{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T05:46:24Z","timestamp":1791870384394,"version":"4.3.4"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Study Objectives<\/jats:title>\n                    <jats:p>Loss of cerebrospinal fluid (CSF) hypocretin-1\/orexin-A (Hcrt-1) immunoreactivity is a biomarker for narcolepsy type 1 (NT1). The current radioimmunoassay (RIA) does not allow precise quantification, limiting the assessment of disease severity and evolution. This study aimed to reproduce previously proposed workflows to quantify Hcrt-1 and Hcrt-2 by liquid chromatography coupled to tandem mass spectrometry (LC\u2013MS\/MS), identify RIA antibody targets, and to compare two purification methods in their ability to identify patients with NT1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Solid phase extraction (SPE) and LC\u2013MS\/MS measurements of Hcrt-1 and -2 levels from 10 NT1 patients and 21 controls were implemented based on existing literature. Immunoprecipitation (IP) with magnetic beads coupled to the RIA antibody (Phoenix) was performed and peptides identified by MS. Finally, Hcrt-1 (full-length) and Hcrt-1 fragment1-16 levels were analyzed in 4 patients and 4 controls prepared from both workflows by nano-LC coupled to high-resolution mass spectrometry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Despite linear calibration curves for Hcrt-1 and Hcrt-2 (R2\u2009&amp;gt;\u20090.99) could be assessed with LC\u2013MS\/MS, full-length Hcrt-1 concentrations were at the low end of the calibration curve with slightly lower levels in NT1 (p\u2009=\u20090.04). Hcrt-2 was undetectable. The discovery experiment with IP most reliably identified Hcrt-1 fragment1-16. SPE revealed much higher concentrations than IP. Hcrt-11-16-levels allowed distinguishing patients and controls after SPE and IP, whereas full-length Hcrt-1-levels after IP did not.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Hcrt-11-16 appears stable and abundant in CSF of controls, allows identification of patients with NT1 and is a promising surrogate marker. SPE seems more suitable for further method validation in clinical routine.<\/jats:p>\n                    <jats:p>Statement of Significance This proof-of-concept study is a systematic approach to the mass-spectrometric quantification of the neuropeptide hypocretin-1\/orexin-A (Hcrt-1) in the cerebrospinal fluid, since the currently used radioimmunoassay (RIA) does not allow precise quantification. It reveals Hcrt-1 N-terminal derived fragment1-16 as one main target of the RIA-antibody, and strengthens its potential role as a new surrogate marker for Hcrt-1 for targeted quantification. Hcrt-11-16 is significantly reduced in patients with narcolepsy type 1 and appears to serve as a possible marker to discriminate NT1 from controls using two different purification methods, prior to measurements by nano-liquid chromatography coupled to high resolution mass spectrometry. Findings will need replication in a larger and more diverse cohort, including patients with different central disorders of hypersomnolence and intermediate RIA measured hypocretin levels to further determine their clinical significance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/sleep\/zsag115","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T11:47:26Z","timestamp":1778672846000},"source":"Crossref","is-referenced-by-count":2,"title":["Hypocretin-1\/orexin-A fragment1-16 as a potential surrogate marker for diagnosing narcolepsy type 1"],"prefix":"10.1093","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6231-3358","authenticated-orcid":false,"given":"Elena S","family":"Wenz","sequence":"first","affiliation":[{"name":"Department of Neurology, Inselspital, Bern University Hospital, University of Bern , Bern ,","place":["Switzerland"]},{"name":"Graduate School of Health Sciences, University of Bern , Bern 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D","family":"Warncke","sequence":"additional","affiliation":[{"name":"Department of Neurology, Inselspital, Bern University Hospital, University of Bern , Bern ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Luginb\u00fchl","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern , Bern ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick Y","family":"Wuethrich","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern , Bern ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedrich","family":"Lersch","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern , Bern ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Schankin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Inselspital, Bern University Hospital, University of Bern , Bern ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Filchenko","sequence":"additional","affiliation":[{"name":"Department of Neurology, Inselspital, Bern University Hospital, University of Bern , Bern ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia","family":"Fregolente","sequence":"additional","affiliation":[{"name":"Department of Neurology, Inselspital, Bern University Hospital, University of Bern , Bern ,","place":["Switzerland"]},{"name":"Graduate School of Health Sciences, University of Bern , Bern ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kseniia","family":"Zub","sequence":"additional","affiliation":[{"name":"Department of Neurology, Inselspital, Bern University Hospital, University of Bern , Bern ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the iSPHYNCS consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3959-2886","authenticated-orcid":false,"given":"Seiji","family":"Nishino","sequence":"additional","affiliation":[{"name":"Sleep and Circadian Neurobiology Laboratory, School of Medicine, Stanford University , Stanford, CA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo R","family":"Largiad\u00e8r","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern , Bern ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Heller","sequence":"additional","affiliation":[{"name":"Department for Biomedical Research, Core Facility Proteomics & Mass Spectrometry, University of Bern , Bern ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehdi","family":"Tafti","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Lausanne , Lausanne ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3299-1318","authenticated-orcid":false,"given":"Markus H","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Neurology, Inselspital, Bern University Hospital, University of Bern , Bern ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio L 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