Rapid eye movement sleep disruption and sleep fragmentation are associated with increased orexin-A cerebrospinal-fluid levels in mild cognitive impairment due to Alzheimer's disease

The orexin system has been investigated in patients affected by mild cognitive impairment (MCI) due to Alzheimer's disease (AD) by measuring orexin-A concentrations in the cerebrospinal fluid (CSF), and correlated to subjective and objective sleep parameters, quantified by questionnaires and polysomnography, respectively. Twenty drug-naïve patients with MCI due to AD were studied and compared with a population of 26 age and/or sex matched controls, divided into subgroups on the basis of the Pittsburgh Sleep Quality Index (PSQI) score. Increased CSF-orexin levels were detected in patients with MCI due to AD in comparison with controls (p < 0.05). In particular, CSF-orexin concentrations were higher in MCI patients suffering from sleep complaints (PSQI ≥5, n = 10) compared with MCI patients with a regular sleep-wake cycle (PSQI <5, n = 10, p < 0.001) and compared with both control groups (with sleep complaints, PSQI ≥5, n = 11, p < 0.001; without sleep complaints, PSQI <5, n = 15, p < 0.001). Moreover, REM sleep was reduced in MCI patients compared with controls (p < 0.01), and had a negative correlation coupled with a reciprocal influence at the multiple regression analysis with CSF-orexin levels (R = -0.65; β = -8.90). REM sleep disruption and sleep fragmentation are related to higher CSF-orexin levels in patients with MCI due to AD, thus suggesting that the orexin system may be involved even in the earliest stages of AD, resulting in prolonged sleep latency, reduced sleep efficiency, and REM sleep impairment.