Unrefreshing naps and sleep architecture during the multiple sleep latency test in idiopathic hypersomnia.

Patients with idiopathic hypersomnia frequently report having unrefreshing naps. However, whether they have abnormal sleep architecture during naps that may explain their unrefreshing aspect is unknown. We compared sleep architecture during short daytime naps in patients with idiopathic hypersomnia reporting unrefreshing and refreshing naps. One-hundred and thirty-four patients tested with one-night polysomnography, followed by an adapted version of the Multiple Sleep Latency Test with four naps, were included. They were asked about the refreshing aspect of their habitual naps during a clinical interview. They were classified as having objective (Multiple Sleep Latency Test ≤ 8 min) or subjective idiopathic hypersomnia (Multiple Sleep Latency Test > 8 min), and as presenting refreshing or unrefreshing naps. We tested Group differences (refreshing versus unrefreshing naps) on nap sleep architecture in the whole sample and for subjective and objective idiopathic hypersomnia subgroups separately using ANCOVAs. No Group effects were observed in the Multiple Sleep Latency Test architecture in the whole sample and in objective and subjective idiopathic hypersomnia subgroups. This study provides preliminary evidence that reporting unrefreshing naps is not associated with clinically significant findings in Multiple Sleep Latency Test sleep architecture in patients with idiopathic hypersomnia. Given that naps taken by patients with idiopathic hypersomnia are typically long, future studies should investigate longer daytime sleep episodes.

Altered fornix integrity is associated with sleep apnea-related hypoxemia in mild cognitive impairment.

INTRODUCTION: The limbic system is critical for memory function and degenerates early in the Alzheimer's disease continuum. Whether obstructive sleep apnea (OSA) is associated with alterations in the limbic white matter tracts remains understudied. METHODS: Polysomnography, neurocognitive assessment, and brain magnetic resonance imaging (MRI) were performed in 126 individuals aged 55-86 years, including 70 cognitively unimpaired participants and 56 participants with mild cognitive impairment (MCI). OSA measures of interest were the apnea-hypopnea index and composite variables of sleep fragmentation and hypoxemia. Microstructural properties of the cingulum, fornix, and uncinate fasciculus were estimated using free water-corrected diffusion tensor imaging. RESULTS: Higher levels of OSA-related hypoxemia were associated with higher left fornix diffusivities only in participants with MCI. Microstructure of the other white matter tracts was not associated with OSA measures. Higher left fornix diffusivities correlated with poorer episodic verbal memory. DISCUSSION: OSA may contribute to fornix damage and memory dysfunction in MCI. HIGHLIGHTS: Sleep apnea-related hypoxemia was associated with altered fornix integrity in MCI. Altered fornix integrity correlated with poorer memory function. Sleep apnea may contribute to fornix damage and memory dysfunction in MCI.

Longitudinal study of childhood sleep trajectories and adolescent mental health problems.

Study Objective: To investigate whether childhood sleep trajectories are associated with mental health symptoms such as social phobia, generalized anxiety, depression, attention deficit hyperactivity disorder (ADHD), conduct problems, and opposition at age 15. Methods: A total of 2120 children took part in the Quebec Longitudinal Study of Child Development. Childhood sleep trajectories were computed from maternal reports at 2.5, 3.5, 4, 6, 8, 10, and/or 12 years. At age 15, 1446 adolescents filled out mental health and sleep questions. A path analysis model was assessed in the full sample. Results: Four childhood nocturnal sleep duration trajectories were identified: (1) a short pattern (7.5%), (2) a short-increasing pattern (5.8%), (3) a 10 hours pattern (50.7%), and (4) an 11 hours pattern (36.0%). Three childhood sleep latency trajectories were found: (1) a short pattern (31.7%), (2) an intermediate pattern (59.9%), and (3) a long pattern (8.4%). Finally, two childhood wakefulness after sleep-onset trajectories were found: (1) a normative pattern (73.0%) and (2) a long pattern (27.0%). The path analysis model indicated that children following a long childhood sleep latency trajectory were more likely to experience symptoms of depression (ß = 0.06, 95% CI: 0.01 to 0.12), ADHD (ß = 0.07, 95% CI: 0.02 to 0.13), conduct problems (ß = 0.05, 95% CI: 0.00 to 0.10) and opposition (ß = 0.08, 95% CI: 0.02 to 0.13) at age 15. Conclusions: This longitudinal study revealed that children presenting a long sleep latency throughout childhood are at greater risk of symptoms of depression, ADHD, conduct problems, and opposition in adolescence.

Technical challenges in REM sleep microstructure classification: A study of patients with REM sleep behaviour disorder.

While commonly treated as a uniform state in practice, rapid eye movement sleep contains two distinct microstructures-phasic (presence of rapid eye movement) and tonic (no rapid eye movement). This study aims to identify technical challenges during rapid eye movement sleep microstructure visual classification in patients with rapid eye movement sleep behaviour disorder, and to propose solutions to enhance reliability between scorers. Fifty-seven sleep recordings were randomly allocated into three subsequent batches (n = 10, 13 and 34) for scoring. To reduce single-centre bias, we recruited three raters/scorers, with each trained from a different institution. Two raters independently scored each 30-s rapid eye movement sleep into 10â€…× fSEM3-s phasic/tonic microstructures based on the AASM guidelines. The third rater acted as an "arbitrator" to resolve opposite opinions persisting during the revision between batches. Besides interrater differences in artefact rejection rate, interrater variance frequently occurred due to transitioning between microstructures and moderate-to-severe muscular/electrode artefact interference. To enhance interrater agreement, a rapid eye movement scoring schematic graph was developed, incorporating proxy electrode use, filters and cut-offs for microstructure transitioning. To assess potential effectiveness of the schematic graph proposed, raters were instructed to systematically apply it in scoring for the third batch. Of the 34 recordings, 27 reached a Cohen's kappa score above 0.8 (i.e. almost perfect agreement between raters), significantly improved from the prior batches (p = 0.0003, Kruskal-Wallis test). Our study illustrated potential solutions and guidance for challenges that may be encountered during rapid eye movement sleep microstructure classification.

REM sleep is reduced in late middle-aged and older APOE4 allele carriers.

STUDY OBJECTIVES: Apolipoprotein E ɛ4 (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD). In addition, APOE4 carriers may exhibit sleep disturbances, but conflicting results have been reported, such that there is no clear consensus regarding which aspects of sleep are impacted. Our objective was to compare objective sleep architecture between APOE4 carriers and non-carriers, and to investigate the modulating impact of age, sex, cognitive status and obstructive sleep apnea. METHODS: 198 dementia-free participants aged >55 years old (mean age: 68.7 ± 8.08 years old, 40.91% women, 41 APOE4 carriers) were recruited in this cross-sectional study. They underwent polysomnography, APOE4 genotyping and a neuropsychological evaluation. ANCOVAs assessed the effect of APOE4 status on sleep architecture, controlling for age, sex, cognitive status and the apnea-hypopnea index. Interaction terms were added between APOE4 status and covariates. RESULTS: REM sleep percentage (F=9.95, p=0.002, ηp2=0.049) and duration (F=9.23, p=0.003, ηp2=0.047) were lower in APOE4 carriers. The results were replicated in a subsample of 112 participants without moderate-to-severe obstructive sleep apnea. There were no significant interactions between APOE4 status and age, sex, cognitive status and obstructive sleep apnea in the whole sample. CONCLUSIONS: Our results show that APOE4 carriers exhibit lower REM sleep duration, including in cognitively unimpaired individuals, possibly resulting from early neurodegenerative processes in regions involved in REM sleep generation and maintenance.

99mTc-HMPAO SPECT Perfusion Signatures Associated With Clinical Progression in Patients With Isolated REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Idiopathic/isolated REM sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies and Parkinson disease. Despite evidence of abnormal cerebral perfusion in iRBD, there is currently no pattern that can predict whether an individual will develop dementia with Lewy bodies or Parkinson disease. The objective was to identify a perfusion signature associated with conversion to dementia with Lewy bodies in iRBD. METHODS: Patients with iRBD underwent video-polysomnography, neurologic and neuropsychological assessments, and baseline 99mTc-HMPAO SPECT to assess relative cerebral blood flow. Partial least squares correlation was used to identify latent variables that maximized covariance between 27 clinical features and relative gray matter perfusion. Patient-specific scores on the latent variables were used to test the association with conversion to dementia with Lewy bodies compared with that with Parkinson disease. The signature's expression was also assessed in 24 patients with iRBD who underwent a second perfusion scan, 22 healthy controls, and 19 individuals with Parkinson disease. RESULTS: Of the 137 participants, 93 underwent SPECT processing, namely 52 patients with iRBD (67.9 years, 73% men), 19 patients with Parkinson disease (67.3 years, 37% men), and 22 controls (67.0 years, 73% men). Of the 47 patients with iRBD followed up longitudinally (4.5 years), 12 (26%) developed a manifest synucleinopathy (4 dementia with Lewy bodies and 8 Parkinson disease). Analysis revealed 2 latent variables between relative blood flow and clinical features: the first was associated with a broad set of features that included motor, cognitive, and perceptual variables, age, and sex; the second was mostly associated with cognitive features and RBD duration. When brought back into the patient's space, the expression of the first variable was associated with conversion to a manifest synucleinopathy, whereas the second was associated with conversion to dementia with Lewy bodies. The expression of the patterns changed over time and was associated with worse motor features. DISCUSSION: This study identified a brain perfusion signature associated with cognitive impairment in iRBD and transition to dementia with Lewy bodies. This signature, which can be derived from individual scans, has the potential to be developed into a biomarker that predicts dementia with Lewy bodies in at-risk individuals.

Montreal Cognitive Assessment and the Clock Drawing Test to Identify MCI and Predict Dementia in Isolated REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: Patients with isolated/idiopathic REM sleep behavior disorder (iRBD) are at high risk for developing mild cognitive impairment (MCI) and dementia with Lewy bodies (DLB). However, there is a lack of scientific knowledge regarding the accuracy of cognitive screening tools to identify these conditions in iRBD. This study aimed to determine in iRBD the psychometrics of 2 screening tests to discriminate patients with MCI and those at risk of DLB. METHODS: We retrospectively selected and followed 64 patients with polysomnography-confirmed iRBD seen in sleep clinic between 2006 and 2021, 32 with MCI (mean age 68.44 years, 72% men), 32 without MCI (67.78 years, 66% men), and 32 controls (69.84 years, 47% men). Participants underwent a neurologic evaluation and neuropsychological assessment for MCI diagnosis. They also completed the Montreal Cognitive Assessment (MoCA) and Clock Drawing Test (CDT). Fifty-three patients were followed (mean of 5.10 ± 2.64 years); 6 developed DLB, and 16 developed Parkinson disease. An independent cohort of 10 patients with iRBD who later developed DLB was also recruited and followed. Receiver operating characteristic curves with area under the curve (AUC) were performed assessing the discriminant value of the MoCA and CDT. RESULTS: The cut-off values that best differentiated patients who developed DLB from controls were on the MoCA total score (≤25/30 with 100% [95% CI 61%-100%] sensitivity and 78% [61%-89%] specificity, AUC = 0.888) and delayed recall (≤3/5 with 83% [44%-97%] sensitivity and 78% [61%-89%] specificity, AUC = 0.875). Both values yielded a sensitivity of 90% (60%-98%) to detect patients at risk of DLB in the independent cohort. Cutoffs that best discriminated patients with MCI from controls were: ≤25/30 (MoCA total score) with 72% [55%-84%] sensitivity, 78% [61%-89%] specificity, AUC = 0.803 and ≤2/5 (MoCA delayed recall) with 63% [45%-77%] sensitivity, 94% [80%-98%] specificity, AUC = 0.843. No acceptable optimal values were found for the CDT. DISCUSSION: In iRBD, the MoCA demonstrates adequate psychometric properties to identify patients most at risk of developing DLB and to screen for MCI, whereas the CDT does not. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the MoCA, but not the CDT, is useful in screening patients with iRBD for the risk of developing DLB.

Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study.

INTRODUCTION: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia. METHODS: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing. RESULTS: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes. DISCUSSION: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion. HIGHLIGHTS: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion.

Spoken Language Alterations can Predict Phenoconversion in Isolated Rapid Eye Movement Sleep Behavior Disorder: A Multicenter Study.

OBJECTIVE: This study assessed the relationship between speech and language impairment and outcome in a multicenter cohort of isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: Patients with iRBD from 7 centers speaking Czech, English, German, French, and Italian languages underwent a detailed speech assessment at baseline. Story-tale narratives were transcribed and linguistically annotated using fully automated methods based on automatic speech recognition and natural language processing algorithms, leading to the 3 distinctive linguistic and 2 acoustic patterns of language deterioration and associated composite indexes of their overall severity. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The Cox proportional hazard was performed to evaluate the predictive value of language patterns for phenoconversion over a follow-up period of 5 years. RESULTS: Of 180 patients free of parkinsonism or dementia, 156 provided follow-up information. After a mean follow-up of 2.7 years, 42 (26.9%) patients developed neurodegenerative disease. Patients with higher severity of linguistic abnormalities (hazard ratio [HR = 2.35]) and acoustic abnormalities (HR = 1.92) were more likely to develop a defined neurodegenerative disease, with converters having lower content richness (HR = 1.74), slower articulation rate (HR = 1.58), and prolonged pauses (HR = 1.46). Dementia-first (n = 16) and parkinsonism-first with mild cognitive impairment (n = 9) converters had higher severity of linguistic abnormalities than parkinsonism-first with normal cognition converters (n = 17). INTERPRETATION: Automated language analysis might provide a predictor of phenoconversion from iRBD into synucleinopathy subtypes with cognitive impairment, and thus can be used to stratify patients for neuroprotective trials. ANN NEUROL 2024;95:530-543.

Is REM Sleep Behavior Disorder Changing? Secular Changes Versus Referral Patterns.

Background: Since 2014, there has been increasing public outreach effort regarding isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) in Montreal. Objective: To assess if, over time, milder iRBD cases are presenting earlier. Methods: Disease-free survival was compared in two iRBD recruitment epochs: 2004 to 2013 ("earlier") versus 2014to 2022 ("later") and by referral type ("self-referral" vs. "conventional-referral") in three large centers. Results: In Montreal, among 209 subjects followed prospectively, shorter time to phenoconversion was observed in the earlier epoch (5-year phenoconversion = 42% earlier vs. 23% later); diagnosis before 2014 had a 1.8-fold phenoconversion hazard. However, no difference was observed in 248 subjects from Barcelona and 166 from Innsbruck. Analysis of Montreal data found that increased survival in the later epoch was driven by an increasing number of self-referrals, who phenoconverted at 1/3 the rate of physician-referred subjects. Conclusions: Increased patient awareness of iRBD results in earlier presentation to clinical attention, with a longer time to phenoconversion.

[Assessments of sleepiness in adolescents: A key tool for better intervene in mental health]. / Évaluer la somnolence diurne auprès des adolescents : un incontournable pour mieux intervenir en santé mentale.

Objectives Daytime sleepiness in adolescents has negative impacts on physical, cognitive, and emotional health, with direct or indirect consequences on their mental health. This review aims to describe specialized tools assessing daytime sleepiness in adolescents so that mental health professionals can screen for a variety of sleep disorders, from the rarest ones, such as narcolepsy, to the most common ones, such as sleep-wake cycle delay in adolescents. Method Articles were selected in Medline (https://pubmed.ncbi.nlm.nih.gov/) and targeted adolescents aged between 13 and 18 or the keyword "adolescent*". The keywords used were: "sleepiness test" AND "questionnaire*". Only articles in French or English and published until January 9, 2023 were included. A total of 277 scientific articles were screened. Final sample included a total of 35 articles describing sleepiness measurement tools in adolescents. Results Among the 35 articles, a total of seven daytime sleepiness measurement tools in adolescents were identified. Four of them were subjective: 1) the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), 2) the Pediatric Daytime Sleepiness Scale (PDSS), 3) the Cleveland Adolescent Sleepiness Questionnaire (CASQ) and 4) the French Sleepiness Scale for Adolescents (FSSA). These self-reported questionnaires are less expensive and they can be used easily by mental health professionals as opposed to objective tools. Three objective tools have been identified: 1) the multiple sleep latency test (MSLT), 2) the maintenance of wakefulness test or called the "Maintenance Wakefulness Test" (MWT) and 3) the pupillographic sleepiness test (PST). Conclusion Given that adolescents end-of the-day sleep pressure, often resulting in a greater opportunity to light exposure, they are more at risk for daytime sleepiness and consequently to mental health challenges. Mental health professionals should therefore systematically screen for daytime sleepiness in adolescents using subjective tools. There are reliable and validated tools that are translated into French, such as the FSSA and the ESS-CHAD to measure daytime sleepiness in adolescents and lifestyles problems associated with sleep loss When daytime sleepiness suggests the presence of medical-based sleep disorders, such as narcolepsy, restless sleep disorders or sleep apnea, it is important to pursue an investigation with objective tools (nocturnal polysomnography, MLST and MWT) in collaboration with the adolescent's physician.

REM sleep is associated with the volume of the cholinergic basal forebrain in aMCI individuals.

BACKGROUND: Rapid-eye movement (REM) sleep highly depends on the activity of cholinergic basal forebrain (BF) neurons and is reduced in Alzheimer's disease. Here, we investigated the associations between the volume of BF nuclei and REM sleep characteristics, and the impact of cognitive status on these links, in late middle-aged and older participants. METHODS: Thirty-one cognitively healthy controls (66.8 ± 7.2 years old, 13 women) and 31 participants with amnestic Mild Cognitive Impairment (aMCI) (68.3 ± 8.8 years old, 7 women) were included in this cross-sectional study. All participants underwent polysomnography, a comprehensive neuropsychological assessment and Magnetic Resonance Imaging examination. REM sleep characteristics (i.e., percentage, latency and efficiency) were derived from polysomnographic recordings. T1-weighted images were preprocessed using CAT12 and the DARTEL algorithm, and we extracted the gray matter volume of BF regions of interest using a probabilistic atlas implemented in the JuBrain Anatomy Toolbox. Multiple linear regressions were performed between the volume of BF nuclei and REM sleep characteristics controlling for age, sex and total intracranial volume, in the whole cohort and in subgroups stratified by cognitive status. RESULTS: In the whole sample, lower REM sleep percentage was significantly associated to lower nucleus basalis of Meynert (Ch4) volume (ß = 0.32, p = 0.009). When stratifying the cohort according to cognitive status, lower REM sleep percentage was significantly associated to both lower Ch4 (ß = 0.48, p = 0.012) and total BF volumes (ß = 0.44, p = 0.014) in aMCI individuals, but not in cognitively unimpaired participants. No significant associations were observed between the volume of the BF and wake after sleep onset or non-REM sleep variables. DISCUSSION: These results suggest that REM sleep disturbances may be an early manifestation of the degeneration of the BF cholinergic system before the onset of dementia, especially in participants with mild memory deficits.

Altered resting-state functional connectivity patterns in late middle-aged and older adults with obstructive sleep apnea.

Introduction: Obstructive sleep apnea (OSA) is increasingly recognized as a risk factor for cognitive decline, and has been associated with structural brain alterations in regions relevant to memory processes and Alzheimer's disease. However, it is unclear whether OSA is associated with disrupted functional connectivity (FC) patterns between these regions in late middle-aged and older populations. Thus, we characterized the associations between OSA severity and resting-state FC between the default mode network (DMN) and medial temporal lobe (MTL) regions. Second, we explored whether significant FC changes differed depending on cognitive status and were associated with cognitive performance. Methods: Ninety-four participants [24 women, 65.7 ± 6.9 years old, 41% with Mild Cognitive Impairment (MCI)] underwent a polysomnography, a comprehensive neuropsychological assessment and a resting-state functional magnetic resonance imaging (MRI). General linear models were conducted between OSA severity markers (i.e., the apnea-hypopnea, oxygen desaturation and microarousal indices) and FC values between DMN and MTL regions using CONN toolbox. Partial correlations were then performed between OSA-related FC patterns and (i) OSA severity markers in subgroups stratified by cognitive status (i.e., cognitively unimpaired versus MCI) and (ii) cognitive scores in the whole sample. All analyzes were controlled for age, sex and education, and considered significant at a p < 0.05 threshold corrected for false discovery rate. Results: In the whole sample, a higher apnea-hypopnea index was significantly associated with lower FC between (i) the medial prefrontal cortex and bilateral hippocampi, and (ii) the left hippocampus and both the posterior cingulate cortex and precuneus. FC patterns were not associated with the oxygen desaturation index, or micro-arousal index. When stratifying the sample according to cognitive status, all associations remained significant in cognitively unimpaired individuals but not in the MCI group. No significant associations were observed between cognition and OSA severity or OSA-related FC patterns. Discussion: OSA severity was associated with patterns of lower FC in regions relevant to memory processes and Alzheimer's disease. Since no associations were found with cognitive performance, these FC changes could precede detectable cognitive deficits. Whether these FC patterns predict future cognitive decline over the long-term needs to be investigated.

Are unrefreshing naps associated with nocturnal sleep architecture specificities in idiopathic hypersomnia?

STUDY OBJECTIVES: Unrefreshing naps are supportive clinical features of idiopathic hypersomnia (IH) and are reported by more than 50% of IH patients. They are, however, not mandatory for the diagnosis, and their pathophysiological nature is not understood. This study aimed at verifying whether IH patients with and without unrefreshing naps constitute two subtypes of IH based on their demographic/clinical characteristics, and sleep architecture. METHODS: One hundred twelve IH patients underwent a polysomnography (PSG) followed by a multiple sleep latency test (MSLT). They completed questionnaires on excessive daytime sleepiness, mood, and sleep quality. They were met by sleep medicine physicians who conducted a semi-structured clinical interview and questioned them on refreshing aspects of their naps. Patients who reported unrefreshing naps were compared to patients reporting refreshing naps on questionnaires, MSLT and PSG variables, with age as a covariable. As sensitivity analyses, we performed the same comparisons in participants presenting objective markers of IH and those diagnosed with IH based only on clinical judgment (subjective IH), separately. RESULTS: In the whole sample, 61% of patients reported unrefreshing naps. These participants had less awakenings, a lower percentage of N1 sleep, less sleep stage transitions, and a higher percentage of REM sleep on the nighttime PSG compared to the refreshing naps subgroup. When subjective and objective IH patients were tested separately, more group differences were observed on PSG for subjective IH patients. CONCLUSIONS: Patients with unrefreshing naps have less fragmented sleep compared to those with refreshing naps. Future studies should investigate whether this group difference indicates a weaker arousal drive.

HLA in isolated REM sleep behavior disorder and Lewy body dementia.

Synucleinopathies-related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA-DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95% CI = 1.27-1.93, p = 2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR = 1.26, 95%CI = 1.12-1.41, p = 8.76e-05), 70Q (OR = 0.81, 95%CI = 0.72-0.91, p = 3.65e-04) and 71R (OR = 1.21, 95%CI = 1.08-1.35, p = 1.35e-03). Position 71 (pomnibus = 0.00102) and 70 (pomnibus = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies.

Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy.

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

NPC1 variants are not associated with Parkinson's disease, REM-sleep behavior disorder or dementia with Lewy bodies in European cohorts.

NPC1 encodes a lysosomal protein involved in cholesterol transport. Biallelic mutations in this gene may lead to Niemann-Pick disease type C (NPC), a lysosomal storage disorder. The role of NPC1 in alpha synucleinopathies is still unclear, as different genetic, clinical, and pathological studies have reported contradictory results. This study aimed to evaluate the association of NPC1 variants with the synucleinopathies Parkinson's disease (PD), dementia with Lewy bodies (DLB), and rapid eye movement-sleep behavior disorder (RBD). We analyzed common and rare variants from 3 cohorts of European descent: 1084 RBD cases and 2945 controls, 2852 PD cases and 1686 controls, and 2610 DLB cases and 1920 controls. Logistic regression models were used to assess common variants while optimal sequence Kernel association tests were used to assess rare variants, both adjusted for sex, age, and principal components. No variants were associated with any of the synucleinopathies, supporting that common and rare NPC1 variants do not play an important role in alpha synucleinopathies.

Progression of clinical markers in prodromal Parkinson's disease and dementia with Lewy bodies: a multicentre study.

The neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson's disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson's disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson's disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.

Nocturnal sleep duration trajectories in early childhood and school performance at age 10 years.

Sleep plays a fundamental role in brain development and resultant functions. The aim was to verify whether nocturnal sleep duration during early childhood has long-term associations with academic achievement at age 10 years. The present study is part of the Quebec Longitudinal Study of Child Development, a representative cohort of infants born in 1997-1998 in the province of Quebec, Canada. Children with known neurological conditions were excluded from this cohort. Four trajectories of parent-reported nocturnal sleep duration at ages 2.5, 3, 4, 5 and 6 years were determined using a SAS procedure named PROC TRAJ. Sleep duration at age 10 years was also reported. Teachers provided data on academic performance when the children were age 10 years. These data were available for 910 children (430 boys, 480 girls; 96.6% Caucasians). Univariate and multivariable logistic regressions were performed using SPSS. Children who slept less than 8 hr per night at 2.5 years but normalized later on (Traj1) had three-five times the odds of having grades below the class average in reading, writing, mathematics and science compared with children who slept sufficiently (Traj3-4: 10-11 hr per night). Children who slept about 9 hr per night throughout childhood (Traj2) had two-three times the odds of being below the class average in mathematics and science. Sleep duration at age 10 years was not correlated with the academic performance. These results point to the presence of a very important early period during which sufficient sleep is needed to fine-tune the functions necessary for academic achievement later on.