For the millions of patients suffering from Alzheimer’s, sleep disturbances are an extra burden to their already delicate psyche. For years, doctors knew nothing of why sleep disturbances occurred, but only that they were an effect of Alzheimer’s impact on the brain.
Now new research has uncovered a set of inhibitory neurons, the loss of which results in sleep disruption in animal models. These neurons are substantially diminished in patients with Alzheimer’s and also elderly people, which may explain the irregular sleep patterns they experience.
Disrupted sleep, characterized by difficulty falling asleep and staying asleep, or waking early in the morning, tends to manifest with aging or underlying brain disease. The study, led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and the University of Toronto/Sunnybrook Health Sciences Center, found that the loss of neurons that results in sleep loss and sleep fragmentation may be contributing to various age-related disorders, such as cognitive dysfunction, high blood pressure, vascular diseases, and a tendency to develop type 2 diabetes.
On average, people in their 70s slept one hour less at night than people in their 20s, according to senior author, Clifford B. Saper. The group of inhibitory neurons, called ventrolateral preoptic nucleus, was discovered by Saper and his team in 1996. They found that these neurons were functioning as a “sleep switch” in rats, turning off the brain’s ability to stimulate sleep. "Our experiments in animals showed that loss of these neurons produced profound insomnia, with animals sleeping only about 50 percent as much as normal and their remaining sleep being fragmented and disrupted," said Saper in a statement.
A group of cells in the human brain, the intermediate nucleus, is located in a similar location and has the same inhibitory neurotransmitter, galanin, as the vetrolateral preoptic nucleus in rats. The researchers believe that if the intermediate nucleus performs a similar function as the vetrolateral preoptic nucleus does in animals, then it may be the key to the regulation of sleep-wake cycles in humans.
The team tested this theory by dipping into data they got from the Rush Memory and Aging Project, a community-based study of aging and dementia, which began in 1997 and has been tracking close to 1,000 participants who entered the study as healthy 65-year-olds and will be followed until their deaths — at which point their brains will be donated for research.
"Since 2005, most of the subjects in the Memory and Aging Project have been undergoing actigraphic recording every two years. This consists of their wearing a small wristwatch-type device on their non-dominant arm for seven to 10 days," explained first author Andrew S. P. Lim.
The device is worn by the subjects 24/7 and thus records all movements divided into 15-second intervals. "Our previous work had determined that these actigraphic recordings are a good measure of the amount and quality of sleep," Lim added.
The researchers examined the brains of 45 study subjects whose median death-age was 889.2 years (median age at death, 89.2). They identified the ventrolateral preoptic neurons by staining the brains for the neurotransmitter galanin. They then correlated the actigraphic rest-activity behavior of the 45 individuals in the year prior to their deaths with the number of remaining ventrolateral preoptic neurons at autopsy. They found that in patients without Alzheimer’s the number of ventrolateral preoptic neurons and the amount of sleep fragmentation is inversely proportional.
"The fewer the neurons, the more fragmented the sleep became," Saper said.
The subjects with the largest amount of neurons (greater than 6,000) spent 50 percent or more of total rest time in the prolonged periods of non-movement most likely to represent sleep while subjects with the fewest ventrolateral preoptic neurons (less than 3,000) spent less than 40 percent of total rest time in extended periods of rest.
The results also showed that in Alzheimer's patients, sleep impairment occurred most in subjects who had lost significant number of ventrolateral preoptic neurons.
"These findings provide the first evidence that the ventrolateral preoptic nucleus in humans probably plays a key role in causing sleep, and functions in a similar way to other species that have been studied," Saper said. "The loss of these neurons with aging and with Alzheimer's disease may be an important reason why older individuals often face sleep disruptions,” he said, adding that with these results new interventions need to be devised to reduce sleep problems in the aged and prevent sleep-deprivation related confusion and exhaustion in people with dementia.
Source: Saper C, Lim A, Ellison B, et al. Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer’s disease. Brain. 2014.