Spike In Orexin, A Neurotransmitter, Causes Disruption Of Sleep-Wake Cycle Linked To Alzheimer’s

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A new study finds a relationship between the nightly awakenings of patients with Alzheimer’s disease and increased levels of the neurotransmitter orexin. Photo courtesy of Shutterstock.

Orexin, sometimes called hypocretin, is a neurotransmitter that contributes to the regulation of our sleep-wake cycle. A new study finds a relationship between the nightly awakenings of patients with Alzheimer’s disease and increased levels of orexin in their cerebrospinal fluid. “The main result of our study is the increase of the [spinal fluid] orexin levels found in Alzheimer’s patients with moderate to severe cognitive decline,” wrote the researchers, who further suggest these negative effects worsen as the disease progresses.

Years ago, researchers first observed the unusual presence of beta-amyloid plaques and tangles of tau proteins in the brains of patients with Alzheimer’s. Scientists immediately recognized these factors as causing a dramatic loss of neurons and synapses that resulted in the characteristic memory loss and derangement of the illness. However, Azheimer’s disease (AD) not only causes a decline in mental ability but also disturbs the sleep of sufferers. Today, scientists are looking more closely at the brain regions and networks involved in the sleep-wake rhythm. In particular, they are focusing on a neurotransmitter produced in the hypothalamus, which helps us stay awake: Orexin A, (also referred to as hypocretin 1), a leading actor in the orexinergic system. In fact, the lack of this neurotransmitter is what causes the most common form of narcolepsy.

For the current study, researchers measured cerebrospinal fluid orexin levels in drug-free Alzheimer’s patients and compared them with healthy controls. The study ran from August 2012, through May 2013 and included 48 untreated Alzheimer’s patients at the Neurological Clinic of the University Hospital of Rome Tor Vergata. After examination, the researchers divided the group into 21 patients with mild AD and 27 patients with moderate to severe AD. The control group consisted of nondemented participants of similar age and sex.

The researchers discovered patients with moderate to severe AD presented with higher than average orexin levels compared with controls and they had more impaired sleep compared with controls as well as the patients with mild AD. In the overall AD group, orexin levels were associated with total tau protein levels and sleep impairment. Cognitive impairment was associated with sleep deterioration.

“With a rising prevalence of AD around the world, there is an urgent need to identify opportunities for prevention and treatment of the disease,” noted Dr. Luigi Ferini-Strambi, of the Universitá Vita-Salute, Milan, in his related commentary. "Further research should clarity how to modify or improve sleep for mitigating the risk of future AD or for slowing AD progression.”

Sources: Liguori C, Romigi A, Nuccatelli M, et al. Orexinergic System Dysregulation, Sleep Impairment, and Cognitive Decline in Alzheimer Disease. JAMA. 2014.

Ferini-Strambi L. Possible Role of Orexin in the Pathogenesis of Alzheimer Disease. JAMA. 2014.

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