Improving blood vessel health in brain may help combat Alzheimer's

December 5, 2019

Science Daily/Massachusetts General Hospital

Researchers have found that very slow spontaneous blood vessel pulsations drive the clearance of substances from the brain, indicating that targeting and improving this process may help to prevent or treat amyloid-beta accumulation.

In patients with Alzheimer's disease, amyloid-beta protein fragments accumulate in the tissue and blood vessels of the brain, likely due to a faulty clearance mechanism. In experiments conducted in mice, investigators at Massachusetts General Hospital (MGH) have found that very slow spontaneous vessel pulsations -- also known as 'vasomotion' -- drive the clearance of substances from the brain, indicating that targeting and improving this process may help to prevent or treat amyloid-beta accumulation.

In their study published in Neuron, the researchers injected a fluorescently labeled carbohydrate called dextran into the brains of awake mice, and they conducted imaging tests to follow its clearance. Their experiments revealed that vasomotion was critical for clearing dextran from the brain and stimulating an increase of the amplitude of these vessel pulsations could increase clearance. Also, in mice with cerebral amyloid angiopathy, a condition that causes amyloid-beta to build up in the walls of the brain's blood vessels, vessel pulsations were hindered and clearance rates were reduced.

"We were able to show for the first time that large dilations and contractions of vessels that happen spontaneously at an ultra-low frequency are a major driving force to clear waste products from the brain," said lead author Susanne van Veluw, PhD, an investigator in the department of Neurology at MGH. "Our findings highlight the importance of the vasculature in the pathophysiology of Alzheimer's disease. If we direct therapeutic strategies towards promoting healthy vasculature and therefore improve clearance of amyloid-beta from the brain, we may be able to prevent or delay the onset of Alzheimer's disease in the future."

https://www.sciencedaily.com/releases/2019/12/191205073031.htm

Inflammatory processes drive progression of Alzheimer's and other brain diseases

New insights into disease mechanisms, report in Nature

November 20, 2019

Science Daily/DZNE - German Center for Neurodegenerative Diseases

Inflammation drives the progression of neurodegenerative brain diseases and plays a major role in the accumulation of tau proteins within neurons. An international research team led by the German Center for Neurodegenerative Diseases (DZNE) and the University of Bonn comes to this conclusion in the journal Nature. The findings are based on the analyses of human brain tissue and further lab studies. In the particular case of Alzheimer's the results reveal a hitherto unknown connection between Abeta and tau pathology. Furthermore, the results indicate that inflammatory processes represent a potential target for future therapies.

Tau proteins usually stabilize a neuron's skeleton. However, in Alzheimer's disease, frontotemporal dementia (FTD), and other "tauopathies" these proteins are chemically altered, they detach from the cytoskeleton and stick together. As a consequence, the cell's mechanical stability is compromised to such an extent that it dies off. In essence, "tau pathology" gives neurons the deathblow. The current study led by Prof. Michael Heneka, director of the Department of Neurodegenerative Diseases and Gerontopsychiatry at the University of Bonn and a senior researcher at the DZNE, provides new insights into why tau proteins are transformed. As it turns out, inflammatory processes triggered by the brain's immune system are a driving force.

A Molecular Switch

A particular protein complex, the "NLRP3 inflammasome," plays a central role for these processes, the researchers report in Nature. Heneka and colleagues already studied this macromolecule, which is located inside the brain's immune cells, in previous studies. It is a molecular switch that can trigger the release of inflammatory substances. For the current study, the researchers examined tissue samples from the brains of deceased FTD patients, cultured brain cells, and mice that exhibited hallmarks of Alzheimer's and FTD.

"Our results indicate that the inflammasome and the inflammatory reactions it triggers, play an important role in the emergence of tau pathology," Heneka said. In particular, the researchers discovered that the inflammasome influences enzymes that induce a "hyperphosphorylation" of tau proteins. This chemical change ultimately causes them to separate from the scaffold of neurons and clump together. "It appears that inflammatory processes mediated by the inflammasome are of central importance for most, if not all, neurodegenerative diseases with tau pathology."

A Link between Abeta and Tau

This especially applies to Alzheimer's disease. Here another molecule comes into play: "amyloid beta" (Abeta). In Alzheimer's, this protein also accumulates in the brain. In contrast to tau proteins, this does not happen within the neurons but between them. In addition, deposition of Abeta starts in early phases of the disease, while aggregation of tau proteins occurs later.

In previous studies, Heneka and colleagues were able to show that the inflammasome can promote the aggregation of Abeta. Here is where the connection to the recent findings comes in. "Our results support the amyloid cascade hypothesis for the development of Alzheimer's. According to this hypothesis, deposits of Abeta ultimately lead to the development of tau pathology and thus to cell death," said Heneka. "Our current study shows that the inflammasome is the decisive and hitherto missing link in this chain of events, because it bridges the development from Abeta pathology to tau pathology. It passes the baton, so to speak." Thus, deposits of Abeta activate the inflammasome. As a result, formation of further deposits of Abeta is promoted. On the other hand, chemical changes occur to the tau proteins resulting into their aggregation.

A Possible Starting Point for Therapies

"Inflammatory processes promote the development of Abeta pathology, and as we have now been able to show, of tau pathology as well. Thus, the inflammasome plays a key role in Alzheimer's and other brain diseases," said Heneka, who is involved in the Bonn-based "ImmunoSensation" cluster of excellence and who also teaches at the University of Massachusetts Medical School. With these findings, the neuroscientist sees opportunities for new treatment methods. "The idea of influencing tau pathology is obvious. Future drugs could tackle exactly this aspect by modulating the immune response. With the development of tau pathology, mental abilities decline more and more. Therefore, if tau pathology could be contained, this would be an important step towards a better therapy."

https://www.sciencedaily.com/releases/2019/11/191120131318.htm

Are we 'brainwashed' during sleep?

Cerebrospinal fluid washes in and out of brain during sleep

October 31, 2019

Science Daily/Boston University

New research from Boston University suggests that tonight while you sleep, something amazing will happen within your brain. Your neurons will go quiet. A few seconds later, blood will flow out of your head. Then, a watery liquid called cerebrospinal fluid (CSF) will flow in, washing through your brain in rhythmic, pulsing waves.

The study, published on October 31 in Science, is the first to illustrate that the brain's CSF pulses during sleep, and that these motions are closely tied with brain wave activity and blood flow.

"We've known for a while that there are these electrical waves of activity in the neurons," says study coauthor Laura Lewis, a BU College of Engineering assistant professor of biomedical engineering and a Center for Systems Neuroscience faculty member. "But before now, we didn't realize that there are actually waves in the CSF, too."

This research may also be the first-ever study to take images of CSF during sleep. And Lewis hopes that it will one day lead to insights about a variety of neurological and psychological disorders that are frequently associated with disrupted sleep patterns, including autism and Alzheimer's disease.

The coupling of brain waves with the flow of blood and CSF could provide insights about normal age-related impairments as well. Earlier studies have suggested that CSF flow and slow-wave activity both help flush toxic, memory-impairing proteins from the brain. As people age, their brains often generate fewer slow waves. In turn, this could affect the blood flow in the brain and reduce the pulsing of CSF during sleep, leading to a buildup of toxic proteins and a decline in memory abilities. Although researchers have tended to evaluate these processes separately, it now appears that they are very closely linked.

To further explore how aging might affect sleep's flow of blood and CSF in the brain, Lewis and her team plan to recruit older adults for their next study, as the 13 subjects in the current study were all between the ages of 23 and 33. Lewis says they also hope to come up with a more sleep-conducive method of imaging CSF. Wearing EEG caps to measure their brain waves, these initial 13 subjects were tasked with dozing off inside an extremely noisy MRI machine, which, as anyone who has had an MRI can imagine, is no easy feat.

"We have so many people who are really excited to participate because they want to get paid to sleep," Lewis says with a laugh. "But it turns out that their job is actually -- secretly -- almost the hardest part of our study. We have all this fancy equipment and complicated technologies, and often a big problem is that people can't fall asleep because they're in a really loud metal tube, and it's just a weird environment."

But for now, she is glad to have the opportunity to take images of CSF at all. One of the most fascinating yields of this research, Lewis says, is that they can tell if a person is sleeping simply by examining a little bit of CSF on a brain scan.

"It's such a dramatic effect," she says. "[CSF pulsing during sleep] was something we didn't know happened at all, and now we can just glance at one brain region and immediately have a readout of the brain state someone's in."

As their research continues to move forward, Lewis' team has another puzzle they want to solve: How exactly are our brain waves, blood flow, and CSF coordinating so perfectly with one another? "We do see that the neural change always seems to happen first, and then it's followed by a flow of blood out of the head, and then a wave of CSF into the head," says Lewis.

One explanation may be that when the neurons shut off, they don't require as much oxygen, so blood leaves the area. As the blood leaves, pressure in the brain drops, and CSF quickly flows in to maintain pressure at a safe level.

"But that's just one possibility," Lewis says. "What are the causal links? Is one of these processes causing the others? Or is there some hidden force that is driving all of them?"

https://www.sciencedaily.com/releases/2019/10/191031174650.htm

High-intensity exercise improves memory in seniors

October 31, 2019

Science Daily/McMaster University

Researchers at McMaster University who examine the impact of exercise on the brain have found that high-intensity workouts improve memory in older adults.

The study, published in the journal Applied Physiology, Nutrition and Metabolism, has widespread implications for treating dementia, a catastrophic disease that affects approximately half a million Canadians and is expected to rise dramatically over the next decade.

Researchers suggest that intensity is critical. Seniors who exercised using short, bursts of activity saw an improvement of up to 30% in memory performance while participants who worked out moderately saw no improvement, on average.

"There is urgent need for interventions that reduce dementia risk in healthy older adults. Only recently have we begun to appreciate the role that lifestyle plays, and the greatest modifying risk factor of all is physical activity," says Jennifer Heisz, an associate professor in the Department of Kinesiology at McMaster University and lead author of the study.

"This work will help to inform the public on exercise prescriptions for brain health so they know exactly what types of exercises boost memory and keep dementia at bay," she says.

For the study, researchers recruited dozens of sedentary but otherwise healthy older adults between the ages of 60 and 88 who were monitored over a 12-week period and participated in three sessions per week. Some performed high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) while a separate control group engaged in stretching only.

The HIIT protocol included four sets of high-intensity exercise on a treadmill for four minutes, followed by a recovery period. The MICT protocol included one set of moderate-intensity aerobic exercise for nearly 50 minutes.

To capture exercise-related improvements in memory, researchers used a specific test that taps into the function of the newborn neurons generated by exercise which are more active than mature ones and are ideal for forming new connections and creating new memories.

They found older adults in the HIIT group had a substantial increase in high-interference memory compared to the MICT or control groups. This form of memory allows us to distinguish one car from another of the same make or model, for example.

Researchers also found that improvements in fitness levels directly correlated with improvement in memory performance.

"It's never too late to get the brain health benefits of being physically active, but if you are starting late and want to see results fast, our research suggests you may need to increase the intensity of your exercise," says Heisz.

She cautions that it is important to tailor exercise to current fitness levels, but adding intensity can be as simple as adding hills to a daily walk or increasing pace between street lamps.

"Exercise is a promising intervention for delaying the onset of dementia. However, guidelines for effective prevention do not exist. Our hope is this research will help form those guidelines."

https://www.sciencedaily.com/releases/2019/10/191031112522.htm

How will your thinking and memory change with age?

October 30, 2019

Science Daily/American Academy of Neurology

How well eight-year-olds score on a test of thinking skills may be a predictor of how they will perform on tests of thinking and memory skills when they are 70 years old, according to a study published in the October 30, 2019, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study also found that education level and socioeconomic status were also predictors of thinking and memory performance. Socioeconomic status was determined by people's occupation at age 53.

"Finding these predictors is important because if we can understand what influences an individual's cognitive performance in later life, we can determine which aspects might be modifiable by education or lifestyle changes like exercise, diet or sleep, which may in turn slow the development of cognitive decline," said study author Jonathan M. Schott, MD, FRCP, of University College London in the United Kingdom and a member of the American Academy of Neurology.

The study involved 502 people all born during the same week in 1946 in Great Britain who took cognitive tests when they were eight years old. Between the ages of 69 and 71, participants took thinking and memory tests again. One test, similar to a test they completed as children, involved looking at various arrangements of geometric shapes and identifying the missing piece from five options. Other tests evaluated skills like memory, attention, orientation and language.

Participants had positron emission tomography (PET) scans to see if they had amyloid-beta plaques in the brain associated with Alzheimer's disease. They also had detailed brain magnetic resonance imaging scans (MRI).

Researchers found that childhood thinking skills were associated with scores on the cognitive tests taken more than 60 years later. For example, someone whose cognitive performance was in the top 25 percent as a child, was likely to remain in the top 25 percent at age 70. Even accounting for differences in childhood test scores, there was an additional effect of education. For example, participants who completed a college degree scored around 16 percent higher than participants who left school before the age of 16. Having a higher socioeconomic status also predicted slightly better cognitive performance at age 70, but the effect was very small. For example, those who had worked in professional jobs tended to recall an average of 12 details from a short story, compared to 11 details for those who had worked in manual jobs. Women performed better than men in test of memory and thinking speed.

In addition, researchers found that participants with amyloid-beta plaques had lower scores on cognitive testing. For example, on the missing pieces test, they scored 8 percent lower on average. In other words, they got 23 out of 32 items correct on average -- 2 points lower than participants without amyloid-beta plaques. However the presence of these plaques was not associated with sex, childhood cognitive skills, education or socioeconomic status.

"Our study found that small differences in thinking and memory associated with amyloid plaques in the brain are detectible in older adults even at an age when those who are destined to develop dementia are still likely to be many years away from having symptoms," said Schott. "It also found that childhood cognitive skills, education and socioeconomic status all independently influence cognitive performance at age 70. Continued follow-up of these individuals, and future studies are needed to determine how to best use these findings to more accurately predict how a person's thinking and memory will change as they age."

A limitation of the study is that all participants were white, so the results may not represent the general population.

The study was supported by Alzheimer's Research UK, the Medical Research Council Dementia Platform UK and the Wolfson Foundation. Brain Research UK funded the genetic analyses. AVID Radiopharmaceuticals provided florbetapir amyloid tracer for the PET scans, but had no part in the design of the study.

https://www.sciencedaily.com/releases/2019/10/191030170554.htm

Living in a noisy area increases the risk of suffering a more serious stroke

The work analysed data from nearly 3,000 patients treated at Hospital del Mar

October 29, 2019

Science Daily/IMIM (Hospital del Mar Medical Research Institute)

The high levels of environmental noise we are subjected to in large cities can increase both the severity and consequences of an ischaemic stroke. More precisely, researchers from the Hospital del Mar Medical Research Institute (IMIM) and doctors from Hospital del Mar, together with researchers from the Barcelona Institute for Global Health (ISGlobal), CIBER in Epidemiology and Public Health (CIBERESP), and Brown University, in the United States, put the increased risk at 30% for people living in noisier areas. In contrast, living close to green areas brings down this risk by up to 25%. This is the first time that these factors have been analysed in relation to stroke severity. The study has been published in the journal Environmental Research.

The researchers looked at the influence of noise levels, air pollution (particularly suspended particles smaller than 2.5 microns; PM2.5), and exposure to green areas on nearly 3,000 ischaemic stroke patients treated at Hospital del Mar between 2005 and 2014. To do this, they used data from the Cartographic Institute of Catalonia, as well as models to analyse atmospheric pollutant levels, the noise map of Barcelona, and satellite images to define areas with vegetation. Also taken into account was the socioeconomic level of the place the patients lived.

Dr. Rosa María Vivanco, from the IMIM's Neurovascular Research Group and first author of the study, points out that the study gives us initial insight into how noise levels and exposure to green spaces influences the severity of ischaemic stroke. "We have observed a gradient: the more green spaces, the less serious the stroke. And the more noise, the more serious it is. This suggests that factors other than those traditionally associated with stroke may play an independent role in the condition," she explains. At the same time, Dr. Xavier Basagaña, one of the authors of the study and a researcher at ISGlobal, a centre supported by "la Caixa," stresses that "exposure to green spaces can benefit human health through various mechanisms. For example, it can reduce stress, encourage social interaction, and increase levels of physical activity." However, in this study no link was seen with atmospheric pollution. The researchers warn that one of the limitations of the work was the lack of variability in pollutant concentrations to which the study population is exposed. This made it difficult to draw conclusions, and they point out that more studies are needed in this field.

More noise, greater stroke severity

"Previous studies have demonstrated that living in places with high levels of air pollution or noise, or with fewer green areas, exposes the population to a higher risk of suffering an ischaemic stroke. This work broadens our knowledge in this field, showing that the place where we live affects not only the risk of suffering a stroke, but also its severity if it occurs," explains Dr Gregory A. Wellenius, from the Epidemiology Department at Brown University and final author of the study. In this sense, the results indicate that patients living in noisier areas presented more severe strokes on arrival at hospital.

The researchers have analysed the effects of stroke on neurological deficits, such as speech impairment and mobility, using the NIHSS (National Institute of Health Stroke Scale). "The severity of a stroke depends on various factors, including the extent of the brain injury, the specific area of brain affected, the subtype of stroke, the existence of associated risk factors (diabetes, atrial fibrillation, atherosclerotic load), and so on. The fact that we have demonstrated, in addition to all these factors, that environmental aspects like green spaces and urban noise levels affect the severity of a stroke and therefore our health, shows that this information must be taken into account by political and health planners," emphasises Dr. Jaume Roquer, head of the Neurology Service at Hospital del Mar, coordinator of the IMIM's Neurovascular Research Group, and one of the main authors of the work.

The researchers did not aim to determine which noise levels lead to increased risk, but rather to detect a gradient by comparing patients living in noisier areas with those living in quieter areas. Indeed, the World Health Organisation (WHO) recommends traffic noise limits of a maximum of 53 decibels during the day and 45 decibels at night. "The average noise level to which patients have been exposed, as well as the general population of the study area, requires reflection, as it is considerably above the WHO recommendations," points out Carla Avellaneda, an IMIM researcher and author of the work. The same researchers have already revealed that high levels of air pollution from diesel engines increase the risk of suffering atherothrombotic stroke by 20%.

Stroke

In Spain, stroke is the leading cause of death in women and the third ranked in men, and is estimated to affect 1 in 6 people throughout their lives (in 2012, it caused the death of 6.7 million people around the world, according to WHO data). In Catalonia there are 13,000 cases and 3,800 deaths from stroke each year. The two main types of stroke are haemorrhagic and ischaemic.

Ischaemic stroke is due to the obstruction of a blood vessel in the brain and accounts for 80-85% of all cases. This lack of blood flow in the affected area of the brain can lead to permanent damage. The risk of having a stroke is closely related to factors including age, smoking, high blood pressure, diabetes, obesity, a sedentary lifestyle and, as recently demonstrated, other factors like air pollution.

https://www.sciencedaily.com/releases/2019/10/191029103311.htm

Projected doubling of Americans living with dementia

Women are at much greater risk and shoulder the majority of costs

October 29, 2019

Science Daily/Milken Institute

The number of Americans living with Alzheimer's disease or other dementias will double to nearly 13 million over the next 20 years, according to the new Milken Institute report "Reducing the Cost and Risk of Dementia: Recommendations to Improve Brain Health and Decrease Disparities."

Milken Institute research estimates that by 2020, roughly 4.7 million women in the US will have dementia, accounting for nearly two-thirds of all people living with the condition.

The number of both women and men living with dementia is projected to nearly double by 2040, with the number of women projected to rise to 8.5 million, and the number of men expected to reach 4.5 million (up from 2.6 million in 2020), according to the report, which was released at the 2019 Milken Institute Future of Health Summit in Washington, D.C.

Over the next 20 years, the economic burden of dementia will exceed $2 trillion, with women shouldering more than 80 percent of the cumulative costs.

"Longer lifespans are perhaps one of the greatest success stories of our modern public health system," explains Nora Super, lead author of the report and senior director of the Milken Institute Center for the Future of Aging. "But along with this success comes one of our greatest challenges. Our risk of developing dementia doubles every five years after we turn 65; by age 85, nearly one in three of us will have the disease."

"With no cure in sight, we must double down on efforts to reduce the cost and risk of dementia," she added. "Emerging evidence shows that despite family history and personal genetics, lifestyle changes such as diet, exercise, and better sleep can improve health at all ages."

In collaboration with partners such as UsAgainstAlzheimer's, AARP and Bank of America, Super and her co-authors, Rajiv Ahuja and Kevin Proff, have developed detailed recommendations and goals for policymakers, businesses, and communities to improve brain health, reduce disparities, and ultimately change the trajectory of this devastating disease.

1) Promote strategies to maintain and improve brain health for all ages, genders, and across diverse populations

 2) Increase access to cognitive testing and early diagnosis

 3) Increase opportunities for diverse participation in research and prioritize funding to address health disparities

 4) Build a dementia-capable workforce across the care continuum

 5) Establish services and policies that promote supportive communities and workplaces for people with dementia and their caregivers

"As this important new report shows, dementia is one of the greatest public health challenges of our time," said Sarah Lenz Lock, SVP, Policy & Brain Health at AARP. "It also demonstrates that we have the power to create change, whether by helping consumers maintain and improve their brain health, advancing research on the causes and treatment of dementia, or supporting caregivers who bear so much of the burden of this disease. We at AARP look forward to working with the Milken Institute and other key partners to achieve these goals."

"Brain health broadens the fight against Alzheimer's to include everyone and is the key to defeating stigma, increasing early detection, speeding up research -- and ending this disease," said Jill Lesser, a founding board member of UsAgainstAlzheimer's. "This new look by the Milken Institute offers important recommendations and actions to help move us to an optimal system of brain health care in this country."

Among the breakthrough findings, new data have "unveiled key discoveries about the differences between men's and women's brains, and how they age. Moreover, women typically take on greater caregiver responsibilities than men. Women caregivers are more likely to be impacted financially and leave their jobs or miss work to care for a family member. And research demonstrates that spousal caregivers may be at a higher risk of cognitive impairment or dementia than non-caregivers."

"With this research, the Milken Institute has taken an important step to better understand the impacts of dementia on diverse populations," said Lorna Sabbia, Head of Retirement and Personal Wealth Solutions, Bank of America. "This study, together with our own research on life stages, women, health and wellness, plays a critically important role in our efforts to educate and provide guidance to individuals and families throughout their financial lives."

https://www.sciencedaily.com/releases/2019/10/191029084315.htm

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

No link found between youth contact sports and cognitive, mental health problems

October 21, 2019

Science Daily/University of Colorado at Boulder

Adolescents who play contact sports, including football, are no more likely to experience cognitive impairment, depression or suicidal thoughts in early adulthood than their peers, suggests a new University of Colorado Boulder study of nearly 11,000 youth followed for 14 years.

The study, published this month in the Orthopaedic Journal of Sports Medicine, also found that those who play sports are less likely to suffer from mental health issues by their late 20s to early 30s.

"There is a common perception that there's a direct causal link between youth contact sports, head injuries and downstream adverse effects like impaired cognitive ability and mental health," said lead author Adam Bohr, PhD, a postdoctoral researcher in the Department of Integrative Physiology. "We did not find that."

The study comes on the heels of several highly-publicized papers linking sport-related concussion among former professional football players to chronic traumatic encephalopathy (CTE), cognitive decline and mental health issues later in life. Such reports have led many to question the safety of youth tackle football, and participation is declining nationally.

But few studies have looked specifically at adolescent participation in contact sports.

"When people talk about NFL players, they are talking about an elite subset of the population," said senior author Matthew McQueen, an associate professor of integrative physiology. "We wanted to look specifically at kids and determine if there are true harms that are showing up early in adulthood."

The study analyzed data from 10,951 participants in the National Longitudinal Study of Adolescent to Adult Health (Add Health), a representative sample of youth in seventh through 12th grades who have been interviewed and tested repeatedly since 1994.

Participants were categorized into groups: those who, in 1994, said they intended to participate in contact sports; those who intended to play non-contact sports; and those who did not intend to play sports. Among males, 26% said they intended to play football.

After controlling for socioeconomic status, education, race and other factors, the researchers analyzed scores through 2008 on word and number recall and questionnaires asking whether participants had been diagnosed with depression or attempted or thought about suicide.

"We were unable to find any meaningful difference between individuals who participated in contact sports and those who participated in non-contact sports. Across the board, across all measures, they looked more or less the same later in life," said Bohr.

Football players -- for reasons that are not clear -- actually had a lower incidence of depression in early adulthood than other groups.

Those who reported they did not intend to participate in sports at age 8 to 14 were 22% more likely to suffer depression in their late 20s and 30s.

"Right now, football is in many ways being compared to cigarette smoking -- no benefit and all harm," said McQueen, who is also director for the Pac-12 Concussion Coordinating Unit. "It is absolutely true that there is a subset of NFL players who have experienced horrible neurological decline, and we need to continue to research to improve our understanding of that important issue."

But, he said, "the idea that playing football in high school will lead to similar outcomes later in life as those who played in the NFL is not consistent with the evidence. In fact, we and others have found there is some benefit to playing youth sports."

A recent University of Pennsylvania study of 3,000 men who had graduated high school in Wisconsin in 1957 found that those who played football were no more likely to suffer depression or cognitive impairment later. But some pointed out that the sport had changed radically since the 1950s.

The new study is among the largest to date and looks at those who played football in the 1990s.

The authors note that, due to the design of the dataset, they were only able to measure "intended" participation. (Due to the timing of the questionnaires, however, it is likely that those who reported participation in football actually did participate.)

They also could not tell how long an adolescent played, what position or whether a concussion or sub-concussive head injury was ever sustained. Further studies should be done exploring those factors, they said.

"Few current public health issues are as contentious and controversial as the safety and consequences of participation in football," they concluded. "Research on the risks of participation weighed with the risks of not participating in sports will enable parents and young athletes to make educated, informed decisions based on solid evidence."

A new CU Boulder study, looking at the long-term mental and physical health of CU student-athlete alumni, is already underway.

https://www.sciencedaily.com/releases/2019/10/191021082749.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

Dementia spreads via connected brain networks

Brain maps allow individualized predictions of frontotemporal dementia progression

October 14, 2019

Science Daily/University of California - San Francisco

Scientists used maps of brain connections to predict how brain atrophy would spread in individual patients with frontotemporal dementia (FTD), adding to growing evidence that the loss of brain cells associated with dementia spreads via the synaptic connections between established brain networks.

In a new study, UC San Francisco scientists used maps of brain connections to predict how brain atrophy would spread in individual patients with frontotemporal dementia (FTD), adding to growing evidence that the loss of brain cells associated with dementia spreads via the synaptic connections between established brain networks. The results advance scientists' knowledge of how neurodegeneration spreads and could lead to new clinical tools to evaluate how well novel treatments slow or block the predicted trajectory of these diseases.

"Knowing how dementia spreads opens a window onto the biological mechanisms of the disease -- what parts of our cells or neural circuits are most vulnerable," said study lead author Jesse Brown, PhD, an assistant professor of neurology at the UCSF Memory and Aging Center and UCSF Weill Institute for Neurosciences. "You can't really design a treatment until you know what you're treating."

FTD, the most common form of dementia in people under the age of 60, comprises a group of neurodegenerative conditions with diverse linguistic and behavioral symptoms. As in Alzheimer's disease, the diversity of FTD symptoms reflects significant differences in how the neurodegenerative disease spreads through patients' brains. This variability makes it difficult for scientists searching for cures to pin down the biological drivers of brain atrophy and for clinical trials to evaluate whether a novel treatment is making a difference in the progression of a patient's disease.

Previous research by the study's senior author, William Seeley, MD, a professor of neurology and pathology at the Memory and Aging Center and Weill Institute, set off a sea change in dementia research by showing that patterns of brain atrophy in many forms of dementia map closely onto well-known brain networks -- groups of functionally related brain regions that work cooperatively via their synaptic connections, sometimes over long distances. In other words, Seeley's work proposed that neurodegenerative diseases don't spread evenly in all directions like a tumor, but can jump from one part of the brain to another along the anatomical circuits that wire these networks together.

In their new study -- published October 14 in Neuron -- Brown, Seeley and colleagues provided further evidence supporting this idea by examining how well neural network maps based on brain scans in healthy individuals could predict the spread of brain atrophy in FTD patients over the course of a year.

The researchers recruited 42 patients at the UCSF Memory and Aging Center with behavioral variant fronto-temporal dementia (bvFTD), a form of FTD that causes patients to exhibit inappropriate social behaviors, and 30 patients with semantic variant primary progressive aphasia (svPPA), a form of FTD that mainly impacts patients' language abilities. In their first visits to UCSF, each of these patients underwent a "baseline" MRI scan to assess the extent of existing brain degeneration and then had a follow-up scan about a year later to measure how their disease had progressed.

The researchers first estimated where the brain atrophy seen in each patient's baseline scans had begun, based on the hypothesis that brain degeneration begins in some particularly vulnerable location, then spreads out to anatomically connected brain regions. To do this, the researchers built standardized maps of the main functional partners of 175 different brain regions based on functional MRI (fMRI) scans of 75 healthy adults. They then identified which of these networks best matched the pattern of brain atrophy seen in a given FTD patient's baseline brain scans, and defined that network's central hub as the likely epicenter of the patient's degeneration.

They then used the same standardized connectivity maps to predict where the patient's brain atrophy was most likely to have spread in the follow-up scans done one year later, and compared the accuracy of these predictions to others that didn't take functional network connectivity into account.

They found that two particular connectivity measures significantly improved their predictions of a given brain region's chances of developing brain atrophy between the baseline and follow-up brain scans. One, called "shortest path to the epicenter," captured the number of synaptic "steps" that region was from the estimated disease epicenter -- essentially the number of links in the neural chain connecting the two areas -- while the other, called "nodal hazard," represented how many regions connected to a given region were already experiencing significant atrophy.

"It's like with an infectious disease, where your chances of becoming infected can be predicted by how many degrees of separation you have from 'Patient Zero' but also by how many people in your immediate social network are already sick," Brown said.

The researchers showed that on average these two measures of network connectivity did better at predicting the spread of disease to a new brain region than its simple straight-line distance from a patient's existing atrophy. In many cases the disease completely bypassed brain areas that were adjacent but not anatomically connected to already-atrophied regions, instead jumping to more functionally linked regions.

Although this method shows great promise, the researchers emphasize that it is not yet ready for clinical use. They hope to improve the accuracy of their predictions by -- among other approaches -- using individualized network maps for each patient rather than using average connectivity maps, and by developing more specialized prediction models for particular subtypes of FTD.

In addition to the biological insights the discovery provides about the mechanisms of spreading brain atrophy in FTD, which will inform ongoing efforts to develop treatments, the researchers also hope the findings will lead to improved metrics for evaluating therapies already entering clinical trials -- for instance by giving trial scientists early insights into whether the treatment is altering a predicted course of disease progression. Researchers could also use better predictions of how atrophy will spread through the brain to help prepare patients and their families for the symptoms they are likely to experience as their disease progresses.

"We are excited about this result because it represents an important first step toward a more precision medicine type of approach to predicting progression and measuring treatment effects in neurodegenerative disease," Seeley said.

In the future, Brown said, scientists might be able to develop therapies that specifically target the likely next site of disease and perhaps prevent atrophy from spreading from one region to another.

"Just like epidemiologists rely on models of how infectious diseases spread to develop interventions targeted to key hubs or choke points," Brown said. "Neurologists need to understand the underlying biological mechanisms of neurodegeneration to develop ways of slowing or halting the spread of the disease."

https://www.sciencedaily.com/releases/2019/10/191014111730.htm

Slower walkers have older brains and bodies at 45

Slower walkers could have been identified by brain function at age 3

October 11, 2019

Science Daily/Duke University

The walking speed of 45-year-olds, particularly their fastest walking speed without running, can be used as a marker of their aging brains and bodies.

Slower walkers were shown to have "accelerated aging" on a 19-measure scale devised by researchers, and their lungs, teeth and immune systems tended to be in worse shape than the people who walked faster.

"The thing that's really striking is that this is in 45-year-old people, not the geriatric patients who are usually assessed with such measures," said lead researcher Line J.H. Rasmussen, a post-doctoral researcher in the Duke University department of psychology & neuroscience.

Equally striking, neurocognitive testing that these individuals took as children could predict who would become the slower walkers. At age 3, their scores on IQ, understanding language, frustration tolerance, motor skills and emotional control predicted their walking speed at age 45.

"Doctors know that slow walkers in their seventies and eighties tend to die sooner than fast walkers their same age," said senior author Terrie E. Moffitt, the Nannerl O. Keohane University Professor of Psychology at Duke University, and Professor of Social Development at King's College London. "But this study covered the period from the preschool years to midlife, and found that a slow walk is a problem sign decades before old age."

The data come from a long-term study of nearly 1,000 people who were born during a single year in Dunedin, New Zealand. The 904 research participants in the current study have been tested, quizzed and measured their entire lives, mostly recently from April 2017 to April 2019 at age 45.

The study appears Oct. 11 in JAMA Network Open.

MRI exams during their last assessment showed the slower walkers tended to have lower total brain volume, lower mean cortical thickness, less brain surface area and higher incidence of white matter "hyperintensities," small lesions associated with small vessel disease of the brain. In short, their brains appeared somewhat older.

Adding insult to injury perhaps, the slower walkers also looked older to a panel of eight screeners who assessed each participant's 'facial age' from a photograph.

Gait speed has long been used as a measure of health and aging in geriatric patients, but what's new in this study is the relative youth of these study subjects and the ability to see how walking speed matches up with health measures the study has collected during their lives.

"It's a shame we don't have gait speed and brain imaging for them as children," Rasmussen said. (The MRI was invented when they were five, but was not given to children for many years after.)

Some of the differences in health and cognition may be tied to lifestyle choices these individuals have made. But the study also suggests that there are already signs in early life of who would become the slowest walkers, Rasmussen said. "We may have a chance here to see who's going to do better health-wise in later life."

https://www.sciencedaily.com/releases/2019/10/191011112250.htm