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Study links drowsiness in Alzheimer’s to wake-promoting brain regions

JAMA Neurology
Reuters Health - 07/04/2022 - Sleep-related symptoms in Alzheimer's disease correlate with neuron numbers in three subcortical brain areas, according to a new study that suggests the loss of wake-promoting cells is at the root of early sleep disturbances. 

Researchers analyzed sleep-study data from patients with Alzheimer's disease (AD) or progressive supranuclear palsy (PSP), as well as postmortem brain tissue from the same subjects. They report in JAMA Neurology that in the context of significant neuronal loss, quantities of remaining neurons in three wake-promoting regions in the hypothalamus and brainstem correlate strongly with sleep-related characteristics of each disease. 

The study team focused on three brain areas known to promote wakefulness: the locus coeruleus (LC), the lateral hypothalamic area (LHA), and the tuberomammillary nuclei (TMN). All three are known to lose substantial numbers of cells in the earliest stages of Alzheimer's, on the order of 60% to 80% of the cell populations, according to lead study author Joseph Oh, a neurobiologist with the Memory and Aging Center at the University of California, San Francisco (UCSF). 

That cell loss is associated with accumulation of tau protein, and both happen long before memory symptoms or other features of Alzheimer's arise, Oh, along with senior study author Dr. Lea Grinberg of UCSF's Global Brain Health Institute, noted in a telephone interview. 

These three regions "share similar function when it comes to sleep, and they have this amazing capacity to drive wakefulness behavior," Oh said. "Using EEG to examine the electrical activity during sleep and looking at the postmortem neuronal data, we're able to provide very strong evidence that these neurons are absolutely critical in governing sleep and wake physiology in humans and that's a really powerful thing that we show in our paper." 

Because the sleep-related problems in AD and PSP are very different, the researchers added PSP subjects as a "disease control," Dr. Grinberg explained. While AD patients often experience sleepiness during the day, and "sundowning," she said, PSP patients are chronically sleep-deprived because of hyperarousal and diminished sleep drive. 

In both diseases, tau accumulation happens early in the disease process, but in PSP, neurons in the wake-promoting regions are not destroyed, Dr. Grinberg said. Instead, sleep-promoting cells elsewhere in the brain are lost. 

To see if the loss of wake-promoting cells in AD patients dysregulates the remaining cells, the study team analyzed EEG/polysomnographic data from 10 AD patients, 9 PSP patients, and 32 age-matched healthy controls who underwent sleep studies. The researchers also examined neurotransmitters, tau, and total neuron counts in the LC, TMN, and LHA of the AD and PSP brains. 

After adjusting for primary diagnosis, age, sex, and the roughly two to three-year lag time between the sleep studies and postmortem brain donation, the authors found "robust" correlations between the cell numbers and sleep symptoms and architecture. 

In the sleep studies, the AD patients had significantly greater sleep drive, including higher total sleep time, higher sleep maintenance, and lower percentage of wake-after-sleep-onset compared to the PSP group. 

In the brain analyses, a greater number of the orexinergic LHA neurons and the histaminergic TMN cells was associated with decreased sleep drive, as shown by lesser time-to-sleep, lesser sleep maintenance, and greater wake-after-sleep-onset. Larger numbers of histaminergic neurons were also associated with lesser NREM2-stage sleep, and less REM sleep, while a greater number of noradrenergic LC neurons was mainly associated with lesser time-to-sleep and greater REM latency, the study found. 

"In this paper, in addition to understanding the correlation between each of these metrics, we created very sophisticated statistical models to understand how one system compensates the other and the clinical consequence of this," Dr. Grinberg said. "We believe that having this multidimensional data, we'll really be able to understand what's going on." 

Understanding the exact roles of protein accumulation, neuron loss, and loss of homeostasis in the remaining wake-promoting cells is very important for treating sleep-related complaints, Dr. Grinberg noted. "What we see when we look at these brains is progressive stages of the disease, that neurons start to die very early in the disease, but then for a while, the other surviving neurons try to compensate, so you might even have an excess of whatever neurotransmitter at the beginning instead of a deficit." 

"At the end of the day, the kind of treatment we will provide, it will vary according to the disease stage - at the beginning, we will like to correct some signal, instead of increasing it, and then slowly we will try to increase it," she said. 

Ultimately, though, the researchers believe the goal should be clearing out the accumulated tau that is linked to early neuron loss in these brain regions, not only in AD, but also in age-related sleep disturbances generally. That could restore homeostatic functioning to cells before they're lost forever. 

"What we've been learning lately is that it's not because you have protein accumulation that you definitely have neuron loss - it depends on the neurons, some are more resistant, some are more vulnerable," Dr. Grinberg said. "Even though, if you have a protein accumulation there, you always have a level of dysfunction of the cell, (the cells) are rectable, so this is the good news." 

SOURCE: https://bit.ly/3uQsbGg  JAMA Neurology, online April 4, 2022. 

By Christine Soares 

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