Abstract
Objective: To examine relationships between cerebrospinal fluid (CSF) Alzheimer' disease (AD) biomarkers and hypocretin-1 levels in patients with cognitive abnormalities and hypocretin-deficient narcolepsy-cataplexy (NC), estimate diagnostic accuracy, and determine correlations with sleep disturbances.Background: Sleep disturbances are frequent in AD. Interactions between brain β-amyloid (Aβ) aggregation and a wake-related neurotransmitter hypocretin have been reported in a mouse model of AD.Methods: Ninety-one cognitive patients (37 AD, 16 mild cognitive impairment—MCI that converts to AD, 38 other dementias) and 15 elderly patients with NC were recruited. Patients were diagnosed blind to CSF results. CSF Aβ42, total tau, ptau181, and hypocretin-1 were measured. Sleep disturbances were assessed with questionnaires in 32 cognitive patients.Results: Lower CSF Aβ42 but higher tau and P-tau levels were found in AD and MCI compared to other dementias. CSF hypocretin-1 levels were higher in patients with MCI due to AD compared to other dementias, with a similar tendency for patients with advanced AD. CSF hypocretin-1 was significantly and independently associated with AD/MCI due to AD, with an OR of 2.70 after full adjustment, exceeding that for Aβ42. Aβ42 correlated positively with hypocretin-1 levels in advanced stage AD. No association was found between sleep disturbances and CSF biomarkers. No patients with NC achieved pathological cutoffs for Aβ42, with respectively one and four patients with NC above tau and P-tau cutoffs and no correlations between hypocretin-1 and other biomarkers.Conclusions: Our results suggest a pathophysiological relationship between Aβ42 and hypocretin-1 in the AD process, with higher CSF hypocretin-1 levels in early disease stages. Further longitudinal studies are needed to validate these biomarker interactions and to determine the cause-effect relationship and the role of wake/sleep behavior in amyloid plaque regulation.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder that is expected to become a disastrous worldwide epidemic within 40 years unless treatments to delay or halt the disease are developed
Lower cerebrospinal fluid (CSF) Aβ42 but higher tau and P-tau levels were found in AD and mild cognitive impairment (MCI) compared to other dementias
CSF hypocretin-1 levels were higher in patients with MCI due to AD compared to other dementias, with a similar tendency for patients with advanced AD
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder that is expected to become a disastrous worldwide epidemic within 40 years unless treatments to delay or halt the disease are developed. Sleep disturbances are frequently reported in AD, with both daytime sleepiness and nighttime awakenings (Dauvilliers, 2007; Ju et al, 2013; Spira et al, 2013). Non-specific factors associated with the ageing process and more specific ones, including disrupted sleep and circadian rhythm regulatory systems, are involved in sleep/wake disturbances (Montplaisir et al, 1995; Dauvilliers, 2007; Ju et al, 2013; Slats et al, 2013; Spira et al, 2013). Interactions between the amyloid process and the sleep-wake switching system have been proposed. Brain interstitial fluid Aβ concentration increased during wakefulness and decreased during sleep in an APP transgenic mouse model of AD (Kang et al, 2009). Interactions between brain β-amyloid (Aβ) aggregation and a wake-related neurotransmitter hypocretin have been reported in a mouse model of AD
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