Citations

Abstract Introduction High sodium intake can increase blood pressure (BP) and future cardiovascular risk. Individuals with narcolepsy have an elevated cardiovascular comorbidity burden before considering medication-specific risks. Low-sodium oxybate (LXB; Xywav®) is approved by the US Food and Drug Administration (FDA) to treat excessive daytime sleepiness or cataplexy in patients ≥7 years of age with narcolepsy and idiopathic hypersomnia in adults. LXB has the same active moiety as high-sodium oxybates (sodium oxybate [SXB, Xyrem®] and fixed-dose SXB [Lumryz™]) but contains 92% less sodium. The objective of XYLO is to measure ambulatory and in-clinic systolic BP (SBP) changes after switching to LXB from a high-sodium oxybate in participants with narcolepsy (NCT05869773). Methods This 6-week, open-label, multicenter, switch study is enrolling participants 18–70 years of age with narcolepsy (type 1 or 2) taking 6–9 g/night of high-sodium oxybate for ≥6 weeks. Hybrid enrollment supports both on-site and decentralized (monitored at the participant’s home by mobile health professionals) participation, and may broaden the pool of eligible participants. After ≥2 weeks on stable high-sodium oxybate dose/regimens (screening period), participants switch to the same dose/regimen of LXB for 6 weeks (intervention period). The primary endpoint is the change in 24-hour SBP from baseline (the most recent screening measurement prior to switching) to the end-of-treatment visit (approximately 6 weeks after switching) measured via 24-hour ambulatory BP monitoring (ABPM). Secondary endpoints evaluate change from baseline to end-of-treatment visit in-clinic SBP, as well as daytime average SBP and nighttime average SBP measured via 24-hour ABPM. Results Recruitment began in June 2023. This study uses a group sequential design with an adaptive sample size target of 57–77 participants completing the 6-week intervention period. This design provides 90% power to detect a mean difference of 3.5 mmHg (a clinically relevant change) in 24-hour SBP (assuming a standard deviation of the differences in 24-hour SBP of 8 mmHg). Conclusion XYLO will enable the assessment of 24-hour BP changes following transition from a high-sodium oxybate to LXB. Planned hybrid enrollment with a decentralized option may increase study access leading to a more diverse clinical trial population. Support (if any) Jazz Pharmaceuticals

Abstract Introduction Sleep disordered breathing (SDB: obstructive & central sleep apnea) and insomnia are common in heart failure (HF). However, most studies have not addressed the presence of combined SDB and insomnia (COMISA). The purposes of this study were to (1) describe COMISA among adults with stable chronic HF; (2) compare the clinical and demographic characteristics between groups with COMISA, insomnia, SDB, and normal sleep; and (3) examine the risk of COMISA in the presence of normal sleep, insomnia, SDB and other clinical and demographic characteristics. Methods Secondary analysis of an observational study of sleep among adults with stable HF. COMISA was defined as an apnea hypopnea index (AHI) > 15 with difficulty initiating or maintaining sleep or waking too early in the morning (Insomnia). We measured self-reported (Pittsburgh Sleep Quality Index) and objective sleep characteristics (polysomnography – PSG), symptoms (depression, sleepiness); used chi-square and ANOVA; and calculated the risks of COMISA for normal sleepers and with insomnia or SDB under different conditions (depression, poor sleep quality, left ventricular ejection fraction, age, race, and sex). Results The sample included 170 [(M age = 60.3 ± 16.8 years; n = 60 (35%] female. They had normal sleep (n = 37/22%); insomnia only (n = 48/28%): SDB only (n = 46/27%); and COMISA (n = 39/23%). Those with COMISA were significantly more likely to be obese (32.1%) compared to others [13.6% -29.6%, p = 0.0128]. They had the shortest total sleep time (TST) (mean = 291 ± 109 mins) and poorest sleep efficiency (M = 65.8 ± 20.5%) (p = .05). Women with insomnia were less likely to have COMISA than men (36% vs. 51%), while 74% of adults with SDB who were depressed had COMISA, compared with 41% of those with insomnia. Conclusion Risk of COMISA is associated with depression and poor sleep among adults with stable HF and SDB. Future study is needed to better understand the risks of COMISA among adults with chronic HF outcomes and to address the need for intervention that addresses it beyond a focus on only SDB or insomnia. Support (if any)

Abstract Introduction To further characterize the many struggles and unmet needs of people with narcolepsy (PWN), passive social listening was used to explore how PWN describe the condition using their own words. Methods MyNarcolepsyTeam is a social network where members can organically share their experiences living with narcolepsy with one another. Following an online survey, organic posts, comments, questions, and answers posted from January 2022 to present were analyzed. Results Of 110 survey respondents, 31% reported that the time from symptom onset to diagnosis was ≥10 years. Social listening highlighted both misdiagnoses (eg, depression) and “missed” diagnoses (eg, sleep apnea but not narcolepsy). Almost half (43%) of respondents reported pain as a comorbidity. Social listening revealed the burden of painful comorbidities (eg, fibromyalgia, migraines, neuropathy), which often lead to additional medications and further sleep disruption. While 90% of respondents reported excessive daytime sleepiness, 81% also reported sleep disturbances. Nighttime disruptions experienced by PWN included poor sleep quality, vivid dreams, frequent awakenings, sleep paralysis, and abnormal REM cycles. Structured routines helped improve sleep for some PWN. Additionally, 33% of respondents reporting cataplexy always experienced full body cataplexy; 21% always experienced localized cataplexy; 43% experienced a mix of both, with the remaining answering ‘not sure.’ Social listening highlighted the dangers of cataplexy, including falls/fractures. Organic conversations also brought to bear the full range of emotions that can trigger an attack – from laughter, to being startled, to feeling stressed. In total, 65% of respondents were taking ≥2 medications to treat daytime and/or nighttime narcolepsy symptoms. Organic conversations highlighted the challenges PWN experience managing complex treatment regimens in an attempt to cope with the full spectrum of narcolepsy symptoms. Conclusion Insight into how narcolepsy is experienced in patients’ own words and how patients try to mitigate their symptoms will help sleep specialists better understand the challenges and needs of PWN, which can lead to both faster diagnosis and more effective, individualized treatment. Support (if any) Avadel Pharmaceuticals

Abstract Introduction The ICSD-3-TR defines idiopathic hypersomnia in terms of objective sleep times as sleeping at least 11 hours using 24-hour polysomnography or wrist actigraphy averaged over at least 7 days. Published studies on sleep duration are generally limited by lower sleep duration cut-offs (e.g., ≥ 9 hours), so prevalence data on longer sleep durations are missing. This study used clinical questionnaire data from Mayo Clinic patients to characterize longer sleep times and excessive daytime sleepiness in this population. Methods We retrospectively identified patients who answered questions about subjective sleep times and excessive daytime sleepiness, using the Epworth Sleepiness Scale (ESS), as part of their evaluation in a sleep clinic across the Mayo Clinic Enterprise from 2017 to 2023. Demographic data and sleep disorder diagnoses were then analyzed. Results Patients (N=25,480) with subjective nocturnal sleep times of ≥ 9 (n=2721, 10.7%), ≥ 10 (n=1059, 4.2%), and ≥ 11 hours (n=349, 1.4%) had an ESS ≥ 10 in 33.5%, 41.0%, and 51.3% of the time, respectively. 3.6% (age 53.2±19.7; 58.9% female), 1.7% (age 53.1±20.4; 58.1% female), and 0.7% (age 49.8±19.9; 58.1% female) of the patients reported an ESS ≥ 10 and subjective nocturnal sleep times of ≥ 9, ≥ 10, and ≥ 11 hours per night, respectively. After adjusting for age and sex, patients with more than one diagnostic entry compared to those with one or fewer diagnostic entries for idiopathic hypersomnia with long sleep time (OR=12.75, 95% CI [6.09, 24.52], p< 0.001) and narcolepsy with cataplexy (OR=5.53, 95% CI [1.31, 15.84], p=0.005) were significantly more likely to report ESS ≥ 10 and subjective nocturnal sleep times ≥ 11 hours per night. Conclusion Less than 1% of patients presenting to a Mayo Clinic sleep specialist have self-reported metrics (i.e., ESS ≥ 10 and subjective nocturnal sleep times ≥ 11 per night) consistent with basic clinical features of idiopathic hypersomnia with long sleep time. Additional data analyses (e.g., comorbid conditions, social history, and laboratory results) are underway. Support (if any)

Abstract Introduction A prospective, longitudinal, multicenter study was designed to test the hypothesis that sleep-disordered breathing (SDB) is ubiquitous among newborns with myelomeningocele (MMC). We evaluated variability in polysomnography (PSG) scoring and interpretation. Methods Nine US pediatric centers participated. Neonates with MMC born at >30 weeks gestation underwent bedside PSG at ≥35 weeks postmenstrual age, before hospital discharge. PSGs were scored by registered technologists (RPSGTs) at each site using AASM Scoring Manual infant criteria and interpreted by a board-certified sleep medicine physician (BCSMP). A single, central RPSGT blinded to clinical outcomes then re-scored all PSGs. One of two pediatric BCSMPs reviewed each study; the two BCSMPs jointly determined diagnoses for consensus central reports. Differences in scoring and overall PSG interpretation were evaluated with kappa and intraclass correlation coefficients (ICC). Results For 110 neonates with MMC, the median apnea-hypopnea index (AHI) was 26.5 [11.3-43.3] as reported by sites, and 23.0 [IQR 13.0-44.8] as reported centrally (к 0.81). The central apnea index (CAI) was also scored similarly by sites (3.3 [0.9-7.0]) and centrally (2.6 [0.6-7.3]; к 0.88), as were hypopneas (15.2 [7.5;26.9]) and 14.1 [6.4;27.9]; к 0.82). However, the obstructive apnea index (OAI) was reported to be much higher by sites (10.0 [1.9-29.1]) than centrally (1.5 [0.5 – 4.1]; к 0.29). Moreover, overall PSG interpretation differed between sites and central reviewers. Obstructive sleep apnea (OSA) was reported as a diagnosis by sites for 57.6% of neonates, vs. 10.9% by central review (ICC 0.06); central sleep apnea was reported by sites for 26.6% of neonates, vs. 14.5% by central review (ICC 0.50). When hypopneas were the most prevalent respiratory events, central review favored a less specific diagnosis of sleep-disordered breathing. Conclusion Considerable variability in scoring of obstructive apneas, and in polysomnography-based diagnoses, may exist for neonates. Sites may have designated hypopneas as obstructive, driving the diagnosis of OSA, while central review noted equivocal features of neonatal hypopneas, leading to a less specific diagnosis of sleep-disordered breathing. Further work to develop infant respiratory scoring rules, and diagnostic criteria, and to evaluate their clinical use may be warranted. Support (if any) This study is supported by NIH (R01 HL147261).

Abstract Introduction Meta-analytic studies support that insomnia is a risk factor for cognitive decline and dementia, but limited accounting of confounders reduces their validity. Further, it is unclear whether these associations are driven by specific insomnia phenotypes. In this study, we aimed to assess the relationship between insomnia and longitudinal global cognitive decline in community-dwelling older adults after considering self-reported sleep duration changes and other important characteristics. Methods From the Mayo Clinic Study of Aging (MCSA) cohort, we identified all (age>=50yo) cognitively unimpaired participants at baseline without comorbid neurological disease with at least two previous comprehensive neuropsychological evaluations. Participants with at least two occurrences of insomnia ICD diagnosis (by EMR and Rochester Epidemiological Project data) at least 30 days apart were classified as having insomnia, and those without any instance of diagnosis were considered negative for insomnia. Changes in sleep duration were assessed using the question #16 of BDI-2 and categorized in reduced sleep (yes/no). We fit mixed-effect regression models to assess whether insomnia was associated with standardized global cognitive scores, after adjusting for age, sex, education, APOEe4, composite cardiovascular and metabolic conditions scores, anxiety/depression, reduced sleep, OSA (ICD diagnosis), alcoholism (CAGE≥2), and pain (NSAIDs use). Number of cognitive assessments and time from baseline were included as both fixed and random effects. Multiple interactions (e.g. insomnia*reduced sleep) were included. A backward stepwise procedure maintaining the hierarchical principal for interactions was utilized to reach the most parsimonious models. Results 3063 participants (50.24% males, aged 70±9.73 at baseline) were included. Insomnia alone was not associated with a decrease in global cognition, but when combined with subjective reduction in sleep duration at baseline it was associated with a -0.19 (95% CI: -0.32, -0.07; interaction p=0.01) reduction in global cognitive scores. This was equivalent to approximately 3 additional years of age or 6 cardiometabolic comorbidities at baseline. The effect size was greater than those associated with baseline cognition for having any APOE e4 allele (-0.12) and alcoholism (-0.15). Conclusion Insomnia with reduced sleep duration phenotype is a potentially modifiable risk factor for cognitive decline in older adults. Further studies with objective sleep measures are necessary for objective confirmation. Support (if any) NIA/NIH

Abstract Introduction OSA is caused by the interaction of impaired upper airway anatomy and dysfunctional upper airway muscle response to airway narrowing during sleep. Oropharyngeal exercises focused on training upper airway muscles are effective in reducing OSA severity and symptoms. However, similar to other physical therapy programs, oropharyngeal exercises require patients to complete multiple therapy sessions which affects patient compliance. To address this, we developed a smartphone application to provide oropharyngeal exercise and tested the effect of adding gamification and habit formation techniques on therapy adherence. Methods The experimental app which included oropharyngeal exercise therapy administered using voice-controlled games, a reward system, a reminder system, and supportive video content was compared to the control app that included text-based exercise therapy instructions and limited video content. Participants with mild to moderate OSA were randomly assigned (1:1) to either group. Demographics, sleep apnea variables, therapy progress, self-reported snoring severity questionnaires were collected for both groups. Appropriate descriptive statistics were used to summarize baseline and outcome data. Results 30 participants (13 male), mean age 60.7 ± 11.1 years were randomized equally to the experimental and control groups. 9 participants (6 in the experimental group and 3 in the control group) were unable to complete the study due to technical challenges with the apps and were excluded from analysis. No statistically significant differences were noted in either group’s baseline demographic and OSA measures. 7/9 (78%) participants in the experimental group vs 7/12 (58%) in the control group met the prespecified compliance thresholds for the 8 weeks therapy period. Self-reported snoring severity mean scores were significantly reduced in the experimental group (from 2.86 to 1.43, p-value 0.04) compared to the control group (from 2.14 to 1.77, p-value 0.21). Conclusion Addition of gamification and therapy monitoring techniques improve compliance to the prescribed oropharyngeal exercises in patients with OSA. Further studies are needed to establish the efficacy of gamified oropharyngeal therapy in the treatment of OSA. Support (if any) Research reported in this abstract was supported by NHLBI of the NIH under award number: R43HL152948-01.

Abstract Introduction The definition of respiratory events has evolved over decades. The current American Academy of Sleep Medicine scoring manual recommends hypopneas be defined by a ≥ 30% airflow reduction with either ≥ 3% desaturation or an arousal, while the prior “recommended” criteria of a ≥ 30% airflow reduction and associated ≥ 4% oxygen desaturation (with no requirement of arousal) was changed to “optional”. Consequently, events previously characterized as a respiratory effort related arousal (RERA) may now be defined as a 3% hypopnea. We hypothesized that while the 3% apnea-hypopnea index (3%AHI) will be higher than the 4%AHI, the 3%AHI will be similar to the 4% respiratory disturbance index (4%RDI), and that the measurement of RERAs under 3% scoring criteria will be clinically insignificant. Methods We prospectively collected 70 consecutive in-lab polysomnography results in 4 adult age groups. We re-scored the respiratory events utilizing the 3% hypopnea rule, and compared the differences between 3% and 4% scoring criteria. Results Among the 70 studies (mean age 50, males 46%), the 3%AHI was significantly higher than the 4%AHI (+9.247 ± 1.161, p< 0.001). This was mainly due to increased hypopnea events (+10.313 ± 1.617, p< 0.001). The 3%AHI was significantly different from the 4%RDI (+7.096 ± 1.133, p< 0.001). There were no significant differences between the 3% and 4% RERA indices, with both values being minimal. Results were similar in both diagnostic and titration phases of testing. Conclusion As previously shown, utilizing the 3% hypopnea rule results in an increased AHI. Most of this difference is related to hypopneas with negligible influence of RERAs. This may lead to increased diagnosis and severity of sleep-disordered breathing in the adult population, and potentially be associated with payer ramifications. Our findings demonstrated negligible RERA indices on average with either rule, thus calling into question the clinical significance of this index in most patients. Support (if any) NA

Abstract Introduction In this pilot study, sleep biomarker-based neurodegenerative disorder (NDD) risk was assessed in a clinical cohort of patients diagnosed with varying severity of obstructive sleep apnea (OSA). Methods Consecutive in-home multi-night Sleep Profiler records from a community sleep clinic were screened for age >54 years old. Cases with comorbid restless leg syndrome, hypersomnia, missing apnea-hypopnea indexes (AHI), AHI< 5 or single-night recordings were excluded. The 67 remaining records were 40% female, ages 63 + 7.4 years and up to 84 years old. NDD risk was assigned using a machine-learning algorithm combining age and nine sleep biomarkers to assign group probabilities: for Alzheimer’s disease, Lewy Body disease, prodromal synucleinopathy and controls (CG). Sleep biomarkers included: time-REM, non-REM hypertonia, autonomic-activation index, spindle-duration, atypical-N3, time-supine, sleep-efficiency, relative-theta, and theta/alpha. Those with CG probability score >70% were classified as “Probably-normal”. Those with CG probability between 45 - 70% were classified as “Likely-normal”. Insomnia severity >14 and a PHQ 9 > 5 were used as cutoffs for clinical insomnia and depression. Mann-Whitney U-tests were used to evaluate group differences. Results This cohort had 37% mild, 34% moderate, and 29% severe OSA. Self-reported comorbid insomnia and depression were present in 43%. Seventy-three percent of patients were classified as “Probably-normal”, 16% “Likely-normal”, 11% “Likely-NDD” or “Probable-NDD”. The “Probably-normal” group was younger than the rest of the cohort (62 + 6.2 years vs. 68 + 8.6 years, p< 0.01). Of those classified as “Probably-normal” (n=49), OSA was mild in 16, moderate in 17 and severe in 16. Mean AHI trended higher in the “Probably-normal” group than in those with elevated NDD risk (29 + 23.9 vs. 19 + 13.6 events/h, p=0.085). Conclusion Approximately 89% of the clinical cohort was classified as “Probably-normal” or “Likely-normal”. NDD risk was age-dependent. Interactions between OSA severity and NDD risk were not apparent in these findings, possibly related to group-wide effects. NDD risk, as measured by this model, did not appear to be adversely biased by untreated OSA. These results suggest a need for longitudinal studies to compare NDD risk in untreated OSA versus controls without sleep disordered breathing. Support (if any) NIH grants R44AG050326, R44AG054256, RO1AG060477, R33AG064271, ULRR024150, and R34AG056639.

ABSTRACTMitochondrial membrane translocator protein 18 kDa (TSPO) expression is increased in activated microglia, established as a plausible target of neuroinflammation imaging. [11C]ER176, specifically binding to TSPO, has been developed as the third generation of radioligand for PET imaging of TSPO, which showed the potential in better quantifying neuroinflammation than its predecessors. In the current study, we developed an automated radiosynthesis with an improved HPLC purification method for [11C]ER176 clinical production. The improved HPLC separation was integrated into the automated production of [11C]ER176 using a reverse phase semi‐preparative HPLC column with an isocratic pump and the mixture of methanol and 50 mM ammonium acetate as the mobile phase. The fraction corresponding to [11C]ER176 was collected around 8.5–9.0 min without the risk of getting contaminations from nearby impurities. The automated production process took about 30 min after end of bombardment (EOB) and the quality of the final product [11C]ER176 met all specifications for clinical use based on current US Pharmacopeia and FDA CGMP requirements.