Narcolepsy Type Research Articles

Clinical challenges in narcolepsy: From delayed diagnosis to daytime function impairments during treatment.

Clinical challenges in narcolepsy: From delayed diagnosis to daytime function impairments during treatment.

Characteristics of Maintenance of Wakefulness Test (MWT) in drug-naïve patients with narcolepsy type 1 and type 2, and relationship with other measures of sleepiness.

We aimed to describe the characteristics of standard maintenance of wakefulness test (MWT), outside of clinical trials, in a sample of drug-naïve patients with narcolepsy type 1 (NT1) and type 2 (NT2). Consecutive drug-naïve patients with narcolepsy underwent two days of continuous PSG recording, the multiple sleep latency test (MSLT), then night-PSG and, on the following day, MWT. MWT results were correlated with MSLT and Epworth Sleepiness Scale (ESS). Patients in the two lower tertiles of MWT mean sleep latency (mSL) were compared to those in the upper tertile. Seventy-eight NT1 (30.6 ± 11.4years, 35 males) and 19 NT2 (31.0 ± 9.9years, 12 males) were included. MWT results showed a bimodal distribution with a large peak with reduced mSL and a small peak with values towards 40minutes. MWT mSL was lower in NT1 than in NT2 (10.7 ± 10.8min vs 23.9 ± 11.5min, p<.001). In the entire sample, lower MWT mSL was moderately correlated with lower MSLT mSL (Rho = 0.347, p=.001) and higher ESS (Rho = -0.398, p<.001). Patients with NT1 with MWT mSL in the two lower tertiles (≤11.2min) had higher ESS than those in the upper tertile, without any difference in other clinical or neurophysiological features. In NT2, no significant correlations emerged between MWT, MSLT, and ESS. MWT mSL is reduced in drug-naive narcolepsy, more severely in NT1 than in NT2. However, a minority of patients show normal MWT results. MSLT, MWT, and ESS measure different aspects of sleepiness in narcolepsy, and none can be considered a comprehensive measure of its severity.

Present and Future of Central Disorders of Hypersomnolence.

Central disorders of hypersomnolence (CDH) are rare neurological conditions lumped by excessive daytime sleepiness (EDS) as primary complaint mostly arising at young age, including narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), idiopathic hypersomnia (IH), and Kleine-Levin syndrome (KLS). Advances in clinical and translational research have deepened our understanding of NT1, particularly the loss of hypothalamic hypocretin/orexin-producing neurons, establishing hypocretin deficiency as a reliable disease specific biomarker, although the exact mechanisms of neuronal loss remain unknown. Conversely, the pathophysiological mechanisms underlying NT2, IH, and KLS are still poorly understood, as well as their natural course. Standard diagnostic evaluation primarily relies on clinical symptoms, polysomnography and the multiple sleep latency test, with alternative neurophysiological markers (long term polysomnographic recordings), quantitative signal analysis, and wearables technologies being explored as potential innovative tools. Management remains symptomatic, combining pharmacological treatments such as stimulants, sodium oxybate, and emerging hypocretin/orexin receptor agonists, with nonpharmacological strategies tailored to improve patient quality of life. Notably, new therapies targeting orexin signalling offer promising avenues for transforming treatment approaches, particularly in NT1. Looking ahead, advancing precision medicine approaches and addressing unmet needs in CDH are essential to improve patient outcomes. This review summarises current knowledge and highlights future research directions in CDH pathophysiology, diagnostic approaches and pharmacological management.

Alteration of Metabolic Profile in Patients with Narcolepsy Type 1

Background: Narcolepsy type 1 (NT1) is a rare neurological sleep disorder characterized by excessive daytime sleepiness and cataplexy. NT1 is thought to be caused by the loss of hypocretin-producing neurons in the hypothalamus due to autoimmunity. Since cerebrospinal fluid hypocretin testing is invasive and not always feasible in clinical practice, there is a critical need for less invasive biomarkers to improve diagnostic accuracy and accessibility. Very few studies have explored serum-based biomolecules that could serve as biomarkers for NT1. Methods: This study examines the differential abundance of serum metabolites in patients with NT1 using an LC-MS/MS-based comprehensive metabolomics approach. Results: An untargeted analysis identified a total of 1491 metabolites, 453 of which were differentially abundant compared to the control cohort. Ingenuity pathway analysis revealed that key pathways, such as the inflammatory response (p-value of 0.01, activation z-score of 0.5), generation and synthesis of reactive oxygen species (p-value of 0.0008, z-score of 1.3), and neuronal cell death (p-value of 0.04, z-score of 0.4), are predicted to be activated in NT1. A targeted analysis using parallel reaction monitoring validated 49 metabolites, including important downregulated metabolites such as uridine (fold change (FC) of 0.004), epinephrine (FC of 0.05), colchicine (FC of 0.2), corticosterone (FC of 0.3), and arginine (FC of 0.6), as well as upregulated metabolites such as p-cresol sulfate (FC of 2601.7), taurine (FC of 1315.4), inosine (FC of 429.7), and malic acid (FC of 7.9). Conclusions: Understanding the pathways identified in this study and further investigating the differentially abundant metabolites associated with them may pave the way for gaining insight into disease pathogenesis and developing novel therapeutic interventions.

Benefits of oveporexton in narcolepsy type 1.

Benefits of oveporexton in narcolepsy type 1.

Diagnostic value of nocturnal sleep-onset rapid eye movement sleep period for narcolepsy type 1 and 2 in a tertiary sleep centre.

Diagnostic value of nocturnal sleep-onset rapid eye movement sleep period for narcolepsy type 1 and 2 in a tertiary sleep centre.

Unraveling the pathophysiology of narcolepsy type 1 through hypothesis-driven and hypothesis-generating approaches.

Unraveling the pathophysiology of narcolepsy type 1 through hypothesis-driven and hypothesis-generating approaches.

Phenotypic clusters of narcolepsy type 1: Insights from age of onset, weight gain, sleep patterns, and impulsivity.

Phenotypic clusters of narcolepsy type 1: Insights from age of onset, weight gain, sleep patterns, and impulsivity.

Sex effect on time to diagnosis and clinical features of narcolepsy type 1 and 2.

Sex influences sleep through physiological differences and impacts the clinical presentation and quality of life in patients with sleep disorders. However, there is a paucity of evidence regarding differences between men and women affected by narcolepsy. This study aimed to explore the sex-based dissimilarities in time to diagnosis and clinical features in narcolepsy. This retrospective observational study included adult patients with narcolepsy type 1 (NT1) and type 2 (NT2). Clinical, polysomnographic, and biofluid parameters were compared between men and women. The study analyzed 42 patients: 27 with NT1 (64.3%) and 15 with NT2 (35.7%). Among these, 18 were male (42.9%; mean age 34.72±12.89 years) and 24 were female (57.1%; mean age 37.96±13.2 years). No significant sex differences were observed in the age at onset of symptoms. Notably, females had significantly longer diagnostic delay compared to males (p=0.04) and a higher rate of misdiagnosis before receiving the diagnosis of narcolepsy (p<0.001). Male patients exhibited significantly longer stage 2 of Non-REM sleep percentage compared to females patients (p=0.024). There were no significant differences in psychiatric comorbidities (p=0.30). Women with narcolepsy experience longer time to obtain the correct diagnosis and are more frequently misdiagnosed with other disorders compared to men. The present findings highlight a potential sex-based disparity in diagnostic practices that may negatively impact the well-being of women with narcolepsy, as their symptoms are more commonly misdiagnosed.

Abnormal brain functional network dynamics in narcolepsy type 1 patients.

Abnormal brain functional network dynamics in narcolepsy type 1 patients.

Post-vaccination hypersomnia - occurrence of idiopathic hypersomnia and narcolepsy type 2 after Pandemrix vaccination in a case- series from Sweden and Finland.

Post-vaccination hypersomnia - occurrence of idiopathic hypersomnia and narcolepsy type 2 after Pandemrix vaccination in a case- series from Sweden and Finland.

Rapid eye movement sleep muscle activity in routine polysomnography as a marker for narcolepsy

Abstract Narcolepsy is a chronic neurological disorder characterized by excessive daytime sleepiness and associated symptoms, including cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disrupted nocturnal sleep. It is classified into two subtypes: narcolepsy type 1 (NT1), which involves cataplexy and/or low cerebrospinal fluid (CSF) hypocretin‐1 levels, and narcolepsy type 2 (NT2), which lacks cataplexy and has normal or intermediate CSF hypocretin‐1 levels. Diagnosis is often delayed or missed due to symptom overlap with other sleep disorders, limited access to specialized testing, and low clinician awareness. Current diagnostic methods include the presence of cataplexy (specific to NT1), sleep‐onset rapid eye movement periods (SOREMPs) detected through polysomnography (PSG) and multiple sleep latency tests, and low CSF hypocretin‐1 levels (primarily for NT1). However, these methods have limitations, such as the invasiveness of CSF testing, variability in SOREMPs, and the absence of specific biomarkers for NT2. Emerging research suggests that electromyographic (EMG) activity during routine PSG, particularly elevated REM sleep without atonia, could serve as an alternative diagnostic marker for narcolepsy. This review explores the potential of EMG activity during REM sleep and the procedure of quantification in routine PSG, with the aim of improving early detection and reducing diagnostic delays in narcolepsy.

The Role of Actigraphy in the Assessment of Central Disorders of Hypersomnolence: A Systematic Review and Meta-Analysis.

Actigraphy provides an objective measure of sleepiness and is recommended by the American Academy of Sleep Medicine for use 7-14 days prior to multiple sleep latency testing. It plays a valuable role in the differential diagnosis of hypersomnolence. Our aim was to provide a comprehensive summary of actigraphy features in central disorders of hypersomnolence (CDH). Data were sourced from six bibliographic databases. Fixed- or random-effects models were applied to compare patients with narcolepsy type 1 (NT1) to controls. Of the 1,737 publications identified in our search, 8 studies met the inclusion criteria. The total sample consisted of 473 participants, encompassing patients with NT1, idiopathic hypersomnia (IH), hypersomnolence with normal CSF hypocretin-1 levels, Kleine-Levin syndrome (KLS), traumatic brain injury (TBI), major depressive disorder (MDD), myotonic dystrophy (MD), primary insomnia and healthy controls. Actigraphy devices varied across studies. Compared to control subjects, NT1 patients had lower total sleep time (TST), sleep efficiency and daytime motor activity, with increased wake after sleep onset, awakenings, nocturnal motor activity and longest nap duration. In KLS, TST was higher during hypersomnia episodes than during asymptomatic phases. TBI and MDD patients had a higher TST than the control group, while MD patients had a lower TST than patients with IH. Actigraphy is a valuable tool for objectively assessing sleep and can assist in detecting CDH. However, the absence of standardized guidelines limits their broader implementation in clinical practice.

The prevalence, incidence, and impact of narcolepsy and idiopathic hypersomnia in Taiwan: comparison between the National Health Insurance Research Claims Database and a hospital cohort database

Abstract Study Objectives We investigated the prevalence and incidence of narcolepsy (types 1 and 2) and idiopathic hypersomnia (IH) in Taiwan using the National Health Insurance Research Database (NHIRD), and compared disease impact with patients identified from a “gold-standard” hospital database. Methods This study employed retrospective cohort and cross-sectional designs to analyze data from the NHIRD and the hospital database cohort between 2009 and 2019. Analyses comprised prevalence and incidence of narcolepsy and IH, with diagnoses validated against the hospital database, and comparison of demographics, prescriptions, comorbidities, healthcare utilization, and costs with a control cohort. Categorical variables were analyzed using the chi-squared test; continuous variables were assessed via analysis of variance or Kruskal–Wallis tests. Results From both databases, 24 317 patients were identified as having narcolepsy or IH. The diagnosed prevalence of narcolepsy was 9.98 per 100 000 individuals. Annual increases in prevalence and incidence were observed, particularly in young adults (aged 21–30 years). Patients with narcolepsy and IH exhibited higher rates of comorbidities and received more psychotropics compared with controls. However, fewer patients from the NHIRD received treatment for hypersomnolence than those from the hospital cohort. Healthcare utilization and costs were higher among patients with narcolepsy and IH compared with controls. Conclusions Increased narcolepsy prevalence over time was observed, particularly among young adults, but the overall prevalence in Taiwan appears to be lower than in other countries, potentially indicating underdiagnosis or inadequate treatment. High comorbidity rates and healthcare utilization underscore the substantial disease impact in patients with central hypersomnia.

0801 Polysomnographic Characteristics Differentiating the Central Disorders of Hypersomnolence

Abstract Introduction Central Disorders of Hypersomnolence (CDH) are classified primarily by polysomnography-multiple sleep latency test (PSG-MSLT). Lack of biomarkers and variable MSLT results in disorders other than narcolepsy type 1 (NT1) contribute to under- and mis-diagnosis. Limited studies explore PSG characteristics that may differentiate CDH subtypes using large datasets. Methods This retrospective cohort included 1,330 patients who underwent PSG-MSLT for hypersomnolence (January 2003-August 2024) at Cleveland Clinic. Cases were classified as NT1, narcolepsy type 2 (NT2), idiopathic hypersomnia (IH) and undifferentiated hypersomnia (UH; not meeting CDH criteria) based on physician clinical diagnosis. 557 patients with disorders associated with hypersomnia (i.e. OSA) were excluded. Demographic and PSG characteristics were compared with ANOVA, Kruskal-Wallis, and Pearson chi-square tests. Results Of 773 patients (33.7±14.0 yr, 79.4% female), 72(9.3%) had NT1,121(15.7%) NT2, 296(38.3%) IH, and 284(36.7%) UH. While groups did not differ in age or gender, more Caucasians had IH and UH than NT1(78.6, 80.8 vs. 62.5%, p=0.001). Epworth Sleepiness Scale scores were lower in UH than CDH groups (12.6±5.0 vs NT1-15.9±5.6,NT2-16.1±5.1,IH-14.2±5.2, p&amp;lt; 0.001). Self-reported sleep time was longer for UH than NT2 without other group differences (UH-9.1±2.1,NT2-8.4±1.7,NT1-8.6±2.1,IH-8.8±1.9 hours, p=0.003). PSG sleep onset REM periods (SOREMPs) were more common in NT1 and NT2 than IH and UH (NT1-27.8%,NT2-9.1%,IH-1.01%,UH-1.06%, p&amp;lt; 0.001). NT1 and NT2 had shorter REM latency than IH and UH(NT1-73.5[7.0,123.0],NT2-74.0[53.0,112.0],IH-103.0[71.0,161.5],UH-105.0[74.5,183.0] min, p&amp;lt; 0.001). NT1 and UH showed more wakefulness after sleep onset than NT2 and IH (NT1-43.5[26.0,97.0],UH-47.5[25.5, 85.0],NT2-32.5[17.3,61.5],IH-30.5[17.5, 62.5] min, p&amp;lt; 0.001). Sleep latency was shorter in CDH than UH (NT1-10.8[4.5,26.0],NT2-14.0[6.0,24.5],IH-17.5[7.8,30.5],UH-24.5[12.5,39.0] min, p&amp;lt; 0.001), and sleep efficiency higher in NT2 and IH than UH (NT2-87.4±7.3,IH-86.3±8.8,UH-82.0±10.0, p&amp;lt; 0.001). NT1 had greater, though non-significant, arousal index, stage shifts, and N1 percentage, along with lower sleep efficiency than NT2 and IH. No significant differences were observed between NT2 and IH in sleep latency, sleep efficiency, arousal index, WASO, stage shifts, or stage percentages. Conclusion We found significant differences in PSG variables between CDH that confirm and extend prior observations. Minimal differences between NT2 and IH support a common pathophysiology. Recognizing the larger group of UH with distinct PSG features from CDH is important in clinical practice. Support (if any)

0811 Characterizing Patient-Reported Cognitive Symptoms and Their Impact on Daily Life in Narcolepsy Type 1

Abstract Introduction Narcolepsy type 1 (NT1) is a chronic, rare neurological disorder with a significant impact on daily life. It is characterized by a pentad of symptoms including excessive daytime sleepiness (EDS), cataplexy, disrupted nighttime sleep, hypnagogic and hypnopompic hallucinations, and sleep paralysis. Cognitive symptoms associated with narcolepsy are understudied in NT1 but have substantial impacts on daily life. This study investigated the nature of cognitive symptoms experienced by adults with NT1 and the impact on daily life using semi-structured interviews. Methods In-depth, qualitative interviews were conducted with adults diagnosed with NT1 in the USA. Participants were recruited through 1) a patient advocacy organization (via social media and the organization’s website); 2) a professional market research organization; and 3) participant referrals. Individual interviews were conducted by telephone, followed a semi-structured guide and lasted ~90 minutes. The qualitative analysis was informed by an adapted grounded theory approach. Analyses identified key conceptual themes related to cognitive symptoms associated with NT1 in adults and their consequences for daily life. Results Of the 46 participants, 45 (98%) reported cognitive symptoms, with the most common being trouble remembering (89%, n=41) and difficulty with focus/sustained attention (87%, n=40). Most participants characterized cognitive symptoms as severe or moderate (79%, n=33/42) and reported symptoms occurring daily (73%, n=30/41). Of participants who rated the current impact of cognitive symptoms on their functioning/daily life, two-thirds (67%, n=22/33) reported that cognitive symptoms had a severe or moderate impact. Notably, 12/45 (27%) participants reported no improvement and 29/45 (64%) reported incomplete resolution of cognitive symptoms following drug treatments for NT1 symptoms, including EDS; 4/45 (9%) participants did not provide a response. Conclusion This investigation showed that cognitive symptoms among adults with NT1 are frequent, severe, and interfere with daily life activities. As such, the current pentad of narcolepsy symptoms represents an incomplete clinical picture. These findings suggest that cognitive symptoms should be considered a core feature of the disease. In many participants, cognitive symptoms persisted despite treatment. These data highlight a clear unmet need to assess cognitive function in people with NT1 and identify treatments that address NT1-associated cognitive symptoms. Support (if any) Funded by Takeda Development Center Americas, Inc.

0818 Discrepancy Between Clinical Phenotyping and ICSD-3 Criteria Contributes to Misdiagnosis in Central Disorders of Hypersomnolence

Abstract Introduction Central Disorders of Hypersomnolence (CDH) are classified primarily by polysomnography-multiple sleep latency test (PSG-MSLT). Lack of biomarkers, variable MSLT results in disorders other than narcolepsy type 1 (NT1) and inaccessibility of 24-hr PSG and actigraphy in most U.S. sleep centers contribute to misdiagnoses. We compared CDH diagnoses by sleep expert clinical phenotyping and ICSD-3 criteria to estimate the magnitude of potential misdiagnosis in a U.S. quaternary care sleep center. Methods This retrospective study included patients evaluated for hypersomnolence at Cleveland Clinic (January 2003 - August 2024). Patient with a clinical diagnosis of NT1, NT2, and IH based on sleep physician clinical history were included. ICSD-3 diagnoses were based on PSG/MSLT SOREMPs and MSLT mean sleep latency (MSL): narcolepsy: MSL&amp;lt; 8 min + &amp;gt;2SOREMPs; IH: MSL&amp;lt; 8 min + &amp;lt; 2SOREMPs. Those not meeting ICSD-3 criteria were considered undiagnosed. ICSD-3 diagnoses were analyzed between clinical groups using ANOVA, Kruskal-Wallis, and Pearson chi-square tests, followed by pairwise comparisons. Results Of 489 patients (33.6±13.6 yrs, 78.7% female), 72(14.7%) had NT1, 121(24.7%) NT2, and 296(60.5%) IH. More NT1 and NT2 patients had &amp;gt;2 SOREMPs than IH (NT1-81.9%, NT2-71.1%, IH-12.4%, p&amp;lt; 0.001). MSL was longer in IH than narcolepsy (IH-8.1±4., NT1-4.9±3.8, NT2-5.4±3.2 min, p&amp;lt; 0.001). Percentage agreement between ICSD-3 and clinical diagnoses was 100% for NT1, but lower for NT2 and IH (NT2-61.2%,IH-58.1%, p&amp;lt; 0.001). Among clinical NT1, 26.4% did not meet PSG-MSLT criteria. Among clinical NT2, 38.9% had different ICSD-3 diagnoses: 24% reclassified as IH and 14.9% were undiagnosed. Among clinical IH, 41.9% had different ICSD-3 diagnosis: 0.6% reclassified as NT2 and 41.2% were undiagnosed. Overall, 28.6% of CDH patients diagnosed based on clinical criteria were not diagnosed as CDH by ICSD-3 criteria due to lack of sleep laboratory findings. Conclusion This study showed diagnostic discrepancies between clinical phenotyping and ICSD-3 criteria for NT2 and IH, while NT1 diagnoses aligned. Over a quarter of clinically diagnosed patients remained undiagnosed by ICSD-3 criteria. These findings illustrate limitations of current diagnostic criteria and the need for to improve diagnostic accuracy in the evaluation of CDH. Support (if any)

0846 Actigraphy-Based Assessment of the Impact of TAK-861 on Daytime Napping in People with Narcolepsy Type 1

Abstract Introduction Excessive daytime sleepiness (EDS) is a hallmark symptom of narcolepsy that profoundly impacts daily life. Naps are a clinically meaningful indicator of EDS, and wrist-worn accelerometers offer a convenient and accurate measurement method. We aimed to develop and validate an objective actigraphy-based algorithm for detecting daytime naps in people with narcolepsy type 1 (NT1). Methods The Multi-Ethnic Study of Atherosclerosis (MESA) dataset included manually annotated naps from 2,237 participants with wrist-worn actigraphy devices across seven days. Using MESA data, we developed an algorithm that predicted sleep-wake epochs from activity counts, grouped these predictions into naps (sleep periods lasting ≥5min between 9AM and 9PM), then applied decision rules (pruning and fusion) to optimize agreement with manually annotated naps. Following validation, our algorithm was applied in a phase 0 non-interventional study of 16 participants with NT1 and 16 healthy sex- and age-matched controls (NCT04445129), and a phase 2 interventional study of orexin receptor 2-selective agonist TAK-861 in 112 participants with NT1 (NCT05687903). Algorithm-derived measures included the proportion of nap-free days and total minutes of daytime sleep on days with ≥1 nap. Results In MESA, our nap detection algorithm yielded high sensitivity (86.5%) and F1 area (84.6%), and nominal correlations (R=-0.16, p&amp;lt; 0.001; R=0.15, p&amp;lt; 0.001; n=2,237) between napping and self-reported sleepiness measured via Epworth Sleepiness Scale (ESS), suggesting sleepiness is weakly associated with less nap-free days and more daytime sleep. In the non-interventional trial, participants with NT1 had 11.5 fewer nap-free days (p&amp;lt; 0.001; n=16) in a 4-week period and slept 37.5 more minutes during the day (p&amp;lt; 0.001; n=16) than controls. In the interventional trial, relative to baseline, TAK-861-treated participants with NT1 experienced a statistically significant increase in nap-free days in a 4-week period and slept less time per day across TAK-861 dose groups (0.5mg/0.5mg: n=23, 2mg/2mg: n=21, 2mg/5mg: n=23, 7mg: n=23; all p&amp;lt; 0.001). No significant effects were observed with placebo (n=22). Conclusion We developed a highly sensitive and specific actigraphy-based nap-detection algorithm which identified two important nap-related findings: increased napping in untreated participants with NT1, and substantially reduced daytime napping in TAK-861-treated participants with NT1. Support (if any) Funded by Takeda Development Center Americas, Inc.

0826 Impaired Attention in Pediatric Narcolepsy Type 1 Using Psychomotor Vigilance Task

Abstract Introduction Decreased attention is common in pediatric Narcolepsy Type 1 (NT1). However, objective data assessing attention dysfunction in this population are limited. The psychomotor vigilance task (PVT) has been used to measure attention in adults with central disorders of hypersomnolence but understudied in pediatric NT1. In this study, we compare PVT metrics between pediatric NT1 patients and healthy controls (HC) in the evening and morning with a between interval of nocturnal sleep measured by in-lab polysomnography (PSG). We hypothesized that attention dysfunction would be worse in NT1 vs HC in evening and morning and both sessions would be associated with self-reported sleepiness. Methods 28 pediatric NT1 participants (mean age 15.9) and 27 healthy controls (mean age 13.6) completed 3-minute PVT testing in the evening before PSG and upon awakening in the morning. Before each PVT, participants rated their sleepiness on 3-item visual analog scale. We compared PVT metrics between NT1 and HC, adjusting for age (including non-linear effects) and gender. Outcomes included mean 1/reaction time (RT), lapses (RT ≥ 500 ms), lapses355 (RT ≥ 355 ms), and slowest 10% 1/RT. Results NT1 participants showed reduced attention across various PVT metrics vs. HC. In the evening, mean 1/RT was significantly worse in NT1 participants (p =.008) but we found no significant group differences in lapses, lapses355, or slowest 10% 1/RT. In the morning, NT1 participants performed significantly worse than controls on mean 1/RT (p =.002), lapses355 (p &amp;lt;.001), and slowest 10% 1/RT (p =.004). Age but not gender significantly predicted all PVT measures (p &amp;lt;.01). Contrary to our hypothesis, none of the PVT measures were associated with self-reported sleepiness. Conclusion Pediatric NT1 participants exhibit objective and significantly impaired objective attention vs HC. Slower mean reactions times were evident in evening and morning but lapses and slowest reactions times were more evident in the morning. Given that self-reported sleepiness did not predict PVT outcomes, it is possible other narcolepsy features such as disrupted nighttime sleep play contributing roles. Overall, the PVT could be useful for assessing attention in children/adolescents with NT1 in clinical and school based settings. Support (if any) NIH K23 NS104267 (Maski)

0802 Polysomnographic Non-Rapid Eye Movement Sleep Biomarkers to Stratify Central Disorders of Hypersomnolence

Abstract Introduction Central disorders of hypersomnolence (CDH) including narcolepsy and idiopathic hypersomnia are chronic and debilitating conditions characterized by profound daytime sleepiness. However, they are heterogeneous and diagnostic delays of 5 to 10 years are common, exacerbating disease burden. The multiple sleep latency test (MSLT) is commonly used for diagnosis but has poor validity and reliability. There is a critical need for objective biomarkers from standard overnight polysomnograms (PSG) to stratify patients and enhance diagnostic accuracy. Methods As part of an ongoing study, we are harmonizing PSGs from CDH cases across multiple cohorts. Here we report results from the initial cohort (Mignot Nature Communications) of 469 CDH cases (including 259 with narcolepsy type 1 (NT1)) and 342 controls. After automated staging, artifact detection and filtering using Luna, we derived macro- and micro-architecture EEG metrics including stage duration/transition, spectral power, spindle and slow oscillation occurrence, morphology and coupling, as well as indices of ultradian dynamics and evaluated group-level differences. Results Comparing the two groups (NT1 and other hypersomnolence (OH)) to controls, both exhibited increased sleep time (p &amp;lt; 0.01 for all results reported), whereas only NT1 showed increased WASO and sleep fragmentation. Both groups showed reduced REM latency. After excluding individuals with sleep onset REM (&amp;lt; 15 minutes), only OH cases showed reduced REM latency. Quantifying the relative timing of each stage within the sleep period, both groups showed “earlier” N1 but N2/N3 sleep was earlier in NT1 and later in OH. Considering NREM EEG metrics, slow/delta power (and slow oscillation (SO) rate and amplitude) was increased in both groups. Spindles showed qualitatively distinct associations: slow spindles had reduced density in OH and fast spindles were reduced in NT1. In contrast, both NT1 and OH had altered SO/spindle coupling vs. controls. Conclusion We observed both shared and unique – or even qualitatively different – PSG alterations in NT1 and OH patients. These group-level effects can inform unbiased clustering of CDH patients and ultimately provide diagnostic alternatives to the MSLT, to predict disease progression, and treatment responsiveness. Support (if any) This work was funded by NIH NINDS grant 1R61NS130215-01A1 awarded to Kiran Maski.