in P2Y 11 signalling through both Ca 2 + and cAMP signalling pathways. In conclusion, our data show that decreased P2Y 11 signalling plays an important role in the development of narcolepsy with cataplexy.
Scientific Reports, 2016
I 125 radioimmunoassay (RIA) is currently the standard technique for quantifying cerebrospinal fl... more I 125 radioimmunoassay (RIA) is currently the standard technique for quantifying cerebrospinal fluid (CSF) orexin-A/hypocretin-1, a biomarker used to diagnose narcolepsy type 1. However, orexin-A RIA is liable to undergo cross-reactions with matrix constituents generating interference, high variability between batches, low precision and accuracy, and requires special radioactivity precautions. Here we developed the first quantitative mass spectrometry assay of orexin-A based on a multiple reaction monitoring (MRM) approach. This method was tested in keeping with the Clinical and Laboratory Standards Institute (CLSI) guidelines and its clinical relevance was confirmed by comparing patients with narcolepsy type 1 versus patients with other neurological conditions. The results obtained using MRM and RIA methods were highly correlated, and Bland-Altman analysis established their interchangeability. However, the MRM values had a wider distribution and were 2.5 time lower than the RIA findings. In conclusion, this method of assay provides a useful alternative to RIA to quantify orexin-A, and may well replace it not only in narcolepsy type 1, but also in the increasing number of pathologies in which the quantification of this analyte is relevant. The hypocretins (Hcrt), which are also known as orexins, consist of two neuropeptides, orexin-A/hypocretin-1 (Orex-A/Hcrt-1) and orexin-B/hypocretin-2 (Orex-B/Hcrt-2). They originated from the same precursor gene (preprohypocretin) present in a few thousand neurons localized in the perifornical area of the lateral hypothalamus 1,2. The longer peptide of the two, Orex-A/Hcrt-1, contains 33 amino acids, and the shorter one, Orex-B/ Hcrt-2, 28 amino acids 3. After being released, these peptides bind to two 7-transmembrane G-coupled receptors, Hcrt receptor 1 (Hcrt-1R) and 2 (Hcrt-2R) 3. Hcrt-1R is abundantly expressed in the locus coeruleus and the dorsal raphe nucleus, and has a preferential binding affinity for hypocretin-1, whereas Hcrt-2R is expressed in several brain regions and binds to both forms of Hcrt with a similar affinity 4-6. Hcrt-containing neurons project widely in the brain to target sites involved in sleep/wake regulation and arousal processes, reward-motivated behavior, endocrine homeostasis, and stress states 7-9. More than a decade ago, a dramatic decrease (85-95%) in the number of Hcrt neurons was identified as the cause of human narcolepsy with cataplexy 10,11. Narcolepsy was further divided in the third revised International Classification of Sleep Disorders into narcolepsy type 1 (NT1), which is also known as hypocretin deficiency syndrome, and narcolepsy type 2 (narcolepsy with normal hcrt levels) rather than being classified as previously as narcolepsy with and without cataplexy 12. Highly specific and sensitive methods of measuring patients' CSF hcrt-1 levels are therefore required for diagnosing NT1 1. Recent studies have also suggested that these levels are
Sleep, Jan 6, 2015
Basic experiments support the impact of hypocretin on hyperarousal and motivated state required f... more Basic experiments support the impact of hypocretin on hyperarousal and motivated state required for increasing drug craving. Our aim was to assess the frequencies of smoking, alcohol and drug use, abuse and dependence in narcolepsy type 1 (NT1, hypocretin-deficient), narcolepsy type 2 (NT2), idiopathic hypersomnia (IH) (non-hypocretin-deficient conditions), in comparison to controls. We hypothesized that NT1 patients would be less vulnerable to drug abuse and addiction compared to other hypersomniac patients and controls from general population. We performed a cross-sectional study in French reference centres for rare hypersomnia diseases and included 450 adult patients (median age 35 years; 41.3% men) with NT1 (n = 243), NT2 (n = 116), IH (n = 91), and 710 adult controls. All participants were evaluated for alcohol consumption, smoking habits, and substance (alcohol and illicit drug) abuse and dependence diagnosis during the past year using the Mini International Neuropsychiatric I...
Sleep medicine reviews, Jan 27, 2014
Sleep and sleep disorders are complex and highly variable phenotypes regulated by many genes and ... more Sleep and sleep disorders are complex and highly variable phenotypes regulated by many genes and environment. The catechol-O-methyltransferase (COMT) gene is an interesting candidate, being one of the major mammalian enzymes involved in the catabolism of catecholamines. The activity of COMT enzyme is genetically polymorphic due to a guanine-to-adenine transition at codon 158, resulting in a valine (Val) to methionine (Met) substitution. Individuals homozygous for the Val allele show higher COMT activity, and lower dopaminergic signaling in prefrontal cortex (PFC) than subjects homozygous for the Met allele. Since COMT has a crucial role in metabolising dopamine, it was suggested that the common functional polymorphism in the COMT gene impacts on cognitive function related to PFC, sleep-wake regulation, and potentially on sleep pathologies. The COMT Val158Met polymorphism may predict inter-individual differences in brain electroencephalography (EEG) alpha oscillations and recovery pr...
Sleep medicine, 2015
Despite published treatment recommendations and the availability of approved and off-label pharma... more Despite published treatment recommendations and the availability of approved and off-label pharmacologic therapies for narcolepsy, the clinical management of this incurable, chronic neurologic disorder remains challenging. While treatment is generally symptomatically driven, decisions regarding which drug(s) to use need to take into account a variety of factors that may affect adherence, efficacy, and tolerability. Type 1 narcolepsy (predominantly excessive daytime sleepiness with cataplexy) or type 2 narcolepsy (excessive daytime sleepiness without cataplexy) may drive treatment decisions, with consideration given either to a single drug that targets multiple symptoms or to multiple drugs that each treat a specific symptom. Other drug-related characteristics that affect drug choice are dosing regimens, tolerability, and potential drug-drug interactions. Additionally, the patient should be an active participant in treatment decisions, and the main symptomatic complaints, treatment g...
Frontiers in aging neuroscience, 2014
To examine relationships between cerebrospinal fluid (CSF) Alzheimer' disease (AD) biomarkers... more To examine relationships between cerebrospinal fluid (CSF) Alzheimer' disease (AD) biomarkers and hypocretin-1 levels in patients with cognitive abnormalities and hypocretin-deficient narcolepsy-cataplexy (NC), estimate diagnostic accuracy, and determine correlations with sleep disturbances. Sleep disturbances are frequent in AD. Interactions between brain β-amyloid (Aβ) aggregation and a wake-related neurotransmitter hypocretin have been reported in a mouse model of AD. Ninety-one cognitive patients (37 AD, 16 mild cognitive impairment-MCI that converts to AD, 38 other dementias) and 15 elderly patients with NC were recruited. Patients were diagnosed blind to CSF results. CSF Aβ42, total tau, ptau181, and hypocretin-1 were measured. Sleep disturbances were assessed with questionnaires in 32 cognitive patients. Lower CSF Aβ42 but higher tau and P-tau levels were found in AD and MCI compared to other dementias. CSF hypocretin-1 levels were higher in patients with MCI due to AD co...
To assess the presence of polysomnographic characteristics of REM sleep behavior disorder (RBD) i... more To assess the presence of polysomnographic characteristics of REM sleep behavior disorder (RBD) in narcolepsy; and to quantify REM sleep parameters in patients with narcolepsy, in patients with "idiopathic" RBD, and in normal controls. Design: Sleep laboratory study Participants: Sixteen patients with narcolepsy and cataplexy matched for age and sex with 16 patients with "idiopathic" RBD and with 16 normal controls were studied. Measurements and Results: Higher percentages of REM sleep without atonia, phasic electromyographic (EMG) activity, and REM density were found in patients with narcolepsy than normal controls. In contrast, RBD patients had a higher percentage of REM sleep without atonia but a lower REM density than patients with narcolepsy and normal controls. Based on a threshold of 80% for percentage of REM sleep with atonia, 50% of narcoleptics and 87.5% of RBD patients had abnormal REM sleep muscle activity. No significant behavioral manifestation in REM sleep was noted in either narcoleptics or controls. We also found a higher frequency of periodic leg movements during wake (PLMW) and during sleep (PLMS) in narcoleptic patients compared to controls. Conclusions: The present study demonstrates abnormalities in REM sleep motor regulation with an increased frequency of REM sleep without atonia, phasic EMG events and PLMS in narcoleptic patients when compared to controls. These abnormalities were seen more prominently in patients with RBD than in narcoleptics, with the exception of the PLMS index. We proposed that dysfunctions in hypocretin/dopaminergic system may lead to motor dyscontrol in REM sleep that results in dissociated sleep/wake states.
Archives of general psychiatry, 2012
Excessive sleepiness (ES) is poorly defined in epidemiologic studies, although its adverse implic... more Excessive sleepiness (ES) is poorly defined in epidemiologic studies, although its adverse implications for safety, health, and optimal social and vocational functioning have been extensively reported. To determine the importance of ES definition, measurement, and prevalence in the general population, together with its coexisting conditions. Cross-sectional telephone study. A total of 15 929 individuals representative of the adult general population of 15 states in the United States. Interviews were carried out using Sleep-EVAL, a knowledge-based expert system for use in epidemiologic studies, focusing on sleep, as well as physical and mental disorders, according to classification in DSM-IV and the second edition of the International Classification of Sleep Disorders. The interviews elicited information on ES, naps, frequency, duration, impairment, and distress associated with ES symptoms. Excessive sleepiness was reported by 27.8% (95% CI, 27.1%-28.5%) of the sample. Excessive slee...
SLEEP, 2014
Narcolepsy without Cataplexy-Baumann et al. 1. INTRODUCTION Narcolepsy with Cataplexy is usually ... more Narcolepsy without Cataplexy-Baumann et al. 1. INTRODUCTION Narcolepsy with Cataplexy is usually easy to diagnose as cataplexy is often distinctive and occurs in almost no other conditions. In contrast, Narcolepsy without Cataplexy is often a challenging diagnosis, even for highly experienced clinicians. This uncertainty arises from the nonspecific nature of the symptoms, the limitations of our current diagnostic tests, and the lack of useful biomarkers. The problem is further compounded by the fact that in some patients, narcolepsy may evolve over time; for example, patients in whom daytime sleepiness is the sole initial manifestation may develop cataplexy many years later. To advance understanding of Narcolepsy without Cataplexy, a group of clinician scientists experienced in narcolepsy convened in June 2012 to discuss these diagnostic challenges. The participants have all published extensively on narcolepsy, and the meeting (but not the writing of this paper) was funded by Jazz Pharmaceuticals. This meeting helped clarify aspects of this disorder and inspired us to write this manuscript. The goals of this paper are to review briefly what is known about Narcolepsy without Cataplexy, to discuss the usefulness
PLoS ONE, 2012
Background: Patients with narcolepsy-cataplexy (NC) mostly exhibit undetectable hypocretin levels... more Background: Patients with narcolepsy-cataplexy (NC) mostly exhibit undetectable hypocretin levels. Hypocretin system is one of the key players in the complex interaction between sleep and the cardiovascular system. We tested the hypothesis that hypocretin deficiency affects cardiovascular risk factors by measuring nighttime and daytime ambulatory blood pressure (BP) and the night-today BP ratio as well as endothelial dysfunction by the digital pulse amplitude response in drug-free patients with NC compared to controls. Methodology: Sleep, clinical and biological cardiovascular risk factors, fingertip peripheral arterial tonometry, and 24-hour ambulatory BP monitoring were recorded in 50 drug-free patients with NC and 42 healthy control subjects, except for BP monitoring available in all controls but in 36 patients with NC.