Cerebrospinal Fluid Hypocretin-1 Research Articles

CSF-profile and hypocretin levels in children with narcolepsy type 1 and 2

BackgroundNarcolepsy is a rare neurological disease caused by dysfunction of hypocretin-producing neurons. Hypocretin concentrations in the cerebrospinal fluid (CSF) of less than 110 pg/ml are considered pathological in adults. ObjectivesTo compare hypocretin levels of children with narcolepsy type 1, type 2 and disease control groups, in addition to a detailed CSF analysis, clinical and polysomnographic parameters. MethodsIn a retrospective, cross-sectional study, children diagnosed with narcolepsy based on clinical and polysomnographic parameters, who received a CSF analysis and hypocretin measurement, in addition to controls, were included. CSF was analyzed for the presence of cells, total protein, lactate, intrathecal synthesis of antibodies against measles, rubella and/or varicella zoster, and oligoclonal bands. All children had a complete sleep study including a multiple sleep latency test (MSLT). Results49 children with narcolepsy type 1, 15 children with type 2 and 37 children with other (suspected) neurological diseases were included. CSF routine analysis did not reveal any differences between the three groups. All children with narcolepsy type 1 had hypocretin levels of less than 110 pg/ml (range: 10 - 101 pg/ml). Hypocretin levels in type 2 patients ranged from 43 to 436 pg/ml (median 157 pg/ml). The median hypocretin level in the control cohort was 365 pg/ml (range: 153 - 583 pg/ml). In 4 children with narcolepsy type 2 the diagnosis was changed to narcolepsy level 1 because of a CSF hypocretin level of less than 110 pg/ml according to the recently proposed criteria, which consider the measurement of hypocretin in CSF. ConclusionChildren with narcolepsy type 1 showed significantly lower CSF hypocretin levels than children with narcolepsy type 2 and controls. As suggested by the recently published narcolepsy criteria, hypocretin levels of less than 110 pg/ml should be used as an additional criterion for the presence of narcolepsy type 1 in children.

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.

Narcolepsy in a 4-Year-Old

Narcolepsy is a disabling neurodegenerative condition that is characterized by the hallmark of excessive daytime sleepiness. Diagnosis of narcolepsy can be difficult in all aged patients, but especially so in children less than 5 years old. We present a unique case of a 4-year-old girl who presented with slurred speech, behavioral changes, and hypersomnolence. After a thorough evaluation, she was diagnosed with narcolepsy type 1. We provide a literature review about this diagnosis and discuss the signs, symptoms, and workup, with a focus on the challenges associated with determining the definitive diagnosis. The role of obtaining cerebrospinal fluid hypocretin-1 levels in the diagnostic evaluation of patient with suspected narcolepsy is emphasized.

A series of 7 cases of patients with narcolepsy with hypocretin deficiency without the HLA DQB1*06:02 allele.

We report data collected from 2 reference European sleep centers on a series of patients with narcolepsy with hypocretin-1 deficiency and absence of the human leukocyte antigens (HLA) DQB1*06:02 allele. Clinical data, HLA DQ markers, and cerebrospinal fluid assessments were collected retrospectively from Caucasian patients with a diagnosis of narcolepsy type 1 with cerebrospinal fluid hypocretin-1 deficiency (< 110 pg/ml) and absence of the HLA DQB1*06:02 allele, with follow-up with at least 1 visit within the last 4 years, consecutively admitted to 2 European sleep centers (Lugano, Switzerland and Montpellier, France). Seven patients (3 of 29 patients in Lugano and 4 of 328 in Montpellier) were diagnosed with narcolepsy with hypocretin-1 deficiency and absence of HLA DQB1*06:02 (ie, 2% of patients with narcolepsy type 1). Regarding the HLA-DQB1 genotyping, 4 cases were positive for HLA DQB1*03:01, 1 for DQB1*03:02, and 3 for DQB1*02:01. Three patients had atypical cataplexy and 1 had no cataplexy. Only 2 patients had both a mean sleep latency of less than 8 minutes and more than 2 sleep onset rapid eye movement periods on the Multiple Sleep Latency Test, indicative of a less severe condition. Although rare, this series of 7 cases confirms that hypocretin-deficient narcolepsy should not be excluded in the absence of HLA DQB1*06:02, especially if patients are carriers of other high-risk HLA-DQB1 alleles (DQB1*03:01, *03:02, *02:01). These data support the hypothesis that narcolepsy type 1 is a wider disease spectrum linked to the loss of hypocretin peptide. Miano S, Barateau L, De Pieri M, etal. A series of 7 cases of patients with narcolepsy with hypocretin deficiency without the HLA DQB1*06:02 allele. J Clin Sleep Med. 2023;19(12):2053-2057.

Repeated polysomnography and multiple sleep latency test in narcolepsy type 1 and other hypersomnolence disorders

BackgroundThe diagnosis of narcolepsy is based on clinical information, combined with polysomnography (PSG) and the Multiple Sleep Latency Test (MSLT). PSG and the MSLT are moderately reliable at diagnosing narcolepsy type 1 (NT1) but unreliable for diagnosing narcolepsy type 2 (NT2). This is a problem, especially given the increased risk of a false-positive MSLT in the context of circadian misalignment or sleep deprivation, both of which commonly occur in the general population. AimWe aimed to clarify the accuracy of PSG/MSLT testing in diagnosing NT1 versus controls without sleep disorders. Repeatability and reliability of PSG/MSLT testing and temporal changes in clinical findings of patients with NT1 versus patients with hypersomnolence with normal hypocretin-1 were compared. Method84 patients with NT1 and 100 patients with non-NT1-hypersomnolence disorders, all with congruent cerebrospinal fluid hypocretin-1 (CSF-hcrt-1) levels, were included. Twenty-five of the 84 NT1 patients and all the hypersomnolence disorder patients underwent a follow-up evaluation consisting of clinical assessment, PSG, and a modified MSLT. An additional 68 controls with no sleep disorders were assessed at baseline. ConclusionConfirming results from previous studies, we found that PSG and our modified MSLT accurately and reliably diagnosed hypocretin-deficient NT1 (accuracy = 0.88, reliability = 0.80). Patients with NT1 had stable clinical and electrophysiological presentations over time that suggested a stable phenotype. In contrast, the PSG/MSLT results of patients with hypersomnolence, and normal CSF-hcrt-1 had poor reliability (0.32) and low repeatability.

Associations between psychiatric comorbid disorders and executive dysfunctions in hypocretin-1 deficient pediatric narcolepsy type1

Objective/BackgroundPsychiatric symptoms and cognitive deficits add significantly to impairment in academic achievement and quality of life in patients with narcolepsy. The primary aim of this study was to evaluate the prevalence of psychiatric disorders and executive dysfunctions, secondly to explore the association between psychiatric comorbidity, executive dysfunctions, subjective and objective sleep measures, and severity of cerebrospinal fluid (CSF) hypocretin-1 deficiency in pediatric narcolepsy type 1 (PNT1). Patients/MethodsCross-sectional study of 59 consecutively included PNT1 patients (age: 6-20 years; 34:25 girls: boys; 54/59 H1N1 (Pandemrix®)-vaccinated). Core narcolepsy symptoms including subjective sleepiness, polysomnography and multiple sleep latency test results, CSF hypocretin-1 levels, psychiatric disorders (by semistructured diagnostic interview Kaufmann Schedule for Affective Disorders and Schizophrenia Present and Lifetime version (KSADS)), and executive dysfunction (by Behavior Rating of Executive Function (BRIEF)) were assessed. Results52.5% of the patients had one or more psychiatric comorbid disorder, and 64.7% had executive dysfunction in a clinically relevant range, with no sex difference in prevalence, while older age was associated with poorer executive function (p=0.013). Having any psychiatric comorbid disorder was associated with poorer executive functions (p=0.001). CSF hypocretin-1 deficiency severity was significantly associated with presence of psychiatric comorbidity (p=0.022) and poorer executive functions (p=0.030), and poorer executive functions was associated with subjective sleepiness (p=0.009). ConclusionsThe high occurrence of, and association between, psychiatric comorbidity and executive dysfunction underlines the importance of close attention to both these comorbidities in clinical care of NT1.

1017 Laughing in the Face of Laughter: Narcolepsy with severe cataplexy refractory to medication: A case report

Abstract Introduction Cataplexy, a transient muscle atonia, typically occurs in response to positive emotions such as laughter or mirth. Cataplexy occurs in association with hypocretin deficiency/narcolepsy type 1 (NT1) and involves descending REM sleep-motor inhibition pathways. 1. Here we present a case with late – onset NT1, refractory to medication. Report of case(s) A 65-year-old man with a normal BMI presented to the autonomic clinic for presumed syncope, facial and leg weakness, occurring up to 50 times daily, triggered by laughter and a stressful life event from 4 years prior. Tilt testing and brain magnetic resonance imaging, were unremarkable, while sleep–deprived electroencephalogram was concerning for cataplectic versus functional attacks. He underwent diagnostic polysomnography (PSG) that showed severe obstructive sleep apnea (OSA) and was treated with bilevel positive airway pressure (BPAP). A repeat PSG after his OSA was controlled on BPAP, followed by a multiple sleep latency test the next day, showed a mean sleep latency of 2.7, and sleep onset rapid eye movement in 3 of 5 naps; cerebrospinal fluid hypocretin was undetectable and DQB1*06:02 was positive. He denied sleep paralysis and sleepiness, and jovial by nature, he joked as a hobby, leading to cataplexy. Trials of sodium oxybate was ineffective causing vivid dreams and hallucinations. Venlafaxine was subsequently added, initially controlling his cataplexy, but lost efficacy, warranting a trial of duloxetine, also ineffective. He was then started on solriamfetol, which improved sleepiness. We attempted to enroll him in a clinical trial of Reboxetine, thereby discontinuing duloxetine; severe OSA disqualified him from the trial. Subsequently, status cataplecticus ensued, leading to abolished reflexes and multiple falls. Clomipramine 100mg and Modafinil 200mg was started, reportedly reducing the frequency of cataplexy to 12 episodes daily. Conclusion Our case is notable because of the challenges working through the differential of drop attacks, and his late onset of severe NT1. One suggestion is an associated functional component to the disease could be involved, and though the diagnosis is solid, an additional functional overlay, or his joking personality, render symptom control unusually difficult. This case illustrates complexities of some cases with late-onset NT1. Support (if any)

Indicaciones de pruebas diagnósticas complementarias en los trastornos del sueño

A primary sleep disorder should be considered when there is a qualitative or quantitative sleep deficit or excess sleep. In this protocol, we will review the evaluation of patients with sleep disorders, which starts with a case history and physical examination with the use of generic or specific questionnaires and additional objective tests. In all cases, the medical history is the pillar of the initial evaluation of patients. Although polysomnography is the fundamental diagnostic test in sleep medicine, there are others performed in the hospital (multiple sleep latency tests, maintenance of wakefulness test), at the patient's home (actigraphy, polygraphy), or through biochemical analysis (melatonin test, determination of hypocretin in cerebrospinal fluid). In any case, knowing their methodology, indications, and limitations is essential for reaching a correct diagnosis.

Repeated measures of hypocretin-1 in Danish and Italian patients with narcolepsy and in controls

Study objectivesThe assay currently used worldwide to measure cerebrospinal fluid hypocretin-1 (CSF-hcrt-1) for diagnosing narcolepsy uses a competitive radioimmunoassay with polyclonal anti-hcrt-1 antibodies. This assay detects multiple hypocretin-1 immunoreactive species in the CSF that are all derived from full-length hcrt-1. We aimed to revalidate CSF-hcrt-1 cut-offs for narcolepsy type 1 (NT1) diagnosis and to evaluate temporal changes in CSF-hcrt-1 levels in patients suspected of having central hypersomnia. MethodWe carried out a repeat lumbar puncture with a mean follow-up of 4.0 years, to measure CSF-hcrt-1 in patients suspected of having central hypersomnia in a follow-up study. Data from CSF samples of patients with NT1 and of controls without known hypersomnia, from the Italian–Stanford and Danish populations, were examined using a receiver-operating characteristic analysis. ResultsThe optimal CSF-hcrt-1 cut-offs for identifying NT1 were 129 pg/ml and 179 pg/ml for the Italian-Stanford and Danish populations, respectively. The sensitivity was 0.93–0.99 and the specificity was 1.Follow-up lumbar puncture measurements of CSF-hcrt-1 were obtained from 73 patients. 30 of 32 patients with low CSF-hcrt-1 levels continued to be categorized as low, with an unaltered diagnosis; two patients showed a marked increase in CSF-hcrt-1, attaining normal values at follow-up. One of these patients relapsed to low CSF-hcrt-1 after follow-up. All 41 patients with normal CSF-hcrt-1 at baseline had normal CSF-hcrt-1 at follow-up. ConclusionCSF-hcrt-1 measurement can provide an accurate test for diagnosing NT1, although it is important to validate the CSF-hcrt-1 cut-off for specific testing locations. Stable CSF-hcrt-1 levels support the already established prognosis of narcolepsy as permanent once the disorder has fully developed.

Intermediate hypocretin-1 cerebrospinal fluid levels and typical cataplexy: their significance in the diagnosis of narcolepsy type 1.

Study ObjectivesThe diagnosis of narcolepsy type 1 (NT1) is based upon the presence of cataplexy and/or a cerebrospinal fluid (CSF) hypocretin-1/orexin-A level ≤ 110 pg/mL. We determined the clinical and diagnostic characteristics of patients with intermediate hypocretin-1 levels (111–200 pg/mL) and the diagnostic value of cataplexy characteristics in individuals with central disorders of hypersomnolence.MethodsRetrospective cross-sectional study of 355 people with known CSF hypocretin-1 levels who visited specialized Sleep-Wake Centers in the Netherlands. For n = 271, we had full data on cataplexy type (“typical” or “atypical” cataplexy).ResultsCompared to those with normal hypocretin-1 levels (>200 pg/mL), a higher percentage of individuals with intermediate hypocretin-1 levels had typical cataplexy (75% or 12/16 vs 9% or 8/88, p < .05), and/or met the diagnostic polysomnographic (PSG) and Multiple Sleep Latency Test (MSLT) criteria for narcolepsy (50 vs 6%, p < .001). Of those with typical cataplexy, 88% had low, 7% intermediate, and 5% normal hypocretin-1 levels (p < .001). Atypical cataplexy was also associated with hypocretin deficiency but to a lesser extent. A hypocretin-1 cutoff of 150 pg/mL best predicted the presence of typical cataplexy and/or positive PSG and MSLT findings.ConclusionIndividuals with intermediate hypocretin-1 levels or typical cataplexy more often have outcomes fitting the PSG and MSLT criteria for narcolepsy than those with normal levels or atypical cataplexy. In addition, typical cataplexy has a much stronger association with hypocretin-1 deficiency than atypical cataplexy. We suggest increasing the NT1 diagnostic hypocretin-1 cutoff and adding the presence of clearly defined typical cataplexy to the diagnostic criteria of NT1. Clinical trial information: This study is not registered in a clinical trial register, as it has a retrospective database design.

Narcolepsy with intermediate cerebrospinal level of hypocretin-1

To describe the phenotype of narcolepsy with intermediate cerebrospinal fluid hypocretin-1 levels (CSF hcrt-1). From 1600 consecutive patients with narcolepsy from Bologna and Montpellier sleep centers, we selected patients with intermediate CSF hcrt-1 levels (110-200 pg/mL). Clinical, neurophysiological, and biological data were contrasted for the presence of cataplexy, human leukocyte haplotype (HLA)-DQB1*06:02, and median CSF hcrt-1 levels (149.34 pg/mL). Forty-five (55% males, aged 35 ± 17 years) patients (2.8% of all cases) were included. Thirty-three (73%) were HLA-DQB1*06:02, 29 (64%) reported cataplexy (21, 72.4% with typical features), and 5 (11%) had presumed secondary etiology. Cataplexy was associated with other core narcolepsy symptoms, increased sleep onset rapid eye movement periods, and nocturnal sleep disruption. Cataplexy and irrepressible daytime sleep were more frequent in HLA-DQB1*06:02 positive patients. Lower CSF hcrt-1 levels were associated with hallucinations. Narcolepsy with intermediate CSF hcrt-1 level is a rare condition with heterogeneous phenotype. HLA-DQB1*06:02 and lower CSF hcrt-1 were associated with typical narcolepsy features, calling for future research to distinguish incomplete from secondary narcolepsy forms.

Kleine-levin syndrome (kls)-a review

Kleine-Levin Syndrome is a rare sleep disease characterized by relapsing episodes of hypersomnia interconnected with behavioral and cognitive disorders along with hyperphagia and hypersexuality. This disease occurs more often in young male adolescents. The diagnosis was clinical, primarily based on the nosologic distinction of non-identical forms of recurrent hypersomnia. The brief duration of KLS varies from 7 days to 2 months and the people affected are completely asymptomatic between episodes but during episodes, electroencephalography shows diffuse or local slow activity. Investigations for KLS comprise of medical history, magnetic resonance imaging, polysomnography, 24- hours time profile of growth hormone, melatonin, TSH, and cortisol. The Pathophysiology of this sleeping beauty syndrome is based on Neuropathological examinations, cerebrospinal fluid hypocretin-1 monitoring, clinical patterns, and neuroimaging. Imaging of brain function reveals the hypoactivity in thalamic and hypothalamic regions and imaging along with the cognitive capacity evaluation gives insights into neurobiological mechanisms of KLS. No effective treatment, as well as indefinite pathology, has been identified even though the illness is having clearly defined clinical features but some medications like stimulants and mood stabilizers can be beneficial in the treatment of severe cases.

Diagnostic value of actigraphy in hypersomnolence disorders

ObjectiveDifferentiating between the central hypersomnias presents a challenge to the diagnosis of patients with hypersomnolence. Actitigraphy may support efforts to distinguish them.We aimed to evaluate: 1) the ability of actigraphy to quantify sleep continuity measures in comparison with polysomnography in patients with hypersomnolence; 2) whether actigraphy can distinguish patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid from patients with narcolepsy type 1 and from sleep-healthy controls; and 3) the distinct activity profiles and circadian rhythms of patients with narcolepsy type 1, patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid, and sleep-healthy controls. MethodPolysomnography, multiple sleep latency tests and actigraphy were conducted in 14 patients with narcolepsy type 1, 29 patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid and 15 sleep-healthy controls. ResultsActigraphy quantified several sleep continuity measures consistently with polysomnography in all the patients. Actigraphy distinguished patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid from patients with narcolepsy type 1 and sleep-healthy controls. Patients with narcolepsy type 1 had poor sleep quality and altered circadian rest-activity rhythm compared with controls. ConclusionActigraphy is an adequate tool for establishing the amount of night sleep and supports the differential diagnosis of patients with hypersomnolence.

Changes of Hypocretin (Orexin) System in Schizophrenia: From Plasma to Brain

Hypocretin (also called orexin) regulates various functions, such as sleep-wake rhythms, attention, cognition, and energy balance, which show significant changes in schizophrenia (SCZ). We aimed to identify alterations in the hypocretin system in SCZ patients. We measured plasma hypocretin-1 levels in SCZ patients and healthy controls and found significantly decreased plasma hypocretin-1 levels in SCZ patients, which was mainly due to a significant decrease in female SCZ patients compared with female controls. In addition, we measured postmortem hypothalamic hypocretin-1-immunoreactivity (ir), ventricular cerebrospinal fluid (CSF) hypocretin-1 levels, and hypocretin receptor (Hcrt-R) mRNA expression in the superior frontal gyrus (SFG) in SCZ patients and controls We observed a significant decrease in the amount of hypothalamic hypocretin-1 ir in SCZ patients, which was due to decreased amounts in female but not male patients. Moreover, Hcrt-R2 mRNA in the SFG was decreased in female SCZ patients compared with female controls, while male SCZ patients showed a trend of increased Hcrt-R1 mRNA and Hcrt-R2 mRNA expression compared with male controls. We conclude that central hypocretin neurotransmission is decreased in SCZ patients, especially female patients, and this is reflected in the plasma.

831 Diagnostic and Treatment Challenges in a Child with Type 1 Narcolepsy

Abstract Introduction The diagnosis and management of Narcolepsy can be challenging in young children. We present a case of abrupt onset severe type 1 narcolepsy complicated by tactile hallucinations with stimulant medication therapy. Report of case(s) A previously healthy 7-year-old African American female presented to us at the beginning of the current pandemic with one week of excessive daytime sleepiness (EDS) with associated enuresis, hyperphagia and two episodes of cataplexy. She also presented with hypnagogic hallucinations and dream enactment behaviors. She was extremely sleepy with a score of 24/24 on the Epworth Sleepiness Scale. Her neurological exam was negative except for facial twitching appearing to be cataplectic facies. Extensive work up including urine toxicology, serology and cerebrospinal fluid (CSF) tests were undertaken to rule out infectious and demyelinating conditions; the results of these tests were negative. Brain magnetic resonance imaging as well as electroencephalogram testing were unremarkable. Overnight polysomnography demonstrated short sleep latency and rapid eye movement (REM) sleep without atonia and a multiple sleep latency test showed a mean sleep latency of less than 2 minutes and 4/4 sleep onset REM periods, highly suggestive of narcolepsy. Her HLA DQB1*0602 haplotype was positive but CSF Hypocretin testing was not done. She was given a diagnosis of Narcolepsy type I and started treatment on low dose Methylphenidate and Venlafaxine to address her EDS and cataplexy, respectively. Her EDS was gradually controlled with a higher dose of Methylphenidate but she developed severe tactile hallucinations. She complained of feeling bugs crawling under her skin and could not keep her clothes on due to constant discomfort. The tactile hallucinations improved with discontinuation of methylphenidate but reappeared with introduction of a different class of stimulants. Modafinil was ineffective in controlling her EDS symptoms. Her EDS, cataplexy and enuresis were better controlled after starting her on Sodium Oxybate. She continues to suffer from moderate to severe EDS with optimally dosed Sodium Oxybate with suboptimal response to various typical and atypical stimulants. Conclusion This case illustrates the difficulties in diagnosing and treating pediatric narcolepsy patients and a unique challenge of tactile hallucinations with stimulant medications. Support (if any):

In Vitro Treg Immunosuppression Assay of GITR Proteins Could Elucidate the Autoimmune-mediated Mechanism Underlying Type 1 Narcolepsy

Abstract: Type 1 narcolepsy is a hypersomnia sleep disorder characterized by excessive daytime sleep and shallow NREM nighttime sleep. Deficiency of hypocretin-1 secreting neurons in the lateral hypothalamus is the primary cause of the disorder and studies demonstrated that these neurons were solely diminished in a brain region of remarkable heterogeneous neuronal population. Specific destruction of targeted neurons could be achieved via antigen presentation to immune cells, a characteristic of cell-mediated response in the adaptive immune system. Given that hypocretin-1 neurons were exclusively targeted, this cultivated significant interest in searching for an autoimmune-mediated mechanism but studies currently lack adequate knowledge and consistent results. In this research proposal, it is hypothesized that enhanced glucocorticoid-induced TNFR-related (GITR) protein expression in T regulatory (Treg) cells results in defective suppression capacity of CD4+CD25+ T helper cells and defective self-tolerance thereby promoting destruction of hypocretin-1 secreting-neurons in the lateral hypothalamus of narcoleptics. The proposal devises a correlational study to measure cerebrospinal fluid (CSF) hypocretin-1 levels that were inversely proportional to GITR expression levels in Treg cells to assess the autoimmune nature of the disorder. This study is aimed at investigating how defective T regulatory cells respond in type 1 narcolepsy patients via CSF hypocretin-1 measurement and in vitro human T regulatory cell suppression assay.

Pre-treatment of blood samples reveal normal blood hypocretin/orexin signal in narcolepsy type 1.

The hypocretin/orexin system regulates arousal through central nervous system mechanisms and plays an important role in sleep, wakefulness and energy homeostasis. It is unclear whether hypocretin peptides are also present in blood due to difficulties in measuring reliable and reproducible levels of the peptides in blood samples. Lack of hypocretin signalling causes the sleep disorder narcolepsy type 1, and low concentration of cerebrospinal fluid hypocretin-1/orexin-A peptide is a hallmark of the disease. This measurement has high diagnostic value, but performing a lumbar puncture is not without discomfort and possible complications for the patient. A blood-based test to assess hypocretin-1 deficiency would therefore be of obvious benefit. We here demonstrate that heating plasma or serum samples to 65°C for 30 min at pH 8 significantly increases hypocretin-1 immunoreactivity enabling stable and reproducible measurement of hypocretin-1 in blood samples. Specificity of the signal was verified by high-performance liquid chromatography and by measuring blood samples from mice lacking hypocretin. Unspecific background signal in the assay was high. Using our method, we show that hypocretin-1 immunoreactivity in blood samples from narcolepsy type 1 patients does not differ from the levels detected in control samples. The data presented here suggest that hypocretin-1 is present in the blood stream in the low picograms per millilitres range and that peripheral hypocretin-1 concentrations are unchanged in narcolepsy type 1.

Cerebrospinal Fluid Hypocretin and Nightmares in Dementia Syndromes

Background/Aims: Hypocretin promotes wakefulness and modulates REM sleep. Alterations in the hypocretin system are increasingly implicated in dementia. We evaluated relationships among hypocretin, dementia biomarkers, and sleep symptoms in elderly participants, most of whom had dementia. Methods: One-hundred twenty-six adults (mean age 66.2 ± 8.4 years) were recruited from the Emory Cognitive Clinic. Diagnoses were Alzheimer disease (AD; n = 60), frontotemporal dementia (FTD; n = 21), and dementia with Lewy bodies (DLB; n = 20). We also included cognitively normal controls (n = 25). Participants and/or caregivers completed sleep questionnaires and lumbar puncture was performed for cerebrospinal fluid (CSF) assessments. Results: Except for sleepiness (worst in DLB) and nocturia (worse in DLB and FTD) sleep symptoms did not differ by diagnosis. CSF hypocretin concentrations were available for 87 participants and normal in 70, intermediate in 16, and low in 1. Hypocretin levels did not differ by diagnosis. Hypocretin levels correlated with CSF total τ levels only in men (r = 0.34; p = 0.02). Lower hypocretin levels were related to frequency of nightmares (203.9 ± 29.8 pg/mL in those with frequent nightmares vs. 240.4 ± 46.1 pg/mL in those without; p = 0.05) and vivid dreams (209.1 ± 28.3 vs. 239.5 ± 47.8 pg/mL; p = 0.014). Cholinesterase inhibitor use was not associated with nightmares or vivid dreaming. Conclusion: Hypocretin levels did not distinguish between dementia syndromes. Disturbing dreams in dementia patients may be related to lower hypocretin concentrations in CSF.

Sleep Disturbances Associated with Neurological Autoimmunity.

Associations between sleep disorders and neurological autoimmunity have been notably expanding recently. Potential immune-mediated etiopathogenesis has been proposed for various sleep disorders including narcolepsy, Kleine-Levin syndrome, and Morvan syndrome. Sleep manifestations are also common in various autoimmune neurological syndromes, but may be underestimated as overriding presenting (and potentially dangerous) neurological symptoms often require more urgent attention. Even so, sleep dysfunction has been described with various neural-specific antibody biomarkers, including IgLON5; leucine-rich, glioma-inactivated protein 1 (LGI1); contactin-associated protein 2 (CASPR2); N-methyl-D-aspartate (NMDA)-receptor; Ma2; dipeptidyl-peptidase-like protein-6 (DPPX); alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R); anti-neuronal nuclear antibody type-1 (ANNA-1, i.e., Hu); anti-neuronal nuclear antibody type-2 (ANNA-2, i.e., Ri); gamma-aminobutyric acid (GABA)-B-receptor (GABA-B-R); metabotropic glutamate receptor 5 (mGluR5); and aquaporin-4 (AQP-4). Given potentially distinctive findings, it is possible that sleep testing could potentially provide objective biomarkers (polysomnography, quantitative muscle activity during REM sleep, cerebrospinal fluid hypocretin-1) to support an autoimmune diagnosis, monitor therapeutic response, or disease progression/relapse. However, more comprehensive characterization of sleep manifestations is needed to better understand the underlying sleep disruption with neurological autoimmunity.

Decreased concentration of klotho and increased concentration of FGF23 in the cerebrospinal fluid of patients with narcolepsy

Objectiveto explore the status of concentration of klotho and fibroblast growth factor 23 (FGF23) in cerebrospinal fluid (CSF) of patients with narcolepsy. Patients/methods59 patients with narcolepsy and 17 control individuals were enrolled. We used radioimmunoassay, human klotho enzyme-linked immunosorbent assay (ELISA), human intact FGF23 ELISA and spectrophotometry to measure hypocretin-1, klotho, FGF-23 and phosphorus, respectively. T-Student Test was used to compare klotho and phosphate concentrations, Mann–Whitney U Test were used to compare FGF-23 levels between groups. ANOVA Test was used to compare klotho and phosphate CSF concentrations among narcolepsy patients with CSF hypocretin-1 <110 pg/ml (HCRT-) and narcolepsy patients with CSF hypocretin-1 >110 pg/ml (HCRT+) versus control subjects. ResultsKlotho and phosphorus CSF levels were lower in narcoleptic patients than in control (908.18 ± 405.51 versus 1265.78 ± 523.26 pg/ml; p = 0.004 and 1.34 ± 0.25 versus 1.58 ± 0.23 mg/dl; p = 0.001, respectively). We found higher FGF-23 levels in narcoleptic patients (5.51 versus 4.00 pg/mL; p = 0.001). Klotho and phosphorus CSF levels were lower in both HCRT- and HCRT+ than controls. Moreover, there were higher FGF-23 levels in both HCRT-/HCRT+ groups versus controls. However, we did not find differences comparing HCRT- and HCRT+ groups, analyzing CSF klotho, FGF-23 or phosphorus levels. ConclusionsPatients with narcolepsy have decreased CSF concentration of klotho and increased CSF levels of FGF-23. These findings may play a role in understanding the pathogenesis of narcolepsy.