Not all sleep is equal when it comes to cleaning the brain
February 27, 2019
Science Daily/University of Rochester Medical Center
New research shows how the depth of sleep can impact our brain's ability to efficiently wash away waste and toxic proteins. Because sleep often becomes increasingly lighter and more disrupted as we become older, the study reinforces and potentially explains the links between aging, sleep deprivation, and heightened risk for Alzheimer's disease.
"Sleep is critical to the function of the brain's waste removal system and this study shows that the deeper the sleep the better," said Maiken Nedergaard, M.D., D.M.Sc., co-director of the Center for Translational Neuromedicine at the University of Rochester Medical Center (URMC) and lead author of the study. "These findings also add to the increasingly clear evidence that quality of sleep or sleep deprivation can predict the onset of Alzheimer's and dementia."
The study, which appears in the journal Science Advances, indicates that the slow and steady brain and cardiopulmonary activity associated with deep non-REM sleep are optimal for the function of the glymphatic system, the brain's unique process of removing waste. The findings may also explain why some forms of anesthesia can lead to cognitive impairment in older adults.
The previously unknown glymphatic system was first described by Nedergaard and her colleagues in 2012. Prior to that point, scientists did not fully understand how the brain, which maintains its own closed ecosystem, removed waste. The study revealed a system of plumbing which piggybacks on blood vessels and pumps cerebral spinal fluid (CSF) through brain tissue to wash away waste. A subsequent study showed that this system primarily works while we sleep.
Because the accumulation of toxic proteins such as beta amyloid and tau in the brain are associated with Alzheimer's disease, researchers have speculated that impairment of the glymphatic system due to disrupted sleep could be a driver of the disease. This squares with clinical observations which show an association between sleep deprivation and heightened risk for Alzheimer's.
In the current study, researchers conducted experiments with mice that were anesthetized with six different anesthetic regimens. While the animals were under anesthesia, the researchers tracked brain electrical activity, cardiovascular activity, and the cleansing flow of CSF through the brain. The team observed that a combination of the drugs ketamine and xylazine (K/X) most closely replicated the slow and steady electrical activity in the brain and slow heart rate associated with deep non-REM sleep. Furthermore, the electrical activity in the brains of mice administered K/X appeared to be optimal for function of the glymphatic system.
"The synchronized waves of neural activity during deep slow-wave sleep, specifically firing patterns that move from front of the brain to the back, coincide with what we know about the flow of CSF in the glymphatic system," said Lauren Hablitz, Ph.D., a postdoctoral associate in Nedergaard's lab and first author of the study. "It appears that the chemicals involved in the firing of neurons, namely ions, drive a process of osmosis which helps pull the fluid through brain tissue."
The study raises several important clinical questions. It further bolsters the link between sleep, aging, and Alzheimer's disease. It is known that as we age it becomes more difficult to consistently achieve deep non-REM sleep, and the study reinforces the importance of deep sleep to the proper function of the glymphatic system. The study also demonstrates that the glymphatic system can be manipulated by enhancing sleep, a finding that may point to potential clinical approaches, such as sleep therapy or other methods to boost the quality of sleep, for at-risk populations.
Furthermore, because several of the compounds used in the study were analogous to anesthetics used in clinical settings, the study also sheds light on the cognitive difficulties that older patients often experience after surgery and suggests classes of drugs that could be used to avoid this phenomenon. Mice in the study that were exposed to anesthetics that did not induce slow brain activity saw diminished glymphatic activity.
"Cognitive impairment after anesthesia and surgery is a major problem," said Tuomas Lilius, M.D., Ph.D., with the Center for Translational Neuromedicine at the University of Copenhagen in Denmark and co-author of the study. "A significant percentage of elderly patients that undergo surgery experience a postoperative period of delirium or have a new or worsened cognitive impairment at discharge."
https://www.sciencedaily.com/releases/2019/02/190227173111.htm
Moderate to high intensity exercise does not slow cognitive decline in people with dementia
May 16, 2018
Science Daily/BMJ
Moderate to high intensity exercise does not slow cognitive (mental) impairment in older people with dementia, finds a new trial.
Although the exercise programme improved physical fitness, it cannot be recommended as a treatment option for cognitive impairment in dementia, say the researchers.
Nearly 47.5 million people worldwide have dementia and the view that exercise might slow cognitive decline has gained widespread popularity. But recent reviews of trials of exercise training in people with dementia have shown conflicting results.
To try and resolve this uncertainty, a team of UK researchers decided to estimate the effect of a moderate to high intensity aerobic and strength exercise training programme on cognitive impairment and other outcomes in people with dementia.
The trial involved 494 people with mild to moderate dementia (average age 77 years) living in the community across 15 regions of England.
General health and fitness was assessed at the start of the study and participants were randomly assigned to either a supervised exercise and support programme (329 patients) or to usual care (165 patients).
The programme consisted of 60-90 minute group sessions in a gym twice a week for four months, plus home exercises for one additional hour each week with ongoing support.
The main (primary) outcome was an Alzheimer's disease assessment score (ADAS-cog) at 12 months. Other (secondary) outcomes included activities of daily living, number of falls, and quality of life.
Compliance with exercise was good and participants were assessed again at six and 12 months.
After taking account of potentially influential factors, the researchers found that cognitive impairment declined over the 12-month follow-up in both groups.
The exercise group showed improved physical fitness in the short term, but higher ADAS-cog scores at 12 months (25.2 v 23.8) compared with the usual care group, indicating worse cognitive impairment. However, the average difference was small and clinical relevance was uncertain.
No differences were found in secondary outcomes, including number of falls and quality of life, or after further analyses to test the strength of the results.
The researchers point to some trial limitations. For example, participants and carers knew which group they were in, and the period of structured exercise may have been too short to produce positive benefits. However, strengths over previous trials included a substantially larger sample size and high levels of follow-up.
"This trial suggests that people with mild to moderate dementia can engage and comply with moderate to high intensity aerobic and strengthening exercise and improve physical fitness," say the authors.
"These benefits do not, however, translate into improvements in cognitive impairment, activities in daily living, behaviour, or health related quality of life," they add.
They suggest that future trials should explore other forms of exercise, and that investigators "should consider the possibility that some types of exercise intervention might worsen cognitive impairment."
https://www.sciencedaily.com/releases/2018/05/180516184930.htm
Can training improve memory, thinking abilities in older adults with cognitive impairment?
January 16, 2018
Science Daily/American Geriatrics Society
A new, first-of-its-kind study was designed to assess whether cognitive training, a medication-free treatment, could improve MCI. Studies show that activities that stimulate your brain, such as cognitive training, can protect against a decline in your mental abilities. Even older adults who have MCI can still learn and use new mental skills.
Cognition is the ability to think and make decisions. Medication-free treatments that maintain cognitive health as we age are attracting the attention of medical experts. Maintaining the ability to think clearly and make decisions is crucial to older adults' well-being and vitality.
Mild cognitive impairment (MCI) is a condition that affects people who are in the early stages of dementia or Alzheimer's disease. People with MCI may have mild memory loss or other difficulties completing tasks that involve cognitive abilities. MCI may eventually develop into dementia or Alzheimer's disease. Depression and anxiety also can accompany MCI. Having these conditions can increase the risk of mental decline as people age.
A new, first-of-its-kind study was published in the Journal of the American Geriatrics Society by scientists from research centers in Montreal and Quebec City, Canada. They designed a study to learn whether cognitive training, a medication-free treatment, could improve MCI. Studies show that activities that stimulate your brain, such as cognitive training, can protect against a decline in your mental abilities. Even older adults who have MCI can still learn and use new mental skills.
For their study, researchers recruited 145 older adults around the age of 72 from Canadian memory clinics. The participants had been diagnosed with MCI, and were assigned to one of three groups. Each group included four or five participants, and met for eight weekly sessions for 120 minutes.
The three groups were:
· Cognitive training group. Members of this group participated in the MEMO program (MEMO stands for a French phrase that translates to "training method for optimal memory"). They received special training to improve their memory and attention span.
· Psycho-social group. Participants in this group were encouraged to improve their general well-being. They learned to focus on the positive aspects of their lives and find ways to increase positive situations.
· Control group. Participants had no contact with researchers and didn't follow a program.
During the time the training sessions took place, 128 of the participants completed the project. After six months, 104 completed all the sessions they were assigned.
People in the MEMO group increased their memory scores by 35 to 40 percent, said Sylvie Belleville, PhD, a senior author of the study. "Most importantly, they maintained their scores over a six-month period."
What's more, the improvement was the largest for older adults with "delayed recall." This means memory for words measured just 10 minutes after people have studied them. Because delayed memory is one of the earliest signs of Alzheimer's disease, this was a key finding.
Those who participated in the MEMO group said they used the training they learned in their daily lives. The training gave them different ways to remember things. For example, they learned to use visual images to remember names of new people, and to use associations to remember shopping lists. These lessons allowed them to continue maintaining their memory improvements after the study ended.
The people in the psycho-social group and the control group didn't experience memory benefits or improvement in their mood.
https://www.sciencedaily.com/releases/2018/01/180116144246.htm
Brain changes linked to sleep need
June 14, 2018
Science Daily/UT Southwestern Medical Center
We've all experienced going to bed tired and waking up refreshed, yet how that happens at the molecular level remains a mystery. An international study sheds new light on the biochemistry of sleep need in the brain.
According to the American Sleep Association, 50 million to 70 million U.S. adults have a sleep disorder with almost 1 in 3 experiencing short-term insomnia and about 1 in 10 suffering from chronic insomnia. Sleep loss is known to compromise thinking and decision-making, which decreases work performance and productivity while increasing the risk of auto and industrial accidents. Understanding sleep regulators could benefit society by leading to the development of novel, more effective treatments for sleeplessness.
The new research reports the first whole-brain, quantitative study of a fundamental molecular process called phosphorylation in the context of sleep need. It features a clever comparison of two different groups of tired mice: sleep-deprived normal mice and Sleepy mutant mice, a variety with a genetic mutation that confers an unusually high sleep need despite increased sleep amount.
The Sleepy mouse was identified in a collaborative study between Dr. Masashi Yanagisawa and Dr. Joseph Takahashi initiated at UT Southwestern's Peter O'Donnell Jr. Brain Institute, where Dr. Takahashi is Chair of Neuroscience, a Howard Hughes Medical Institute Investigator, and holder of the Loyd B. Sands Distinguished Chair in Neuroscience. Dr. Yanagisawa, Director of the University of Tsukuba's International Institute for Integrative Sleep Medicine (WPI-IIIS) in Japan, is a Professor of Molecular Genetics at UT Southwestern. Dr. Yanagisawa and Dr. Qinghua Liu, an Associate Professor in UTSW's Center for the Genetics of Host Defense and of Neuroscience, are two of the study's three corresponding authors. Dr. Liu also has joint appointments at the WPI-IIIS and at the National Institute of Biological Sciences (NIBS) in Beijing.
"Although sleep exists in all animals, why sleep is needed and how sleep is regulated remain a mystery. We set out to investigate the molecules that govern sleep need (or sleep pressure)," said Dr. Liu, a W.A. "Tex" Moncrief Jr. Scholar in Medical Research. Sleep need is the feeling of tiredness that builds up during waking hours, he said.
Dr. Joseph Takahashi describes the 2016 study from the Peter O'Donnell Jr. Brain Institute that identified the Sleepy mouse.
"Each animal exhibits a set point of total sleep time. In adult humans, that usually means about 8 out of 24 hours. Everyone has experienced staying up too late and feeling a need to 'make up for lost sleep.' Even simple jellyfish need to rest longer after being forced to remain awake," he said, adding that it has been hypothesized that a substance accumulates in the brain during waking and dissipates during sleep.
"A long-term goal in sleep research is to identify the actual molecular factor or factors involved in sleep need," he said. Currently, the majority of sleep medicines are mimics of GABA, an inhibitory neurotransmitter that simply shuts off the brain, and they induce nonnatural sleep with many side effects. It would be nice to understand the natural molecules better in order to design improved treatments for sleep problems, he added.
To study the molecules involved in sleep need, researchers devised a novel strategy of comparing phosphorylation in the brains of the sleep-deprived normal mice and Sleepy mutant mice. Phosphorylation is a reversible process that modifies the functions of proteins by adding a phosphate group. The novel strategy comparing the two mice -- one sleepy by circumstance, the other sleepy by nature -- made it possible to exclude variables such as stress that could affect sleepiness, the researchers explained.
Using immunochemical assays and mass spectrometry, the researchers identified 80 proteins that were hyperphosphorylated in the brains of sleep-deprived and Sleepy mice, meaning that the proteins accumulated more phosphate groups the longer the mice stayed awake. They named these proteins Sleep-Need-Index-Phosphoproteins (SNIPPs). They found that the phosphorylation of SNIPPs increased with sleep need and dissipated, or dephosphorylated, throughout the brain during sleep.
"Previous studies suggested a close link between sleep need and synaptic plasticity (the strengthening and weakening of synaptic connections between neurons that is linked to thinking and learning). Intriguingly, the majority of SNIPPs are synaptic proteins, including many regulators of synaptic plasticity," Dr. Liu said.
He added that a literature search found that mutations of multiple SNIPPs have been linked to changes in sleep need. "Thus, we propose that SNIPPs constitute the molecular link between synaptic plasticity and regulation of sleep need or, in lay terms, between thinking and sleepiness," he said.
"The purpose of phosphorylation appears to be to maximize the duration and quality of cognitive (thinking) functions of the brain. While prolonged wakefulness leads to cognitive impairment and sleepiness, sleep refreshes the brain through multiple restorative effects and optimizes cognitive functions for the next waking period," he said. Therefore, the phosphorylation/dephosphorylation cycle of SNIPPs may be an important way for the brain to reset itself every night, restoring both synaptic and sleep-wake balance to maximize clear thinking, he added.
https://www.sciencedaily.com/releases/2018/06/180614212700.htm
Eating fish reduces risk of Alzheimer's disease
December 1, 2011
Science Daily/Radiological Society of North America
People who eat baked or broiled fish on a weekly basis may be improving their brain health and reducing their risk of developing mild cognitive impairment and Alzheimer's disease, according to a new study.
"This is the first study to establish a direct relationship between fish consumption, brain structure and Alzheimer's risk," said Cyrus Raji, M.D., Ph.D., from the University of Pittsburgh Medical Center and the University of Pittsburgh School of Medicine. "The results showed that people who consumed baked or broiled fish at least one time per week had better preservation of gray matter volume on MRI in brain areas at risk for Alzheimer's disease."
Alzheimer's disease is an incurable, progressive brain disease that slowly destroys memory and cognitive skills. According to the National Institute on Aging, as many as 5.1 million Americans may have Alzheimer's disease. In MCI, memory loss is present but to a lesser extent than in Alzheimer's disease. People with MCI often go on to develop Alzheimer's disease.
The findings showed that consumption of baked or broiled fish on a weekly basis was positively associated with gray matter volumes in several areas of the brain. Greater hippocampal, posterior cingulate and orbital frontal cortex volumes in relation to fish consumption reduced the risk for five-year decline to MCI or Alzheimer's by almost five-fold.
"Consuming baked or broiled fish promotes stronger neurons in the brain's gray matter by making them larger and healthier," Dr. Raji said. "This simple lifestyle choice increases the brain's resistance to Alzheimer's disease and lowers risk for the disorder." The results also demonstrated increased levels of cognition in people who ate baked or broiled fish.
"Working memory, which allows people to focus on tasks and commit information to short-term memory, is one of the most important cognitive domains," Dr. Raji said. "Working memory is destroyed by Alzheimer's disease. We found higher levels of working memory in people who ate baked or broiled fish on a weekly basis, even when accounting for other factors, such as education, age, gender and physical activity." Eating fried fish, on the other hand, was not shown to increase brain volume or protect against cognitive decline.
http://www.sciencedaily.com/releases/2011/11/111130095257.htm