Publications by authors named "Isabelle Arnulf"

249 Publications

Proteomic Biomarkers of Kleine-Levin Syndrome.

Sleep 2022 Jul 21. Epub 2022 Jul 21.

Center for Sleep Sciences and Medicine, Stanford University, Palo Alto CA.

Study Objectives: Kleine-Levin Syndrome (KLS) is characterized by relapsing-remitting episodes of hypersomnia, cognitive impairment, and behavioral disturbances. We quantified cerebrospinal fluid (CSF) and serum proteins in KLS cases and controls.

Methods: SomaScan was used to profile 1133 CSF proteins in 30 KLS cases and 134 controls, while 1109 serum proteins were profiled in serum from 26 cases and 65 controls. CSF and serum proteins were both measured in 7 cases. Univariate and multivariate analyses were used to find differentially expressed proteins (DEPs). Pathway and tissue enrichment analyses (TEA) were performed on DEPs.

Results: Univariate analyses found 28 and 141 proteins differentially expressed in CSF and serum, respectively (False Discovery Rate, FDR<0.1%). Upregulated CSF proteins included IL-34, IL-27, TGF-b, IGF-1 and osteonectin, while DKK4 and vWF were downregulated. Pathway analyses revealed microglial alterations and disrupted blood-brain barrier permeability. Serum profiles show upregulation of Src-family kinases (SFKs), proteins implicated in cellular growth, motility and activation. TEA analysis of up- and down-regulated proteins revealed changes in brain proteins (p<6x10 -5), notably from the pons, medulla and midbrain. A multi-variate machine learning classifier performed robustly, achieving a receiver operating curve (ROC) Area Under the Curve of 0.90 (95% CI=0.78-1.0,p=0.0006) in CSF and 1.0 (95% CI=1.0-1.0,p=0.0002) in serum in validation cohorts, with some commonality across tissues, as the model trained on serum sample also discriminated CSF samples of controls versus KLS cases.

Conclusions: Our study identifies proteomic KLS biomarkers with diagnostic potential and provides insight into biological mechanisms that will guide future research in KLS.
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http://dx.doi.org/10.1093/sleep/zsac097DOI Listing
July 2022

Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression.

Brain 2022 May 20. Epub 2022 May 20.

The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal H3A 2B4, Canada.

Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease, or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% men) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e., a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, p = 0.0007) and tissue deformation (r = 0.52, p = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function, and can be recreated using the dynamics of agent-based modelling, structural connectivity, and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology.
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http://dx.doi.org/10.1093/brain/awac187DOI Listing
May 2022

Rapid eye movement sleep behaviour disorder: Past, present, and future.

J Sleep Res 2022 08 25;31(4):e13612. Epub 2022 Apr 25.

Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.

This manuscript presents an overview of REM sleep behaviour disorder (RBD) with a special focus on European contributions. After an introduction examining the history of the disorder, we address the pathophysiological and clinical aspects, as well as the diagnostic issues. Further, implications of RBD diagnosis and biomarkers are discussed. Contributions of European researchers to this field are highlighted.
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http://dx.doi.org/10.1111/jsr.13612DOI Listing
August 2022

Safety and efficacy of subcutaneous night-time only apomorphine infusion to treat insomnia in patients with Parkinson's disease (APOMORPHEE): a multicentre, randomised, controlled, double-blind crossover study.

Lancet Neurol 2022 05;21(5):428-437

AP-HP, Salpetriere Hospital, DMU Neuroscience 6, Paris, France; Sorbonne University, Paris Brain Institute, INSERM, CNRS, Paris, France.

Background: Insomnia is a frequent complaint of patients with Parkinson's disease, and it negatively affects quality of life. Drugs that improve both sleep and parkinsonism would be of major benefit to patients with Parkinson's disease-related insomnia. We aimed to test the safety and efficacy of subcutaneous night-time only apomorphine infusion in patients with Parkinson's disease and insomnia.

Methods: We did a randomised, multicentre, double-blind, placebo-controlled, crossover trial in 11 expert centres in Parkinson's disease and sleep centres in France. Participants aged 35-90 years with fluctuating Parkinson's disease and moderate to severe insomnia (Insomnia Severity Index score ≥15) were randomly assigned to either first receive night-time subcutaneous apomorphine (up to 5 mg/h) or matching placebo. Randomisation was done using a computer-generated plan in blocks of four, stratified by centre. This first intervention was followed by a 14-night washout period, then crossover to the other intervention. The treatment periods consisted of a 10-night titration phase followed by a 7-night fixed-dose phase. The dose was adjusted during the titration phase on the basis of a daily telephone call assessing sleep quality and treatment tolerability. The primary efficacy endpoint was the difference in Parkinson's disease sleep scale (PDSS) scores from the beginning to the end of each treatment period. Analysis was done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT02940912.

Findings: Between Jan 31, 2017, and Jan 29, 2021, 46 participants were enrolled. 25 (54%) patients were randomly assigned to receive apomorphine first and 21 (46%) patients to receive placebo first. Mean change in PDSS score was significantly greater with night-time apomorphine infusion (15·18 [SD 24·34]) compared with placebo (5·23 [21·52]; treatment effect 9·95 [95% CI 0·88-19·03]; p=0·041). Adverse events were reported in 25 (54%) participants during the apomorphine period and in 17 (37%) participants during the placebo period (p=0·16). Apomorphine was associated with more frequent dizziness than was placebo (seven [15%] vs 0; p=0·041).

Interpretation: Subcutaneous night-time only apomorphine infusion improved sleep disturbances according to difference on PDSS score, with an overall safety profile consistent with previous studies in Parkinson's disease. This treatment might be useful to manage sleep disturbances in patients with advanced Parkinson's disease and moderate to severe insomnia.

Funding: Orkyn and Aguettant Pharma.

Translation: For the French translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1474-4422(22)00085-0DOI Listing
May 2022

Sleep Disorders in Adults with Prader-Willi Syndrome: Review of the Literature and Clinical Recommendations Based on the Experience of the French Reference Centre.

J Clin Med 2022 Apr 2;11(7). Epub 2022 Apr 2.

Centre de Référence des Narcolepsies et Hypersomnies Rares, Service des Pathologies du Sommeil (Département R3S), Hôpital la Pitié-Salpêtrière, APHP-Sorbonne, 75013 Paris, France.

Prader-Willi syndrome (PWS) is a rare, genetic, multisymptomatic, neurodevelopmental disease commonly associated with sleep alterations, including sleep-disordered breathing and central disorders of hypersomnolence. Excessive daytime sleepiness represents the main manifestation that should be addressed by eliciting the detrimental effects on quality of life and neurocognitive function from the patients' caregivers. Patients with PWS have impaired ventilatory control and altered pulmonary mechanics caused by hypotonia, respiratory muscle weakness, scoliosis and obesity. Consequently, respiratory abnormalities are frequent and, in most cases, severe, particularly during sleep. Adults with PWS frequently suffer from sleep apnoea syndrome, sleep hypoxemia and sleep hypoventilation. When excessive daytime sleepiness persists after adequate control of sleep-disordered breathing, a sleep study on ventilatory treatment, followed by an objective measurement of excessive daytime sleepiness, is recommended. These tests frequently identify central disorders of hypersomnolence, including narcolepsy, central hypersomnia or a borderline hypersomnolent phenotype. The use of wake-enhancing drugs (modafinil, pitolisant) is discussed in multidisciplinary expert centres for these kinds of cases to ensure the right balance between the benefits on quality of life and the risk of psychological and cardiovascular side effects.
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http://dx.doi.org/10.3390/jcm11071986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8999159PMC
April 2022

Sleep Recording for the Diagnosis and Treatment of Paraplegia.

JAMA Neurol 2022 06;79(6):627

Neurology Department, Avicenne Hospital, APHP, Sorbonne Paris Nord University, Bobigny, France.

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http://dx.doi.org/10.1001/jamaneurol.2022.0619DOI Listing
June 2022

Sleepwalking, sleep terrors, sexsomnia and other disorders of arousal: the old and the new.

J Sleep Res 2022 08 6;31(4):e13596. Epub 2022 Apr 6.

Sorbonne University, Paris, France.

Disorders of arousal (DOA) is an umbrella term initially covering classical sleepwalking, sleep terrors, and confusional arousals, and now including a wider spectrum of specialised forms of non rapid eye movement (non REM) parasomnias such as sexsomnia, sleep-related eating disorder, and sleep-related choking syndrome. Growing evidence has shown that DOA are not restricted to children but are also prevalent in adults (2%-4% of the adult population). While DOA run in family, genetics studies remain scarce and inconclusive. In addition to the risk of injury on themselves and others (including sexual assaults in sexsomnia), adults with DOA frequently suffer from excessive daytime sleepiness, pain, and altered quality of life. The widespread view of DOA as automatic and amnesiac behaviours has now been challenged by subjective (dream reports) and objective (dream-enacting behaviours documented on video-polysomnography) observations, suggesting that sleepwalkers are 'dream walking' during their episodes. Behavioural, experiential, cognitive, and brain (scalp electroencephalography [EEG], stereo-EEG, high density-EEG, functional brain imaging) data converge in showing a dissociated pattern during the episodes. This dissociated pattern resembles the new concept of local arousal with a wake-like activation in motor and limbic regions and a preserved (or even increased) sleep intensity over a frontoparietal network. EEG and behavioural criteria supporting the DOA diagnosis with high sensitivity and specificity are now available. However, treatment is still based on controlling priming and precipitating factors, as well as on clinicians' personal experience with sedative drugs. Placebo-controlled trials are needed to improve patients' treatment. DOA deserve more attention from sleep researchers and clinicians.
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http://dx.doi.org/10.1111/jsr.13596DOI Listing
August 2022

Eye movement patterns correlate with overt emotional behaviours in rapid eye movement sleep.

Sci Rep 2022 02 2;12(1):1770. Epub 2022 Feb 2.

Sleep Disorder Unit, Pitie-Salpetriere University Hospital, APHP, Paris, France.

Growing evidence suggests that sleep plays a key role in regulating emotions. Rapid eye movements (REMs) in REM sleep could be associated with dreams emotions, but supporting evidence is indirect. To highlight this association, we studied the REM sleep during video-polysomnography of 20 subjects with REM sleep behaviour disorder (RBD), a model of enacted dreams offering direct access to the emotional content of the sleeper (face expression, speeches, behaviour). Video and the electro-oculography recordings were divided into 3 s time intervals and classified as non-behavioural, or behavioural (neutral, positive or negative emotions), and as containing no eye movements (EMs), slow eye movements (SEMs) or REMs (isolated or bursts). Compared to the absence of EMs, neutral behaviours successively increased in the presence of SEMs (odd ratio, OR = 1.4), then isolated REMs (OR = 2.8) and then REM bursts (OR = 4.6). Positive behaviours increased with SEMs (OR = 2.8) but did not increase further with isolated REMs (OR = 2.8) and REM bursts (OR = 3). Negative behaviours were absent with SEMs, increased with isolated REMs (OR = 2.6) and further with REM bursts (OR = 10.1). These results support an association between REMs and SEMs, and dream emotions.
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http://dx.doi.org/10.1038/s41598-022-05905-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8810754PMC
February 2022

Deep Learning-Based Neuromelanin MRI Changes of Isolated REM Sleep Behavior Disorder.

Mov Disord 2022 05 1;37(5):1064-1069. Epub 2022 Feb 1.

Center for NeuroImaging Research (CENIR), Paris Brain Institute-ICM, Paris, France.

Background: Isolated REM sleep behavior disorder (iRBD) is considered a prodromal stage of parkinsonism. Neurodegenerative changes in the substantia nigra pars compacta (SNc) in parkinsonism can be detected using neuromelanin-sensitive MRI.

Objective: To investigate SNc neuromelanin changes in iRBD patients using fully automatic segmentation.

Methods: We included 47 iRBD patients, 134 early Parkinson's disease (PD) patients and 55 healthy volunteers (HVs) scanned at 3 Tesla. SNc regions-of-interest were delineated automatically using convolutional neural network. SNc volumes, volumes corrected by total intracranial volume, signal-to-noise ratio (SNR) and contrast-to-noise ratio were computed. One-way general linear models (GLM) analysis of covariance (ANCOVA) was conducted while adjusting for age and sex.

Results: All SNc measurements differed significantly between the three groups (except SNR in iRBD). Changes in iRBD were intermediate between those in PD and HVs.

Conclusions: Using fully automated SNc segmentation method and neuromelanin-sensitive imaging, iRBD patients showed neurodegenerative changes in the SNc at a lower level than in PD patients. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9302679PMC
May 2022

Moving the dial on behavioral interventions for idiopathic hypersomnia.

J Clin Sleep Med 2022 05;18(5):1473-1474

Sleep Disorders Unit, University Hospital Pitié-Salpêtrière, APHP-Sorbonne, Paris, France.

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http://dx.doi.org/10.5664/jcsm.9914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9059601PMC
May 2022

Voice characteristics from isolated rapid eye movement sleep behavior disorder to early Parkinson's disease.

Parkinsonism Relat Disord 2022 02 8;95:86-91. Epub 2022 Jan 8.

Paris Brain Institute - ICM, Centre de NeuroImagerie de Recherche - CENIR, Paris, France; Sorbonne University, Inserm, CNRS, Paris Brain Institute - ICM, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Department of Neuroradiology, Paris, France.

Background: Speech disorders are amongst the first symptoms to appear in Parkinson's disease (PD).

Objectives: We aimed to characterize PD voice signature from the prodromal stage (isolated rapid eye movement sleep behavior disorder, iRBD) to early PD using an automated acoustic analysis and compare male and female patients. We carried out supervised learning classifications to automatically detect patients using voice only.

Methods: Speech samples were acquired in 256 French speakers (117 participants with early PD, 41 with iRBD, and 98 healthy controls), with a professional quality microphone, a computer microphone and their own telephone. High-level features related to prosody, phonation, speech fluency and rhythm abilities were extracted. Group analyses were performed to determine the most discriminant features, as well as the impact of sex, vocal tasks, and microphone type. These speech features were used as inputs of a support vector machine and were combined with classifiers using low-level features.

Results: PD related impairments were found in prosody, pause durations and rhythmic abilities, from the prodromal stage. These alterations were more pronounced in men than in women. Early PD detection was achieved with a balanced accuracy of 89% in males and 70% in females. Participants with iRBD were detected with a balanced accuracy of 63% (reaching 70% in the subgroup with mild motor symptoms).

Conclusion: This study provides new insight in the characterization of sex-dependent early PD speech impairments, and demonstrates the valuable benefit of including automated voice analysis in future diagnostic procedures of prodromal PD.
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http://dx.doi.org/10.1016/j.parkreldis.2022.01.003DOI Listing
February 2022

Osteopathic Manipulation of the Sphenopalatine Ganglia Versus Sham Manipulation, in Obstructive Sleep Apnoea Syndrom: A Randomised Controlled Trial.

J Clin Med 2021 Dec 24;11(1). Epub 2021 Dec 24.

UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, INSERM, Sorbonne Université, 75005 Paris, France.

(1) Background: osteopathic manipulation of the sphenopalatine ganglia (SPG) blocks the action of postganglionic sensory fibres. This neuromodulation can reduce nasal obstruction and enhance upper airway stability. We investigated the manipulation of the SPG in 31 patients with obstructive sleep apnoea syndrome (OSAS); (2) Methods: Randomised, controlled, double-blind, crossover study. Participants received active (AM), then sham manipulation (SM), or vice versa. The primary endpoint was apnoea-hypopnoea index (AHI). Secondary endpoints were variation of nasal obstruction evaluated by peak nasal inspiratory flow (PNIF) and upper airways stability evaluated by awake critical closing pressure [awake Pcrit]), at 30 min and 24 h. Schirmer's test and pain were assessed immediately post-manipulation. Tactile/gustatory/olfactory/auditory/nociceptive/visual sensations were recorded. Adverse events were collected throughout. (3) Results: SPG manipulation did not reduce AHI ( = 0.670). PNIF increased post-AM but not post-SM at 30 min (AM-SM: 18 [10; 38] L/min, = 0.0001) and 24 h (23 [10; 30] L/min, = 0.001). There was no significant difference on awake Pcrit (AM-SM) at 30 min or 24 h). Sensations were more commonly reported post-AM (100% of patients) than post-SM (37%). Few adverse events and no serious adverse events were reported. (4) Conclusions: SPG manipulation is not supported as a treatment for OSAS but reduced nasal obstruction. This effect remains to be confirmed in a larger sample before using this approach to reduce nasal congestion in CPAP-treated patients or in mild OSAS.
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http://dx.doi.org/10.3390/jcm11010099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745154PMC
December 2021

Comorbid parasomnias in narcolepsy and idiopathic hypersomnia: more REM than NREM parasomnias.

J Clin Sleep Med 2022 05;18(5):1355-1364

Sleep Disorders, Pitié-Salpêtrière University Hospital, AP-HP Sorbonne, Paris, France.

Study Objectives: To assess the frequency, determinants, and clinical impact of clinical rapid eye movement (REM) and non-REM (NREM) parasomnias in adult patients with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia compared with healthy controls.

Methods: Familial and past and current personal parasomnias were assessed by questionnaire and medical interviews in 710 patients (220 NT1, 199 NT2, and 221 idiopathic hypersomnia) and 595 healthy controls.

Results: Except for sleep-related eating disorder, current NREM parasomnias were rare in all patient groups and controls. Sleep-related eating disorder was more frequent in NT1 patients (7.9% vs 1.8% in NT2 patients, 2.1% in patients with idiopathic hypersomnia, and 1% in controls) and associated with disrupted nighttime sleep (odds ratio = 3.9) and nocturnal eating in full awareness (odds ratio = 6.9) but not with sex. Clinical REM sleep behavior disorder was more frequent in NT1 patients (41.4%, half being violent) than in NT2 patients (13.2%) and affected men more often than women (odds ratio = 2.4). It was associated with disrupted nighttime sleep, depressive symptoms, and antidepressant use. Frequent (> 1/week) nightmares were reported by 39% of patients with NT1, 29% with NT2, and 27.8% with idiopathic hypersomnia (vs 8.3% in controls) and were associated with depressive symptoms in narcolepsy. No parasomnia (except sleep-related hallucinations) worsened daytime sleepiness.

Conclusions: In patients with central disorders of hypersomnolence, comorbid NREM parasomnias (except for sleep-related eating disorder) are rare and do not worsen sleepiness. In contrast, REM parasomnias are prevalent (especially in NT1) and are associated with male sex, disrupted nighttime sleep, depressive symptoms, and antidepressant use.

Citation: Leu-Semenescu S, Maranci J-B, Lopez R, et al. Comorbid parasomnias in narcolepsy and idiopathic hypersomnia: more REM than NREM parasomnias. . 2022;18(5):1355-1364.
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http://dx.doi.org/10.5664/jcsm.9862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9059608PMC
May 2022

Risk Factors for Phenoconversion in Rapid Eye Movement Sleep Behavior Disorder.

Ann Neurol 2022 03 24;91(3):404-416. Epub 2022 Jan 24.

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

Objective: This study was undertaken to follow up predictive factors for α-synuclein-related neurodegenerative diseases in a multicenter cohort of idiopathic/isolated rapid eye movement sleep behavior disorder (iRBD).

Methods: Patients with iRBD from 12 centers underwent a detailed assessment for potential environmental and lifestyle risk factors via a standardized questionnaire at baseline. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The cumulative incidence of parkinsonism or dementia was estimated with competing risk analysis. Cox regression analyses were used to evaluate the predictive value of environmental/lifestyle factors over a follow-up period of 11 years, adjusting for age, sex, and center.

Results: Of 319 patients who were free of parkinsonism or dementia, 281 provided follow-up information. After a mean follow-up of 5.8 years, 130 (46.3%) patients developed neurodegenerative disease. The overall phenoconversion rate was 24.2% after 3 years, 44.8% after 6 years, and 67.5% after 10 years. Patients with older age (adjusted hazard ratio [aHR] = 1.05) and nitrate derivative use (aHR = 2.18) were more likely to phenoconvert, whereas prior pesticide exposure (aHR = 0.21-0.64), rural living (aHR = 0.53), lipid-lowering medication use (aHR = 0.59), and respiratory medication use (aHR = 0.36) were associated with lower phenoconversion risk. Risk factors for those converting to primary dementia and parkinsonism were generally similar, with dementia-first converters having lower coffee intake and beta-blocker intake, and higher occurrence of family history of dementia.

Interpretation: Our findings elucidate the predictive values of environmental factors and comorbid conditions in identifying RBD patients at higher risk of phenoconversion. ANN NEUROL 2022;91:404-416.
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http://dx.doi.org/10.1002/ana.26298DOI Listing
March 2022

Movements and behaviors during spontaneous arousals in healthy young adults: an intermediary stage between wakefulness and sleep?

Sleep Med 2022 01 7;89:93-96. Epub 2021 Dec 7.

Sleep Disorders Unit, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France. Electronic address:

Background: Arousals are common, sudden and transient elevations of the vigilance level during normal sleep, but arousal-associated behaviors have not yet been studied.

Objective: We aimed to describe the duration as well as motor and autonomic patterns associated with arousals across sleep stages in normal subjects.

Methods: The spontaneous arousals of 25 healthy young adults were randomly analyzed on polysomnography with body- and face-oriented video cameras. The duration of the heart rate response as well as the frequency, amplitude, speed, body segment and semiology of associated movements were measured.

Results: Among 624 arousals (258 in N2, 140 in N3 and 226 in REM sleep), REM sleep arousals had the shortest duration, and N3 arousals were associated with greater heart rate acceleration. Movements and behaviors (mostly involving the head and neck, then the upper limbs, with rare eyes opening and no turning in bed) were frequent during arousals (69.4% during N2 sleep, 89.3% during N3 and 93.8% during REM sleep). Arousals more frequently included ample, prolonged and whole-body movements during N3 sleep and fast movements and facial expressions during REM sleep. During N2 arousals, chewing was the most prevalent behavior. Some movements resembled orientation and comfort behaviors (flexing/rotating the neck and trunk, scratching, pulling the sheets, rubbing the nose, yawning, smiling, frowning and speaking), whereas others resembled sleep-associated automatisms (swallowing, chewing).

Conclusion: In contrast with previous assumptions, most arousals are associated with movements. The type of movements suggests that arousal is an intermediary state between wakefulness and sleep.
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http://dx.doi.org/10.1016/j.sleep.2021.11.012DOI Listing
January 2022

Safety and efficacy of lower-sodium oxybate in adults with idiopathic hypersomnia: a phase 3, placebo-controlled, double-blind, randomised withdrawal study.

Lancet Neurol 2022 01;21(1):53-65

University of South Carolina School of Medicine, Columbia, SC, USA.

Background: Idiopathic hypersomnia is a central hypersomnolence disorder mainly characterised by excessive daytime sleepiness, with prolonged night-time sleep and pronounced sleep inertia. Until August, 2021, no medication had regulatory approval for the treatment of idiopathic hypersomnia. This study aimed to evaluate the safety and efficacy of lower-sodium oxybate in idiopathic hypersomnia.

Methods: This was a phase 3, multicentre (50 specialist sleep centres; six EU countries and the USA), placebo-controlled, double-blind, randomised withdrawal study. Participants (aged 18-75 years) with idiopathic hypersomnia (meeting criteria from the International Classification of Sleep Disorders, 2nd or 3rd editions) began lower-sodium oxybate treatment (oral solution once or twice nightly) in an open-label titration and optimisation period (10-14 weeks), followed by a 2-week, open-label, stable-dose period. After these open-label periods, participants were randomised (1:1) by means of an interactive web recognition system, stratified by participants' baseline medication use, to either placebo or lower-sodium oxybate (individually optimised dose; range 2·5-9·0 g/night) during a 2-week, double-blind, randomised withdrawal period. To maintain masking of treatment assignment, placebo and lower-sodium oxybate oral solutions were matched in volume, appearance, and taste. During the double-blind, randomised withdrawal period, participants and investigators were unaware of treatment assignments. The primary efficacy endpoint was change in Epworth Sleepiness Scale (ESS) score from the end of the stable-dose period to the end of the double-blind, randomised withdrawal period, which was assessed in the modified intention-to-treat population (defined as all participants who were randomly assigned, took at least one dose of study medication during the double blind, randomised withdrawal period, and had at least one set of post-randomisation assessments for the primary or key secondary endpoints). Adverse events were assessed in the safety population (defined as all participants who took at least one dose of study medication). This study is registered at ClinicalTrials.gov, NCT03533114, and at EU Clinical Trials, 2018-001311-79, and is complete.

Findings: Between Nov 27, 2018, and March 6, 2020, 154 participants were enrolled and comprised the safety population. ESS scores decreased from a mean of 15·7 (SD 3·8) at baseline to 6·1 (4·0) by the end of the stable-dose period. After the open-label periods, 115 participants were randomly assigned either placebo (n=59) or lower-sodium oxybate (n=56) and comprised the modified intention-to-treat population. During the double-blind, randomised withdrawal period, ESS scores increased (worsened) in participants randomly assigned to placebo but remained stable in those assigned to lower-sodium oxybate (least squares mean difference -6·5; 95% CI -8·0 to -5·0; p<0·0001). Treatment-emergent adverse events included nausea (34 [22%] of 154), headache (27 [18%] of 154), dizziness (19 [12%] of 154), anxiety (17 [11%] 154), and vomiting (17 [11%] 154). No deaths were reported during the study.

Interpretation: Lower-sodium oxybate treatment resulted in a clinically meaningful improvement in idiopathic hypersomnia symptoms, with an overall safety profile consistent with that reported for narcolepsy. Lower-sodium oxybate was approved in August, 2021, by the US Food and Drug Administration for the treatment of idiopathic hypersomnia in adults.

Funding: Jazz Pharmaceuticals.
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http://dx.doi.org/10.1016/S1474-4422(21)00368-9DOI Listing
January 2022

The Myelin-Weighted Connectome in Parkinson's Disease.

Mov Disord 2022 04 22;37(4):724-733. Epub 2021 Dec 22.

NeuroPoly Lab, Polytechnique Montréal, Montréal, Quebec, Canada.

Background: Even though Parkinson's disease (PD) is typically viewed as largely affecting gray matter, there is growing evidence that there are also structural changes in the white matter. Traditional connectomics methods that study PD may not be specific to underlying microstructural changes, such as myelin loss.

Objective: The primary objective of this study is to investigate the PD-induced changes in myelin content in the connections emerging from the basal ganglia and the brainstem. For the weighting of the connectome, we used the longitudinal relaxation rate as a biologically grounded myelin-sensitive metric.

Methods: We computed the myelin-weighted connectome in 35 healthy control subjects and 81 patients with PD. We used partial least squares to highlight the differences between patients with PD and healthy control subjects. Then, a ring analysis was performed on selected brainstem and subcortical regions to evaluate each node's potential role as an epicenter for disease propagation. Then, we used behavioral partial least squares to relate the myelin alterations with clinical scores.

Results: Most connections (~80%) emerging from the basal ganglia showed a reduced myelin content. The connections emerging from potential epicentral nodes (substantia nigra, nucleus basalis of Meynert, amygdala, hippocampus, and midbrain) showed significant decrease in the longitudinal relaxation rate (P < 0.05). This effect was not seen for the medulla and the pons.

Conclusions: The myelin-weighted connectome was able to identify alteration of the myelin content in PD in basal ganglia connections. This could provide a different view on the importance of myelination in neurodegeneration and disease progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303520PMC
April 2022

Validation of the Dutch translation of the Paris Arousal Disorders Severity Scale for non-REM parasomnias in a 1-year and 1-month version.

J Clin Sleep Med 2022 04;18(4):1135-1143

Sleep Medicine Center Kempenhaeghe, Heeze, The Netherlands.

Study Objectives: We created a Dutch version of the Paris Arousal Disorders Severity Scale (PADSS), which assesses non-rapid eye movement (NREM) parasomnia symptoms over the past year (PADSS-year). This questionnaire was previously validated in patients with sleep walking and/or sleep terrors (SW/ST). We validated the questionnaire in SW/ST patients, and in a broader population, including patients with confusional arousals, comorbidities, and medication users ("other NREM parasomnias"). Furthermore, we introduced a version covering the past month (PADSS-month), with the potential purpose of evaluating symptom evolution and treatment response.

Methods: We compared PADSS scores among 54 SW/ST patients, 34 age-matched controls, and 23 patients with other NREM parasomnias. We evaluated discriminative capacity, internal consistency, and construct validity. Furthermore, we assessed the test-retest reliability and treatment response of PADSS-month.

Results: Healthy controls scored significantly lower than both patient groups. We found an excellent diagnostic accuracy (area under the curve PADSS-year 0.990, PADSS-month 0.987) and an acceptable internal consistency. Exploratory factor analysis identified 3 components: "behaviors outside the bed," "behaviors in/around the bed," and "violent behaviors," with the former 2 factors reflecting the distinction between SW and ST. PADSS-month showed an acceptable test-retest reliability (0.75). Additionally, PADSS-month significantly decreased after pharmaceutical and/or behavioral treatment. This change was correlated with the clinical impression of the caregiver, implying that PADSS-month is sensitive to treatment effects.

Conclusions: The Dutch PADSS questionnaire can be used as a screening tool in a broad population of patients with NREM parasomnia, not only SW/ST. Furthermore, we validated a PADSS-month version to assess the evolution of symptoms and treatment effect.

Citation: van Mierlo P, Hermans L, Arnulf I, Pijpers A, Overeem S, van Gilst M. Validation of the Dutch translation of the Paris Arousal Disorders Severity Scale for non-REM parasomnias in a 1-year and 1-month version. . 2022;18(4):1135-1143.
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http://dx.doi.org/10.5664/jcsm.9830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8974369PMC
April 2022

Sleep onset is a creative sweet spot.

Sci Adv 2021 Dec 8;7(50):eabj5866. Epub 2021 Dec 8.

Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Paris 75013, France.

The ability to think creatively is paramount to facing new challenges, but how creativity arises remains mysterious. Here, we show that the brain activity common to the twilight zone between sleep and wakefulness (nonrapid eye movement sleep stage 1 or N1) ignites creative sparks. Participants ( = 103) were exposed to mathematical problems without knowing that a hidden rule allowed solving them almost instantly. We found that spending at least 15 s in N1 during a resting period tripled the chance to discover the hidden rule (83% versus 30% when participants remained awake), and this effect vanished if subjects reached deeper sleep. Our findings suggest that there is a creative sweet spot within the sleep-onset period, and hitting it requires individuals balancing falling asleep easily against falling asleep too deeply.
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http://dx.doi.org/10.1126/sciadv.abj5866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654287PMC
December 2021

Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder.

J Parkinsons Dis 2022 ;12(1):333-340

Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy.

Background: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy.

Objective: To examine the role of PSAP mutations in iRBD.

Methods: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018).

Results: Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more.

Conclusion: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.
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http://dx.doi.org/10.3233/JPD-212867DOI Listing
April 2022

From burlesque to horror: a century of sleepwalking on the silver screen.

Sleep Med 2021 09 21;85:172-183. Epub 2021 Jul 21.

Sleep Disorder Unit, Pitié Salpêtrière Hospital, Sorbonne University, Paris, France. Electronic address:

Background: Long before being described as a disorder, sleepwalking was considered as a mysterious phenomenon inspiring artwork. From the early beginning of cinema, sleepwalkers were shown to populations, playing a crucial role in storytelling and collective knowledge.

Objective: We characterized how sleepwalking has been portrayed in a large number of movies from the origins of cinema to recent years.

Methods: Movies containing the words "sleepwalking" or "somnambulism" were searched for in International Movie Databases. Types of movies, sleepwalking characters, postures and behaviors during episodes, triggers, and suggested treatments were collected.

Results: Production of 87 movies and 22 cartoons portraying sleepwalkers was clustered around two peaks, in the 1910s and 2010s. Comedies predominated before 1960, and thriller/horror movies as a dominant genre after 1960. In contrast with real-life sleepwalking epidemiology, sleepwalkers are more often portrayed as women than men (and often wearing a transparent white nightgown), as adults more than children on-screen, and 23% suffered psychiatric comorbidities. The unrealistic posture of outstretched arms and eyes closed was found in 20% of movies and 79% of cartoons. Night terrors, sexsomnias (kissing, having sex, initiated pregnancy), sleep-related eating and sleep driving were also featured. Homicides and falls while sleepwalking were recurrent fear-inducing topics. The first sleep EEG was featured in a sleepwalking movie in 1985, and a sleep specialist gave his first advice in 1997.

Discussion: The representation of sleepwalking on the screen seems to have evolved from popular, unrealistic stereotypes of somnambulism towards a medical condition, paralleling the development of sleep medicine.
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http://dx.doi.org/10.1016/j.sleep.2021.07.015DOI Listing
September 2021

Sleeping through a pandemic: impact of COVID-19-related restrictions on narcolepsy and idiopathic hypersomnia.

J Clin Sleep Med 2022 01;18(1):255-263

Sleep Disorders Unit, University Hospital Pitié-Salpêtrière, APHP-Sorbonne, Paris, France.

Study Objectives: To assess the impact of coronavirus disease 2019 (COVID-19)-related restrictions on narcolepsy type 1 (NT2), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH).

Methods: Participants with NT1, NT2, and IH followed in a university hospital completed an online 78-question survey assessing demographic, clinical, and occupational features of the population during the first COVID-19-related lockdown.

Results: A total of 219 of 851 (25.7%) respondents of the survey reported a mean increase of 1.2 ± 1.9 hours ( < .001) in night sleep time and a mean decrease of 1.0 ± 3.4 points ( < .001) on the Epworth Sleepiness Scale during lockdown. Bedtime was delayed by 46.1% of participants and wakeup time was delayed by 59.6%, driven primarily by participants with IH. Teleworkers (but not in-person workers) reported a mean increase of 0.9 ± 1.2 hours in night sleep ( < .001) and a mean decrease in sleepiness score of 1.6 ± 3.1 ( < .001). Cataplexy improved in 54.1% of participants with NT1. Sleepiness correlated with psychological wellness ( = .3, < .001). As many as 42.5% enjoyed the lockdown, thanks to reallocation of time usually spent commuting toward longer sleep time, hobbies, and family time, and appreciated a freer napping schedule. Conversely, 13.2% disliked the lockdown, feeling isolation and psychological distress.

Conclusions: Extended sleep time, circadian delay (in patients with IH), and teleworking resulted in decreased symptoms of central hypersomnias. These findings suggest that people with IH, NT1, and NT2 may benefit from a decrease in social and professional constraints on sleep-wake habits, and support advocacy efforts aimed at facilitating workplace and schedule accommodations for this population.

Citation: Nigam M, Hippolyte A, Dodet P, et al. Sleeping through a pandemic: impact of COVID-19-related restrictions on narcolepsy and idiopathic hypersomnia. . 2022;18(1):255-263.
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http://dx.doi.org/10.5664/jcsm.9556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807898PMC
January 2022

Functional brain imaging using 18F-fluorodeoxyglucose positron emission tomography/computerized tomography in 138 patients with Kleine-Levin syndrome: an early marker?

Brain Commun 2021 17;3(2):fcab130. Epub 2021 Jun 17.

Sorbonne University, Paris Brain Institute (ICM), Inserm UMR-S975, CNRS UMR7225, Paris 75013, France.

Kleine-Levin syndrome is a rare disorder characterized by relapsing-remitting episodes of severe hypersomnia, cognitive impairment, apathy, derealization and behavioural disturbances. Between episodes, most patients experience normal sleep, mood and behaviour, but they may have some residual abnormalities in brain functional imaging; however, the frequency, localization and significance of abnormal imaging are unknown, as brain functional imaging have been scarce and heterogenous [including scintigraphy 18F-fluorodeoxyglucose positron emission tomography/computerized tomography (FDG-PET/CT) and functional MRI during resting state and cognitive effort] and based on case reports or on group analysis in small groups. Using visual individual analysis of 18F-fluorodeoxyglucose positron emission tomography/computerized tomography at the time of Kleine-Levin syndrome diagnosis, we examined the frequency, localization and clinical determinants of hypo- and hypermetabolism in a cross-sectional study. Among 179 patients with Kleine-Levin syndrome who underwent 18F-fluorodeoxyglucose positron emission tomography/computerized tomography, the visual analysis was restricted to the 138 untreated patients studied during asymptomatic periods. As many as 70% of patients had hypometabolism, mostly affecting the posterior associative cortex and the hippocampus. Hypometabolism was associated with younger age, recent (<3years) disease course and a higher number of episodes during the preceding year. The hypometabolism was more extensive (from the left temporo-occipital junction to the entire homolateral and then the bilateral posterior associative cortex) at the beginning of the disorder. In contrast, there was hypermetabolism in the prefrontal dorsolateral cortex in half of the patients (almost all having concomitant hypometabolism in the posterior areas), which was also associated with younger age and shorter disease course. The cognitive performances (including episodic memory) were similar in patients with versus without hippocampus hypometabolism. In conclusion, hypometabolism is frequently observed upon individual visual analysis of 18F-fluorodeoxyglucose positron emission tomography/computerized tomography during asymptomatic Kleine-Levin syndrome periods; it is mostly affecting the posterior associative cortex and the hippocampus and is mostly in young patients with recent-onset disease. Hypometabolism provides a trait marker during the first years of Kleine-Levin syndrome, which could help clinicians during the diagnosis process.
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http://dx.doi.org/10.1093/braincomms/fcab130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226192PMC
June 2021

Sweet or Bland Dreams? Taste Loss in Isolated REM-Sleep Behavior Disorder and Parkinson's Disease.

Mov Disord 2021 10 12;36(10):2431-2435. Epub 2021 Jun 12.

Sleep Disorders Unit, University Hospital Pitié-Salpêtrière, APHP-Sorbonne, Paris, France.

Background: Hyposmia and isolated REM sleep behavior disorder are well-established features of prodromal Parkinson's disease (PD).

Objectives: The objective of the present study was to evaluate whether taste loss (reported in PD and possibly suggesting brain stem involvement) is present at the isolated REM sleep behavior disorder stage.

Methods: We assessed taste function using the Taste Strip Test (evaluating 4 concentrations of bitter, sweet, sour, and salty) in 44 participants with isolated REM sleep behavior disorder, 19 with PD, and 29 controls. All participants underwent video-polysomnography, standardized questionnaires, and clinical examination, including olfactory assessment.

Results: Participants with isolated REM sleep behavior disorder and PD had lower taste scores than controls. There was no difference between isolated REM sleep behavior disorder and PD cohorts, nor was there any correlation between taste and olfaction, age, disease duration, cognition, or autonomic function.

Conclusion: This study demonstrates for the first time the presence of taste impairment in isolated REM sleep behavior disorder that is independent of olfactory dysfunction and comparable to participants with PD. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28692DOI Listing
October 2021

Delayed Benefit From Aggressive Immunotherapy in Waxing and Waning Anti-IgLON5 Disease.

Neurol Neuroimmunol Neuroinflamm 2021 07 13;8(4). Epub 2021 May 13.

From the Department of Neurology (P.S., A.H., C.M., C.D., C.L., A.M.), Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Department of Neurology (D.Z., J.S., F.P.), Versailles Hospital, Le Chesnay, France; Department of Neurology (D.Z.), CHU Yalgado Ouédraogo, Ouagadougou, Burkina Faso; Department of Neurophysiology (B.G.), Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Sorbonne University (C.L., I.A., A.M.), Paris, France; Sleep Disorder Unit (I.A., A.G.), Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Service de Neurologie 2-Mazarin (D.P.), Groupe Hospitalier Pitié-Salpêtrière et Université Pierre et Marie Curie-Paris 6, AP-HP, Centre de Compétence des Syndromes Neurologiques Paranéoplasiques et Encéphalites Autoimmunes, Paris, France; French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (J.H.), Hospices Civils de Lyon, Institut NeuroMyoGene, INSERM U1217/CNRS UMR5310, Université de Lyon, Université Claude Bernard Lyon 1, France.

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http://dx.doi.org/10.1212/NXI.0000000000001009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192057PMC
July 2021

The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson's disease.

Brain 2021 11;144(10):3114-3125

Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, INSERM, CNRS, 75013 Paris, France.

In Parkinson's disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson's disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson's disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson's disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal intergroup difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson's disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; and voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content.
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http://dx.doi.org/10.1093/brain/awab191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634084PMC
November 2021

Association of Central Hypersomnia and Fatigue in Patients With Multiple Sclerosis: A Polysomnographic Study.

Neurology 2021 07 30;97(1):e23-e33. Epub 2021 Apr 30.

From the Neurology Department (A.-L.D., B.S.), Saint Antoine Hospital, AP-HP; Sleep Disorders Unit and National Reference Center for Narcolepsy and Hypersomnia (A.-L.D., I.A.), Department of Biostatistics (S.T.d.M.), and Neurology Department (R.A., C.P., C.L.), Pitié-Salpêtrière University Hospital, APHP, Paris; Neurology Department (F.V., M.C.) and Neurophysiology Department (M.T.), Purpan Hospital, Toulouse; and Institut du Cerveau et de la Moelle Épinière (C.L., I.A., B.S.), Sorbonne Université, Hôpital de la Pitié Salpêtrière, Inserm UMR S 1127, CNRS UMR 7225, Paris, France.

Objective: To evaluate sleepiness and central hypersomnia in multiple sclerosis (MS)-associated fatigue, we performed long-term polysomnography in patients with MS and healthy controls.

Methods: Patients with MS and healthy controls completed questionnaires on sleep, fatigue, sleepiness, and depression. They underwent nocturnal polysomnography, multiple sleep latency tests, and bed rest 24-hour polysomnography. Patients were divided into 3 groups (fatigue and sleepiness, fatigue and no sleepiness, neither fatigue nor sleepiness).

Results: Among 44 patients with MS, 19 (43.2%) had fatigue and sleepiness, 15 (34%) had only fatigue, and 10 (22.7%) had neither fatigue nor sleepiness. Compared to 24 controls, patients with fatigue and sleepiness had higher REM sleep percentages (median [interquartile range] 20.5% [19.6-24.7] vs 18.1% [12.6-20.6]), lower arousal indexes (12.7 [7.5-17.0] vs 22.4 [14.3-34.4]), and shorter daytime mean sleep latencies (8.6 [6.3-14.3] vs 16.6 [12.6-19.5] min). Restless leg syndrome, periodic leg movements, and sleep apnea had similar frequencies between groups. Central hypersomnia was found in 10 (53%) patients with fatigue and sleepiness (narcolepsy type 2, n = 2), in 2 (13%) patients with fatigue only, and in 3 (30%) patients with neither fatigue nor sleepiness. Patients with central hypersomnia were younger and sleepier than those without hypersomnia, but had similar levels of fatigue, disability, depression, cognitive performance, and frequencies of the human leukocyte antigen DQB1*0602 genotype. The severity of fatigue increased with higher depression scores, higher sleepiness severity, and lower sleep efficacy.

Conclusion: Central hypersomnias are frequent in MS when fatigue and sleepiness are present. Screening them through polysomnography studies is recommended.
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http://dx.doi.org/10.1212/WNL.0000000000012120DOI Listing
July 2021

Grumpy face during adult sleep: A clue to negative emotion during sleep?

J Sleep Res 2021 12 29;30(6):e13369. Epub 2021 Apr 29.

Sleep Disorder Unit, APHP, Pitie-Salpetriere University Hospital, Paris, France.

Negative facial expressions and frowns have been studied (albeit more rarely than smiles) in fetus' and neonate' sleep, but they have not been investigated during adult sleep. Video polysomnography (including corrugator muscle electromyography and face-focussed video) was used to study negative facial expressions in sleeping adults, including healthy subjects and patients with/out parasomnia. Frowns were observed during sleep in 89/91 (97.8%) adults during normal (29 healthy subjects) and abnormal sleep (29 patients without parasomnia, 15 patients with disorders of arousal and 18 patients with rapid eye movement [REM] sleep behaviour disorder [RBD]). In healthy subjects, the following events occurred in decreasing frequency: isometric corrugator activations, brief frowns, and then prolonged frowns and raised eyebrows (both similarly rare). Frowns predominated in REM sleep, and had a lower frequency in non-REM sleep. In healthy subjects, frowns were elementary and not associated with other face movements to the point of composing negative expressions. In contrast, frowns were occasionally associated with overt negative facial expressions in REM sleep in patients with RBD and a young patient with night terrors. They included mostly painful expressions and rarely sadness and anger in connection with apparently negative behaviours (shouts, painful moaning, and speeches). Frowns persist during normal sleep (mostly in REM sleep) in adults, but overt negative facial expressions are restricted to patients with parasomnia. Whether elementary frowns translate a negative dream emotion should be determined, but overt negative facial expressions during RBD could be used as a direct access to dream emotions.
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http://dx.doi.org/10.1111/jsr.13369DOI Listing
December 2021

Diagnostic approach to sleep disordered-breathing among patients with grade III obesity.

Sleep Med 2021 06 29;82:18-22. Epub 2021 Mar 29.

AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, site Pitié-Salpêtrière, Service de Pathologies Du Sommeil (Département R3S), F-75013 Paris, France; Sorbonne Université, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France.

Sleep apnea test (SAT) is a cost-effective approach to evaluate subjects without associated comorbidities suspected for obstructive sleep apnea (OSA), a disorder particularly common in obese subjects. The association of obesity with awake hypercapnia (carbon dioxide arterial pressure, PaCO ≥45 mmHg) defines the obesity-hypoventilation syndrome (OHS), which in turn results in increased morbidity and mortality compared to simple OSA. Isolated hypoventilation during sleep in obese patients (obesity-related sleep hypoventilation, ORSH) is now considered as an early stage of OHS. The aim of this study was to assess the performance of SAT in diagnosing OSA and predicting the presence of ORHS among patients with grade III obesity without awake hypercapnia.

Methods: Over a 14-months period, patients with grade III obesity (body mass index≥40 kg/m) presenting moderate-to-severe OSA (apnea-hypopnea index [AHI]≥15) upon SAT and normal awake PaCO at arterial blood gas analysis, systematically underwent in-lab nocturnal polysomnography combined with transcutaneous carbon dioxide pressure (PtcCO) monitoring.

Results: Among 48 patients included in the study, 16 (33%) presented an AHI<15 upon polysomnography and 14 (29%) had ORSH. The test revealed no difference in ORSH prevalence between patients with AHI <15 or ≥15 (31% vs. 25%). No SAT variables were independently associated with increased PtCO.

Conclusions: This study shows that SAT overestimates OSA severity and ORSH affects one third of patients with grade III obesity without awake hypercapnia and with moderate-to-severe OSA at SAT, suggesting how polysomnography combined with PtCO monitoring is the most appropriate diagnostic approach for OSA and ORSH in this population.
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http://dx.doi.org/10.1016/j.sleep.2021.03.024DOI Listing
June 2021
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