Hypocretin-1 Levels Associate with Fragmented Sleep in Patients with Narcolepsy Type 1.
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ABSTRACT:
SUBMITTER: Alakuijala A
PROVIDER: S-EPMC4835302 | biostudies-other | 2016 May
REPOSITORIES: biostudies-other
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Hypocretin-1 Levels Associate with Fragmented Sleep in Patients with Narcolepsy Type 1.
Alakuijala Anniina A Sarkanen Tomi T Partinen Markku M
Sleep 20160501 5
<h4>Study objectives</h4>We aimed to analyze nocturnal sleep characteristics of patients with narcolepsy type 1 (narcolepsy with cataplexy) measured by actigraphy in respect to cerebrospinal fluid hypocretin-1 levels of the same patients.<h4>Methods</h4>Actigraphy recording of 1-2 w and hypocretin-1 concentration analysis were done to thirty-six unmedicated patients, aged 7 to 63 y, 50% female. Twenty-six of them had hypocretin-1 levels under 30 pg/mL and the rest had levels of 31-79 pg/mL.<h4>R ...[more]
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Project description:ImportanceNarcolepsy, a disorder associated with HLA-DQB1*06:02 and caused by hypocretin (orexin) deficiency, is diagnosed using the Multiple Sleep Latency Test (MSLT) following nocturnal polysomnography (NPSG). In many patients, a short rapid eye movement sleep latency (REML) during the NPSG is also observed but not used diagnostically.ObjectiveTo determine diagnostic accuracy and clinical utility of nocturnal REML measures in narcolepsy/hypocretin deficiency.Design, setting, and participantsObservational study using receiver operating characteristic curves for NPSG REML and MSLT findings (sleep studies performed between May 1976 and September 2011 at university medical centers in the United States, China, Korea, and Europe) to determine optimal diagnostic cutoffs for narcolepsy/hypocretin deficiency compared with different samples: controls, patients with other sleep disorders, patients with other hypersomnias, and patients with narcolepsy with normal hypocretin levels. Increasingly stringent comparisons were made. In a first comparison, 516 age- and sex-matched patients with narcolepsy/hypocretin deficiency were selected from 1749 patients and compared with 516 controls. In a second comparison, 749 successive patients undergoing sleep evaluation for any sleep disorders (low pretest probability for narcolepsy) were compared within groups by final diagnosis of narcolepsy/hypocretin deficiency. In the third comparison, 254 patients with a high pretest probability of having narcolepsy were compared within group by their final diagnosis. Finally, 118 patients with narcolepsy/hypocretin deficiency were compared with 118 age- and sex-matched patients with a diagnosis of narcolepsy but with normal hypocretin levels.Main outcome and measuresSensitivity and specificity of NPSG REML and MSLT as diagnostic tests for narcolepsy/hypocretin deficiency. This diagnosis was defined as narcolepsy associated with cataplexy plus HLA-DQB1*06:02 positivity (no cerebrospinal fluid hypocretin-1 results available) or narcolepsy with documented low (≤ 110 pg/mL) cerebrospinal fluid hypocretin-1 level.ResultsShort REML (≤15 minutes) during NPSG was highly specific (99.2% [95% CI, 98.5%-100.0%] of 516 and 99.6% [95% CI, 99.1%-100.0%] of 735) but not sensitive (50.6% [95% CI, 46.3%-54.9%] of 516 and 35.7% [95% CI, 10.6%-60.8%] of 14) for patients with narcolepsy/hypocretin deficiency vs population-based controls or all patients with sleep disorders undergoing a nocturnal sleep study (area under the curve, 0.799 [95% CI, 0.771-0.826] and 0.704 [95% CI, 0.524-0.907], respectively). In patients with central hypersomnia and thus a high pretest probability for narcolepsy, short REML remained highly specific (95.4% [95% CI, 90.4%-98.3%] of 132) and similarly sensitive (57.4% [95% CI, 48.1%-66.3%] of 122) for narcolepsy/hypocretin deficiency (area under the curve, 0.765 [95% CI, 0.707-0.831]). Positive predictive value in this high pretest probability sample was 92.1% (95% CI, 83.6%-97.0%).Conclusions and relevanceAmong patients being evaluated for possible narcolepsy, short REML (≤15 minutes) at NPSG had high specificity and positive predictive value and may be considered diagnostic without the use of an MSLT; absence of short REML, however, requires a subsequent MSLT.
| S-EPMC4170796 | biostudies-literature
Project description:Narcolepsy type 1 is accompanied by a selective loss of orexin/hypocretin (hcrt) neurons in the lateral hypothalamus caused by yet unknown mechanisms. Epidemiologic and genetic associations strongly suggest an immune-mediated pathogenesis of the disease. We compared specific T-cell reactivity to orexin/hcrt peptides in peripheral blood mononuclear cells of narcolepsy type 1 patients to healthy controls by a carboxyfluorescein succinimidyl ester proliferation assay. Orexin/hcrt-specific T-cell reactivity was also determined by cytokine (interferon gamma and granulocyte-macrophage colony-stimulating factor) analysis. Individuals were considered as responders if the cell division index of CD3+CD4+ T cells and both stimulation indices of cytokine secretion exceeded the cutoff 3. Additionally, T-cell reactivity to orexin/hcrt had to be confirmed by showing reactivity to single peptides present in different peptide pools. Using these criteria, 3/15 patients (20%) and 0/13 controls (0%) showed orexin/hcrt-specific CD4+ T-cell proliferation (p = .2262). The heterogeneous reactivity pattern did not allow the identification of a preferential target epitope. A significant role of orexin/hcrt-specific T cells in narcolepsy type 1 patients could not be confirmed in this study. Further studies are needed to assess the exact role of CD4+ T cells and possible target antigens in narcolepsy type 1 patients.
| S-EPMC5806576 | biostudies-literature
Project description:Study objectiveTo determine whether hypocretin receptor gene (hcrtR1 and hcrtR2) expression is affected after long-term hypocretin ligand loss in humans and animal models of narcolepsy.DesignAnimal and human study. We measured hcrtR1 and hcrtR2 expression in the frontal cortex and pons using the RT-PCR method in murine models (8-week-old and 27-week-old orexin/ataxin-3 transgenic (TG) hypocretin cell ablated mice and wild-type mice from the same litter, 10 mice for each group), in canine models (8 genetically narcoleptic Dobermans with null mutations in the hcrtR2, 9 control Dobermans, 3 sporadic ligand-deficient narcoleptics, and 4 small breed controls), and in humans (5 narcolepsy-cataplexy patients with hypocretin deficiency (average age 77.0 years) and 5 control subjects (72.6 years).Measurement and results27-week-old (but not 8-week-old) TG mice showed significant decreases in hcrtR1 expression, suggesting the influence of the long-term ligand loss on the receptor expression. Both sporadic narcoleptic dogs and human narcolepsy-cataplexy subjects showed a significant decrease in hcrtR1 expression, while declines in hcrtR2 expression were not significant in these cases. HcrtR2-mutated narcoleptic Dobermans (with normal ligand production) showed no alteration in hcrtR1 expression.ConclusionsModerate declines in hcrtR expressions, possibly due to long-term postnatal loss of ligand production, were observed in hypocretin-ligand deficient narcoleptic subjects. These declines are not likely to be progressive and complete. The relative preservation of hcrtR2 expression also suggests that hypocretin based therapies are likely to be a viable therapeutic options in human narcolepsy-cataplexy.
| S-EPMC2542958 | biostudies-literature
Project description:Type 1 narcolepsy (T1N) is caused by hypocretin/orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and vaccination (Pandemrix). Peptides derived from HCRT and influenza A, including pH1N1, were screened for DQ0602 binding and presence of cognate DQ0602 tetramer-peptide-specific CD4+ T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA273-287 (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP17-31 and C-amidated but not native version of HCRT54-66 and HCRT86-97 (HCRTNH2) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3? TRBV4-2-CASSQETQGRNYGYTF in HCRTNH2 and pHA273-287-tetramers, suggesting molecular mimicry. This public CDR3? uses TRBV4-2, a segment modulated by T1N-associated SNP rs1008599, suggesting causality. TCR-?/? CDR3 motifs of HCRT54-66-NH2 and HCRT86-97-NH2 tetramers were extensively shared: notably public CDR3?, TRAV2-CAVETDSWGKLQF-TRAJ24, that uses TRAJ24, a chain modulated by T1N-associated SNPs rs1154155 and rs1483979. TCR-?/? CDR3 sequences found in pHA273-287, NP17-31, and HCRTNH2 tetramer-positive CD4+ cells were also retrieved in single INF-?-secreting CD4+ sorted cells stimulated with Pandemrix, independently confirming these results. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.
| S-EPMC6310865 | biostudies-literature
Project description:Narcolepsy is a chronic sleep disorder caused by a loss of hypocretin (hcrt) neurons in the hypothalamus. Cerebrospinal fluid (CSF) hcrt-1 measurement has been well established as a gold standard of narcolepsy diagnosis, although some portions of narcoleptic patients show normal hcrt-1 levels. We aimed to examine peptide degradation of hcrt-1 and its abnormality in the CSF of patients by using high performance liquid chromatography (HPLC) followed by radioimmunoassay (RIA). CSF was collected from healthy controls, narcoleptic patients of type 1 with hcrt-1 deficiency, type 1 with normal hcrt-1 level, and type 2 with normal hcrt-1 level. We found that the majority of hcrt-1 immunoreactivity in extracted CSF was derived from unauthentic hcrt-1 peaks, which are predicted to be inactive metabolites, and the intact hcrt-1 peptide was less than 10% of the gross amount, suggesting that the regular RIA for CSF hcrt-1 measures largely reflect the unauthentic hcrt-1-related metabolites rather than the intact one. As expected, all hcrt-1-related peaks were abolished in type 1 with hcrt-1 deficiency. Importantly, we also found that the sum of the authentic hcrt-1 peptide (peaks 3 and 4) significantly decreased in non-deficient type 1 and tended to decrease in type 2 narcoleptic patients although the levels with the regular RIA in non-extracted CSF was equivalent to healthy controls. Immunoreactivity with unauthentic hcrt-1 metabolites may masks the possible decline in authentic hcrt-1 level caused by the partial loss of hcrt neurons. Our findings may provide new insights into the degradation of the hcrt-1 peptide and the pathophysiology of narcolepsy.
| S-EPMC6346108 | biostudies-literature
Project description:Study objectivesTo evaluate the reliability of nocturnal sleep dynamics in the differential diagnosis of central disorders of hypersomnolence.DesignCross-sectional.SettingSleep laboratory.PatientsOne hundred seventy-five patients with hypocretin-deficient narcolepsy type 1 (NT1, n = 79), narcolepsy type 2 (NT2, n = 22), idiopathic hypersomnia (IH, n = 22), and "subjective" hypersomnolence (sHS, n = 52).InterventionsNone.MethodsPolysomnographic (PSG) work-up included 48 h of continuous PSG recording. From nocturnal PSG conventional sleep macrostructure, occurrence of sleep onset rapid eye movement period (SOREMP), sleep stages distribution, and sleep stage transitions were calculated. Patient groups were compared, and receiver operating characteristic (ROC) curve analysis was used to test the diagnostic utility of nocturnal PSG data to identify NT1.ResultsSleep macrostructure was substantially stable in the 2 nights of each diagnostic group. NT1 and NT2 patients had lower latency to rapid eye movement (REM) sleep, and NT1 patients showed the highest number of awakenings, sleep stage transitions, and more time spent in N1 sleep, as well as most SOREMPs at daytime PSG and at multiple sleep latency test (MSLT) than all other groups. ROC curve analysis showed that nocturnal SOREMP (area under the curve of 0.724 ± 0.041, P < 0.0001), percent of total sleep time spent in N1 (0.896 ± 0.023, P < 0.0001), and the wakefulness-sleep transition index (0.796 ± 0.034, P < 0.0001) had a good sensitivity and specificity profile to identify NT1 sleep, especially when used in combination (0.903 ± 0.023, P < 0.0001), similarly to SOREMP number at continuous daytime PSG (0.899 ± 0.026, P < 0.0001) and at MSLT (0.956 ± 0.015, P < 0.0001).ConclusionsSleep macrostructure (i.e. SOREMP, N1 timing) including stage transitions reliably identifies hypocretin-deficient narcolepsy type 1 among central disorders of hypersomnolence.
| S-EPMC4507733 | biostudies-literature
Project description:Individuals with narcolepsy suffer from abnormal sleep patterns due to loss of neurons that uniquely supply hypocretin (HCRT). Previous studies found the associations of narcolepsy with human leukocyte antigen (HLA)-DQ6 allele and T-cell receptor α (TRA) J24 gene segment and also suggested that in vitro-stimulated T cells can target HCRT. However, DQ6+ individuals generate DQ6-HCRT tetramer+/TRAJ24+ TCRs. Without a proof that an HCRT-reactive cell expressing such TCRs has expanded in vivo, T cell-mediated autoimmunity in narcolepsy remains speculative. Here, we isolated DQ6-HCRT tetramer+/CD4+ T cells (low frequency, <0.04%) from DQ6+ individuals with/without narcolepsy. Within 74 informative TRAJ24+ TCRαβ from 8/12 patients and 11/12 controls, we identified a conserved family of clonotypes shared by 2 patients and 2 controls using identical α/β genes. TRAJ24-G allele+ clonotypes only expanded in the two patients, whereas a TRAJ24-C allele+ clonotype expanded in a control. A representative tetramer+/G-allele+ TCR showed signaling reactivity to the physiologically modified form of the epitope HCRT87-97. Clonally expanded G-allele+ T cells also exhibited an unconventional effector phenotype. In vivo expansion of HCRT-reactive TRAJ24-G allele+ cells provides critical evidence for an autoimmune contribution to narcolepsy development.
2019-10-15 | GSE135852 | GEO
Project description: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.
| S-EPMC8100001 | biostudies-literature
Project description:Narcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness (EDS), cataplexy, sleep paralysis and hypnagogic hallucinations. Both sporadic (95%) and familial (5%) forms of narcolepsy exist in humans. The major pathophysiology of human narcolepsy has been recently discovered based on the discovery of narcolepsy genes in animals; the genes involved in the pathology of the hypocretin/orexin ligand and its receptor. Mutations in hypocretin-related genes are rare in humans, but hypocretin ligand deficiency is found in a large majority of narcolepsy with cataplexy. Hypocretin ligand deficiency in human narcolepsy is probably due to the post-natal cell death of hypocretin neurones. Although a close association between human leucocyte antigen (HLA) and human narcolepsy with cataplexy suggests an involvement of autoimmune mechanisms, this has not yet been proved. Hypocretin deficiency is also found in symptomatic cases of narcolepsy and EDS with various neurological conditions, including immune-mediated neurological disorders, such as Guillain-Barre syndrome, MA2-positive paraneoplastic syndrome and neuromyelitis optica (NMO)-related disorder. The findings in symptomatic narcoleptic cases may have significant clinical relevance to the understanding of the mechanisms of hypocretin cell death and choice of treatment option. The discoveries in human cases lead to the establishment of the new diagnostic test of narcolepsy (i.e. low cerebrospinal fluid hypocretin-1 levels for 'narcolepsy with cataplexy' and 'narcolepsy due to medical condition'). As a large majority of human narcolepsy patients are ligand deficient, hypocretin replacement therapy may be a promising new therapeutic option, and animal experiments using gene therapy and cell transplantations are in progress.
| S-EPMC2860658 | biostudies-literature
Project description:Study objectivesNarcolepsy type 1 (NT1) is associated with hypocretin neuron loss. However, there are still unexplained phenotypic NT1 features. We investigated the associations between clinical and sleep phenotypic characteristics, the NT1-associated P2RY11 polymorphism rs2305795, and P2Y11 protein levels in T lymphocytes in patients with NT1, their first-degree relatives and unrelated controls.MethodsThe P2RY11 SNP was genotyped in 100 patients (90/100 H1N1-(Pandemrix)-vaccinated), 119 related and 123 non-related controls. CD4 and CD8 T lymphocyte P2Y11 protein levels were quantified using flow cytometry in 167 patients and relatives. Symptoms and sleep recording parameters were also collected.ResultsWe found an association between NT1 and the rs2305795 A allele (OR = 2, 95% CI (1.3, 3.0), p = 0.001). T lymphocyte P2Y11 protein levels were significantly lower in patients and relatives homozygous for the rs2305795 risk A allele (CD4: p = 0.012; CD8: p = 0.007). The nocturnal sleep fragmentation index was significantly negatively correlated with patients' P2Y11 protein levels (CD4: p = 0.004; CD8: p = 0.006). Mean MSLT sleep latency, REM-sleep latency, and core clinical symptoms were not associated with P2Y11 protein levels.ConclusionsWe confirmed that the P2RY11 polymorphism rs2305795 is associated with NT1 also in a mainly H1N1-(Pandemrix)-vaccinated cohort. We demonstrated that homozygosity for the A risk allele is associated with lower P2Y11 protein levels. A high level of nocturnal sleep fragmentation was associated with low P2Y11 levels in patients. This suggests that P2Y11 has a previously unknown function in sleep-wake stabilization that affects the severity of NT1.
| S-EPMC8361345 | biostudies-literature