Background:Blood-based biomarkers offer a scalable alternative to cerebrospinal fluid and PET imaging for Alzheimer's disease (AD) detection, yet traditional venipuncture limits participation among rural and socioeconomically disadvantaged populations. Self-collection using the Tasso+ capillary device could reduce access barriers, but its feasibility and validity for AD plasma biomarkers remain uncertain, particularly with real-world delays prior to processing. Methods:Adults aged 45-90 years from the Wisconsin SHOW cohort who were underrepresented in AD research (Black or Hispanic race/ethnicity, rural residence, or <bachelor's degree) were recruited (n=28). At community "pop-up" clinics participants completed: (1) self-collection of capillary blood via Tasso+; (2) experience surveys; (3) Montreal Cognitive Assessment; and (4) standard venipuncture. To simulate home-based collection and mail return, Tasso+ samples were held at room temperature for 24 hours before centrifugation, whereas venous samples were processed within 30 minutes. Plasma Aβ40, Aβ42, Aβ42/40, GFAP, NfL, and pTau217 were measured on the Quanterix Simoa platform. Between-method agreement was evaluated using Pearson/Spearman correlations, Lin's concordance correlation coefficients (CCC), Bland-Altman analyses, and relative bias. Predictors of percent difference were explored with univariate regression. Results:Tasso+ collection was successful for 96% of participants; 64% rated it very easy and 86% reported comfort/no pain, yet 57% preferred future venipuncture-particularly Black, lower-income, and lower-education participants. Agreement varied markedly by biomarker. GFAP and NfL demonstrated excellent concordance (CCC 0.97-0.98) with minimal bias (-6% to -8%). Aβ40 and Aβ42 showed modest correlations (r=0.40-0.47) and substantial underestimation (-60% to -70%). Aβ42/40 and pTau217 exhibited poor correlation and extreme positive bias for pTau217 (~+2600%). Hemolysis was more frequent in Tasso+ samples and contributed to disagreement for several markers; processing lag and sample volume were not strong predictors. Conclusions:Remote capillary self-collection with a 24-hour delay is suitable for measuring GFAP and NfL but not currently reliable for Aβ or pTau217 without improved handling (e.g., temperature control, hemolysis reduction). Although user experience was favorable, trust and logistical concerns limited preference among underrepresented groups. Community-informed strategies and optimized pre-analytics are essential before deploying Tasso+ in large AD studies.

Slow waves during non-rapid eye movement (NREM) sleep are associated with the restorative aspects of sleep. Previous research has suggested reduced normalized slow wave activity (SWA), particularly in the first cycle of NREM sleep, as a feature of hypersomnolence disorder (HD); however, the scarcity of existing research highlights the need for replication studies. Thus, the aim of this investigation was to evaluate normalized SWA in patients with HD, relative to healthy sleeper controls (HSC). Nocturnal polysomnography from 37 unmedicated HD clinical patients were compared against 29 HSC. Six-channel electroencephalographic data from polysomnography was processed according to consensus standards. Normalized SWA (0.5-4.5hz) was calculated from artefact-free NREM epochs for all-night data, as well as sleep cycle 1, 2, and 3. Normalized SWA was compared across groups, with adjusted analyses accounting for age, sex, body mass index, and depressive symptomatology. Post hoc analyses compared HD who met objective criteria for idiopathic hypersomnia (HD/IH+), those who did not (HD/IH-), and HSC. HD demonstrated significantly reduced all-night, normalized SWA in unadjusted analyses across all channels, without significant differences observed in fully adjusted analyses. In cycle 1, HD displayed significantly reduced normalized SWA across all channels in both unadjusted and adjusted analyses. HD/IH+ and HD/IH- were statistically comparable in normalized SWA across all analyses. This study provides further evidence of reduced SWA, particularly during cycle 1 of NREM sleep, as a core feature of HD. Future studies that investigate the causal role of slow waves in the pathophysiology of HD are warranted.

Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) was a phase 4, prospective, multicenter, single-arm, open-label, multiple-cohort study of individuals with idiopathic hypersomnia or narcolepsy evaluating safety and effectiveness of low-sodium oxybate (LXB; Xywav®) treatment on sleep and daytime symptoms. Results from the idiopathic hypersomnia cohort are reported here. The DUET study included a screening period (with a 2-week washout for current oxybate users), an 8-day baseline (BL) period, a 2- to 8-week LXB titration period, a 2-week stable-dose period, an 8-day end-of-treatment period (EOT) period, and a 2-week safety follow-up. The primary endpoint was the change in Epworth Sleepiness Scale (ESS) score from BL to EOT. Secondary endpoints for the idiopathic hypersomnia cohort included change in Idiopathic Hypersomnia Severity Scale (IHSS) total score; Patient Global Impression of Change (PGI-C) and Severity (PGI-S) for overall idiopathic hypersomnia disease, sleep inertia, and fatigue; and changes in sleep quality and feeling rested upon awakening (from self-reported daily sleep diary). Exploratory outcomes included sleep patterns measured by actigraphy, the British Columbia Cognitive Complaints Inventory, Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10), and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem. Incidence and severity of treatment-emergent adverse events (TEAEs) were assessed. Forty-six participants with idiopathic hypersomnia enrolled and took LXB for ≥ 1 night after the BL period; n = 40 completed. Most enrolled participants were female (80.4 Calcium, magnesium, potassium, and sodium oxybates (also called low-sodium oxybate [LXB; Xywav®]) is approved for treating adults with idiopathic hypersomnia. Low-sodium oxybate is also approved for treating excessive daytime sleepiness or cataplexy in people aged ≥ 7 years with narcolepsy. The DUET study tested sleep and daytime symptoms and daily activities in people with idiopathic hypersomnia who took LXB. Before starting LXB, people completed tests to measure their symptoms. They then started taking LXB. The study doctors adjusted the LXB dosage over 2–8 weeks to find the best dosage for each person. Once found, patients remained on this dosage for 2 more weeks. At the end of the study, tests were repeated to see how the best dosage of LXB affected their sleep and daytime symptoms, daily tasks, and work. Forty-six people with idiopathic hypersomnia started taking LXB, and 40 people completed the study. After LXB treatment, patients had less severe idiopathic hypersomnia symptoms. They felt less sleepy during the day and had less fatigue. They felt that their sleepiness after waking (sleep inertia) was improved. People spent less time sleeping at night and had fewer awakenings. They also said they had better sleep and felt more rested after waking up. Daily tasks and work productivity also improved. The most common side effects with LXB were nausea, dizziness, headache, and vomiting, which happened in more than 10

Purpose:Limited self-reported data on the real-world burden of idiopathic hypersomnia exist from a representative sample of the US general adult population. This study described the clinical, humanistic, and economic burden of adults with idiopathic hypersomnia compared to matched adults without idiopathic hypersomnia. Patients and Methods:This cross-sectional study used 2021 and 2023 US National Health and Wellness Survey data. Propensity score matching (1:2) was performed for adults (≥18 years) who self-reported a physician diagnosis of idiopathic hypersomnia and adults without idiopathic hypersomnia (non-idiopathic hypersomnia cohort). Post matching, outcomes were compared between cohorts using cluster-robust regression models; P values for primary outcomes were not adjusted for multiplicity. Results:Included were 163 adults with idiopathic hypersomnia (64.4% female, mean age 38.45 years) and 326 matched adults without idiopathic hypersomnia (66.0% female, mean age 39.60 years). The idiopathic hypersomnia cohort had higher prevalence of comorbidities (eg cardiovascular, cardiometabolic, sleep, psychiatric), higher mean Charlson comorbidity index scores (1.43 vs 0.34), and reported worse depression (PHQ-9) and anxiety (GAD-7) and poorer mental health, physical function (SF-36v2, RAND-36), and HRQoL (EQ-5D-5L, SF-6D, EQ-VAS) compared to the matched non-idiopathic hypersomnia cohort (P < 0.01). The idiopathic hypersomnia cohort reported more mean healthcare provider visits (13.34 vs 3.14), emergency department visits (0.88 vs 0.45), and hospitalizations (0.95 vs 0.35) in the past 6 months and higher annualized direct medical costs ($46,424.39 vs $14,700.21) than the matched non-idiopathic hypersomnia cohort (P < 0.05). The idiopathic hypersomnia cohort reported greater mean work productivity loss (49.07 vs 32.28) and activity impairment (48.22 vs 30.77), and annualized indirect costs ($15,269.22 vs $10,576.96) than the matched non-idiopathic hypersomnia cohort (P < 0.05). Conclusion:This study highlights the substantial real-world burden, including comorbidity, HRQoL, and economic, of idiopathic hypersomnia compared to the matched non-idiopathic hypersomnia cohort.

BACKGROUND:The clinical potential of orexin 2 receptor (OX2R) agonism for improving measures of wakefulness and cataplexy in patients with narcolepsy type 1 has been described in a phase 2 study. Here, we aimed to evaluate the safety, tolerability, and efficacy of alixorexton, another oral OX2R agonist, in narcolepsy type 1. METHODS:In this randomised, double-blind, placebo-controlled, phase 2 trial, adult participants (aged 18-70 years) with narcolepsy type 1 were recruited from 46 hospitals and private research centres across the USA, Europe, and Australia. Participants were centrally randomly assigned (1:1:1:1) in blocks of four via an interactive response technology system stratified by region and baseline weekly cataplexy rate (WCR) to receive 4 mg, 6 mg, or 8 mg tablets of alixorexton or placebo once daily for 6 weeks, followed by an optional 7-week open-label extension. Participants had narcolepsy type 1, diagnosed per the International Classification of Sleep Disorders, Third Edition, and confirmed by overnight polysomnography and the Multiple Sleep Latency Test or cerebrospinal hypocretin-1 concentrations. The sponsor, assessors, investigators, and participants were masked during the randomised double-blind treatment period. Efficacy and safety assessments were conducted in participants who received at least one dose of study drug. The primary endpoint was change from baseline to week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT). Safety endpoints included treatment-emergent adverse events. This trial was registered with ClinicalTrials.gov (NCT06358950) and is completed. FINDINGS:Between May 24, 2024, and May 5, 2025, 153 individuals were screened and 92 participants were randomly assigned to receive alixorexton 4 mg (n=23), 6 mg (n=22), 8 mg (n=24), or placebo (n=23). Mean age was 33·5 years (SD 12·1), 57 (62%) were women, and 35 (38%) were men. At week 6, the observed MSL on the MWT was 2·3 min (SD 2·7) for placebo, 24·0 min (8·7) for alixorexton 4 mg, 25·9 min (9·4) for 6 mg, and 28·2 min (11·4) for 8 mg. Alixorexton improved MSL on the MWT, with a least-squares mean placebo-corrected change from baseline of 22·2 min (95% CI 17·2-27·2) for alixorexton 4 mg, 24·1 min (19·0-29·1) for 6 mg, and 26·0 min (21·0-31·0) for 8 mg (adjusted p=0·0099 for 4 mg, adjusted p<0·0001 for 6 mg and 8 mg). Treatment-emergent adverse events occurring in at least 5% of participants given alixorexton and more frequently than those given placebo up to week 6 were pollakiuria (38 [55%]), insomnia (19 [28%]), salivary hypersecretion (17 [25%]), micturition urgency (ten [14%]), blurred vision (ten [14%]), and hyperhidrosis (five [7%]). INTERPRETATION:In this phase 2 trial, once-daily oral alixorexton provided clinically meaningful improvements at 6 weeks for participants with narcolepsy type 1, including in wakefulness, excessive daytime sleepiness, and cataplexy. The treatment was generally well tolerated, with adverse events consistent with the known on-target effects of OX2R agonists. Together, these findings support the further phase 3 evaluation of alixorexton as a potential therapeutic option for people with narcolepsy type 1. FUNDING:Alkermes.

Abstract Background Gait variability is a hallmark of Parkinson’s disease (PD) and has been linked to cognitive deficits and fall risk. Rapid eye movement sleep behavior disorder (RBD) is a strong predictor of synucleinopathies, yet evidence for gait changes in RBD is inconsistent. Performing a dual task increases gait variability, an effect that can be quantified using a cost function. Objective Determine the degree to which dual task cost differs between control, RBD, and PD participants at baseline, and between RBD converters versus non-converters at follow-up. Methods 46 RBD, 23 control, and 14 PD participants completed standardized gait analysis at baseline. Parameters chosen for analysis included enhanced gait variability index (eGVI), functional ambulation performance (FAP), velocity, step length, cadence, base of support, and double support time. Medical records were surveilled for 3 years following participant enrollment, determining that 6 RBD participants converted to PD or dementia. Baseline gait indices and dual task costs were compared between control, RBD, and PD groups at enrollment, and between RBD stable and RBD converters at follow-up. Results The PD group had greater eGVI, as well as greater dual task cost for FAP, cadence, width, and double support time. No differences in gait variability were identified between RBD and control groups at baseline. Compared to the stable group, RBD converters had greater dual task cost for FAP, velocity, cadence, and double support time. Conclusions Increased gait variability during dual task may identify RBD patients at imminent risk of phenoconversion.

Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) is a phase 4, prospective, multicenter, single-arm, multiple-cohort, open-label study (NCT05875974) evaluating the effectiveness of low-sodium oxybate (LXB, Xywav®) treatment on outcomes including polysomnography (PSG)-based sleep architecture in participants with idiopathic hypersomnia or narcolepsy. This abstract will include results from the idiopathic hypersomnia cohort. DUET included a screening period (2-week washout for current oxybate users), an 8-day baseline (BL) period, a 2- to 8-week LXB titration period, a 2-week stable-dose period (SDP), an 8-day end-of-treatment period (EOT), and a 2-week safety follow-up. Participants underwent nocturnal PSG using an ad libitum protocol at BL and EOT. PSGs were scheduled to allow a minimum of 10 hours in bed, unless the participant naturally awakened earlier; bedtime was determined by habitual bedtime. PSG recordings were centrally scored. Data were analyzed for participants in the idiopathic hypersomnia cohort completer set. P-values were uncontrolled for multiplicity and therefore considered nominal. Forty-six participants with idiopathic hypersomnia enrolled; 40 completed the study. Most were female (80%) and White (85%) with a mean±SD age of 38.1±11.8 years. Mean±SD total sleep time (TST) at BL and EOT was 467.5±111.9 and 413.4±97.9 minutes, respectively (LSM change [95% CI], –54.1 [–81.3, –26.9]; P=.0003). Mean±SD number of total shifts from deeper to lighter sleep stages at BL and EOT was 60.8±30.1 and 43.7±27.0, respectively (LSM [95% CI], –17.1 [–23.7, –10.5]; P<.0001). Mean±SD time spent in N1 at BL and EOT was 47.8±26.1 and 33.0±22.4 minutes (LSM [95% CI], –14.8 [–20.3, –9.3]; P<.0001), % of stage was 10.3% and 8.0% (P=.0017); in N2, 270.0±64.8 and 225.8±72.8 minutes (LSM [95% CI], –44.3 [–66.7, –21.9]; P=.0003), 58.5% and 54.2% (P=.0286); in N3, 51.9±35.3 and 92.5±53.5 minutes (LSM [95% CI], 40.6 [25.8, 55.4]; P<.0001), 11.2% and 22.8% (P<.0001); and in REM, 97.7±47.0 and 62.1±35.4 minutes (LSM [95% CI], –35.7 [–46.0, –25.3]; P<.0001), 20.0% and 15.0% (P<.0001). Participants with idiopathic hypersomnia treated with open-label LXB demonstrated reduced TST on ad libitum polysomnography compared with baseline, increases in N3 sleep, and changes in sleep architecture. Jazz Pharmaceuticals

Study Objectives:Narcolepsy is a chronic condition affecting the sleep/wake cycle that is challenging to diagnose. Epidemiological data from large US-focused studies remain limited, with no validated claims-based case selection definitions for narcolepsy. We estimated the prevalence/incidence of diagnosed narcolepsy (type 1 [NT1], type 2 [NT2], overall) in an insured US population using validated, claims-based narcolepsy case definitions. Materials and Methods:This observational study used HealthVerity administrative claims-linked electronic medical records to develop case definitions identifying individuals with NT1, NT2, and overall narcolepsy from diagnosis, medication, and procedure codes. Claims-based case definition performance (NT1, NT2, overall narcolepsy) was assessed using positive predictive values (PPVs). Prevalence (per 100 000 persons, on December 31, 2023) and annual incidence (per 100 000 person-years [PY], 2020 - 2023) were calculated/adjusted using PPVs for each case definition. Results:Unadjusted point prevalence among individuals with ≥12 months of continuous enrollment were 15.5/100 000 (NT1), 51.1/100 000 (NT2), and 67.0/100 000 (overall narcolepsy). Unadjusted incidence rates were stable from 2020 - 2023 for NT1 (range, 2.0 - 2.3/100 000 PY) but declined across years for NT2 (9.1 - 7.6/100 000 PY) and overall narcolepsy (11.3 - 9.6/100 000 PY). PPVs (95% confidence interval) of NT1, NT2, and overall narcolepsy were 0.81 (0.72 - 0.88), 0.84 (0.75 - 0.91), and 0.80 (0.71 - 0.87), contributing to epidemiologic estimates being reduced by ~20% after PPV adjustment. Prevalence and incidence were higher in females than males. Individuals with NT1 were ~ 4 years younger versus NT2. Conclusions:Validated definitions for narcolepsy can reduce potential misclassification. Our findings highlight a relatively low NT1 prevalence in the US. In contrast, NT2 prevalence estimates were > 3 times higher than NT1.

Study Objectives:National prevalence estimates for idiopathic hypersomnia (IH) are difficult to obtain. This study estimated the diagnosed IH prevalence among US adults. Methods:Symphony Integrated Dataverse claims (01/2015-12/2023) were analyzed. Eligible patients were aged ≥18 years with at least one medical/prescription claim in the year of interest (2019-2023) and prior year. IH was defined by ≥1 medical claim with an IH diagnosis code. Prevalence was estimated among all eligible patients in two ways: annual (IH diagnoses during year of interest) and all-time (IH diagnoses looking back all-time in the database from 2015 through year of interest). Age- and sex-adjusted prevalence estimates were also calculated using the US Census Bureau. Results:Over 179, 182, 193, 205, and 198 million adults were assessed for diagnosed IH prevalence in each respective year 2019-2023. Unweighted annual prevalence of diagnosed IH from 2019 to 2023 was 12.1, 11.1, 11.0, 10.5, and 11.1 per 100 000 persons, respectively. Unweighted all-time lookback prevalence of diagnosed IH from 2019 to 2023 was 32.7, 37.3, 40.6, 43.3, and 49.0 per 100 000 persons, respectively. From 2019 to 2023, estimated standardized numbers of US adults diagnosed with IH were 30 563, 27 975, 27 859, 26 624, and 28 754 based on annual prevalence, and 82 027, 93 768, 101 766, 107 763, and 124 905 based on all-time prevalence. Conclusions:Annual prevalence estimates (i.e. proportions of individuals with diagnosed IH during each year of interest) remained consistent across the follow-up period, ranging from 10.5 to 12.1 per 100 000 persons, signifying the rarity of the diagnosis.

BACKGROUND AND OBJECTIVES:There is a paucity of research on the role of circadian rhythm disruption in Alzheimer disease (AD)-related cognitive impairments in adults with Down syndrome (DS). The aim of this study was to examine the association of the 24-hour rest-activity rhythm with cognition, dementia symptoms, and clinical AD status in adults with DS. METHODS:In this cross-sectional study, adults with DS aged 25-61 years in the Alzheimer's Biomarkers Consortium-Down Syndrome underwent wrist-worn actigraphy (≥4 days) and cognitive assessment. Primary variables included interdaily stability, intradaily variability, relative amplitude, most active 10-hour period (M10), and least active 5-hour period (L5). Secondary measures included coefficient of variation of total sleep time, sleep midpoint, sleep efficiency, and the sleep regularity index. Cognitive outcomes included modified Cued Recall Test (mCRT), Wechsler Block Design with Haxby Extension (Block Design), Purdue Pegboard, Cat and Dog Modified Stroop Task, DS Mental Status Examination (DSMSE), National Task Group-Early Detection Screen for Dementia (NTG-EDSD), Dementia Questionnaire for People with Learning Disabilities (DLD), and clinical AD status based on a case consensus process (stable vs mild cognitive impairment [MCI]/dementia). Linear and logistic regression models were adjusted for age, sex, intellectual disability level, site, and obstructive sleep apnea severity, with false discovery rate (FDR) correction. RESULTS:Of 115 participants (mean age 40.0 ± 9.2 years; 43.5% female), higher interdaily stability was associated with higher DSMSE scores B = 20.6 (95% CI 5.0-36.2). Higher intradaily variability was associated with worse cognitive performance and increased dementia symptoms: mCRT B = -9.2 (95% CI -15.2 to -3.1), Block Design B = -11.0 (95% CI -19.0 to -3.0), DSMSE B = -12.0 (95% CI -20.1 to -3.9), and DLD-cognitive B = 6.3 (95% CI 3.0-10.5). Lower M10 was associated with increased dementia symptoms: NTG-EDSD B = -0.004 (95% CI -0.008 to -0.001); DLD-cognitive B = -0.004 (95% CI -0.006 to -0.001), and DLD-social B = -0.003 (95% CI -0.005 to -0.0008). All associations remained significant after FDR correction (p < 0.05). Fifteen participants had MCI/dementia. Higher intradaily variability was associated with increased odds of MCI/dementia (OR: 1.45; 95% CI 1.04-2.29) although this was not significant after FDR correction. DISCUSSION:Fragmentation and low amplitude of the 24-hour rest-activity rhythm are associated with AD-related cognitive impairment, dementia symptoms, and increased odds of MCI/dementia in adults with DS. Circadian rhythm disruption may contribute to AD-related outcomes in adults with DS and potentially serve as a modifiable risk factor.

BACKGROUND:Previous research assessing sleep health in collegiate athletes has relied predominantly upon self-report measures. This investigation leveraged a modern, consumer-grade wearable device to examine sleep duration (SD) and timing across a 5-month window, including both preseason and in-season periods, in a sample of female National Collegiate Athletic Association (NCAA) Division I volleyball athletes. HYPOTHESIS:Shorter SD and earlier waketimes would associate with worse self-reported wellbeing (mood, muscle recovery, and energy). SD would be shorter and waketimes would be earlier during preseason, relative to in-season, as well as on weekdays, relative to weekends. STUDY DESIGN:Prospective cohort study. LEVEL OF EVIDENCE:Level 3. METHODS:Data from female NCAA Division I volleyball athletes were collected across a 5-month window. Oura ring measured SD, bedtimes, and waketimes, with wellbeing ratings self-reported each morning. An analytic dataset of 1361 sleep nights from 13 athletes was constructed. Mixed-effects models examined relationships between sleep and wellbeing variables, as well as differences in these variables between preseason versus in-season and weekdays versus weekends. RESULTS:Shorter SD and earlier waketimes were associated significantly with lower self-reported mood and energy. SD was significantly longer in-season, relative to preseason (6.98 ± 0.13 hours) (7.42 ± 0.09 vs 6.98 ± 0.12 hours, P < 0.01). Waketimes were significantly later in-season, relative to preseason (08:20 ± 00:08 vs 07:03 ± 00:05, P < 0.01), and significantly later on weekends, relative to weekdays (08:18 ± 00:08 vs 07:37 ± 00:07, P < 0.01). The shortest SD (6.91 ± 0.13 hours) and earliest waketimes (06:44 ± 00:05) occurred on weekdays during preseason. CONCLUSION:Short SD and early waketimes were associated with lower self-reported mood and energy in collegiate volleyball athletes. Athletes were most vulnerable to insufficient SD on weekdays during the preseason, seemingly as a consequence of earlier waketimes. CLINICAL RELEVANCE:Interventions to facilitate later waketimes, such as delaying early morning training times, may be useful for supporting athlete sleep health and wellbeing.

The objectives of this paper are to identify areas of data deficiencies most relevant to classification of sleep-wake disorders, present existing evidence that informs decisions, and suggest research goals to elucidate classification decisions. A panel of experts in nosology, consisting of ICSD-3-TR task force members and work group chairs, identified key questions related to the classification of sleep disorders. The panel reviewed the literature based on systematic and targeted searches and developed research priorities to address these questions. Numerous unresolved issues were identified following preparation of ICSD-3-TR, including whether insomnia with objective short sleep duration should be a formal subtype of chronic insomnia disorder and nocturnal muscle cramps should be removed as a sleep–wake disorder. In addition, the panel identified the following issues for inclusion: (1) defining diagnostic metrics for COMISA, (2) refining metrics for obstructive sleep apnea and subtypes, (3) clarifying the pathological significance of central sleep apnea, (4) subtyping of idiopathic hypersomnia, (5) evaluating circadian biomarkers and subtyping of delayed sleep–wake phase disorder, (6) revising criteria for periodic limb movement disorder, and (7) establishing REM atonia loss thresholds for REM sleep behavior disorder Research directions and methodologies are outlined for each area. Accurate diagnosis is essential for effective treatment. Imprecise criteria risk unnecessary or missed treatments. Greater investment in diagnostic research is needed to advance data-driven classification systems. The International Classification of Sleep Disorders (American Academy of Sleep Medicine, 2023) [1] is the major nosological system for sleep-wake disorders. It is developed by content experts, employing an evidence-based approach to the formulation of diagnostic criteria and related text. However, through this process, ICSD-3-TR task force members and work group chairs identified areas that lack adequate data for formulation of diagnostic criteria, resulting in diagnostic ambiguity and uncertainty. In this article, this panel reports the identified key issues, presents currently available data, and suggests research strategies to improve accuracy and reliability of diagnosis.

Since sleep inertia and hypersomnolence, broadly, have not been adequately studied in the context of neurocognitive performance, this investigation examined associations between sleep inertia severity, other measures of hypersomnolence, and outcomes from a standardized, cognitive testing battery in a well-characterized community-based sample of older adults. Wisconsin Sleep Cohort participants completed the Sleep Inertia Questionnaire (SIQ), Epworth Sleepiness Scale (ESS), Hypersomnia Severity Index (HSI) and six widely used cognitive tests. Linear regression examined relationships between hypersomnolence measures (SIQ, ESS, and HSI) and cognitive outcomes. Secondary analyses assessed relationships between SIQ subscales (physiological, cognitive, emotional, and responses) and cognitive outcomes. Adjusted models included covariates capturing demographic, psychosocial, sleep, and testing characteristics. The sample (N = 461) was predominantly non-Hispanic white older adults (average age = 73.84 ± 6.66 years), with majority being male (55.8

INTRODUCTION:Obstructive sleep apnea (OSA), common in geriatric patients, has been associated with neurocognitive memory disorders such as Alzheimer's disease and other related dementias. An unusual pattern of memory testing has been found to be associated with OSA in a retrospective study (Dexter and Ebert, 2019). This atypical pattern is reported when immediate memory performance is lower than delayed memory performance on the repeatable battery for the assessment of neurological status (RBANS). The current study examines this cognitive testing results pattern coupled with snoring for predicting OSA in geriatric memory patients presenting to a university-based memory clinic. METHODS:A convenience sample of patients presenting to the University of Wisconsin Hospitals and Clinics geriatric memory clinic from 2016-2020 for cognitive assessments comprised the study population. Patients completed the mini-mental state examination (MMSE) and obtained a score of 25 out of 30 points or greater and the patients were given the RBANS. Patients were referred for a sleep evaluation if they snored and their immediate memory index score was one or more points lower than their delayed memory index score on the RBANS. No other test score requirements were utilized to trigger the referral. RESULTS:Of the 251 patients (138 men; 113 women) referred based only on these two criteria to the associated sleep clinic, 158 (80%) were found to have OSA. CONCLUSION:The prevalence of positive sleep studies suggests that memory clinic patients who snore and present this unusual pattern of results on the RBANS should be referred for a sleep evaluation for possible OSA.

Pitolisant is FDA approved for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy and for the treatment of EDS in pediatric patients ≥6 years with narcolepsy. Given the adjacency between IH and narcolepsy and pharmacological treatments for IH are limited, the efficacy of pitolisant is being evaluated in adult patients with IH. The present analyses focused on a 4-week double-blind randomized withdrawal period (DBRWP) within a 12-week phase 3 clinical trial to evaluate the safety and efficacy of pitolisant in adult patients with IH (NCT05156047). Patients (213) initially received pitolisant for an 8-week open-label period (OLP) and then were assessed for their treatment response. Treatment responders (≥3-point reduction in their Epworth Sleepiness Scale [ESS] scores across the OLP) entered the DBRWP and were randomized to continue receiving dose-matched pitolisant or placebo. Primary and key-secondary efficacy measures included the ESS and the Idiopathic Hypersomnia Severity Scale (IHSS), respectively; change scores were evaluated from the end of the OLP to the end of the 4-week DBRWP for pitolisant compared with placebo. Among the 173/213 patients who completed the OLP (81.2%), 139 (80.3%) of them were considered treatment responders and entered the DBRWP (mean±SD age: 39.9±11.91 years; 78.6% female). During the DBRWP the LSM difference (95% CI) in total score between the pitolisant and placebo treatment groups was not statistically significant for the ESS (-0.85 [-2.24, 0.54]; P=0.228) and narrowly missed nominal statistical significance for the IHSS (-2.27 [-4.62, 0.08]; P=0.058). When statistically adjusting for the suspected placebo effect and suspected regression to the mean, there was a nominally statistically significant difference between pitolisant and placebo on the ESS (-1.51 [-2.84, -0.18] P=0.026) and the IHSS (-3.20 [-5.49, -0.90] P=0.006). No new safety signals were observed. During the 4-week DBRWP, positive trends favoring pitolisant were observed on the ESS and IHSS; however, they did not reach prespecified statistical significance. Ad hoc analyses showed nominally statistically significant improvements in ESS and IHSS. Pitolisant may offer a favorable benefit-risk profile and could be a potential treatment option for patients with IH. Harmony Biosciences

Prior studies suggest that obstructive sleep apnea (OSA) may be associated with Alzheimer’s disease (AD) pathology, including Aβ42/Aβ40 and p-Tau181. However, less is known about relationships between OSA and non-AD pathology, including neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), S100, chitinase 3-like 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), as well as the effect of potential moderating factors. The present study investigated the relationship between the apnea-hypopnea index (AHI) and cerebrospinal fluid (CSF) biomarkers of AD and related pathology. In this cross-sectional study, 73 cognitively unimpaired adults with no prior OSA diagnosis underwent an overnight PSG and/or testing with an at home ApneaLink. Participants completed a lumbar puncture to determine Aβ42/Aβ40, pTau181, NfL, GFAP, s100, YKL-40, and sTREM2 as part of the Roche NeuroToolKit research platform (Roche International). Relationships between AHI and CSF biomarkers were tested using multiple linear regression adjusting for age, sex, APOE genotype, and BMI. Given prior studies suggesting potential interaction effects, we also examined interactions between AHI and APOE and interactions between AHI and BMI. AHI determined using PSG and at home Apnealink were highly correlated (r = 0.78, p < 0.01). There were no significant main effects of AHI on any of the CSF biomarkers, controlling for covariates (p > 0.05). Further, there was no significant interaction between APOE and AHI (p > 0.05). We found a significant interaction between BMI and AHI, such that participants with lower BMI showed higher sTREM2 with greater AHI, (p = 0.02; Figure 1). However, this positive relationship diminished with higher BMI. OSA and obesity are intrinsically linked processes, however prior studies in sleep have also shown that these factors have interactive effects on several outcomes, including measures of inflammation and cognitive function. Here, we found that individuals who had lower BMI showed a potentially deleterious effect of AHI on measures of microglial activation. Additional studies are needed to determine whether these results are due to possible protective effects of higher BMI, or differences in sleep quality among individuals with high and low BMI.

Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) is a phase 4, prospective, multicenter, single-arm, multiple-cohort, open-label study (NCT05875974) evaluating the effectiveness of low-sodium oxybate (LXB, Xywav®) treatment on outcomes including sleep quality (using polysomnography [PSG] and self-reported questionnaires) in participants with idiopathic hypersomnia or narcolepsy. Data reported here are from the idiopathic hypersomnia cohort. DUET included a screening period (with 2-week washout for current oxybate users), an 8-day baseline (BL) period, a 2- to 8-week LXB titration period, a 2-week stable-dose period (SDP), an 8-day end-of-treatment (EOT) period, and a 2-week safety follow-up. Participants underwent nocturnal PSG (ad libitum protocol) at BL and EOT. The Karolinska Sleepiness Scale (KSS) was administered 90 minutes post-awakening from PSG to measure situational sleepiness (9-point scale; 1=“extremely alert” to 9=“extremely sleepy, can’t keep awake”). Participants completed an electronic sleep diary (eDiary) daily during the BL and EOT periods, including questions regarding nightly sleep patterns, total sleep time (TST), sleep quality (5-point scale; “very good” to “very poor”), and how rested/refreshed the participant felt upon awakening (5-point scale; “very well” to “not at all”). Completion of ≥5 eDiary days during the 8-day assessment before PSG visits was required for analysis. eDiary and KSS data were analyzed in the completer set (enrolled participants who were dosed with LXB and completed SDP and PSG at EOT). Forty-six participants with idiopathic hypersomnia enrolled (completer set, n=40). Most were female (37/46; 80%) and White (39/46; 85%); mean (SD) age was 38.1 (11.8) years. Mean (SD) self-reported nocturnal TST at BL (n=36) and EOT (n=30) was 8.6 (2.0) and 8.4 (2.7) hours, respectively. The percent of participants rating their sleep quality as “very good”/“good” increased from 19.4% (BL) to 56.7% (EOT). The percent of participants with rested sleep (“very well”/“well”/“somewhat” rested) increased from 22.2% (BL) to 73.3% (EOT). Likewise, mean (SD) rating of self-reported sleepiness decreased from 5.7 (2.0) at BL to 3.5 (2.0) at EOT. Following open-label LXB treatment, participants with idiopathic hypersomnia reported improvements in sleep quality and feeling more rested and less sleepy upon awakening. Jazz Pharmaceuticals