Gut instincts: Researchers discover first clues on how gut health influences brain health
October 23, 2019
Science Daily/Weill Cornell Medicine
New cellular and molecular processes underlying communication between gut microbes and brain cells have been described for the first time by scientists at Weill Cornell Medicine and Cornell's Ithaca campus.
Over the last two decades, scientists have observed a clear link between autoimmune disorders and a variety of psychiatric conditions. For example, people with autoimmune disorders such as inflammatory bowel disease (IBD), psoriasis and multiple sclerosis may also have depleted gut microbiota and experience anxiety, depression and mood disorders. Genetic risks for autoimmune disorders and psychiatric disorders also appear to be closely related. But precisely how gut health affects brain health has been unknown.
"Our study provides new insight into the mechanisms of how the gut and brain communicate at the molecular level," said co-senior author Dr. David Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease, director of the Friedman Center for Nutrition and Inflammation and the Michael Kors Professor of Immunology at Weill Cornell Medicine. "No one yet has understood how IBD and other chronic gastrointestinal conditions influence behavior and mental health. Our study is the beginning of a new way to understand the whole picture."
For the study, published Oct. 23 in Nature, the researchers used mouse models to learn about the changes that occur in brain cells when gut microbiota are depleted. First author Dr. Coco Chu, a postdoctoral associate in the Jill Roberts Institute for Research in Inflammatory Bowel Disease, led a multidisciplinary team of investigators from several departments across Weill Cornell Medicine, Cornell's Ithaca campus, Boyce Thompson Institute, Broad Institute at MIT and Harvard, and Northwell Health with specialized expertise in behavior, advanced gene sequencing techniques and the analysis of small molecules within cells.
Mice treated with antibiotics to reduce their microbial populations, or that were bred to be germ-free, showed a significantly reduced ability to learn that a threatening danger was no longer present. To understand the molecular basis of this result, the scientists sequenced RNA in immune cells called microglia that reside in the brain and discovered that altered gene expression in these cells plays a role in remodeling how brain cells connect during learning processes. These changes were not found in microglia of healthy mice.
"Changes in gene expression in microglia could disrupt the pruning of synapses, the connections between brain cells, interfering with the normal formation of new connections that should occur through learning," said co-principal investigator Dr. Conor Liston, an associate professor of neuroscience in the Feil Family Brain & Mind Research Institute and an associate professor of psychiatry at Weill Cornell Medicine.
The team also looked into chemical changes in the brain of germ-free mice and found that concentrations of several metabolites associated with human neuropsychiatric disorders such as schizophrenia and autism were changed. "Brain chemistry essentially determines how we feel and respond to our environment, and evidence is building that chemicals derived from gut microbes play a major role," said Dr. Frank Schroeder, a professor at the Boyce Thompson Institute and in the Chemistry and Chemical Biology Department at Cornell Ithaca.
Next, the researchers tried to reverse the learning problems in the mice by restoring their gut microbiota at various ages from birth. "We were surprised that we could rescue learning deficits in germ-free mice, but only if we intervened right after birth, suggesting that gut microbiota signals are required very early in life," said Dr. Liston. "This was an interesting finding, given that many psychiatric conditions that are associated with autoimmune disease are associated with problems during early brain development."
"The gut-brain axis impacts every single human being, every day of their lives," said Dr. Artis. "We are beginning to understand more about how the gut influences diseases as diverse as autism, Parkinson's disease, post-traumatic stress disorder and depression. Our study provides a new piece of understanding of how the mechanisms operate."
"We don't know yet, but down the road, there is a potential for identifying promising targets that might be used as treatments for humans in the future," Dr. Liston said. "That's something we will need to test going forward."
https://www.sciencedaily.com/releases/2019/10/191023172106.htm
High-salt diet promotes cognitive impairment through the Alzheimer-linked protein tau
New study in Nature finds that a high-salt diet may negatively affect cognitive function in pre-clinical setting
October 23, 2019
Science Daily/Weill Cornell Medicine
Investigators sought to understand the series of events that occur between salt consumption and poor cognition and concluded that lowering salt intake and maintaining healthy blood vessels in the brain may 'stave off' dementia. Accumulation of tau deposits has been implicated in the development of Alzheimer's disease in humans.
A high-salt diet may negatively affect cognitive function by causing a deficiency of the compound nitric oxide, which is vital for maintaining vascular health in the brain, according to a new study in mice from Weill Cornell Medicine researchers. When nitric oxide levels are too low, chemical changes to the protein tau occur in the brain, contributing to dementia.
In the study, published Oct. 23 in Nature, the investigators sought to understand the series of events that occur between salt consumption and poor cognition and concluded that lowering salt intake and maintaining healthy blood vessels in the brain may "stave off" dementia. Accumulation of tau deposits has been implicated in the development of Alzheimer's disease in humans.
"Our study proposes a new mechanism by which salt mediates cognitive impairment and also provides further evidence of a link between dietary habits and cognitive function," said lead study author Dr. Giuseppe Faraco, an assistant professor of research in neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.
The new study builds upon research published last year in Nature Neuroscience by Dr. Faraco and senior author Dr. Costantino Iadecola, director of the Feil Family Brain and Mind Research Institute and the Anne Parrish Titzell Professor of Neurology at Weill Cornell Medicine.
The 2018 study found that a high-salt diet caused dementia in mice. The rodents became unable to complete daily living tasks such as building their nests and had problems passing memory tests. The research team determined that the high-salt diet was causing cells in the small intestine to release the molecule interleukin-17 (IL-17), which promotes inflammation as part of the body's immune response.
IL-17 then entered the bloodstream and prevented the cells in the walls of blood vessels feeding the brain from producing nitric oxide. This compound works by relaxing and widening the blood vessels, allowing blood to flow. Conversely, a shortage of nitric oxide can restrict blood flow.
Based on these findings, Dr. Iadecola, Dr. Faraco and their colleagues theorized that salt likely caused dementia in mice because it contributed to restricted blood flow to the brain, essentially starving it. However, as they continued their research, they realized that the restricted blood flow in mice was not severe enough to prevent the brain from functioning properly.
"We thought maybe there was something else going on here,'" Dr. Iadecola said. In their new Nature study, the investigators found that decreased nitric oxide production in blood vessels affects the stability of tau proteins in neurons. Tau provides structure for the scaffolding of neurons. This scaffolding, also called the cytoskeleton, helps to transport materials and nutrients across neurons to support their function and health.
"Tau becoming unstable and coming off the cytoskeleton causes trouble," Dr. Iadecola said, adding that tau is not supposed to be free in the cell. Once tau detaches from the cytoskeleton, the protein can accumulate in the brain, causing cognitive problems. The researchers determined that healthy levels of nitric oxide keep tau in check. "It puts the brakes on activity caused by a series of enzymes that leads to tau disease pathology," he said.
To further explore the importance of tau in dementia, the researchers gave mice with a high-salt diet and restricted blood flow to the brain an antibody to promote tau stability. Despite restricted blood flow, researchers observed normal cognition in these mice. "This demonstrated that's what's really causing the dementia was tau and not lack of blood flow," Dr. Iadecola said.
Overall, this study highlights how vascular health is important to the brain. "As we demonstrated, there's more than one way that the blood vessels keep the brain healthy," Dr. Iadecola said.
Although research on salt intake and cognition in humans is needed, the current mouse study is a reminder for people to regulate salt consumption, Dr. Iadecola said. "And the stuff that is bad for us doesn't come from a saltshaker, it comes from processed food and restaurant food," he said. "We've got to keep salt in check. It can alter the blood vessels of the brain and do so in vicious way."
https://www.sciencedaily.com/releases/2019/10/191023132201.htm
Greater understanding of Alzheimer's disease
October 23, 2019
Science Daily/University of Otago
Otago scientists have made an important discovery in understanding the role a particular protein plays to impair memory in Alzheimer's disease, which could lead to more effective treatment in future.
Professor Cliff Abraham and Dr Anurag Singh from the Department of Psychology have identified that a protein in the brain -- tumor necrosis factor-alpha (TNFα) -- normally associated with inflammation, becomes abnormally active in the Alzheimer's brain, impairing the memory mechanism.
The overproduction of this protein (TNFα) may be one of the reasons behind the disease-related impairments of memory formation in the brain.
"While TNFα has been linked previously with Alzheimer's and memory studies, it has not been understood that neural overactivity can drive the production of this protein to inhibit memory mechanisms in the brain," Professor Abraham, a Principal Investigator with the University's Brain Health Research Centre, explains.
"We are pleased with our findings that links this inflammatory protein to impaired memory mechanisms. It's one more step forward towards finding a more effective treatment for Alzheimer's than those currently available."
Research has been carried out internationally using blockers of TNFα as a therapeutic for inflammatory diseases and cancer, Professor Abraham says. However, there are only a few studies testing TNFα therapeutics in Alzheimer's conditions. Getting good penetration of therapeutics into the brain is still a problem that needs solutions, he says.
"There is a huge international effort aimed at preventing Alzheimer's disease onset, or treating it once it develops. Lifestyle changes and improved healthcare are having some impact already in delaying onset," Professor Abraham says.
"However, we still need drugs to treat those with the disease already and we hope our work adds to that body of knowledge to support further work on TNFα-based therapies which will improve the resilience of the brain to the pathological insults."
The Otago scientists have been working on this project for the past six years. Dr Singh explains the finding is significant given the protein has a role to play in regulating memory mechanisms in both healthy and diseased conditions.
"In healthy conditions, TNFα is involved in the sleep/wake cycle, normal learning and in food and water intake however, in diseased conditions it is involved in neurological disorders such as Alzheimer's and Parkinson's Disease."
https://www.sciencedaily.com/releases/2019/10/191023093439.htm
In Alzheimer's research, scientists reveal brain rhythm role
October 23, 2019
Science Daily/Picower Institute at MIT
In the years since her lab discovered that exposing Alzheimer's disease model mice to light flickering at the frequency of a key brain rhythm could stem the disorder's pathology, MIT neuroscientist Li-Huei Tsai and her team at The Picower Institute for Learning and Memory have been working to understand what the phenomenon may mean both for fighting the disease and understanding of how the brain works.
Two papers earlier this year in Cell and in Neuron replicated and substantially extended the initial findings reported in Nature in 2016 and clinical trials with human volunteers recently began. In a special lecture at the Society for Neuroscience Annual Meeting in Chicago Oct. 22, Tsai will share the latest research updates on what she's found -- and the new questions she is asking -- about using light and sound to strengthen the brain' s 40Hz "gamma" rhythm, a technique she calls "GENUS," for Gamma Entrainment Using Sensory stimuli.
"We are eager to learn as much as we can about GENUS for two main reasons," said Tsai, Picower Professor of Neuroscience in the Department of Brain and Cognitive Sciences and a founder of MIT's Aging Brain Initiative. "We hope our findings in mice will translate to helping people with Alzheimer's disease, though it's certainly too soon to tell and many things that have worked in mice have not worked in people. But there also may be exciting implications for fundamental neuroscience in understanding why stimulating a specific rhythm via light or sound can cause profound changes in multiple types of cells in the brain."
Gamma and Alzheimer's disease
In 2016, Tsai and colleagues showed that Alzheimer's disease model mice exposed to a light flickering at 40 Hz for an hour a day for a week had significantly less buildup of amyloid and tau proteins in the visual cortex, the brain region that processes sight, than experimental control mice did. Amyloid plaques and tangles of phosphorylated tau are both considered telltale hallmarks of Alzheimer's disease.
But the study raised new questions: Could GENUS prevent memory loss? Could it prevent the loss of neurons? Does it reach other areas of the brain? And could other senses be stimulated for beneficial effect?
The new studies addressed those questions. In March, the team reported that sound stimulation reduced amyloid and tau not only in the auditory cortex, but also in the hippocampus, a crucial region for learning and memory. GENUS-exposed mice also performed significantly better on memory tests than unstimulated controls. Simultaneous light and sound, meanwhile, reduced amyloid across the cortex, including the prefrontal cortex, a locus of cognition.
In May, another study reported similar advances from exposing Alzheimer's model mice to light for 3 or 6 weeks. Coordinated increases in gamma rhythm power were evident across the brains of GENUS-exposed mice. Memory improved compared to controls. More neurons survived and they maintained more circuit connections, called synapses. In her talk, Tsai will share data showing that longer-term GENUS light exposure also reduced amyloid and tau across the cortex.
Encouraged by the results, the lab has begun human trials. At SfN Tsai will present some initial data, indicating that GENUS safely increases gamma rhythm power and synchrony across the brain in healthy people.
Gamma "signatures" in the brain
Tsai's team has also been working to understand the mechanisms underlying the changes they see. The research has revealed that brain rhythms appear to exert a great deal of influence over the activity of multiple cell types in the brain.
Neuroscientists have known about rhythms for more than a century, but they have only recently begun to acknowledge that they might affect how the brain works. Gamma is associated with brain functions like sensory processing, working memory and spatial navigation, but scientists have long debated whether they are consequential or mere byproducts.
But Tsai will describe how her studies show that increasing gamma power and synchrony with sensory stimulation causes changes in neurons, brain immune cells called microglia, and the brain's vasculature. These changes may be "signatures" of gamma's significance, she says.
Increasing gamma power causes neurons to reduce processing of amyloid precursor protein and changes endosomal physiology as well, the team has found. In Alzheimer's model mice, neuronal gene expression related to synaptic function and biochemical transport within cells is reduced, but with GENUS exposure, gene expression related to those functions improves.
Microglia similarly experience major changes after GENUS exposure, all three studies have found. Gene expression becomes less inflammatory and more consistent with capturing and disposing of amyloid. Indeed, they hunt amyloid more effectively, the data show, and they secrete less of an inflammatory marker.
The March study with audio stimulation showed that amid GENUS exposure, blood vessels in the brain expand and more amyloid co-locates with a protein that draws amyloid to the vessels. The results suggest increased gamma power may help drive a mechanism for clearing amyloid out of the brain.
In several new experiments, Tsai says, the lab is continuing to study these underlying mechanistic changes. Related conference posters from her lab at the conference describe some of that work. The results of these new experiments may both help improve the possibility of translating GENUS for clinical use and further demonstrate the importance of rhythms in affecting brain function.
https://www.sciencedaily.com/releases/2019/10/191023093435.htm
Consuming alcohol leads to epigenetic changes in brain memory centers
October 23, 2019
Science Daily/University of Pennsylvania School of Medicine
New research revealed a surprising pathway that shows alcohol byproducts travel to the brain to promote addiction memory. They show how acetate travels to the brain's learning system and directly alters proteins the regulate DNA function, impacting how some genes are expressed and ultimately affecting how mice behave when given environmental cues to consume alcohol.
Triggers in everyday life such as running into a former drinking buddy, walking by a once-familiar bar, and attending social gatherings can all cause recovering alcoholics to "fall off the wagon." About 40 to 60 percent of people who have gone through treatment for substance abuse will experience some kind of relapse, according to the National Institute on Drug Abuse. But what drives the biology behind these cravings has remained largely unknown.
Now, a team led by researchers from the Perelman School of Medicine at the University of Pennsylvania, have shown, in mouse models, how acetate -- a byproduct of the alcohol breakdown produced mostly in the liver -- travels to the brain's learning system and directly alters proteins that regulate DNA function. This impacts how some genes are expressed and ultimately affects how mice behave when given environmental cues to consume alcohol. Their findings were published today in Nature.
"It was a huge surprise to us that metabolized alcohol is directly used by the body to add chemicals called acetyl groups to the proteins that package DNA, called histones," said the study's senior author Shelley Berger, PhD, the Daniel S. Och University Professor in the departments Cell and Developmental Biology and Biology, and director of the Penn Epigenetics Institute. "To our knowledge, this data provides the first empirical evidence indicating that a portion of acetate derived from alcohol metabolism directly influences epigenetic regulation in the brain."
It has been known that a major source of acetate in the body comes from the breakdown of alcohol in the liver, which leads to rapidly increased blood acetate. In this study, the team, co-led by Philipp Mews, PhD, a former graduate student in the Berger lab who is now a postdoctoral fellow at Mount Sinai, and Gabor Egervari, MD, PhD, a postdoctoral fellow in Berger's lab, sought to determine whether acetate from alcohol breakdown contributes to rapid histone acetylation in the brain. They did so by using stable-isotope labeling of alcohol to show that alcohol metabolism does, in fact, contribute to this process by directly depositing acetyl groups onto histones via an enzyme called ACSS2.
Authors said that "ACSS2, 'fuels' a whole machinery of gene regulators 'on site' in the nucleus of nerve cells to turn on key memory genes that are important for learning. In fact, Berger and colleagues published findings on ACSS2 in a 2017 Nature paper. In that paper and previous work, the researchers found that ACSS2 is needed to form spatial memories.
In the current study, to better understand how the alcohol-induced changes in gene expression ultimately effect behavior, Berger and her team employed a behavioral test. Mice were exposed to "neutral" stimuli and alcohol reward in distinct compartments, distinguished by environmental cues. After this conditioning period, the researchers measured the preference of the mice by allowing them free access to either compartment, and recording the time spent in both the neutral and alcohol-paired chamber. They found that, as expected, mice with normal ACSS2 activity spent more time in the alcohol compartment following the training period.
To test the importance of ACSS2 in this behavior, researchers reduced the protein level of ACSS2 in a brain region important for learning and memory, and observed that, with lowered ACSS2, there was no preference shown for the alcohol-paired compartment.
"This indicates to us that that alcohol-related memory formation requires ACSS2," Egervari said. "Our molecular and behavioral data, when taken together, establish ACSS2 as a possible intervention target in alcohol use disorder -- in which memory of alcohol-associated environmental cues is a primary driver of craving and relapse even after protracted periods of abstinence."
Importantly, these findings suggest that other external or peripheral sources of physiological acetate -- primarily the gut microbiome -- may similarly affect central histone acetylation and brain function, which may either control or foster other metabolic syndromes.
In addition to investigating the impact of alcohol consumption on brain changes in adults, the team also looked into the effects of consumption in pregnant mice and thus the impact of alcohol on brain cells in developing mice. In utero, alcohol causes impaired neurodevelopmental gene expression and can elicit numerous alcohol-associated postnatal disease symptoms such as small head size, low body weight, and hyperactivity. And while the number of those affected by fetal alcohol spectrum disorders (FASDs) -- which includes fetal alcohol syndrome -- is unknown, the Centers for Disease Control and Prevention suggests that the full range of FASDs in the United States and some Western European countries could be as high as one to five percent of the population.
In this arm of the study, researchers found that, upon consumption of alcohol, acetate is delivered through the placenta and into the developing fetus. The fetal brains of these mice showed that alcohol exposure on the level of "binge drinking" in the pregnant female resulted in deposition of alcohol-derived acetyl-groups onto histones in fetal brains in early neural development in the mice.
Much like the primary results of the study being useful for the potential treatment of alcohol-use disorder, these results could have implications for understanding and combating fetal alcohol syndrome.
https://www.sciencedaily.com/releases/2019/10/191023132254.htm
Dementia patients' adult kids diagnosed earlier than their parents
Unknown genetic factors may affect when symptoms arise
October 22, 2019
Science Daily/Washington University School of Medicine
A new study indicates that people with dementia -- whose parents also had dementia -- develop symptoms an average of six years earlier than their parents.
A person's chance of developing dementia is influenced by family history, variations in certain genes, and medical conditions such as cardiovascular disease and diabetes. But less is known about the factors that affect when the first symptoms of forgetfulness and confusion will arise.
A new study from Washington University School of Medicine in St. Louis reveals that people with dementia -- whose parents also had dementia -- develop symptoms an average of six years earlier than their parents. Factors such as education, blood pressure and carrying the genetic variant APOE4, which increases the risk of dementia, accounted for less than a third of the variation in the age at onset - meaning that more than two-thirds remains to be explained.
"It's important to know who is going to get dementia, but it's also important to know when symptoms will develop," said first author Gregory Day, MD, an assistant professor of neurology and an investigator at the Charles F. and Joanne Knight Alzheimer's Disease Research Center (ADRC). "If we can better understand the factors that delay or accelerate the age at onset, we eventually could get to the point where we collect this information at a doctor's visit, put it through our calculator, and determine an expected age at onset for any adult child of a person with dementia."
The study is available online in JAMA Network Open.
Alzheimer's disease is the most common cause of dementia, affecting an estimated 5.8 million people in the United States. Between 10% and 15% of the children of Alzheimer's patients go on to develop symptoms of the disease themselves.
Day and colleagues, including senior author John C. Morris, MD, the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology and head of the Knight ADRC, studied people with dementia who were participating in research studies at the Knight ADRC. They identified 164 people with dementia who had at least one parent who had been diagnosed with dementia.
Using medical records and interviews with participants and knowledgeable friends or family members, the researchers determined the age at onset of dementia for each participant and his or her parent or parents. People with one parent with dementia developed symptoms an average of 6.1 years earlier than the parent had. If both parents had dementia, the age at onset was 13 years earlier than the average of the parents' ages at diagnosis.
Changes over the past few decades in diagnostic criteria and social attitudes toward cognitive decline in later life partially explain why the study participants were diagnosed at younger ages than their parents, the researchers said. But other factors were likely at play as well.
"Nowadays there's less of a tendency to brush off confusion and forgetfulness as signs of getting older," Day said. "People who watched their parents decline with Alzheimer's disease are especially unlikely to dismiss such concerns. What's most interesting, I think, is that people with two parents with dementia developed the disease much younger than people with one parent. That suggests that it's more than just changes in diagnostic criteria or social attitudes. People with two parents with dementia may have a double dose of genetic or other risk factors that pushes them toward a younger age at onset."
As part of this study, the researchers analyzed a large set of known risk factors for Alzheimer's disease. They studied heritable factors such as ethnicity, race, genetic variants and which parent had the disease. They also looked at education, body mass index, diabetes, cardiovascular disease, blood pressure, blood cholesterol level, depression, tobacco use, excessive alcohol use, and histories of traumatic brain injury.
All of the factors together only accounted for 29% of the variability, meaning that most of what influences the age of dementia onset remains to be identified. Intriguingly, the researchers found that people who were diagnosed with Alzheimer's disease at unexpectedly younger or older ages than their parents were more likely than people diagnosed at the expected age to have certain mutations in Alzheimer's genes -- although it wasn't clear what effect these mutations have.
"These people are really interesting. We don't know why their symptoms began earlier or later than expected," Day said. "There were no other risk factors we could identify. We started this project looking for factors that we could target to give people more time before they start experiencing dementia. Although we're not yet at the point where we can modify people's genes, we can begin to explore how these genes may accelerate or slow down the onset of dementia in these individuals. By learning more about the effect of these genes on Alzheimer's disease, we may be able to develop novel treatments."
https://www.sciencedaily.com/releases/2019/10/191022174426.htm
The night gardeners: Immune cells rewire, repair brain while we sleep
October 21, 2019
Science Daily/University of Rochester Medical Center
Science tells us that a lot of good things happen in our brains while we sleep -- learning and memories are consolidated and waste is removed, among other things. New research shows for the first time that important immune cells called microglia -- which play an important role in reorganizing the connections between nerve cells, fighting infections, and repairing damage -- are also primarily active while we sleep.
The findings, which were conducted in mice and appear in the journal Nature Neuroscience, have implications for brain plasticity, diseases like autism spectrum disorders, schizophrenia, and dementia, which arise when the brain's networks are not maintained properly, and the ability of the brain to fight off infection and repair the damage following a stroke or other traumatic injury.
"It has largely been assumed that the dynamic movement of microglial processes is not sensitive to the behavioral state of the animal," said Ania Majewska, Ph.D., a professor in the University of Rochester Medical Center's (URMC) Del Monte Institute for Neuroscience and lead author of the study. "This research shows that the signals in our brain that modulate the sleep and awake state also act as a switch that turns the immune system off and on."
Microglia serve as the brain's first responders, patrolling the brain and spinal cord and springing into action to stamp out infections or gobble up debris from dead cell tissue. It is only recently that Majewska and others have shown that these cells also play an important role in plasticity, the ongoing process by which the complex networks and connections between neurons are wired and rewired during development and to support learning, memory, cognition, and motor function.
In previous studies, Majewska's lab has shown how microglia interact with synapses, the juncture where the axons of one neuron connects and communicates with its neighbors. The microglia help maintain the health and function of the synapses and prune connections between nerve cells when they are no longer necessary for brain function.
The current study points to the role of norepinephrine, a neurotransmitter that signals arousal and stress in the central nervous system. This chemical is present in low levels in the brain while we sleep, but when production ramps up it arouses our nerve cells, causing us to wake up and become alert. The study showed that norepinephrine also acts on a specific receptor, the beta2 adrenergic receptor, which is expressed at high levels in microglia. When this chemical is present in the brain, the microglia slip into a sort of hibernation.
The study, which employed an advanced imaging technology that allows researchers to observe activity in the living brain, showed that when mice were exposed to high levels of norepinephrine, the microglia became inactive and were unable to respond to local injuries and pulled back from their role in rewiring brain networks.
"This work suggests that the enhanced remodeling of neural circuits and repair of lesions during sleep may be mediated in part by the ability of microglia to dynamically interact with the brain," said Rianne Stowell, Ph.D. a postdoctoral associate at URMC and first author of the paper. "Altogether, this research also shows that microglia are exquisitely sensitive to signals that modulate brain function and that microglial dynamics and functions are modulated by the behavioral state of the animal."
The research reinforces to the important relationship between sleep and brain health and could help explain the established relationship between sleep disturbances and the onset of neurodegenerative conditions like Alzheimer's and Parkinson's.
https://www.sciencedaily.com/releases/2019/10/191021111835.htm
Fundamental insight into how memory changes with age
October 17, 2019
Science Daily/King's College London
New research from King's College London and The Open University could help explain why memory in old age is much less flexible than in young adulthood.
Through experiments in mice the researchers discovered that there were dramatic differences in how memories were stored in old age, compared to young adulthood. These differences, at the cellular level, meant that it was much harder to modify the memories made in old age.
Memories are stored in the brain by strengthening the connections between nerve cells, called synapses. Recalling a memory can alter these connections, allowing memories to be updated to adapt to a new situation. Until now researchers did not know whether this memory updating process was affected by age.
The researchers trained young adult and aged mice in a memory task, finding that the animals' age did not affect their overall ability to make new memories. However, when analysing the synapses before and after the memory task, the researchers found fundamental differences between older and younger mice.
New memories were laid down via a completely different mechanism in older animals compared to younger ones. Further, in older mice the synaptic changes linked to new memories were much harder to modify than the changes seen in younger mice.
The basic biological processes for laying down memories is shared by mammals, so it is likely that memory formation in humans follows the same processes discovered in mice.
Lead researcher Professor Karl Peter Giese, from the Institute of Psychiatry, Psychology & Neuroscience at King's, said: 'Our results give a fundamental insight into how memory processes change with age. We found that, unlike in the younger mice, memories in the older mice were not modified when recalled. This 'fixed' nature of memories formed in old age was directly linked to the alternative way the memories were laid down, which our research revealed.'
'Until now it was thought that older people should be able to form memories in just the same way as younger people, so overcoming memory problems would simply involve restoring this ability,' added Professor Giese. 'However, our results suggest this is not true, and that there is an important biological difference in how memories are stored in old age compared to young adulthood.'
The results may have implications for conditions where memory recall is a problem, such as post-traumatic stress disorder (PTSD). Professor Giese suggests that ageing should be taken into consideration when treating patients with PTSD, since confronting and modifying traumatic memories is a core feature of some psychological treatments such as trauma-focused cognitive behavioural therapy.
https://www.sciencedaily.com/releases/2019/10/191017141112.htm
Changes associated with Alzheimer's disease detectable in blood samples
October 15, 2019
Science Daily/University of Turku
Researchers have discovered new changes in blood samples associated with Alzheimer's disease. A new international study was conducted on disease-discordant Finnish twin pairs: one sibling suffering from Alzheimer's disease and the other being cognitively healthy. The researchers utilised the latest genome-wide methods to examine the twins' blood samples for any disease-related differences in epigenetic marks which are sensitive to changes in environmental factors. These differences between the siblings were discovered in multiple different genomic regions.
Development of the late-onset form of Alzheimer's disease is affected by both genetic and environmental factors including lifestyle. Different environmental factors can alter function of the genes associated with the disease by modifying their epigenetic regulation, e.g. by influencing the bond formation of methyl groups in the DNA's regulatory regions which control function of the genes.
By measuring methylation levels in the DNA isolated from the Finnish twins' blood samples, the researchers discovered epigenetic marks which were associated with Alzheimer's disease in multiple different genomic regions. One of the marks appeared stronger also in the brain samples of the patients suffering from Alzheimer's disease. The link between this mark and Alzheimer's disease was confirmed in the Swedish twin cohorts.
The researchers observed that the strength of the mark was influenced not only by the disease, but also age, gender and APOE genotype, which is known to associate with the risk of developing Alzheimer's disease. Furthermore, the mark was stronger in those twins with Alzheimer's disease who had been smoking.
The function of the gene where the mark is located is still not well understood. The gene product is suspected to inhibit activity of certain brain enzymes that edit the code translated from DNA to direct the formation of proteins. In a previous study conducted on mice, it was noticed that removing this genomic region caused learning and memory problems which are central symptoms of Alzheimer's disease.
One of the leaders of the research group, Docent at the University of Turku, Riikka Lund explains that even though the results offer new information about the molecular mechanisms of Alzheimer's disease, more research is needed on whether the discovered epigenetic marks could be utilized in diagnostics.
"The challenges of utilizing these marks include for example the variation of the DNA methylation level between individuals. More research is also needed to clarify potential impact of the marks on disease mechanisms and to identify the brain regions and cell types affected," Lund says.
https://www.sciencedaily.com/releases/2019/10/191015110647.htm
Dementia spreads via connected brain networks
October 14, 2019
Science Daily/St. Michael's Hospital
A systematic review and meta-analysis suggests outdoor activities were more clinically effective than anti-psychotic medication for treating physical aggression in patients with dementia. For patients with physical agitation, massage and touch therapy were more efficacious than usual care or caregiver support.
For patients with dementia who have symptoms of aggression and agitation, interventions such as outdoor activities, massage and touch therapy may be more effective treatments than medication in some cases, suggests a study publishing Oct. 14 in Annals of Internal Medicine.
The systematic review and meta-analysis, led by St. Michael's Hospital of Unity Health Toronto and the University of Calgary, suggest outdoor activities were more clinically effective than anti-psychotic medication for treating physical aggression in patients with dementia. For patients with physical agitation, massage and touch therapy were more efficacious than usual care or caregiver support.
"Dementia affects 50 million people worldwide and as many as three quarters of those living with the disease have reported neuropsychiatric symptoms including aggression, agitation and anxiety," said Dr. Jennifer Watt, a researcher at the Li Ka Shing Knowledge Institute of St. Michael's Hospital.
"Unfortunately, our understanding of the comparative efficacy of medication versus non-medicine interventions for treating psychiatric symptoms has been limited due to a lack of head-to-head randomized controlled trials of the two routes."
To address this gap, researchers led by Dr. Watt, who is also a geriatrician; Dr. Sharon Straus, director of the Knowledge Translation Program at St. Michael's; and Dr. Zahra Goodarzi, a geriatrician and researcher at the University of Calgary, worked with 12 dementia care partners to select study outcomes based on commonly reported neuropsychiatric symptoms of the disease. They identified reports of improvement in aggression and agitation to be the main two outcomes to focus on in the analysis and review.
The study's findings are based on an analysis of 163 randomized controlled trials involving 23,143 people with dementia and the study of pharmacologic or non-pharmacologic interventions to treat aggression and agitation.
Though the study allows for the comparison of the two types of interventions, the researchers point out that neuropsychiatric symptoms of dementia do not have a one-size-fits-all solution.
"Treatment should be tailored to the patient and their specific experience," said Dr. Straus, who is also a geriatrician at St. Michael's. "This study, however, does shed light on the opportunity to consider prioritizing different types of interventions for aggression and agitation when appropriate."
Further research, Dr. Watt said, will aim to understand the influence of individual patient characteristics on their response to interventions. The researchers also note the need for an analysis of the differences in cost between pharmacologic and non-pharmacologic interventions to treat aggression and agitation in patients with dementia.
"This study shows us that multidisciplinary care is efficacious, and that is consistent with a person-centred approach to care," Dr. Watt said. "It points to evidence of the benefit of supporting multidisciplinary teams providing care to patients in the community and nursing home settings."
https://www.sciencedaily.com/releases/2019/10/191014181650.htm