title: Hypocretin (orexin) loss in Alzheimer's disease.
abstract: Sleep disturbances in Alzheimer's disease (AD) patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble core symptoms of narcolepsy, a sleep disorder caused by a general loss of the neurotransmitter hypocretin. AD is a neurodegenerative disorder targeting different brain areas and types of neurons. In this study, we assessed whether the neurodegenerative process of AD also affects hypothalamic hypocretin/orexin neurons. The total number of hypocretin-1 immunoreactive neurons was quantified in postmortem hypothalami of AD patients (n = 10) and matched controls (n = 10). In addition, the hypocretin-1 concentration was measured in postmortem ventricular cerebrospinal fluid of 24 AD patients and 25 controls (including the patients and controls in which the hypothalamic cell counts were performed). The number of hypocretin-1 immunoreactive neurons was significantly decreased by 40% in AD patients (median [25th-75th percentiles]); AD 12,935 neurons (9972-19,051); controls 21,002 neurons (16,439-25,765); p = 0.049). Lower cerebrospinal fluid (CSF) hypocretin-1 levels were found in AD patients compared with controls (AD: 275 pg/mL [197-317]; controls: 320 pg/mL [262-363]; p = 0.038). Two AD patients with documented excessive daytime sleepiness showed the lowest CSF hypocretin-1 concentrations (55 pg/mL and 76 pg/mL). We conclude that the hypocretin system is affected in advanced AD. This is reflected in a 40% decreased cell number, and 14% lower CSF hypocretin-1 levels.
authors.affiliation: Netherlands Institute for Neurosciences, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef, Amsterdam, The Netherlands. r.fronczek@lumc.nl
authors.forename: Rolf
authors.initials: R
authors.lastname: Fronczek
authors.forename: Sarita
authors.initials: S
authors.lastname: van Geest
authors.forename: Marijke
authors.initials: M
authors.lastname: Frölich
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Overeem
authors.forename: Freek W C
authors.initials: FW
authors.lastname: Roelandse
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Lammers
authors.forename: Dick F
authors.initials: DF
authors.lastname: Swaab
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000378:metabolism*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002552:Cerebral Ventricles / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000068797:Orexins
chemical_list: D015415:Biomarkers; C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins