bluuebunny/crossref_metadata_2025 huggingface dataset:
0633 Efficacy and Safety of Low-Sodium Oxybate in Narcolepsy Patients With/Without Psychiatric/Neurologic Comorbidities
Authors: Chepke Craig , Cutler Andrew , Watson Nathaniel , Candler Shawn , Fuller Douglas , Measey Thomas , Scheckner Brian , Akerman Sarah , Macfadden Wayne
Published: April 2024

Introduction

Prior studies report high incidences of psychiatric and/or neurologic comorbidities in patients with narcolepsy. Low-sodium oxybate (LXB; Xywav®) is an FDA-approved treatment for cataplexy or excessive daytime sleepiness in patients ≥7 years old with narcolepsy and for adults with idiopathic hypersomnia. This post hoc analysis of a phase 3 trial (NCT03030599) assessed LXB efficacy and safety in participants with narcolepsy with or without a medical history of psychiatric and/or neurologic comorbidities.

Methods

Participants were adults (18‒70 years) with narcolepsy with cataplexy. Participants optimized/titrated their LXB dose (up to 12 weeks) before a 2-week stable-dose period. During a 2-week double-blind randomized-withdrawal period, participants were either switched to placebo or continued LXB. Epworth Sleepiness Scale (ESS), average weekly number of cataplexy attacks, Patient Global Impression of Change (PGIc) scores, Patient Health Questionnaire-9 (PHQ-9) scores, and treatment-emergent adverse events (TEAEs) were evaluated in participants with and without psychiatric and/or neurologic comorbidities.

Results

Of 201 participants, 84 reported baseline comorbidities (most commonly depression, migraine headaches, anxiety, and headache [non-migraine]). Imbalances between subgroups were observed with regard to sex, race, ethnicity, and body mass index. Participants randomized to placebo in both subgroups showed worsening (increases) in ESS scores compared with participants who continued with LXB treatment (least squares mean differences, LXB vs placebo [95% CI], with comorbidities: −3.7 [−5.6, −1.9], P=0.0001; without comorbidities: −2.0 [−3.5, −0.6]; P=0.0050). Participants randomized to placebo in both subgroups had increased weekly cataplexy attacks compared with those continuing LXB (location shift, LXB vs placebo [95% CI], with comorbidities: −4.0 [−7.0, −1.1], P=0.0026; without comorbidities: −3.5 [−9.1, −1.1], P< 0.0001). Participants randomized to placebo in both subgroups showed worsening in PGIc scores compared with LXB (P< 0.0001, for both). Symptoms of depression, as measured by PHQ-9 scores, remained stable in both subgroups. TEAEs and serious TEAEs occurred in 69 (82.1%) and 1 (1.2%) participants with comorbidities, and 84 (71.8%) and 3 (2.6%) without comorbidities, respectively.

Conclusion

In this post hoc analysis of a phase 3 trial in patients with narcolepsy, the efficacy and safety of LXB in participants with psychiatric and/or neurologic comorbidities were similar to those in participants without such comorbidities.

Support (if any)

Jazz Pharmaceuticals
0639 Long-term Safety and Timing of Adverse Events with Low-Sodium Oxybate in a Phase 3 Idiopathic Hypersomnia Study
Authors: Bogan Richard , Whalen Marisa , Bronson Stefanie , Fuller Douglas , Macfadden Wayne
Published: April 2024

Introduction

Low-sodium oxybate (LXB; Xywav®) is approved by the US Food and Drug Administration for the treatment of idiopathic hypersomnia in adults. To examine the long-term safety of LXB in this population, this post hoc analysis evaluated treatment-emergent adverse events (TEAEs) over time in a phase 3, double-blind, placebo-controlled, randomized withdrawal trial (NCT03533114), including its open-label extension period.

Methods

Participants were adults with idiopathic hypersomnia. TEAEs were analyzed across all study periods (open-label titration,10–14 weeks; stable-dose, 2 weeks; double-blind randomized withdrawal, 2 weeks; open-label extension, 24 weeks; safety follow-up, 2 weeks) in the analysis population (oxybate-naive participants who took ≥1 dose of study drug; N=148). Onset and duration of common TEAEs (≥5% of participants) were reported in the total population and by baseline medication group (treatment-naive, n=66; taking alerting agents [stimulants or wake-promoting agents], n=82). Duration was defined as the time from when a TEAE started until it was reported as ended. Results are presented using descriptive statistics.

Results

The majority of the most frequently reported TEAEs occurred within the first 5 weeks after study onset. In treatment-naive participants, the most common TEAEs (incidence; median duration) were nausea (n=13 [19.7%]; 7.5 days), headache (n=12 [18.2%]; 3.0 days), dizziness (n=11 [16.7%]; 4.0 days), anxiety (n=7 [10.6%]; 9.0 days), and decreased appetite (n=7 [10.6%]; 15.0 days). In participants taking alerting agents, the most common TEAEs were nausea (n=21 [25.6%]; 7.5 days), headache (n=15 [18.3%]; 2.0 days), vomiting (n=14 [17.1%]; 1.5 days), anxiety (n=10 [12.2%]; 28.0 days), insomnia (n=9 [11.0%]; 7.0 days), and tremor (n=9 [11.0%]; 11.0 days). Common TEAEs were of mild or moderate severity and infrequently led to study discontinuation (≤3.7% of participants each). Nine serious TEAEs occurred in 4/148 (2.7%) participants; none were considered related to study drug or led to study discontinuation.

Conclusion

In this study of LXB in participants with idiopathic hypersomnia, the common TEAEs (≥5% of participants) were consistent with the known safety profile of oxybate, peaked early (generally within 5 weeks), and were mild to moderate in severity, in both treatment-naive participants and participants taking alerting agents.

Support (if any)

Jazz Pharmaceuticals
0648 Phase 3 Randomized Placebo-Controlled Trial of Pitolisant for Excessive Daytime Sleepiness in Prader-Willi Syndrome
Authors: Revana Amee , Seiden David , Rapchak Krystle Davis , Adee Ann , Bauer Eric , Runyan Grant , Nomikos George
Published: April 2024

Introduction

Prader-Willi syndrome (PWS) is a genetic, neurodevelopmental disorder characterized by global hypothalamic dysfunction that results in a variety of symptoms including behavioral disturbance, hyperphagia, and excessive daytime sleepiness (EDS). Pitolisant is approved for the treatment of EDS or cataplexy in adults with narcolepsy. In a phase 2, proof-of-concept study, pitolisant showed trends of reduction in EDS relative to placebo in patients with PWS.

Methods

This multicenter, randomized, double-blind, placebo-controlled, phase 3 study will evaluate the efficacy and safety of pitolisant in patients with PWS. The study will enroll patients ≥6 years of age with a genetically confirmed diagnosis of PWS, and have EDS as confirmed by the investigator. Selected exclusion criteria include patients with symptoms or diagnosis of psychosis or schizophrenia, inadequately treated sleep disordered breathing, and moderate or severe hepatic or renal impairment. Eligible patients will be randomly assigned (1:1) to receive pitolisant (weight-based dosing: 8.9-44.5 mg/d) or matching placebo tablets. The 11-week double-blind period will be followed by an optional 52-week open-label extension.

Results

Up to 100 patients per group will be enrolled. The primary endpoint will be change from baseline at Week 11 in EDS as measured by the PROMIS-SRI (Patient-Reported Outcomes Measurement Information System - Sleep Related Impairment [Parent Proxy]). The secondary endpoints will include behavioral disturbance as measured by the Aberrant Behavior Checklist-Community domains (irritability, social withdrawal, stereotypic behavior, hyperactive/noncompliance, and inappropriate speech), Caregiver Impression of Severity for EDS, Clinician Global Impression of Severity for EDS, Epworth Sleepiness Scale for Children and Adolescents, and the Hyperphagia Questionnaire for Clinical Trials in conjunction with the Food Safe Zone Questionnaire. Safety assessments will include incidence and severity of adverse events, clinical laboratory tests, vital signs, and 12-lead ECG. The study is expected to start enrolling patients in 2024.

Conclusion

This study is designed to determine whether pitolisant is efficacious in the treatment of EDS in patients with Prader-Willi syndrome and to further characterize its safety profile in this patient population.

Support (if any)

Harmony Biosciences, LLC
0650 Safety and Efficacy of KP1077 in a Phase 2, Double-Blind, Randomized Trial in Patients with Idiopathic Hypersomnia
Authors: Braeckman Rene , Drake Christopher , Gallo Daniel , Vaughn Ben , AbdelFattah Ihab
Published: April 2024

Introduction

KP1077 is under development as an oral medication for the treatment of rare sleep disorders with Excessive Daytime Sleepiness (EDS), including idiopathic hypersomnia (IH). The active ingredient in KP1077 is serdexmethylphenidate (SDX), a prodrug of d-methylphenidate. The objectives of the study were to assess the safety (primary endpoint) and efficacy of KP1077 in patients with IH.

Methods

Adult patients with IH began KP1077 treatment in a 5-week open-label (OL) titration period. Possible dose levels were 80, 160, 240 and 320 mg/day SDX. Patients were randomized to receive their daily dose either once per day (just before going to sleep), or twice per day (half the daily dose just before going to sleep and half shortly after awakening). After the titration period, patients in each treatment group were randomized to placebo or continued KP1077 (optimized dose) during a 2-week double-blind (DB) withdrawal period. Assessments of safety were based on adverse events (AEs), physical examinations, clinical laboratory tests, vital signs, electrocardiograms, sleep quality, and suicidal ideation. Efficacy assessments included the Epworth Sleepiness Scale (ESS) and Idiopathic Hypersomnia Severity Scale (IHSS). Patients rated their difficulty of waking up in the morning with the Sleep Inertia Visual Analog Scale (SI-VAS) and brain fog throughout the day with an exploratory Brain Fog Scale (BFS).

Results

Safety and efficacy in the OL titration phase were evaluated in an interim analysis when 22 patients completed the study (target: ≥48 completers). KP1077 was well-tolerated for both treatments and all dose levels, with most frequent AEs of insomnia, headache, and nausea. Most AEs were mild, not leading to early discontinuation. Meaningful clinical improvements in scores of ESS, IHSS, SI-VAS, and BFS were observed in both treatment groups. Mean total ESS scores decreased by >9 points after 5 weeks of OL treatment. Results from all patients in the both the OL titration and DB withdrawal periods will be presented.

Conclusion

KP1077 was well-tolerated in patients with IH with AEs typical for a central nervous system stimulant. Meaningful clinical improvements of EDS, sleep inertia and brain fog were observed after 5 weeks of OL KP1077.

Support (if any)

Zevra Therapeutics
0653 Caregiver Preferences for Narcolepsy Treatment: A Discrete Choice Experiment
Authors: Ortiz Luis , Morse Anne , Wermter Ellen , Lavender Maggie , Brooks Diana , Gudeman Jennifer
Published: April 2024

Introduction

Once-nightly sodium oxybate extended-release oral suspension (ON-SXB; LUMRYZ™) is approved to treat excessive daytime sleepiness and cataplexy in adults with narcolepsy. Currently, a once-nightly oxybate option is not available for pediatric patients with narcolepsy. A discrete choice experiment was conducted among caregivers of pediatric patients with narcolepsy to determine drivers of preferences for oxybate therapy.

Methods

Thirty-minute web-based surveys were provided to adult caregivers of a pediatric (< 18 years old) patient with narcolepsy and prior or current use of twice-nightly SXB. Participants were recruited online or via patient advocacy groups. Two hypothetical product profiles with attributes of twice-nightly SXB and ON-SXB were created for 10 choice sets. For each choice set, participants indicated their preferred product overall, the product they would be more adherent to, and the product that would result in less anxiety or stress for the patient when thinking about taking the medication. A hierarchical Bayesian model was used to analyze the results.

Results

Caregivers (n=75) of pediatric patients with narcolepsy participated; 88% of patients cared for were age 10–15 years, 80% of caregivers had a household income of $60,000–$120,000, and 96% of patients currently used twice-nightly SXB. Caregivers indicated that the most important attribute driving overall product choice was dosing frequency (relative attribute importance [RAI], 23.7), with once-nightly preferred over twice-nightly dosing (relative preference weight [RPW], ±45.1), followed by treatment efficacy at the highest dose (RAI, 21.7). The most important attribute driving adherence was the efficacy of the drug at the highest dose (RAI, 25.7), followed by dosing frequency (RAI, 21.6), with once-nightly preferred over twice-nightly dosing (RPW, ±31.3). The most important attributes associated with less anxiety/stress were efficacy of the drug at the highest dose (RAI, 24.6) and side effects (RAI, 18.7).

Conclusion

Among caregivers of pediatric patients with narcolepsy, efficacy and dosing frequency were identified as the most important attributes driving preference for overall treatment choice and adherence; efficacy and side effects were important for reducing patient anxiety/stress. If approved by the US FDA for pediatric patients, ON-SXB will eliminate the chronic, middle-of-the night disruption impacting patients and caregivers.

Support (if any)

Avadel Pharmaceuticals.
0655 Novel Design Elements to Evaluate Sleep Architecture and Outcomes in an Idiopathic Hypersomnia and Narcolepsy Study
Authors: Plante David , Nichols Deborah , Steininger Teresa , Fuller Douglas , Whalen Marisa , Akerman Sarah , Macfadden Wayne
Published: April 2024

Introduction

Although the efficacy and safety of low-sodium oxybate (LXB, Xywav®) in the treatment of idiopathic hypersomnia and narcolepsy are well established, opportunities remain to better understand its impact on sleep architecture and other daytime/nighttime outcomes important to patients and clinicians. Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment; NCT05875974) is a phase 4, prospective, multicenter, single-arm, open-label interventional study designed with novel methodology and expert input to evaluate the impact of LXB on excessive daytime sleepiness, polysomnographic (PSG) sleep parameters, and functional outcomes in adults with idiopathic hypersomnia or narcolepsy (type 1 or 2).

Methods

DUET includes a screening period (with a 2-week washout for participants taking oxybate at study entry), 1-week baseline period (off-treatment), 2- to 8-week titration period (for flexible LXB dosing adjustments based on participants’ needs), 2-week stable-dose period, 1- to 2-week end-of-treatment period (on LXB), and safety follow-up (after 2 weeks). To more comprehensively understand the impact of LXB on sleep architecture and other daytime/nighttime outcomes, novel design elements were integrated into the study. Input from an expert advisory board helped refine the study design and ensure that the most relevant elements for patients and clinicians were incorporated into the final DUET protocol. Responses from a premeeting survey of advisors focused on eligibility criteria, suitability of endpoints, newly created questionnaires, and analyses and were discussed during a 4-hour workshop with the study sponsor.

Results

Advisors were 6 clinicians with expertise in treating patients with idiopathic hypersomnia and narcolepsy and/or with expertise in PSG. Novel design aspects discussed and incorporated into the protocol included PSG conducted with ad libitum sleep duration, objective evaluation of sleep inertia using the Psychomotor Vigilance Test, a new questionnaire for capturing clinician-reported dosing to better understand dosing rationale, evaluation of motor activity during sleep (with PSG), and evaluation of dysautonomia using the Orthostatic Hypotension Questionnaire.

Conclusion

DUET is the first prospective evaluation of the impact of LXB on sleep architecture (PSG) in patients with idiopathic hypersomnia or narcolepsy. Results from these novel elements will provide patients and clinicians with additional information regarding the impact of LXB on nighttime/daytime symptomatology.

Support (if any)

Jazz Pharmaceuticals
0656 Severe Air Pollution as a Possible Triggering Factor for Kleine-levin Syndrome
Authors: Heshmati Arezou
Published: April 2024

Introduction

Kleine-Levin Syndrome (KLS) is a rare neurological disorder characterized by recurrent episodes of hypersomnia, altered behavior, and cognitive disturbances. We report a case where severe air pollution seemingly acted as a trigger for a KLS episode in a patient with a history of viral-triggered and alcohol-associated episodes.

Methods

We present a case of a 17-year-old girl with a history of anxiety and migraine headaches, effectively managed with a stable dose of Lexapro 20 mg per day. The patient experienced multiple episodes of Kleine-Levin Syndrome (KLS) following viral infections and alcohol consumption. However, the fourth episode was distinct, as it coincided with extreme air pollution in New York City. On the day that her symptoms started the Air Quality Index was reported to be above 480 technically off the chart. While there were no other known triggers for this fourth episode and the duration of the fourth episode was similar to the previous three ones.

Results

This case sheds light on potential environmental triggers for KLS and highlights the importance of understanding individual susceptibilities within this rare disorder.

Conclusion

This case emphasizes the need for a comprehensive approach to understanding KLS triggers, including environmental factors. The possibility of severe air pollution acting as a trigger adds a new dimension to our understanding of this enigmatic disorder. Further research is required to elucidate the relationship between air pollution and KLS, potentially offering insights into preventive strategies and tailored interventions for susceptible individuals.

Support (if any)
0669 Oxidative Stress in Hypersomnia Patients: Correlation with Sleep Onset REM Period
Authors: Honda Makoto , Kojima Takashi , Kodama Tohru
Published: April 2024

Introduction

Glutathione is the most abundant cell antioxidants. The ratio of reduced and oxidized glutathione (GSH, GSSG) has been used as a marker for oxidative stress and reduced glutathione levels contributes to the onset and progression of many diseases. In sleep research field, oxidative stress has been studied mostly in sleep apnea syndrome and sleep deprivation but not in hypersomnia. Since GSSG is one of the sleep promoting substances, we hypothesized that oxidative stress contributed to the pathophysiology of hypersomnia and examined the relationship between glutathione and sleep variables in sleepy subjects.

Methods

Participants were patients visiting outpatient clinic for sleep disorders in Koishikawa Tokyo Hospital, Institute of Neuropsychiatry and underwent diagnostic PSG-MSLT from June 2020 to Nov 2023. Written informed consents were obtained. We selected 280 patients (25.6±9.3 years old, f/m=148/132) without medication at sleep study and slept more than 5.5 hours during nocturnal PSG. Fasting blood samples were collected at 7am before MSLT and RBC fraction were stored at -80 degree until use. RBC were deproteinized with perchloric acid and supernatant after centrifugation was measured by HPLC-ECD with boron-doped diamond electrode. GSH proportion of the total glutathione [GSH/(GSH+GSSG)] were calculated and correlation with sleep variables and ESS score were investigated. To adjust possible confounders, regression analyses were performed using Logit transformed GSH proportion as objective variable.

Results

We found that GSH proportion showed negative correlation with age (P<.001) and sex differences (lower in female). We also found that GSH proportion showed positive correlation with presence/absence of SOREMP on MSLT(P=.007) and negative correlation with ESS score (P=.046). Correlation with SOREMP remained significant after adjusting the HLA -DQB1*06:02 status.

Conclusion

Our data showed that those with higher oxidative stress have higher ESS score and those without SOREMP on MSLT showed higher oxidative stress. Subgroup analysis showed that those without SOREMP and HLA-DQB1*06:02 have higher oxidative stress compared to others. SOREMP on MSLT is a diagnostic marker for Narcolepsy type 1 but SOREMP can be observed in general population. Our data could provide biochemical basis for the occurrence SOREMP.

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0672 Sleepiness, Psychomotor Vigilance and Cognition in People with OSA Adherent to PAP Therapy
Authors: Ruiz-Perez Elena , Junco Barbara , Dib Salim , Agudelo Christian , Mclntosh Roger , Wallace Douglas , Rothberg Paola , Ramos Alberto
Published: April 2024

Introduction

Residual excessive daytime sleepiness (EDS) is common in people with obstructive sleep apnea (OSA) using positive airway pressure (PAP) regularly, and has been associated with reduced functional outcomes.We examined the association of EDS using the psychomotor vigilance test (PVT) and cognition in patients with OSA adherent to PAP. We hypothesized that objective sleepiness is associated with worse cognitive function.

Methods

This cross-sectional study included participants aged ≥40 years, from an academic sleep disorder center using PAP therapy for ≥6 months with a minimum use of 6 hours per night. Exclusions were diagnosis of dementia, cognitive impairment, stroke, and sleep disordersincluding narcolepsy, parasomnias and PMLD. Demographics, medical history, behavioral data including the Epworth Sleepiness Scale (ESS), were gathered through questionnaires and medical records.Cognitive data was collected using NeuroTrax™, assessing attention, executive function, memory, processing speed, and global cognition. Linear regression analyses were performed between cognitive domains and PVT outcomes (lapses ≥500ms and average reaction time (RT)).

Results

The cohort included 31 participants (71% Hispanic-Latino, 29% women) with mean age 61 (SD=8.95), and mean AHI 33.13 (SD=22.05). PVT data indicated an average RT of 404.30 ms and an average number of lapses (≥ 500 ms) at 8.20. Cognitive assessments revealed scores for global cognition (m= 103.25, SD=10.83), verbal memory (m= 97.76, SD= 12.50), executive function (m= 106.42, SD= 11.82), attention (m= 101.72, SD= 10.54), and information processing speed (m= 101.66, SD=21.05). Pearson’s test showed a correlation between lapses (≥ 500 ms) and memory (r = -0.44; p = 0.008), and average RT with age (r = 0.46; p = 0.006). No correlation was found between lapses (≥ 500 ms) and ESS (r = 0.21; p = 0.26) or average RT and ESS (r = 0.045; p = 0.81). Linear regression analysis, adjusting for age, showed an association between lapses with worse memory function (β= -0.86, p = 0.017), as well as average RT with worse information processing speed (β = -0.089, p = 0.049). Other cognitive domains were not associated with the PVT.

Conclusion

In people with OSA optimally adherent to PAP, objective sleepiness was associated with worse memory function and information processing speed.

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0674 The Functional Impacts of Narcolepsy Instrument Differentiates Patients with Narcolepsy from Healthy Controls
Authors: Crawford Stephen , Romero Heather , Savva Yulia , McPherson Peter , Doll Helen , Howerter Amy , Swick Todd
Published: April 2024

Introduction

The Functional Impacts of Narcolepsy Instrument (FINI) is a fit-for-purpose patient-reported outcome (PRO) measure developed for the assessment of patients with narcolepsy type 1 (NT1) or type 2 (NT2). To provide a baseline for interpretation in future interventional trials, comparative scores for the FINI domains were obtained from a cohort of healthy volunteers included in a United States observational study.

Methods

Healthy volunteers without excessive daytime sleepiness (EDS; ≤10 on the Epworth Sleepiness Scale [ESS] at screening) or any associated medical disorder were eligible for inclusion. Participants received a link to complete a cross-sectional online survey that included a 23-item, 5-domain form of the FINI (excluding cataplexy items) and additional selected quality of life reference questionnaires (SF-36 and EQ-5D). FINI items evaluate narcolepsy/EDS symptoms and impacts on daily functioning. All items have a 7-day recall period on a 5-point Likert scale of frequency from “never” to “always” or severity from “not at all” to “very much.” For each domain, an average item score is calculated and standardized to a 0–100 scale. Lower scores indicate better health/functioning. Responses were compared to patients with NT1 and NT2 from an observational study (n=126) and a phase 2 trial (NCT04096560; n=125).

Results

Thirty-one healthy volunteers (45.2% female) completed the survey. Participants had a mean age of 44.8 years and a median (range) ESS score of 4.0 (0–10.0) at baseline. FINI domain scores ranged from 10.0 to 22.2 in healthy volunteers, significantly lower than values reported for patients with narcolepsy in observational and phase 2 studies (46.2 to 67.9). Similar patterns were observed for reference PROs, with better quality of life/health status reported for healthy controls than for narcolepsy samples. Mean (SD) FINI domain values for healthy volunteers were: Tiredness: 22.2 (19.8); Cognitive Functioning: 10.0 (10.5); Social Activities: 16.1 (17.1); Everyday Activities: 12.9 (10.7); and Everyday Responsibilities: 11.6 (15.8).

Conclusion

Mean FINI domain scores from healthy volunteers can serve as normative thresholds and provide a benchmark for comparison of FINI responses reported by patients with narcolepsy, allowing for the evaluation of treatment effects in clinical trials.

Support (if any)

Funded by Takeda
0675 Effects of Circadian Acclimation of Performance, Sleep, 6-sulfatoxymelatonin on Heart Rate & Heart Rate Variability
Authors: Patel Milin , Saissan Kiyan , Mak Natalie , Youngstedt Shawn , Patel Salma
Published: April 2024

Introduction

Jet lag is associated with transmeridian travel across at least two time zones, associated with sleep disturbance as well as daytime dysfunction. The presence of jet lag has been hypothesized to be associated with adverse cardiovascular outcomes; however, objective data are not available. Jet lag can have many negative effects on physical and mental health, mental and physiological performance, and sleep. The objective of this study is to understand the impact of simulated jet lag on heart rate.

Methods

Following a baseline circadian rhythm assessment, participants were placed on a 16 hour wake – 8 hour sleep schedule in which the wake-sleep and light-dark schedule was delayed by 8 hours for 3 days (analogous to traveling 8 time zones west). Participants were randomized to one of 3 treatments administered each of the 3 days of the shifted schedule: (A) placebo control, (B) bright light, and (C) bright light + exercise + melatonin. Participants wore an Extended Wear Holter Monitor for the duration of the 6.5 day laboratory stay. Minimum, average and maximum heart rates as well as heart rate variability were evaluated for each phase in the laboratory.

Results

15 of the 22 patients enrolled wore the Holter monitor and completed the study (86.6% men, mean age 28.4 ± 9.56)— 5 were in the placebo arm, 7 in bright light, 3 in the bright light + exercise + melatonin group. In the placebo group, the average heart rate in beats per minute (± SD) increased in the first ultrashort period when compared to baseline (70 (6) vs. 66 (8), p =0.022). In the bright light group, the average heart rate (± SD) decreased during the shifted schedule when compared to baseline (70 (14) vs. 74 (4), p =0.015). No other significant changes were noted.

Conclusion

The initial induction of jet lag seems to have detrimental effects on heart rate, however the body adjusts thereafter and bright light may be helpful to reduce the impact of jet lag on heart rate.

Support (if any)

Department of Defense, Philips, American Academy of Sleep Medicine Foundation, National Institutes of Health, The University of Arizona.
0678 Genetic Variants Associated with Dim Light Melatonin Onset in a Delayed Sleep-Wake Phase Disorder Cohort
Authors: Brzezynski Jennifer , Johnson Caroline , Smieszek Sandra , Bai Haimeng , Polymeropoulos Christos , Birznieks Gunther , Polymeropoulos Mihael
Published: April 2024

Introduction

We are conducting a double-blind, randomized, clinical study in Delayed Sleep-Wake Phase Disorder (DSWPD) participants with extensive clinical phenotyping. We evaluated screening Dim Light Melatonin Onset (DLMO) assessments in participants with a DSWPD diagnosis to determine the proportion of participants with and without a circadian delay.

Methods

Delayed DLMO is DLMO occurring after or within 60 minutes before desired bedtime, and after 22:00. Each DLMO assessment consisted of eight saliva collections performed at five, four, three, two, and one hour before bedtime, at planned bedtime, and one and three hours after bedtime. DLMO assessments were distributed to participants at Visit 1 (screening) and Visit 3 (treatment) with a questionnaire to record planned and actual collection times. Participants were instructed to wear blue-light blocking glasses. The Morningness-Eveningness Questionnaire (MEQ) was also completed by participants at V1 to evaluate circadian and sleep rhythm patterns. DLMO was defined as the clock time when the melatonin concentration exceeded the mean of three low consecutive values, plus twice the standard deviation of these points. Additionally, a sample for whole genome sequencing was collected.

Results

Forty-seven participants with DSWPD completed the screening DLMO assessment, 38 of which had a DLMO after 22:00 (80.9%). Sub-analyses were conducted on these participants who had delayed DLMO. Within this subset, the average DLMO time was 23:41 and the average MEQ score was significantly lower than those without a circadian delay. Of these 38 participants, 19 had a DLMO time after 00:00. Furthermore, we completed a linear regression analysis on DLMO time in a circadian gene set. The top scoring variant was 3’ UTR rs10181401 in PER2, amongst others detected.

Conclusion

These initial data indicate that, on average, participants with DSWPD that completed the screening DLMO assessment had delayed DLMO. Further analyses show that half of this subset had significantly delayed DLMO (00:00 or later). This study is currently ongoing and blinded. Further data will be analyzed as more participants enroll. ‘Phase typing’ will be important in further understanding the underlying pathophysiology and in the treatment selection for patients with DSWPD.

Support (if any)

This work was supported by Vanda Pharmaceuticals Inc.
0689 Automated Detection of Isolated REM Sleep Behaviour Disorder Using Computer Vision
Authors: Abdelfattah Mohamed , Sum-Ping Oliver , Galati Joanna , Marwaha Salonee , Alahi Alexandre , During Emmanuel
Published: April 2024

Introduction

Isolated Rapid Eye Movement (REM) Sleep Behavior Disorder (iRBD) is a marker of neurodegeneration and is currently diagnosed based on REM sleep without atonia (RSWA) and a history of dream enactment. However, even for sleep experts, scoring RSWA can be challenging and incidental RBD cases are easily missed. Previous research focused on the automatic identification of iRBD using 3D video analysis. This study aims at developing a machine learning classifier to detect iRBD using only conventional 2D cameras and evaluating its performance on an expanded cohort.

Methods

We used 2D video data from in-lab video-polysomnography recorded at the Stanford Sleep Center in 78 patients with definite iRBD per ICSD-3 TR criteria and 109 without RBD (41 OSA [AHI > 15], 37 RLS/PLM [PLMi>15], 9 non-RBD parasomnias, 5 insomnia, 2 narcolepsy, 39 with normal sleep). An automatic computer vision algorithm, i.e. optical flow, was applied on the recorded videos to detect periods of movements in REM sleep. Movement periods were divided based on their duration from very brief (0.1s) to extended (>30s) motor behaviors, 1 second of immobility separating each period. Features were movement frequency and proportion of movement periods in REM sleep. Different combinations of these features fed a logistic regression classifier, which was trained and tested in the 10-fold cross-validation scheme.

Results

On average, 58.13 and 42.53 movement periods were detected during REM sleep in cases and controls, respectively. The best performance was achieved using short movements (0.1-2s) with sensitivity of 0.921, specificity of 0.674, accuracy of 0.835 and F1 score of 0.847. With medium (2-15s) and long (15-300s) movements, accuracy was 0.845 and 0.672, sensitivity 0.743 and 0.147, specificity 0.901 and 1.0, and F1 score 0.808 and 0.256, respectively. Adding features of gender, AHI, and PLM index to short movements increased accuracy to 0.886.

Conclusion

One-night video data from conventional video-polysomnography can detect iRDB using machine learning techniques. Automated video analysis of REM sleep could augment our current ability to screen and diagnose RBD in the sleep laboratory setting.

Support (if any)
0701 Perceived Exercise Response Heterogeneity in Adults with Restless Legs Syndrome
Authors: Cederberg Katie , Sikes E Morghen , Mejia Giorgio Ricciardiello , Mignot Emmanuel
Published: April 2024

Introduction

Restless legs syndrome (RLS) is a prevalent, sensorimotor sleep disorder that is temporarily relieved by movement. There is evidence of inter-individual variation in the response to exercise (i.e., response heterogeneity). We examined factors that may account for inter-individual differences in perceived response to exercise as a mode of treatment for RLS symptoms.

Methods

Participants (N=528) completed a mixed-methods survey including items assessing RLS outcomes, physical activity levels, and personal experiences with exercise. Participants were classified as “perceived responders” (i.e., exercise impacts symptoms) and “perceived non-responders” (i.e., exercise does not impact symptoms). Perceived responders were further classified as “positive responders” (i.e., exercise improves symptoms) or “negative responders” (i.e., exercise exacerbates symptoms). In this pilot study, an XGboost classifier was used to predict responsiveness to exercise based on clinical and demographic characteristics. Two binary models were implemented, one for non-responders vs responders (M1) and the other for positive responders vs. negative responders (M2). Each model datasets were split into training and test sets.

Results

There were no significant differences in demographic or clinical characteristics between perceived responders (n=450) and perceived non-responders (n=76). Perceived positive responders (n=172) reported significantly lower BMI, overall RLS severity, and had a lower proportion of people with periodic limb movements than perceived negative responders (n=72). M1 classifier resulted in weighted F1 score, sensitivity, and specificity of 0.92, 0.92 and 1 for training and 0.83, 0.8, 0 for testing, respectively. Whereas the M2 classifier resulted in a weighted F1 score, sensitivity, and specificity of 0.9, 0.90, 0.95 for training and 0.6, 0.79, 0 for testing, respectively. XGBoost feature importance ranked RLS pregnancy incidence, RLS time onset (morning, afternoon), total RLS severity score, physical activity level, BMI, age, and sedentary time as most important.

Conclusion

The present study reveals factors that correlate with individual differences in response to exercise for people with RLS. If confirmed, such individual differences and specific attributes may be useful to optimize individual treatment plans that include exercise as a recommendation.

Support (if any)

This work was supported, in part, by the National Heart, lung, and Blood institute [T32HL110952].
0703 Catch-up Weekend Sleep Duration Is Associated with Abnormal Behavior During Sleep in Adolescents
Authors: Yang Kwang Ik , Park Jongkyu , Kim Jee Hyun , Kim Daeyoung , Hong Seung Bong
Published: April 2024

Introduction

Studies focusing on the association between sleep habit and parasomnia in adolescents are relatively scarce compared to other age group. Our study aimed to investigate the association between sleep duration and abnormal behavior during sleep (ABS) in Korean adolescents.

Methods

In this cross-sectional study, we evaluated 25,789 adolescents between 12 and 18 years of age (mean 15.76 ± 1.73 years; male 48.51%). Global Sleep Assessment Questionnaire and self-report questionnaires were used to assess ABS, sleep habits including catch-up weekend (CUW) sleep duration, and various socio-behavioral factors as covariates.

Results

The prevalence of ABS was 3.39% (n = 873). The analyses of multivariate logistic regression of the adjusted OR for ABS were significantly associated with male (OR, 1.304; 95% CI, 1.111 - 1.532), usually/always snoring (OR, 3.452; 95% CI, 2.800 - 4.257), usually/always witnessed sleep apnea (OR, 5.494; 95% CI, 4.143 - 7.286), weekday sleep duration (OR, 0.850; 95% CI, 0.797 - 0.90), weekend sleep duration (OR, 1.041; 95% CI, 1.004 - 1.080), CUW sleep duration (OR, 1.063; 95% CI, 1.026 - 1.101), perceived insufficient sleep (OR, 1.299; 95% CI, 1.092 - 1.545), increased internet addiction (OR, 1.031; 95% CI, 1.024 - 1.038), often coffee consumption (OR, 1.857; 95% CI, 1.443 - 2.390), often alcohol consumption (OR, 2.377; 95% CI, 1.292 - 4.374), sleeping with a doll or pets (OR, 1.60; 95% CI, 1.351 - 1.895), and keeping TV or radio during sleep (OR, 1.325; 95% CI, 1.084 - 1.619).

Conclusion

Short weekday sleep duration and CUW sleep duration are associated with abnormal behavior during sleep in Korean adolescents.

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0713 Variability of Software Scored PLM's
Authors: Rosenberg Carl , Gandotra Kamal
Published: April 2024

Introduction

Periodic leg movements have been a source of debate as to their clinical significance. Interpretation varies between no clinical significance (Mahowald MW 2001) to a relationship to Heart disease ( Skomo R 2009). Routine technician scoring of PLM’s is rare outside of academic institutions. Insurances, including Medicare and Medicaid, will not approve a repeat study only for evaluation of PLM’s. The following brief study was initiated to review automated software scoring of periodic leg movements based on one sleep study per a patient (Respironics Alice G3).

Methods

Data was obtained from 56 sequential sleep studies with ~240 min of sleep (225 – 434, median 330). “PSG” represents all studies without titration. There were more females (17) than males (8), Ages (24 – 70, median 49.5). This data set is small and not a normal distribution. A technician scored minutes of sleep and AHI, (.4-96.7, median 5.4) while PLM's were autoscored (G3).

Results

There was significant variability in the software generated PLMI, Range 765 (4 –769) median 75.5. • There wasn’t a useful correlation between AGE and PLMI (r2 = .019); thus, of little predictive value in an individual patient’s single test. • The PLMI was not predicted nor differentiated by gender. • There wasn’t a useful correlation between PLMI being related to AHI (r2 = .006), also of little predictive value in an individual patient’s single test.

Conclusion

Most clinicians can rely only on one sleep study, one measure, of PLMI. This brief study suggests that PLM’s scored by software varies greatly when obtained from a single study. Software scored PLMI results must be used with caution in making diagnoses such as PLMD or criteria for RLS. A clinician might have to reject the reported PLMI result.

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0715 NREMembrance of Things Past: Obstructive Sleep Apnea Impacts Sleep Neurophysiology and Memory Retention in Aging
Authors: Dave Abhishek , Lui Kitty K , Sprecher Kate E , Berisha Destiny , Sattari Negin , Chappel-Farley Miranda G , Chen Ivy Y , Riedner Brady , Bendlin Barbara , Mander Bryce , Benca Ruth
Published: April 2024

Introduction

Obstructive sleep apnea (OSA) is associated with sleep disturbances, memory impairment, and dementia risk in older adults. The impact of OSA on sleep neurophysiology and related memory function remains unclear. We examined associations among OSA severity, non-rapid eye movement (NREM) sleep expression, and overnight memory retention in cognitively intact older adults at risk for Alzheimer’s disease (AD).

Methods

Overnight clinical polysomnography (PSG) with 256-channel electroencephalography (EEG) was conducted in 81 cognitively intact older adults (aged 61.68◻5.99 years, 49 female, Apnea/hypopnea Index, AHI: 7.61◻10.64 ), with word-pairs task (WPT) encoding and cued recall occurring prior to and following sleep. AHI, respiratory disturbance index (RDI), and oxygen desaturation index (ODI) were used as measures of OSA severity and cube-root transformed to normality. EEG data underwent preprocessing, artifact rejection, and segmentation into concatenated NREM epochs, and were then processed using multitaper spectral analysis with 11 tapers. Behavioral data, obtained as overnight proportion change in retention of word-pairs, were also cube-root transformed to enhance normality. Topographical correlations were then computed to examine associations between NREM sleep features and OSA severity, using 5000 permutations of threshold-free cluster enhancement (TFCE) for multiple comparisons correction. Multiple linear regression modeling was leveraged to examine whether spatiospectral NREM clusters associated with OSA severity were in turn predictive of overnight memory retention when adjusting for age and sex.

Results

Global, TFCE-significant (p< 0.05 corrected) negative correlations were seen between delta power (1-4.5Hz) and AHI and RDI, theta power (4.5-7.5Hz) and AHI and RDI, alpha power (7.5-11Hz) and RDI, and slow sigma power (11-13Hz) and ODI . Regression models (adjusted for age and sex) using cluster averages of spectral power from prior correlations to predict WPT performance further revealed significant effects for theta power (AHI cluster: B=0.077, p=0.007; RDI cluster: B=0.076, p=0.008), alpha power (RDI cluster: B=0.107, p=0.010), and for slow sigma power (ODI cluster: B=0.203, p=0.007), but not for delta power (both clusters: p>0.33).

Conclusion

These findings indicate that OSA is associated with globally disrupted NREM sleep expression, and that reduced theta, alpha, and spindle activity is further associated with impaired overnight episodic memory retention.

Support (if any)

NIH grants R56AG052698, P50AG033514, F31AG048732, K01AG068353.
0721 Association Between Subjective-Objective Sleep Time Discrepancy and Mortality in Older Men With/Without Insomnia
Authors: Utusumi Tomohiro , Yoshiike Takuya , Aritake-Okada Sayaka , Matsui Kentaro , Nagao Kentaro , Saitoh Kaori , Otsuki Rei , Suzuki Masahiro , Kuriyama Kenichi
Published: April 2024

Introduction

Subjective sleep duration often differs from objective measurements. Our prior research indicates that overestimating sleep duration may be a risk factor for all-cause mortality in older men. Conversely, those with insomnia, which is an another mortality risk factor, typically underestimate their sleep duration. This study investigates how both underestimation and overestimation of sleep duration impact all-cause mortality in community-dwelling older men (aged ≥ 65) comparing with and without insomnia symptoms.

Methods

We conducted a secondary analysis using data from the Osteoporotic Fractures in Men Sleep Study, involving 2,200 participants who underwent in-home polysomnography and completed surveys assessing their subjective sleep duration, without using sleep-affecting medication (such as antidepressants, hypnotics or benzodiazepines). Insomnia was defined by a Pittsburgh Sleep Quality Index (PSQI) score over 5 (N = 816). We examined the relationship between subjective-objective sleep duration discrepancy index (SODI) and mortality using Cox regression. SODI, the ratio of subjective to objective sleep duration, was analyzed categorically, comparing its lowest and highest quartiles to the interquartile range within each group. The study was approved by the Ethics Committee of the National Center of Neurology and Psychiatry.

Results

During follow-up periods (mean: 10.6 years for insomniacs, 11.2 years for non-insomniacs), 504 (61.8%) insomniacs and 774 (55.9%) non-insomniacs died. In the insomnia group, both the lowest (adjusted Hazard Ratio [HR], 1.31; 95% Confidence Interval [CI], 1.02–1.68) and the highest (adjusted HR, 1.31; 95% CI, 1.03–1.66) SODI quartiles were associated with increased mortality compared to the interquartile range. Conversely, in the non-insomnia group, only the highest SODI quartile showed a significant increase in mortality (adjusted HR, 1.30; 95% CI, 1.07–1.59), with the lowest quartile showing no significant mortality association (adjusted HR, 0.94; 95% CI, 0.78–1.14).

Conclusion

Results demonstrate the significant role of subjective-objective sleep duration discrepancy in long-term health outcomes in both the insomnia and the non-insomnia group. Further physiological studies may elucidate the mechanisms of subjective-objective sleep duration discrepancy on mortality.

Support (if any)

This study received a grant-in-aid for scientific research from the Ministry of Health, Labor and Welfare, Government of Japan (grant numbers #19FA1009 and #21FA1002).
0726 Longitudinal Changes in 24-h Sleep-wake Patterns and All-cause Mortality in Older Women
Authors: Leng Yue , Milton Sasha , Cavailles Clemence , Ancoli-Israel Sonia , Ensrud Kristine , Stone Katie
Published: April 2024

Introduction

Sleep-wake patterns generally worsen with advancing age. However, little is known about changes in sleep and circadian patterns in very old adults, and how these changes may be associated with future mortality risk. We examined the association between changes in 24-hour sleep-wake patterns and risk of all-cause mortality in community-dwelling older women.

Methods

We studied 702 women (mean[SD] age = 82.9[2.7] years) who had nighttime sleep (total sleep time [TST]; sleep efficiency; and wake after sleep onset), napping (duration and frequency) and 24-hour rest-activity rhythm (acrophase, amplitude, mesor, and pseudo-F [regularity]) parameters assessed using 4-night/5-day actigraphy at baseline (2002-04) and again 5 years later (2007-08), after which all-cause mortality information was collected using death certificates. The 5-year changes in all parameters were calculated and included in a hierarchical clustering on principal components analysis to identify patterns of sleep changes. We used Cox proportional hazards models to evaluate the longitudinal associations between patterns of sleep changes and all-cause mortality.

Results

During a mean follow-up time of 2.1 years, 90 (12.8%) women died. We identified three patterns of sleep changes: 159 (22.6%) women with Pattern 1 (increased nighttime and daytime sleep and reduced circadian rhythmicity), 233 (33.2%) with Pattern 2 (decreased nighttime sleep quality and duration and reduced circadian rhythmicity), and 310 (44.2%) with Pattern 3 (stable sleep or slight improvement). After adjustment for age, education, body mass index, diabetes, hypertension, heart attack, antidepressant use, and baseline cognition, women with Pattern 1 [HR (95% CI) = 2.23 (1.25,4.01)] or Pattern 2 [HR (95% CI) = 2.26 (1.35,3.79)] had more than twice the mortality risk compared to women with Pattern 3. When individual sleep change parameters were examined, the association with mortality risk was particularly strong for increased TST, napping duration, and reduced circadian amplitude and regularity.

Conclusion

Among women in their 80s, those with increased nighttime and daytime sleep duration, decreased nighttime sleep quality or reduced circadian rhythmicity over 5 years had double the risk of all-cause mortality compared to those with stable sleep. Sleep changes in late life may be important marker or risk factor for adverse aging outcomes.

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