Are Neuropeptide-Reactive T Cells behind Narcolepsy?

Researchers have previously hypothesized autoimmune origins for narcolepsy on the basis of its strong genetic association with an MHC class II allele. In a recent issue of Nature, Latorre et al. (2018) discovered that narcolepsy patients had autoreactive T cells specific to the neuronal antigen hypocretin, providing more evidence of the potential immune origin of the disease.

Genetics and epigenetics of rare hypersomnia.

Herein we focus on connections between genetics and some central disorders of hypersomnolence - narcolepsy types 1 and 2 (NT1, NT2), idiopathic hypersomnia (IH), and Kleine-Levin syndrome (KLS) - for a better understanding of their etiopathogenetic mechanisms and a better diagnostic and therapeutic definition. Gene pleiotropism influences neurological and sleep disorders such as hypersomnia; therefore, genetics allows us to uncover common pathways to different pathologies, with potential new therapeutic perspectives. An important body of evidence has accumulated on NT1 and IH, allowing a better understanding of etiopathogenesis, disease biomarkers, and possible new therapeutic approaches. Further studies are needed in the field of epigenetics, which has a potential role in the modulation of biological specific hypersomnia pathways.

Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1.

BACKGROUND: Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides. METHODS: We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate. RESULTS: Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients. CONCLUSIONS: In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.).

Deficiency of orexin signaling during sleep is involved in abnormal REM sleep architecture in narcolepsy.

Narcolepsy is a sleep disorder caused by deficiency of orexin signaling. However, the neural mechanisms by which deficient orexin signaling causes the abnormal rapid eye movement (REM) sleep characteristics of narcolepsy, such as cataplexy and frequent transitions to REM states, are not fully understood. Here, we determined the activity dynamics of orexin neurons during sleep that suppress the abnormal REM sleep architecture of narcolepsy. Orexin neurons were highly active during wakefulness, showed intermittent synchronous activity during non-REM (NREM) sleep, were quiescent prior to the transition from NREM to REM sleep, and a small subpopulation of these cells was active during REM sleep. Orexin neurons that lacked orexin peptides were less active during REM sleep and were mostly silent during cataplexy. Optogenetic inhibition of orexin neurons established that the activity dynamics of these cells during NREM sleep regulate NREM-REM sleep transitions. Inhibition of orexin neurons during REM sleep increased subsequent REM sleep in "orexin intact" mice and subsequent cataplexy in mice lacking orexin peptides, indicating that the activity of a subpopulation of orexin neurons during the preceding REM sleep suppresses subsequent REM sleep and cataplexy. Thus, these results identify how deficient orexin signaling during sleep results in the abnormal REM sleep architecture characteristic of narcolepsy.

Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy.

Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt, Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the HCRT gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, CRH and Dynorphin (PDYN) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that HCRT, PDYN, and CRH are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.

Characterization of T cell receptors reactive to HCRTNH2, pHA273-287, and NP17-31 in control and narcolepsy patients.

Narcolepsy type 1 (NT1), a disorder caused by hypocretin/orexin (HCRT) cell loss, is associated with human leukocyte antigen (HLA)-DQ0602 (98%) and T cell receptor (TCR) polymorphisms. Increased CD4+ T cell reactivity to HCRT, especially DQ0602-presented amidated C-terminal HCRT (HCRTNH2), has been reported, and homology with pHA273-287 flu antigens from pandemic 2009 H1N1, an established trigger of the disease, suggests molecular mimicry. In this work, we extended DQ0602 tetramer and dextramer data to 77 cases and 44 controls, replicating our prior finding and testing 709 TCRs in Jurkat 76 T cells for functional activation. We found that fewer TCRs isolated with HCRTNH2 (∼11%) versus pHA273-287 or NP17-31 antigens (∼50%) were activated by their ligand. Single-cell characterization did not reveal phenotype differences in influenza versus HCRTNH2-reactive T cells, and analysis of TCR CDR3αß sequences showed TCR clustering by responses to antigens but no cross-peptide class reactivity. Our results do not support the existence of molecular mimicry between HCRT and pHA273-287 or NP17-31.

Orexin 2 receptor-selective agonist danavorexton improves narcolepsy phenotype in a mouse model and in human patients.

Narcolepsy type 1 (NT1) is a sleep disorder caused by a loss of orexinergic neurons. Narcolepsy type 2 (NT2) is heterogeneous; affected individuals typically have normal orexin levels. Following evaluation in mice, the effects of the orexin 2 receptor (OX2R)-selective agonist danavorexton were evaluated in single- and multiple-rising-dose studies in healthy adults, and in individuals with NT1 and NT2. In orexin/ataxin-3 narcolepsy mice, danavorexton reduced sleep/wakefulness fragmentation and cataplexy-like episodes during the active phase. In humans, danavorexton administered intravenously was well tolerated and was associated with marked improvements in sleep latency in both NT1 and NT2. In individuals with NT1, danavorexton dose-dependently increased sleep latency in the Maintenance of Wakefulness Test, up to the ceiling effect of 40 min, in both the single- and multiple-rising-dose studies. These findings indicate that OX2Rs remain functional despite long-term orexin loss in NT1. OX2R-selective agonists are a promising treatment for both NT1 and NT2.

Bi-allelic variants in HCRT cause autosomal recessive narcolepsy.

Narcolepsy with cataplexy is a complex disease with both genetic and environmental risk factors. To gain further insight into the homozygous HCRT-related narcolepsy, we present a case series of five patients from two consanguineous families, each harboring a novel homozygous variant of HCRT c.17_18del. All affected individuals exhibited severe cataplexy accompanied by narcolepsy symptoms during infancy. Additionally, cataplexy symptoms improved or disappeared in the majority of patients over time. Pathogenic variants in HCRT cause autosomal recessive narcolepsy with cataplexy. Genetic testing of the HCRT gene should be conducted in specific subgroups of narcolepsy, particularly those with early onset, familial cases, and a predominantly cataplexy phenotype.

Single cell transcriptomics of cerebrospinal fluid cells from patients with recent-onset narcolepsy.

Narcolepsy is a rare cause of hypersomnolence and may be associated or not with cataplexy, i.e. sudden muscle weakness. These forms are designated narcolepsy-type 1 (NT1) and -type 2 (NT2), respectively. Notable characteristics of narcolepsy are that most patients carry the HLA-DQB1*06:02 allele and NT1-patients have strongly decreased levels of hypocretin-1 (synonym orexin-A) in the cerebrospinal fluid (CSF). The pathogenesis of narcolepsy is still not completely understood but the strong HLA-bias and increased frequencies of CD4+ T cells reactive to hypocretin in the peripheral blood suggest autoimmune processes in the hypothalamus. Here we analyzed the transcriptomes of CSF-cells from twelve NT1 and two NT2 patients by single cell RNAseq (scRNAseq). As controls, we used CSF cells from patients with multiple sclerosis, radiologically isolated syndrome, and idiopathic intracranial hypertension. From 27,255 CSF cells, we identified 20 clusters of different cell types and found significant differences in three CD4+ T cell and one monocyte clusters between narcolepsy and multiple sclerosis patients. Over 1000 genes were differentially regulated between patients with NT1 and other diseases. Surprisingly, the most strongly upregulated genes in narcolepsy patients as compared to controls were coding for the genome-encoded MTRNR2L12 and MTRNR2L8 peptides, which are homologous to the mitochondria-encoded HUMANIN peptide that is known playing a role in other neurological diseases including Alzheimer's disease.

Activated Wake Systems in Narcolepsy Type 1.

OBJECTIVE: Narcolepsy type 1 (NT1) is assumed to be caused solely by a lack of hypocretin (orexin) neurotransmission. Recently, however, we found an 88% reduction in corticotropin-releasing hormone (CRH)-positive neurons in the paraventricular nucleus (PVN). We assessed the remaining CRH neurons in NT1 to determine whether they co-express vasopressin (AVP) to reflect upregulation. We also systematically assessed other wake-systems, since current NT1 treatments target histamine, dopamine, and norepinephrine pathways. METHODS: In postmortem tissue of people with NT1 and matched controls, we immunohistochemically stained and quantified neuronal populations expressing: CRH and AVP in the PVN, and CRH in the Barrington nucleus; the key neuronal histamine-synthesizing enzyme, histidine decarboxylase (HDC) in the hypothalamic tuberomammillary nucleus (TMN); the rate-limited-synthesizing enzyme, tyrosine hydroxylase (TH), for dopamine in the mid-brain and for norepinephrine in the locus coeruleus (LC). RESULTS: In NT1, there was: a 234% increase in the percentage of CRH cells co-expressing AVP, while there was an unchanged integrated optical density of CRH staining in the Barrington nucleus; a 36% increased number of histamine neurons expressing HDC, while the number of typical human TMN neuronal profiles was unchanged; a tendency toward an increased density of TH-positive neurons in the substantia nigra compacta; while the density of TH-positive LC neurons was unchanged. INTERPRETATION: Our findings suggest an upregulation of activity by histamine neurons and remaining CRH neurons in NT1. This may explain earlier reports of normal basal plasma cortisol levels but lower levels after dexamethasone suppression. Alternatively, CRH neurons co-expressing AVP neurons are less vulnerable. ANN NEUROL 2023;94:762-771.

The neurobiological basis of narcolepsy.

Narcolepsy is the most common neurological cause of chronic sleepiness. The discovery about 20 years ago that narcolepsy is caused by selective loss of the neurons producing orexins (also known as hypocretins) sparked great advances in the field. Here, we review the current understanding of how orexin neurons regulate sleep-wake behaviour and the consequences of the loss of orexin neurons. We also summarize the developing evidence that narcolepsy is an autoimmune disorder that may be caused by a T cell-mediated attack on the orexin neurons and explain how these new perspectives can inform better therapeutic approaches.

Psychobehavioural profile in narcolepsy type 1 with and without REM sleep behaviour disorder.

REM sleep behaviour disorder (RBD) is common in narcolepsy type 1 (NT1). Abnormalities in the reward system have been observed in NT1, possibly related to impaired orexin projections towards the mesolimbic reward system, but also in RBD when associated with Parkinson's disease. Our study aimed to explore the psychobehavioural profile of NT1 patients with and without RBD compared with healthy controls (HC). Forty patients with NT1 were compared with 20 sex- and age-matched HC. All patients with NT1 underwent a video-polysomnography including a measure of REM sleep without atonia (RSWA). The following neuropsychobehavioural variables were assessed: apathy, impulsivity, depression, cognition, subjective and objective attention, sensation-seeking, and behavioural addictions. The patient population included 22 patients with NT1-RBD and 18 patients with NT1-noRBD. Compared with the healthy controls, patients with NT1 had higher scores of apathy, impulsivity, and depression; a lower score on global cognition, and poorer self-perceived attention. No differences were found between patients with NT1 with and without RBD in all neuropsychological variables, except for impaired objective attention in patients with NT1-RBD. In patients with NT1, a positive correlation was observed between RSWA and both apathy and impulsivity subscale. Moreover, in patients with NT1-RBD, RSWA was positively correlated with depression. Patients with NT1 showed higher depression, apathy, and impulsivity compared with controls. These measures correlate with the severity of RSWA, suggesting a transdiagnostic association between RBD and abnormalities of the reward system at least for patients with NT1.

Idiopathic hypersomnia years after the diagnosis.

Little attention has been paid to the long-term development of idiopathic hypersomnia symptoms and idiopathic hypersomnia comorbidities. The aim of this study was to describe the general health of patients with idiopathic hypersomnia years after the initial diagnosis, focusing on current subjective hypersomnolence and the presence of its other possible causes. Adult patients diagnosed with idiopathic hypersomnia ≥ 3 years ago at sleep centres in Prague and Kosice were invited to participate in this study. A total of 60 patients were examined (age 47.3 ± SD = 13.2 years, 66.7% women). In all participants, their hypersomnolence could not be explained by any other cause but idiopathic hypersomnia at the time of diagnosis. The mean duration of follow-up was 9.8 + 8.0 years. Fifty patients (83%) reported persisting hypersomnolence, but only 33 (55%) had no other disease that could also explain the patient's excessive daytime sleepiness and/or prolonged sleep. In two patients (3%), the diagnosis in the meantime had changed to narcolepsy type 2, and 15 patients (25%) had developed a disease or diseases potentially causing hypersomnolence since the initial diagnosis. Complete hypersomnolence resolution without stimulant treatment lasting longer than 6 months was reported by 10 patients (17%). To conclude, in a longer interval from the diagnosis of idiopathic hypersomnia, hypersomnolence may disappear or may theoretically be explained by another newly developed disease, or the diagnosis may be changed to narcolepsy type 2. Thus, after 9.8 years, only 55% of the examined patients with idiopathic hypersomnia had a typical clinical picture of idiopathic hypersomnia without doubts about the cause of the current hypersomnolence.

Disentangling the complex landscape of sleep-wake disorders with data-driven phenotyping: A study of the Bernese center.

BACKGROUND AND PURPOSE: The diagnosis of sleep-wake disorders (SWDs) is challenging because of the existence of only few accurate biomarkers and the frequent coexistence of multiple SWDs and/or other comorbidities. The aim of this study was to assess in a large cohort of well-characterized SWD patients the potential of a data-driven approach for the identification of SWDs. METHODS: We included 6958 patients from the Bernese Sleep Registry and 300 variables/biomarkers including questionnaires, results of polysomnography/vigilance tests, and final clinical diagnoses. A pipeline, based on machine learning, was created to extract and cluster the clinical data. Our analysis was performed on three cohorts: patients with central disorders of hypersomnolence (CDHs), a full cohort of patients with SWDs, and a clean cohort without coexisting SWDs. RESULTS: A first analysis focused on the cohort of patients with CDHs and revealed four patient clusters: two clusters for narcolepsy type 1 (NT1) but not for narcolepsy type 2 or idiopathic hypersomnia. In the full cohort of SWDs, nine clusters were found: four contained patients with obstructive and central sleep apnea syndrome, one with NT1, and four with intermixed SWDs. In the cohort of patients without coexisting SWDs, an additional cluster of patients with chronic insomnia disorder was identified. CONCLUSIONS: This study confirms the existence of clear clusters of NT1 in CDHs, but mainly intermixed groups in the full spectrum of SWDs, with the exception of sleep apnea syndromes and NT1. New biomarkers are needed for better phenotyping and diagnosis of SWDs.

T cells in patients with narcolepsy target self-antigens of hypocretin neurons.

Narcolepsy is a chronic sleep disorder caused by the loss of neurons that produce hypocretin. The close association with HLA-DQB1*06:02, evidence for immune dysregulation and increased incidence upon influenza vaccination together suggest that this disorder has an autoimmune origin. However, there is little evidence of autoreactive lymphocytes in patients with narcolepsy. Here we used sensitive cellular screens and detected hypocretin-specific CD4+ T cells in all 19 patients that we tested; T cells specific for tribbles homologue 2-another self-antigen of hypocretin neurons-were found in 8 out of 13 patients. Autoreactive CD4+ T cells were polyclonal, targeted multiple epitopes, were restricted primarily by HLA-DR and did not cross-react with influenza antigens. Hypocretin-specific CD8+ T cells were also detected in the blood and cerebrospinal fluid of several patients with narcolepsy. Autoreactive clonotypes were serially detected in the blood of the same-and even of different-patients, but not in healthy control individuals. These findings solidify the autoimmune aetiology of narcolepsy and provide a basis for rapid diagnosis and treatment of this disease.

Associations between breakfast skipping and outcomes in neuropsychiatric disorders, cognitive performance, and frailty: a Mendelian randomization study.

BACKGROUND: Prior studies have identified a correlation between breakfast skipping and a heightened risk of mental health issues. This investigation aimed to employ a Two-Sample Mendelian Randomization (MR) approach to explore the potential causal links between breakfast skipping and various psychiatric, neurological disorders, cognitive performance, and frailty. METHODS: Utilizing data from genome-wide association studies within European demographics, this research scrutinized the association between breakfast habits and several neuropsychiatric conditions and physical health outcomes, including Alzheimer's disease (AD), Attention Deficit Hyperactivity Disorder (ADHD), Bipolar Disorder (BD), Major Depressive Disorder (MDD), Narcolepsy, Insomnia, cognitive performance, and frailty. In this MR analysis, the Inverse Variance Weighted (IVW) method was primarily utilized for evaluation. Outcomes were reported as Odds Ratios (OR) and regression coefficients (ß), and underwent validation through False Discovery Rate (FDR) corrections, thereby offering a rigorous evaluation of the effects of breakfast habits on both mental and physical health dimensions. RESULTS: Findings demonstrate a significant causal link between skipping breakfast and an increased risk of ADHD (OR = 2.74, 95%CI: 1.54-4.88, PFDR = 0.003) and MDD (OR = 1.7, 95%CI: 1.22-2.37, PFDR = 0.005). Conversely, no substantial causal associations were identified between breakfast skipping and AD, BD, narcolepsy, or insomnia (PFDR > 0.05). Moreover, a notable causal relationship was established between skipping breakfast and a reduction in cognitive performance (ß = -0.16, 95%CI: -0.29-0.04, PFDR = 0.024) and an increase in frailty (ß = 0.29, 95%CI: 0.12-0.45, PFDR = 0.003). CONCLUSION: The MR analysis reveals that skipping breakfast is associated with an increased risk of ADHD, MDD, decreased cognitive performance, and greater frailty, while showing no associations were found with AD, BD, narcolepsy, or insomnia. These findings warrant further investigation into the underlying mechanisms and emphasize the importance of regular breakfast consumption for mental and physical well-being.

Homozygous HLA-DQB1*06:02 combined with T-cell receptor alpha polymorphism results in narcolepsy onset - A familial case report.

Narcolepsy is a life-long neurological disorder with well-established genetic risk factors. Human leukocyte antigen-DQB1*06:02 remains the strongest genetic predeterminant; however, polymorphisms in genes encoding the T-cell receptor alpha chain are also strongly linked. This case report shows the inheritance pathway of these genetic markers contributing to narcolepsy onset in a 17-year-old female.

Evaluating routine blood and cerebrospinal fluid samples in narcolepsy patients.

Cerebrospinal fluid hypocretin-1 is proven to be a precise diagnostic marker of narcolepsy Type 1 (NT1). However other characteristics of cerebrospinal fluid and blood parameters have not yet been described. The objective of this study was to evaluate the differences in routine blood and cerebrospinal fluid analyses between NT1 patients and patients suspected of hypersomnia. We collected retrospectively all measures of cerebrospinal fluid hypocretin-1 between 2019 and 2022. This yielded 612 patients out of which 146 were diagnosed with NT1 and the rest (466 patients) were used as a control group. We selected the most relevant routine samples from both blood, plasma and cerebrospinal fluid and compared the two groups. The only significantly different analytes were plasma lactate dehydrogenase and cerebrospinal fluid hypocretin-1. No other differences were found between the groups including thyroid markers, markers of neuroendocrine function, inflammatory markers in blood or cerebrospinal fluid, markers of permeability of the blood brain barrier or metabolic markers in blood samples. We found no significant differences in routine blood or cerebrospinal fluid components, neuroendocrine function, neuroinflammation and metabolic markers. The results reflect that the hypocretin system does not seem to play a chronic major role in regulation of these markers. None of the parameters routinely measured in blood in these patients could differentiate between NT1 and non-NT1 disorders besides CSF-hcrt-1.

Sequential Presentation of Obsessive-Compulsive Disorder and Narcolepsy in a 10-Year-Old Girl With Wolfram Syndrome 1.

ABSTRACT: Wolfram syndrome 1 (WS1) is a rare, autosomal recessive neurodegenerative disorder characterized by diabetes insipidus, insulin-dependent diabetes mellitus, optic atrophy, and deafness resulting from loss-of-function genetic variants in the WFS1 gene. Individuals with WS1 manifest a spectrum of neuropsychiatric disorders. Here, we report a pediatric case of WS1, which stemmed from a novel biallelic WFS1 loss-of-function genetic variant. The individual initially presented with obsessive-compulsive disorder, which was successfully managed by fluvoxamine. After 2 months, the child manifested excessive daytime sleepiness. Clinical evaluation and sleep recordings revealed a diagnosis of narcolepsy type 2. Excessive daytime sleepiness was improved with methylphenidate. To the best of our knowledge, this is the first report of narcolepsy in WS1, which possibly arose during a progressive neurodegenerative process. We emphasize the need for in-depth screening for neuropsychiatric phenotypes and sleep-related disorders in WS1, for clinical management, which significantly improves the quality of life.

The Burden of Narcolepsy in Adults: A Population Sampling Study Using Personal Media.

OBJECTIVE: To obtain insight in the spectrum of narcolepsy symptoms and associated burden in a large cohort of patients. METHODS: We used the Narcolepsy Monitor, a mobile app, to easily rate the presence and burden of 20 narcolepsy symptoms. Baseline measures were obtained and analyzed from 746 users aged between 18 and 75 years with a reported diagnosis of narcolepsy. RESULTS: Median age was 33.0 years (IQR 25.0-43.0), median Ullanlinna Narcolepsy Scale 19 (IQR 14.0-26.0), 78% reported using narcolepsy pharmacotherapy. Excessive daytime sleepiness (97.2%) and lack of energy were most often present (95.0%) and most often caused a high burden (79.7% and 76.1% respectively). Cognitive symptoms (concentration 93.0%, memory 91.4%) and psychiatric symptoms (mood 76.8%, anxiety/panic 76.4%) were relatively often reported to be present and burdensome. Conversely, sleep paralysis and cataplexy were least often reported as highly bothersome. Females experienced a higher burden for anxiety/panic, memory, and lack of energy. CONCLUSIONS: This study supports the notion of an elaborate narcolepsy symptom spectrum. Each symptom's contribution to the experienced burden varied, but lesser-known symptoms did significantly add to this as well. This emphasizes the need to not only focus treatment on the classical core symptoms of narcolepsy.