Cerebrospinal Fluid Melanin-Concentrating Hormone (MCH) and Hypocretin-1 (HCRT-1, Orexin-A) in Alzheimer’s Disease

Abstract

Ancillary to decline in cognitive abilities, patients with Alzheimer’s disease (AD) frequently suffer from behavioural and psychological symptoms of dementia (BPSD). Hypothalamic polypeptides such as melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) are promoters of sleep-wake regulation and energy homeostasis and are found to impact on cognitive performance. To investigate the role of MCH and HCRT-1 in AD, cerebrospinal fluid (CSF) levels were measured in 33 patients with AD and 33 healthy subjects (HS) using a fluorescence immunoassay (FIA). A significant main effect of diagnosis (F(1,62) = 8.490, p<0.01) on MCH levels was found between AD (93.76±13.47 pg/mL) and HS (84.65±11.40 pg/mL). MCH correlated with T-tau (r = 0.47; p<0.01) and P-tau (r = 0.404; p<0.05) in the AD but not in the HS. CSF-MCH correlated negatively with MMSE scores in the AD (r = −0.362, p<0.05) and was increased in more severely affected patients (MMSE≤20) compared to HS (p<0.001) and BPSD-positive patients compared to HS (p<0.05). In CSF-HCRT-1, a significant main effect of sex (F(1,31) = 4.400, p<0.05) with elevated levels in females (90.93±17.37 pg/mL vs. 82.73±15.39 pg/mL) was found whereas diagnosis and the sex*diagnosis interaction were not significant. Elevated levels of MCH in patients suffering from AD and correlation with Tau and severity of cognitive impairment point towards an impact of MCH in AD. Gender differences of CSF-HCRT-1 controversially portend a previously reported gender dependence of HCRT-1-regulation. Histochemical and actigraphic explorations are warranted to further elucidate alterations of hypothalamic transmitter regulation in AD.

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] .…”

“…They are synthesized in the hypothalamus, a region where senile plaques and neurofibrillary tangles are found. Experimental studies demonstrate that receptors for both peptides can also be found in areas typically affected in the AD patients, such as the cerebral cortex, basal forebrain, amygdala and brain stem [30,31] . 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.…”

Sleep, Cognitive impairment, and Alzheimer’s disease: A Systematic Review and Meta-Analysis

“…Among the 27 studies identified for the meta-analysis, there were 8 cross-sectional, 31,37,44-49 1 case-control, 50 2 retrospective cohort, 33,51 and 16 prospective cohort 32,34,36,[38][39][40][52][53][54][55][56][57][58][59][60][61] (Table 1). Of these, 15 were considered to be of high quality, 10 were of medium quality, and 2 were of low quality.…”

“…Five studies utilized self-constructed questionnaires and 1 study made use of fluorescence immuneassay (FIA) to determine melatonin/hypocretin concentrations. 50 Most studies reported risk estimates for individual symptoms. Multiple symptoms were also assessed in some studies.…”

Spontaneous Physical Activity Defends Against Obesity

“…Although no gender- or sex hormone-dependent differences are present in prepro-orexin mRNA, healthy female mice show higher OXR1 mRNA expression in the hypothalamus than males [100]. Human females also have higher circulating orexin levels in their cerebrospinal fluid [101]. Diet and energy state affect orexin neurons in the LH differently in males and females.…”