title: Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease.
abstract: OBJECTIVE
  Nocturnal sleep disruption develops in Alzheimer disease (AD) owing to the derangement of the sleep-wake cycle regulation pathways. Orexin contributes to the regulation of the sleep-wake cycle by increasing arousal levels and maintaining wakefulness.
  
  
  OBJECTIVE
  To study cerebrospinal fluid levels of orexin in patients with AD, to evaluate the relationship of orexin cerebrospinal fluid levels with the degree of dementia and the cerebrospinal fluid AD biomarkers (tau proteins and β-amyloid 1-42), and to analyze potentially related sleep architecture changes measured by polysomnography.
  
  
  METHODS
  We conducted a case-control study from August 1, 2012, through May 31, 2013. We included 48 drug-naive AD patients referred to the Neurological Clinic of the University Hospital of Rome Tor Vergata. Based on the Mini-Mental State Examination score, 21 patients were included in mild AD group (score, ≥21), whereas 27 were included in the moderate to severe AD group (score, <21). The control group consisted of 29 nondemented participants of similar age and sex.
  
  
  METHODS
  Laboratory assessment of cerebrospinal fluid levels of orexin, tau proteins, and β-amyloid 1-42 and polysomnographic assessment of sleep variables.
  
  
  METHODS
  Levels of orexin, tau proteins, and β-amyloid 1-42; macrostructural variables of nocturnal sleep (total sleep time, sleep efficiency, sleep onset and rapid eye movement [REM] sleep latencies, non-REM and REM sleep stages, and wakefulness after sleep onset); and Mini-Mental State Examination scores.
  
  
  RESULTS
  Patients with moderate to severe AD presented with higher mean (SD) orexin levels compared with controls (154.36 [28.16] vs 131.03 [26.55]; P < .01) and with more impaired nocturnal sleep with respect to controls and patients with mild AD. On the other hand, in the global AD group, orexin levels were positively correlated with total tau protein levels (r = 0.32; P = .03) and strictly related to sleep impairment. Finally, cognitive impairment, as measured by the Mini-Mental State Examination, was correlated with sleep structure deterioration.
  
  
  CONCLUSIONS
  Our results demonstrate that, in AD, increased cerebrospinal fluid orexin levels are related to a parallel sleep deterioration, which appears to be associated with cognitive decline. Therefore, the orexinergic system seems to be dysregulated in AD, and its output and function appear to be overexpressed along the progression of the neurodegenerative process. This overexpression may result from an imbalance of the neurotransmitter networks regulating the wake-sleep cycle toward the orexinergic system promoting wakefulness.
authors.affiliation: Neurophysiopathology Unit, Sleep Medicine Centre, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Liguori
authors.affiliation: Neurophysiopathology Unit, Sleep Medicine Centre, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Romigi
authors.affiliation: Department of Clinical Biochemistry and Molecular Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Nuccetelli
authors.affiliation: Neurophysiopathology Unit, Sleep Medicine Centre, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Zannino
authors.affiliation: Neurology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy4Neuroscience Unit, Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sancesario
authors.affiliation: Neurology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy4Neuroscience Unit, Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Martorana
authors.affiliation: Neurophysiopathology Unit, Sleep Medicine Centre, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Albanese
authors.affiliation: Neurophysiopathology Unit, Sleep Medicine Centre, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy4Neuroscience Unit, Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
authors.forename: Nicola Biagio
authors.initials: NB
authors.lastname: Mercuri
authors.affiliation: Neurophysiopathology Unit, Sleep Medicine Centre, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Izzi
authors.affiliation: Department of Clinical Biochemistry and Molecular Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Bernardini
authors.affiliation: Neurophysiopathology Unit, Sleep Medicine Centre, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nitti
authors.affiliation: Neuroscience Unit, Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
authors.forename: Giulia M
authors.initials: GM
authors.lastname: Sancesario
authors.affiliation: Neurology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sica
authors.affiliation: Neurology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Marciani
authors.affiliation: Neurophysiopathology Unit, Sleep Medicine Centre, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Placidi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000150:complications / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000134:cerebrospinal fluid* / Q000209:etiology / Q000503:physiopathology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000134:cerebrospinal fluid*; D008297:Male; D008875:Middle Aged; D009479:Neuropeptides / Q000134:cerebrospinal fluid*; D000068797:Orexins; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D017286:Polysomnography; D012720:Severity of Illness Index; D012893:Sleep Wake Disorders / Q000134:cerebrospinal fluid* / Q000209:etiology / Q000503:physiopathology; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D047908:Intracellular Signaling Peptides and Proteins; C054369:MAPT protein, human; D009479:Neuropeptides; D000068797:Orexins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins