Association between Hypocretin-1 and Amyloid-β42 Cerebrospinal Fluid Levels in Alzheimer’s Disease and Healthy Controls

Abstract

Alzheimer's disease is associated with sleep disorders. Recently, animal studies demonstrated a link between hypocretin, a sleep-regulation neurotransmitter, and AD pathology. In this study, we investigated the circadian rhythm of hypocretin-1 in Alzheimer's Disease (AD) patients and controls. Moreover, we assessed the relation between CSF hypocretin-1 and amyloid-β. A continuous CSF sampling study via indwelling intrathecal catheter was performed to collect hourly CSF samples of six patients with AD (59-85 yrs, MMSE 16-26) and six healthy volunteers (64-77 yrs). CSF hypocretin-1 and Aβ42 concentrations were determined at 8 individual time points over 24 hours. A circadian pattern was assessed by fitting a 24 hour sine curve to the hypocretin-1 data using mixed model analysis. Clinical diagnosis and Aβ42 were entered into the model as time invariant covariates to determine differences between AD and controls, and correlate Aβ42 to hypocretin-1 levels. A hypocretin-1 circadian rhythm with an amplitude of 11.5 pg/ml was found in clinical AD patients, which did not differ from the control group (7.15 pg/ml). Lower mean CSF Aβ42 levels were related to lower hypocretin-1 levels; 1.6 pg/ml hypocretin-1 per 10 pg/ml Aβ42 (p=0.03), and a higher amplitude of the hypocretin-1 circadian rhythm (0.4 pg/ml, p=0.03). CSF hypocretin-1 has a circadian rhythm for which we could show no difference between AD and controls. However, the association between mean Aβ42 levels and mean hypocretin-1 levels and amplitude may suggest a relationship between AD pathology and hypocretin disturbance, which could hold possibilities for treatment of AD related sleep disorders.

Sleep and Cognitive Decline: A Strong Bidirectional Relationship. It Is Time for Specific Recommendations on Routine Assessment and the Management of Sleep Disorders in Patients with Mild Cognitive Impairment and Dementia

“…There is growing evidence of the impairment of melanin-concentrating hormone and HCRT-1 systems in AD patients, that is, in post-mortem studies of the hypothalamus of AD patients and controls, a decrease in cell number and lower CSF HCRT-1 levels were found. Gender differences in CSF HCRT-1 have also been found, supporting the higher prevalence of sleep disturbances and AD in women [30,32,33] . In both human and mouse models, the level of Aβ increases during wakefulness and decreases during sleep following a circadian rhythm and is regulated by orexin [34][35][36] .…”

Hypocretin and brain β-amyloid peptide interactions in cognitive disorders and narcolepsy

“…A slight correlation between Aβ 42 and hypocretin-1 levels was recently reported in 6 patients with AD and 6 healthy controls, with no between-group difference in CSF hypocretin-1 levels and its circadian amplitude (Slats et al, 2012). In contrast, no association between Aβ 42 and hypocretin-1 was reported in either control subjects or patients with AD in a larger study, but with low hypocretin-1 levels in 9 female patients with LBD (Wennstrom et al, 2012).…”

“…However, several studies have reported a normal range of CSF hypocretin-1 concentration in AD patients (Mignot et al, 2002; Dauvilliers et al, 2003; Baumann et al, 2004; Friedman et al, 2007). One elegant study using an indwelling intrathecal catheter to collect hourly CSF samples in six patients with AD and six controls reported a correlation between hypocretin-1 and Aβ 42 , with no significant between-group differences in hypocretin-1 circadian rhythm amplitude (Slats et al, 2012). Moreover, lower CSF hypocretin-1 levels were found in dementia with Lewy bodies compared to AD and controls, with no associations between hypocretin-1 and Aβ 42 concentrations (Wennstrom et al, 2012).…”

The sleep–wake Cycle and Alzheimer’s Disease: What do We know?

“…Similar to the 3×Tg mouse model, a well-described early feature of human AD pathogenesis is degeneration of the locus coeruleus, the main source of norepinephrine to the cortex and a region critical for maintenance of normal wakefulness [35]. Deficits have also been identified in the wake-promoting molecule, orexin (also known as hypocretin), which is implicated in human narcolepsy: CSF orexin levels are significantly correlated with CSF Aβ42 levels in AD patients, suggesting decreased control of the sleep–wake cycle occurs with decreased Aβ42 levels (used as a surrogate marker for amyloid plaque deposition) [36]. Furthermore, CSF orexin levels have a significant correlation with tau and phosphorylated tau protein levels in the CSF of ten patients with AD compared with ten age-matched controls, indicating a relationship between sleep–wake molecules and tau pathology [37].…”