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Severe Neuron Loss in Wake-Promoting Brain Regions in People With Alzheimer's

August 15, 2019

By Anne Harding

NEW YORK—Alzheimer's disease (AD) patients have extensive tau inclusions and severe neuron loss in wake-promoting nuclei of the brain, new research shows.

The finding "supports the idea that sleep dysfunction is a manifestation of Alzheimer pathology build-up in the brain, rather than a risk factor. It opens opportunities to treat the cause rather than the symptoms," Dr. Lea T. Grinberg of the University of California, San Francisco, the study's senior author, told Reuters Health by email.

AD patients develop sleep-wake disturbances, including excessive daytime napping, early in the course of the disease, Dr. Grinberg and her colleagues note in Alzheimer's and Dementia, online August 12. Most research has focused on sleep problems, rather than difficulties with arousal, they add.

Using postmortem brains from 13 AD patients, seven patients with progressive supranuclear palsy (PSP), seven with corticobasal degeneration (CBD), and seven healthy controls, the authors compared three key wake-promoting nuclei: the locus coeruleus (LC), lateral hypothalamic area (LHA), and tuberomammillary nucleus (TMN). Wake-promoting neurons in each region produce noradrenaline, orexin/hypocretin and histamine, respectively.

In the AD, PSP and CBD brains, all three nuclei contained "considerable amounts of tau inclusions," and showed loss of neurotransmitter-producing neurons. But extensive loss of neurons only appeared in AD.

AD patients had nearly 75% fewer neurons in the LC compared with controls, while patients with PSP or CBD had about half as many. AD brains also had about 72% fewer neurons in the LHA and 62% fewer neurons in the TMN compared with healthy controls, but neuronal loss didn't reach significance in PSP or CBD.

The findings suggest that "even symptomatic treatment for Alzheimer disease can expand from the current ones tackling the cholinergic system to tackling other neurotransmitters such as orexin, noradrenalin and histamine," Dr. Grinberg said. "Such drugs exist, but they haven't been systematically tested in AD yet."

The National Institutes of Health and the Rainwater Charitable Foundation are providing $1.4 million per year to Dr. Grinberg and her group to continue the research, and her UCSF colleagues have launched a clinical trial to improve management of sleep problems in PSP based on their findings.


Alzheimers Dement 2019.

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