Hypocretin-1 Levels Research Articles

Post-Traumatic Narcolepsy Associated with Thalamic/Hypothalamic Injury

Narcolepsy is now suggested as an autoimmune disorder.1 Autoimmune-mediated loss of hypocretin-producing neurons in the hypothalamus and resultant decreased hypocretin levels in the cerebrospinal fluid might be important to the etiology of narcolepsy. Recently, secondary causes such as infection, trauma, tumors, and H1N1 flu vaccination have been identified as causes or triggers of narcolepsy and excessive daytime sleepiness.2-4 Since the first description of post-traumatic narcolepsy, approximately 20 such patients have been reported.5 However, studies showing the location of brain damage are rare.6 Here, we report a patient who developed polysomnography-confirmed post-traumatic narcolepsy after traumatic hypothalamic hemorrhagic injury.

Clinical course of H1N1-vaccine-related narcolepsy

ObjectiveTo follow and analyze the clinical course and quality of life of Pandemrix H1N1-vaccine-related narcolepsy (pNT1). MethodsTwenty-six drug-naïve confirmed pNT1 subjects completed Epworth Sleepiness Scale (ESS), Ullanlinna Narcolepsy Scale (UNS), Swiss Narcolepsy Scale (SNS), Rimon's Brief Depression scale (RDS), and WHO-5 Well-being index questionnaires near the disease onset and in a follow-up a minimum of two years later. The number of cataplexies and body mass index (BMI) were recorded. The effects of hypocretin-1 levels and sleep recording results were analyzed. The findings at the follow-up visit were compared with 25 non-vaccine-related type 1 narcolepsy (NT1) subjects. ResultsIn pNT1, RDS score decreased significantly (mean 10.2, SD 4.7 vs mean 6.7, SD 4.5, p = 0.003). Median of BMI increased from 20.8 kg m−2 to 23.4 kg m−2, p < 0.001. There were no significant differences in other sleep scores. However, deviation and range in questionnaire scores at the follow-up were wide. Subjects with very low or undetectable hypocretin-1 levels had worse scores in UNS (mean 26.4, SD 6.95 vs mean 19.1, SD 3.83, p = 0.006) and ESS (mean 17.9, SD = 4.29 vs mean 14.1, SD = 3.70, p = 0.047) than those with hypocretin-1 levels of 20–110 pg/mL. Most disabling symptoms were excessive daytime sleepiness and disturbed sleep. There were no significant differences between the scores in pNT1 and NT1. ConclusionsClinical course of pNT1 is heterogeneous but the evolution of pNT1 seems similar to NT1. Lower hypocretin levels in pNT1 are associated with a more severe phenotype.

The Roles of Dopamine and Hypocretin in Reward: A Electroencephalographic Study.

The proper functioning of the mesolimbic reward system is largely dependent on the neurotransmitter dopamine. Recent evidence suggests that the hypocretin system has significant projections to this reward system. We examined the distinct effects of reduced dopamine or reduced hypocretin levels on reward activity in patients with Parkinson’s disease, dopamine deficient, as well as patients with narcolepsy-cataplexy, hypocretin depleted, and healthy controls. Participants performed a simple game-like task while high-density electroencephalography was recorded. Topography and timing of event-related potentials for both reward cue, and reward feedback was examined across the entire dataset. While response to reward cue was similar in all groups, two distinct time points were found to distinguish patients and controls for reward feedback. Around 160ms both patient groups had reduced ERP amplitude compared to controls. Later at 250ms, both patient groups also showed a clear event-related potential (ERP), which was absent in controls. The initial differences show that both patient groups show a similar, blunted response to reward delivery. The second potential corresponds to the classic feedback-related negativity (FRN) potential which relies on dopamine activity and reflects reward prediction-error signaling. In particular the mismatch between predicted reward and reward subsequently received was significantly higher in PD compared to NC, independent of reward magnitude and valence. The intermediate FRN response in NC highlights the contribution of hypocretin in reward processing, yet also shows that this is not as detrimental to the reward system as in Parkinson’s. Furthermore, the inability to generate accurate predictions in NC may explain why hypocretin deficiency mediates cataplexy triggered by both positive and negative emotions.

Narcolepsy in African Americans.

Although narcolepsy affects 0.02-0.05% of individuals in various ethnic groups, clinical presentation in different ethnicities has never been fully characterized. Our goal was to study phenotypic expression across ethnicities in the United States. Cases of narcolepsy from 1992 to 2013 were identified from searches of the Stanford Center for Narcolepsy Research database. International Classification of Sleep Disorders, Third Edition diagnosis criteria for type 1 and type 2 narcolepsy were used for inclusion, but subjects were separated as with and without cataplexy for the purpose of data presentation. Information extracted included demographics, ethnicity and clinical data, HLA-DQB1*06:02, polysomnography (PSG), multiple sleep latency test (MSLT) data, and cerebrospinal fluid (CSF) hypocretin-1 level. 182 African-Americans, 839 Caucasians, 35 Asians, and 41 Latinos with narcolepsy. Sex ratio, PSG, and MSLT findings did not differ across ethnicities. Epworth Sleepiness Scale (ESS) score was higher and age of onset of sleepiness earlier in African Americans compared with other ethnicities. HLA-DQB1*06:02 positivity was higher in African Americans (91.0%) versus others (76.6% in Caucasians, 80.0% in Asians, and 65.0% in Latinos). CSF hypocretin-1 level, obtained in 222 patients, was more frequently low (≤ 110 pg/ml) in African Americans (93.9%) versus Caucasians (61.5%), Asians (85.7%) and Latinos (75.0%). In subjects with low CSF hypocretin-1, African Americans (28.3%) were 4.5 fold more likely to be without cataplexy when compared with Caucasians (8.1%). Narcolepsy in African Americans is characterized by earlier symptom onset, higher Epworth Sleepiness Scale score, higher HLA-DQB1*06:02 positivity, and low cerebrospinal fluid hypocretin-1 level in the absence of cataplexy. In African Americans, more subjects without cataplexy have type 1 narcolepsy.

An optimized method for measuring hypocretin-1 peptide in the mouse brain reveals differential circadian regulation of hypocretin-1 levels rostral and caudal to the hypothalamus

The hypocretin/orexin system regulates, among other things, sleep and energy homeostasis. The system is likely regulated by both homeostatic and circadian mechanisms. Little is known about local differences in the regulation of hypocretin activity. The aim of this study was to establish an optimized peptide quantification method for hypocretin-1 extracted from different mouse brain areas and use this method for investigating circadian fluctuations of hypocretin-1 levels in these areas. The results show that hypocretin-1 peptide can be extracted from small pieces of intact tissue, with sufficient yield for measurements in a standard radioimmunoassay. Utilizing the optimized method, it was found that prepro-hypocretin mRNA and peptide show circadian fluctuations in the mouse brain. This study further demonstrates that the hypocretin-1 peptide level in the frontal brain peaks during dark as does prepro-hypocretin mRNA in the hypothalamus. However, in midbrain and brainstem tissue caudal to the hypothalamus, there was less circadian fluctuation and a tendency for higher levels during the light phase. These data suggest that regulation of the hypocretin system differs between brain areas.

Neurobiology and sleep disorders in cluster headache.

Cluster headache is characterized by unilateral attacks of severe pain accompanied by cranial autonomic features. Apart from these there are also sleep-related complaints and strong chronobiological features. The interaction between sleep and headache is complex at any level and evidence suggests that it may be of critical importance in our understanding of primary headache disorders. In cluster headache several interactions between sleep and the severe pain attacks have already been proposed. Supported by endocrinological and radiological findings as well as the chronobiological features, predominant theories revolve around central pathology of the hypothalamus. We aimed to investigate the clinical presentation of chronobiological features, the presence of concurrent sleep disorders and the relationship with particular sleep phases or phenomena, the possible role of hypocretin as well as the possible involvement of cardiac autonomic control. We conducted a questionnaire survey on 275 cluster headache patients and 145 controls as well an in-patient sleep study including 40 CH-patients and 25 healthy controls. The findings include: A distinct circannual connection between cluster occurrence and the amount of daylight, substantially poorer sleep quality in patients compared to controls which was present not only inside the clusters but also outside, affected REM-sleep in patients without a particular temporal connection to nocturnal attacks, equal prevalence of sleep apnea in both patient and control groups, reduced levels of hypocretin-1 in the cerebrospinal fluid of patients and finally a blunted response to the change from supine to tilted position in the head-up tilt table test indicating a weakened sympathoexcitatory or stronger parasympathetic drive. Overall, these findings support a theory of involvement of dysregulation in hypothalamic and brainstem nuclei in cluster headache pathology. Further, it is made plausible that the headache attacks are but one aspect of a more complex syndrome of central dysregulation manifesting as sleep-related complaints, sub-clinical autonomic dysregulation and of course the severe attacks of unilateral headache. Future endeavors should focus on pathological changes which persist in the attack-free periods but also heed the possibility of long-lived, cluster-induced pathology.

14. Resting sympathetic and cardiovascular activities during wake in narcolepsy with cataplexy

Conflicting data have been reported on resting autonomic tone in narcolepsy with cataplexy (NC) including both reduced or increased sympathetic activity. To settle this important point we measured muscle nerve sympathetic activity (MSNA) and cardiovascular activities in NC patients during wakefulness. We studied 19 NC untreated patients and 19 sex-age matched controls. Subjects underwent resting microneurographic recording of MSNA from peroneal nerve and heart rate (HR) whereas blood pressure (BP) was measured with a sphygmomanometer after the end of microneurographic recording. The awake state was continuously monitored by an ambulatory polygraphic recorder. NC patients displayed significantly lower resting MSNA, HR and BP values than controls. Pearson regression analysis showed a significant correlation between CSF hypocretin-1 level and MSNA or HR whereas no correlation was found with BP; however patients with virtually absent hypocretin-1 displayed lower BP than patients with the highest hypocretin-1 value. (1) NC patients displayed decreased resting MSNA, HR and BP during wakefulness lowering their cardiovascular risk profile; (2) a positive correlation supported a direct effect of CSF hypocretin-1 deficiency on MSNA or HR regulation; (3) although hypocretin-1 was not correlated with BP, patients with absent hypocretin-1 had lower BP.

Reduced CSF hypocretin-1 levels are associated with cluster headache.

Cluster headache (CH) is a debilitating disorder characterized by unilateral, severe pain attacks with accompanying autonomic symptoms, often waking the patient from sleep. As it exhibits strong chronobiological traits and genetic studies have suggested a link with the hypocretin (HCRT) system, the objective of this study was to investigate HCRT-1 in CH patients. Cerebrospinal fluid HCRT-1 concentration was measured in 12 chronic and 14 episodic CH patients during an active bout, and in 27 healthy controls. The patients were well characterized and clinical features compared to the HCRT concentration. We found significantly lower HCRT levels both in chronic (p = 0.0221) and episodic CH (p = 0.0005) patients compared with controls. No significant relationship was found with other clinical features. This is the first report of significantly reduced HCRT concentrations in CH patients. We speculate that decreased HCRT may reflect insufficient antinociceptive activity of the hypothalamus. The mechanism of the antinociceptive effect of HCRT is not known and requires further investigation. This study supports the hypothesis of a connection between arousal regulation and CH.

Moebius syndrome and narcolepsy

Moebius syndrome is a rare neurological disease that has a frequent association with parasomnia. We report on a patient with Moebius syndrome and the clinical presentation of a narcolepsy cataplexy syndrome. With the hypoplasia of the brainstem in the cranial magnetic resonance imaging, we were able to show the morphological correlate of Moebius syndrome. Comorbidity was detected by cognitive tests, polysomnography and detection of hypocretin in the cerebrospinal fluid. Despite normal sleep onset latency and only one episode of sleep onset rapid eye movement (REM) in the multiple sleep latency test, where expressiveness is significantly reduced in cases of paralysis of horizontal eye movement, the diagnosis of parasomnia with narcolepsy cataplexy symptoms could be made. The hypocretin level of 132 pg/ml measured in the cerebro spinal fluid is compatible with this diagnosis and shows the relevance of a detailed diagnostic of parasomnia in patients with Moebius syndrome.

Preliminary results on CSF biomarkers for hypothalamic dysfunction in Kleine–Levin syndrome

ObjectiveTo measure CSF biomarkers of hypothalamic dysfunction in patients with typical Kleine–Levin syndrome (KLS) during symptomatic and asymptomatic periods. Patients/methodsTwo patients with typical KLS were admitted during symptomatic and asymptomatic periods to a research Sleep Disorders Center. Cerebrospinalfluid (CSF) hypocretin-1, histamine (HA), and its major metabolite tele-methylhistamine (t-MHA) levels were measured in two KLS patients in and out of episode. ResultsCSF biomarkers of hypothalamic dysfunction measured in two KLS patients in and out of episode revealed low hypocretin levels (within the narcolepsy–cataplexy range) during a hypersomnia episode in the more severe patient, and a 42% decrease (although within normal range) in the second patient. CSF HA and t-MHA measurements in and out of episode revealed a two-fold in-episode decrease in HA in the more severe patient, with no significant change for the second patient, nor for t-MHA levels. ConclusionWe reported reversible changes in CSF hypothalamic biomarkers in a typical patient with KLS that reinforces the hypothesis that in some patients KLS episodes may be caused by recurrent functional alterations of the hypothalamus.

P13. Childhood narcolepsy with cataplexy: Clinical characteristics of 4 cases

Introduction Childhood narcolepsy with cataplexy is a rare lifelong disorder which usually emerges in adolescence. Diagnosis is often delayed for many years due to poor awareness and gradual onset of symptoms. Excessive daytime sleepiness can be mistaken as a physiological phenomenon of the teenage years and cataplexy might be overlooked. Methods 4 proven cases of narcolepsy are presented that were referred to our outpatient clinic during the past 2 years. Results We report on 3 boys and 1 girl aged 6 to 13 years at disease onset. In all patients excessive daytime sleepiness was the main complaint. At the time of first presentation cataplexy was not reported but recognized by patients and parents when asked for. Loss of muscle tone affected the face and the trunk. None of the patients had drop attacks. 1 boy had major weight gain. The girl was the only patient who reported on night-time hallucinations and sleep paralysis and therefore presented with all disease defining symptoms. Rapid disease onset after a viral infection occurred in 2 boys. In 2 patients a peculiar facial expression with unusual tongue protrusion was reported and evident on physical exam. Mood changes and aggressive behaviour occurred in 2 patients. Polysomnography (PSG) and multiple sleep latency (MSLT) tests were performed in all patients and revealed typical findings of narcolepsy with sleep fragmentation, sleep onset REM and short sleep latency in 3 patients, while in 1 patient PSG and MSLT were normal. Carriage of the HLA-DQB1∗0602 haplotype and low CSF hypocretin levels were confirmed in the 3 boys. In one patient intravenous immunoglobulins were administered and lead to a transient symptom relief but failed to induce an increase of CSF hypocretin. Excessive daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS). All patients were treated with methylphenidate resulting in reduction of the ESS score. In 2 patients improvement is not yet considered as sufficient. As expected cataplexy did not respond to treatment. Conclusions Narcolepsy with cataplexy is a severely disabling, most probably autoimmune disease. Early diagnosis and treatment initiation may improve school performance and quality of life during the teenage years and hopefully also the longterm course. Treatment recommendations are adopted from adult medicine but are still controversial due to addictive potential and off-label use of some substances, as sodium oxybate in children.

EHMTI-0149. Low CSF hypocretin-1 levels are associated with cluster headache

Results We found lower HCRT-1 levels in both chronic (388.67 pg/ml, p = 0.0221) and episodic cluster headache (375.36 pg/ml, p = 0.0005) compared with controls (430.96 pg/ml) and a tendency towards relatively higher values in chronic CH compared with episodic CH. A positive relationship between the CH index and HCRT concentrations was found in all patients (R2 = 0.1541, p = 0.0473). We also identified a tendency towards relatively higher HCRT concentrations in patients without chronological rhythmicity.

Lower wake resting sympathetic and cardiovascular activities in narcolepsy with cataplexy

Conflicting data have been reported on resting autonomic tone in narcolepsy with cataplexy (NC), including reduced or increased sympathetic activity; to settle this important point, we aimed to measure the resting sympathetic and cardiovascular activities in patients with NC by direct microneurographic monitoring of muscle sympathetic nerve activity (MSNA) during wakefulness. We studied 19 untreated patients with established criteria for NC and hypocretin deficiency and 19 sex- and age-matched healthy subjects. Subjects underwent resting microneurographic recording of MSNA from peroneal nerve and heart rate (HR), whereas blood pressure (BP) was measured with a sphygmomanometer after the end of microneurographic recording. The awake state was continuously monitored by an ambulatory polygraphic recorder. Patients with NC displayed lower resting MSNA, HR, and BP values than controls. Pearson regression analysis showed a correlation between CSF hypocretin-1 level and MSNA or HR, whereas no correlation was found with BP; however, patients with virtually absent hypocretin-1 displayed lower BP than patients with the highest hypocretin-1 value. (1) Patients with NC displayed decreased resting MSNA, HR, and BP during wakefulness, lowering their cardiovascular risk profile; (2) CSF hypocretin-1 deficiency was correlated with MSNA or HR, supporting a direct effect of hypocretin on autonomic regulation; (3) although hypocretin-1 was not correlated with BP, patients with absent hypocretin-1 had lower BP.

Treatment of disorders of hypersomnolence.

In the absence of sleep deprivation (either because of behavioral or medical causes) or pharmacologically induced sleepiness, hypersomnia is a manifestation of one of the central disorders of hypersomnolence, such as narcolepsy types 1 and 2, idiopathic hypersomnia, and recurrent hypersomnias such as Kleine-Levin syndrome. Narcolepsy and most primary hypersomnias are chronic conditions, thus, before committing an individual to chronic, possibly, life-long treatments, an accurate diagnosis is important. The key to effective management of hypersomnia, thus, lies in a thorough history, detailed physical examination, and appropriate diagnostic tests. Secondary causes of hypersomnia are expected to resolve once these disorders are treated. The treatment of central hypersomnias, on the other hand, is guided by a level of diagnostic certainty as to the etiology of the hypersomnia. Narcolepsy, for example, has well defined pathophysiologic and diagnostic criteria, including low levels of hypocretin in cerebrospinal fluid (CSF) and specific findings on a polysomnography/multiple sleep latency test (PSG/MSLT). For these patients, life-long therapy is the norm and involves initiating treatment usually with modafinil, armodafinil, or sodium oxybate, with methylphenidate, amphetamine-like stimulants, atomoxetine, or antidepressants used as second-line therapy. Pharmacologic therapy is usually done in concert with behavioral modifications such as scheduled napping for the best response. On the other hand, the etiology and pathophysiology of non-hypocretin-related hypersomnias (eg, idiopathic hypersomnia, Kleine-Levine syndrome) are unknown. For these reasons, treatment of these disorders is more challenging and less well defined. A trial of modafinil or armodafinil may be considered as first line therapy along with behavioral modifications. Methylphenidate, amphetamine-based stimulants, and even clarithromycin have also been used. There is no effective cure for hypersomnia, and the current therapy is purely symptomatic. Thus, initial patient education, addressing treatment expectations, as well as continued regular follow-up to monitor treatment response are vital to effective management of hypersomnia. The focus of this article is limited to a discussion of treatment of central disorders of hypersomnolence.

Hypocretin and brain β-amyloid peptide interactions in cognitive disorders and narcolepsy.

Objective: To examine relationships between cerebrospinal fluid (CSF) Alzheimer' disease (AD) biomarkers and hypocretin-1 levels in patients with cognitive abnormalities and hypocretin-deficient narcolepsy-cataplexy (NC), estimate diagnostic accuracy, and determine correlations with sleep disturbances.Background: Sleep disturbances are frequent in AD. Interactions between brain β-amyloid (Aβ) aggregation and a wake-related neurotransmitter hypocretin have been reported in a mouse model of AD.Methods: Ninety-one cognitive patients (37 AD, 16 mild cognitive impairment—MCI that converts to AD, 38 other dementias) and 15 elderly patients with NC were recruited. Patients were diagnosed blind to CSF results. CSF Aβ42, total tau, ptau181, and hypocretin-1 were measured. Sleep disturbances were assessed with questionnaires in 32 cognitive patients.Results: Lower CSF Aβ42 but higher tau and P-tau levels were found in AD and MCI compared to other dementias. CSF hypocretin-1 levels were higher in patients with MCI due to AD compared to other dementias, with a similar tendency for patients with advanced AD. CSF hypocretin-1 was significantly and independently associated with AD/MCI due to AD, with an OR of 2.70 after full adjustment, exceeding that for Aβ42. Aβ42 correlated positively with hypocretin-1 levels in advanced stage AD. No association was found between sleep disturbances and CSF biomarkers. No patients with NC achieved pathological cutoffs for Aβ42, with respectively one and four patients with NC above tau and P-tau cutoffs and no correlations between hypocretin-1 and other biomarkers.Conclusions: Our results suggest a pathophysiological relationship between Aβ42 and hypocretin-1 in the AD process, with higher CSF hypocretin-1 levels in early disease stages. Further longitudinal studies are needed to validate these biomarker interactions and to determine the cause-effect relationship and the role of wake/sleep behavior in amyloid plaque regulation.

P1056: Secondary narcolepsy with intermediate hypocretin level due to brain tumour – a case story

P1056: Secondary narcolepsy with intermediate hypocretin level due to brain tumour – a case story

Challenges in diagnosing narcolepsy without cataplexy: a consensus statement.

Diagnosing narcolepsy without cataplexy is often a challenge as the symptoms are nonspecific, current diagnostic tests are limited, and there are no useful biomarkers. In this report, we review the clinical and physiological aspects of narcolepsy without cataplexy, the limitations of available diagnostic procedures, and the differential diagnoses, and we propose an approach for more accurate diagnosis of narcolepsy without cataplexy. A group of clinician-scientists experienced in narcolepsy reviewed the literature and convened to discuss current diagnostic tools, and to map out directions for research that should lead to a better understanding and more accurate diagnosis of narcolepsy without cataplexy. To aid in the identification of narcolepsy without cataplexy, we review key indicators of narcolepsy and present a diagnostic algorithm. A detailed clinical history is mainly helpful to rule out other possible causes of chronic sleepiness. The multiple sleep latency test remains the most important measure, and prior sleep deprivation, shift work, or circadian disorders should be excluded by actigraphy or sleep logs. A short REM sleep latency (≤ 15 minutes) on polysomnography can aid in the diagnosis of narcolepsy without cataplexy, although sensitivity is low. Finally, measurement of hypocretin levels can helpful, as levels are low to intermediate in 10% to 30% of narcolepsy without cataplexy patients.

A feminist, narrative analysis of drinking stories

The association between narcolepsy with cataplexy and the hypocretinergic system in the central nervous system is strong since up to 75–90% of all patients have cerebrospinal fluid (CSF) hypocretin-1 deficiency. The predominant occurrence of HLADQB1*0602 tissue type in narcolepsy patients and recent results from genome-wide association studies suggest an underlying immunological mechanism. The present study was initiated to clarify whether measurement of nerve cell biomarkers in CSF could give additional knowledge of the pathophysiological mechanisms causing narcolepsy with cataplexy.Two patient groups with narcolepsy, comprising 18 patients with low CSF hypocretin-1 concentrations and typical cataplexy, and 18 patients with normal CSF hypocretin-1 levels and mild cataplexy-like symptoms, were compared to 17 controls. We measured the nerve cell biomarkers beta-amyloid (Aβ42), total tau protein (T-tau), phosphorylated tau (P-tau) and neuron-specific enolase (NSE) in CSF.The concentrations of all biomarkers were significantly elevated in both patient groups compared to the controls. The concentration of beta-amyloid was significantly higher in the patient group with normal CSF hypocretin-1 concentration than in those with low concentrations, whereas the other biomarkers showed no difference between the patient groups.The findings of elevated levels of CSF biomarkers independent of CSF hypocretin-1 reduction may reflect alterations in cell metabolism. The results suggest a more extensive affection of the sleep regulating cellular network, affecting other neuronal sites important in the regulation of sleep, in addition to the hypocretin-producing neurons.

G342(P) Weak at the knees with laughter

Narcolepsy is a chronic neurological disorder characterised by excessive daytime sleepiness, cataplexy, hallucinations in sleep-wake phase and sleep paralysis.Case reports (methods)We present a case series of children with narcolepsy from...

Increased cerebrospinal fluid levels of nerve cell biomarkers in narcolepsy with cataplexy

BackgroundThe association between narcolepsy with cataplexy and the hypocretinergic system in the central nervous system is strong since up to 75–90% of all patients have cerebrospinal fluid (CSF) hypocretin-1 deficiency. The predominant occurrence of HLADQB1*0602 tissue type in narcolepsy patients and recent results from genome-wide association studies suggest an underlying immunological mechanism. The present study was initiated to clarify whether measurement of nerve cell biomarkers in CSF could give additional knowledge of the pathophysiological mechanisms causing narcolepsy with cataplexy. MethodsTwo patient groups with narcolepsy, comprising 18 patients with low CSF hypocretin-1 concentrations and typical cataplexy, and 18 patients with normal CSF hypocretin-1 levels and mild cataplexy-like symptoms, were compared to 17 controls. We measured the nerve cell biomarkers beta-amyloid (Aβ42), total tau protein (T-tau), phosphorylated tau (P-tau) and neuron-specific enolase (NSE) in CSF. ResultsThe concentrations of all biomarkers were significantly elevated in both patient groups compared to the controls. The concentration of beta-amyloid was significantly higher in the patient group with normal CSF hypocretin-1 concentration than in those with low concentrations, whereas the other biomarkers showed no difference between the patient groups. ConclusionThe findings of elevated levels of CSF biomarkers independent of CSF hypocretin-1 reduction may reflect alterations in cell metabolism. The results suggest a more extensive affection of the sleep regulating cellular network, affecting other neuronal sites important in the regulation of sleep, in addition to the hypocretin-producing neurons.