Mushrooms magnify memory by boosting nerve growth

February 10, 2023

Science Daily/University of Queensland

Researchers from The University of Queensland have discovered the active compound from an edible mushroom that boosts nerve growth and enhances memory.

Professor Frederic Meunier from the Queensland Brain Institute said the team had identified new active compounds from the mushroom, Hericium erinaceus.

Researchers have discovered lion's mane mushrooms improve brain cell growth and memory in pre-clinical trials. 

"Extracts from these so-called 'lion's mane' mushrooms have been used in traditional medicine in Asian countries for centuries, but we wanted to scientifically determine their potential effect on brain cells," Professor Meunier said.

"Pre-clinical testing found the lion's mane mushroom had a significant impact on the growth of brain cells and improving memory.

"Laboratory tests measured the neurotrophic effects of compounds isolated from Hericium erinaceus on cultured brain cells, and surprisingly we found that the active compounds promote neuron projections, extending and connecting to other neurons.

"Using super-resolution microscopy, we found the mushroom extract and its active components largely increase the size of growth cones, which are particularly important for brain cells to sense their environment and establish new connections with other neurons in the brain."

Co-author, UQ's Dr Ramon Martinez-Marmol said the discovery had applications that could treat and protect against neurodegenerative cognitive disorders such as Alzheimer's disease.

"Our idea was to identify bioactive compounds from natural sources that could reach the brain and regulate the growth of neurons, resulting in improved memory formation," Dr Martinez-Marmol said.

Dr Dae Hee Lee from CNGBio Co, which has supported and collaborated on the research project, said the properties of lion's mane mushrooms had been used to treat ailments and maintain health in traditional Chinese medicine since antiquity.

"This important research is unravelling the molecular mechanism of lion's mane mushroom compounds and their effects on brain function, particularly memory," Dr Lee said.

https://www.sciencedaily.com/releases/2023/02/230210115544.htm

Learning with all your senses: Multimodal enrichment as the optimal learning strategy of the future

February 1, 2023

Science Daily/Technische Universität Dresden

Many educational approaches assume that integrating complementary sensory and motor information into the learning experience can enhance learning, for example gestures help in learning new vocabulary in foreign language classes. In her recent publication, neuroscientist Katharina von Kriegstein from Technische Universität Dresden and Brian Mathias of the University of Aberdeen summarize these methods under the term "multimodal enrichment." This means enrichment with multiple senses and movement. Numerous current scientific studies prove that multimodal enrichment can enhance learning outcomes. Experiments in classrooms show similar results.

In the review article, the two researchers compare these findings with cognitive, neuroscience, and computational theories of multimodal enrichment. Recent neuroscience research has found that the positive effects of enriched learning are associated with response in brain regions that serve perception and motor function. For example, hearing a recently learned foreign language word, may elicit activity in motor brain regions if the word was associated with the performance of a congruent gesture during learning. These brain responses are causal to the benefits of multimodal enrichment for learning outcome. Computer algorithms confirm this hypothesis.

"The brain is optimized for learning with all the senses and with movement. Brain structures for perception and motor skills work together to promote this type of learning. We hope that our deeper understanding of the brain's learning mechanisms, will facilitate the development of optimal learning strategies in the future," explains Brian Mathias.

Katharina von Kriegstein adds, "The results of the literature we reviewed contribute to our understanding of why several long-used learning strategies, such as parts of the Montessori method, are effective. They also provide clear clues as to why some approaches are not as effective. Recently uncovered neuroscientific mechanisms may inspire the updating of cognitive and computational theories of learning, providing new hypotheses about learning. We anticipate that such an interdisciplinary and evidence-based approach will lead to the optimization of learning and teaching strategies in the future, for both humans and artificial systems."

https://www.sciencedaily.com/releases/2023/02/230201134225.htm

Tuning into brainwave rhythms speeds up learning in adults

January 31, 2023

Science Daily/University of Cambridge

Scientists have shown for the first time that briefly tuning into a person's individual brainwave cycle before they perform a learning task dramatically boosts the speed at which cognitive skills improve.

Calibrating rates of information delivery to match the natural tempo of our brains increases our capacity to absorb and adapt to new information, according to the team behind the study.

University of Cambridge researchers say that these techniques could help us retain "neuroplasticity" much later in life and advance lifelong learning.

"Each brain has its own natural rhythm, generated by the oscillation of neurons working together," said Prof Zoe Kourtzi, senior author of the study from Cambridge's Department of Psychology. "We simulated these fluctuations so the brain is in tune with itself -- and in the best state to flourish."

"Our brain's plasticity is the ability to restructure and learn new things, continually building on previous patterns of neuronal interactions. By harnessing brainwave rhythms, it may be possible to enhance flexible learning across the lifespan, from infancy to older adulthood," Kourtzi said.

The findings, published in the journal Cerebral Cortex, will be explored as part of the Centre for Lifelong Learning and Individualised Cognition: a research collaboration between Cambridge and Nanyang Technological University (NTU), Singapore.

The neuroscientists used electroencephalography -- or EEG -- sensors attached to the head to measure electrical activity in the brain of 80 study participants, and sample brainwave rhythms.

The team took alpha waves readings. The mid-range of the brainwave spectrum, this wave frequency tends to dominate when we are awake and relaxed.

Alpha waves oscillate between eight to twelve hertz: a full cycle every 85-125 milliseconds. However, every person has their own peak alpha frequency within that range.

Scientists used these readings to create an optical "pulse": a white square flickering on a dark background at the same tempo as each person's individual alpha wave.

Participants got a 1.5-second dose of personalised pulse to set their brain working at its natural rhythm -- a technique called "entrainment" -- before being presented with a tricky quick-fire cognitive task: trying to identify specific shapes within a barrage of visual clutter.

A brainwave cycle consists of a peak and trough. Some participants received pulses matching the peak of their waves, some the trough, while some got rhythms that were either random or at the wrong rate (a little faster or slower). Each participant repeated over 800 variations of the cognitive task, and the neuroscientists measured how quickly people improved.

The learning rate for those locked into the right rhythm was at least three times faster than for all the other groups. When participants returned the next day to complete another round of tasks, those who learned much faster under entrainment had maintained their higher performance level.

"It was exciting to uncover the specific conditions you need to get this impressive boost in learning," said first author Dr Elizabeth Michael, now at Cambridge's Cognition and Brain Sciences Unit.

"The intervention itself is very simple, just a brief flicker on a screen, but when we hit the right frequency plus the right phase alignment, it seems to have a strong and lasting effect."

Importantly, entrainment pulses need to chime with the trough of a brainwave. Scientists believe this is the point in a cycle when neurons are in a state of "high receptivity."

"We feel as if we constantly attend to the world, but in fact our brains take rapid snapshots and then our neurons communicate with each other to string the information together," said co-author Prof Victoria Leong, from NTU and Cambridge's Department of Paediatrics.

"Our hypothesis is that by matching information delivery to the optimal phase of a brainwave, we maximise information capture because this is when our neurons are at the height of excitability."

Previous work from Leong's Baby-LINC lab shows that brainwaves of mothers and babies will synchronise when they communicate. Leong believes the mechanism in this latest study is so effective because it mirrors the way we learn as infants.

"We are tapping into a mechanism that allows our brain to align to temporal stimuli in our environment, especially communicative cues like speech, gaze and gesture that are naturally exchanged during interactions between parents and babies," said Leong.

"When adults speak to young children they adopt child-directed speech -- a slow and exaggerated form of speaking. This study suggests that child-directed speech may be a spontaneous way of rate-matching and entraining the slower brainwaves of children to support learning."

The researchers say that, while the new study tested visual perception, these mechanisms are likely to be "domain general": applying to a wide range of tasks and situations, including auditory learning.

They argue that potential applications for brainwave entrainment may sound like the stuff of science fiction, but are increasingly achievable. "While our study used complex EEG machines, there are now simple headband systems that allow you to gauge brain frequencies quite easily," said Kourtzi.

"Children now do so much of their learning in front of screens. One can imagine using brainwave rhythms to enhance aspects of learning for children who struggle in regular classrooms, perhaps due to attentional deficits."

Other early applications of brainwave entrainment to boost learning could involve training in professions where fast learning and quick decision-making is vital, such as pilots or surgeons. "Virtual reality simulations are now an effective part of training in many professions," said Kourtzi.

"Implementing pulses that sync with brainwaves in these virtual environments could give new learners an edge, or help those retraining later in life."

https://www.sciencedaily.com/releases/2023/01/230131101912.htm

Do sleep medications increase your chances of dementia?

January 31, 2023

Science Daily/University of California - San Francisco

A new study shows that sleep medications increase the risk of dementia in whites. But the type and quantity of the medication may be factors in explaining the higher risk.

It follows previous work that shows Blacks have a higher likelihood than whites of developing Alzheimer's, the most common type of dementia, and that they have different risk factors and disease manifestation.

The final corrected draft of the study publishes in the Journal of Alzheimer's Disease on Jan. 31, 2023.

In the study, approximately 3,000 older adults without dementia, who lived outside of nursing homes, were enrolled in the Health, Aging and Body Composition study and followed over an average duration of nine years. Their average age was 74; 42% were Black and 58% were white.

During the study, 20% developed dementia. White participants who "often" or "almost always" took sleep medications had a 79% higher chance of developing dementia compared to those who "never" or "rarely" used them. Among Black participants -- whose consumption of sleep aids was markedly lower -- frequent users had a similar likelihood of developing dementia than those who abstained or rarely used the medications.

Higher-Income Blacks May Be Less Likely to Get Dementia

"Differences may be attributed to socio-economic status" said first author Yue Leng, PhD, of the UCSF Department of Psychiatry and Behavioral Sciences and Weill Institute for Neurosciences. "Black participants who have access to sleep medications might be a select group with high socio-economic status and, thus, greater cognitive reserve, making them less susceptible to dementia.

"It's also possible that some sleep medications were associated with a higher risk of dementia than others."

The researchers found that whites, at 7.7%, were three times as likely as Blacks, at 2.7%, to take sleep medications often, five to 15 times a month, or almost always, 16 times a month to daily. Whites were almost twice as likely to use benzodiazepines, like Halcion, Dalmane and Restoril, prescribed for chronic insomnia.

Whites were also 10 times as likely to take trazodone, an antidepressant known by the trade names of Desyrel and Oleptro, that may also be prescribed as a sleep aid. And they were more than seven times as likely to take "Z-drugs," such as Ambien, a so-called sedative-hypnotic.

While future study may offer clarity on the cognitive risks or rewards of sleep medications and the role that race may play, patients with poor sleep should hesitate before considering medications, according to Leng.

"The first step is to determine what kind of sleep issues patients are dealing with. A sleep test may be required if sleep apnea is a possibility," she said. "If insomnia is diagnosed, cognitive behavioral therapy for insomnia (CBT-i) is the first-line treatment. If medication is to be used, melatonin might be a safer option, but we need more evidence to understand its long-term impact on health."

https://www.sciencedaily.com/releases/2023/01/230131101833.htm

Three or more concussions linked with worse brain function in later life

Experiencing three or more concussions is linked with worsened brain function in later life, according to major new research

January 30, 2023

Science Daily/University of Exeter

Experiencing three or more concussions is linked with worsened brain function in later life, according to major new research.

The study -- the largest of its kind -- also found having just one moderate-to-severe concussion, or traumatic brain injury (TBI), can have a long-term impact on brain function, including memory.

Led by teams at the University of Oxford and the University of Exeter, the research included data from more than 15,000 participants of the online PROTECT study, who were aged between 50 and 90 and based in the UK. They reported the severity and frequency of concussions they had experienced throughout their lives, and completed annual, computerised tests for brain function.

Published in the Journal of Neurotrauma, the paper found that people who reported three or more concussions had significantly worse cognitive function, which got successively worse with each subsequent concussion after that. Attention and completion of complex tasks were particularly affected.

Researchers say people who have had concussions should be warned of the dangers of continuing high-risk sport or work.

Lead investigator Dr Vanessa Raymont, from the University of Oxford, said: "We know that head injuries are a major risk factor for dementia, and this large-scale study gives the greatest detail to date on a stark finding -- the more times you injure your brain in life, the worse your brain function could be as you age.

"Our research indicates that people who have experienced three or more even mild episodes of concussion should be counselled on whether to continue high-risk activities. We should also encourage organisations operating in areas where head impact is more likely to consider how they can protect their athletes or employees."

The team found that participants who reported three episodes of even mild concussion throughout their lives had significantly worse attention and ability to complete complex tasks. Those who had four or more mild concussion episodes also showed worsened processing speed and working memory. Each additional reported concussion was linked to progressively worse cognitive function.

Furthermore, the researchers found that reporting even one moderate-to-severe concussion was associated with worsened attention, completion of complex tasks and processing speed capacity.

In the online PROTECT study, participants share detailed lifestyle information, and complete a suite of cognitive tests every year, for up to 25 years. This rich mine of data helps researchers understand how the brain ages, and the factors involved in maintaining a healthier brain in later life.

Dr Helen Brooker, a study co-author from the University of Exeter, said: "As our population ages, we urgently need new ways to empower people to live healthier lives in later life. This paper highlights the importance of detailed long-term studies like PROTECT in better understating head injuries and the impact to long term cognitive function, particularly as concussion has also been linked to dementia. We're learning that life events that might seem insignificant, life experiencing a mild concussion, can have an impact on the brain. Our findings indicate that cognitive rehabilitation should focus on key functions such as attention and completion of complex tasks, which we found to be susceptible to long-term damage."

Dr Susan Kohlhaas, Director of Research at Alzheimer's Research UK, said: "Studies like this are so important in unravelling the long-term risks of traumatic brain injury, including their effect on dementia risk. These findings should send a clear message to policy makers and sporting bodies, who need to put robust guidelines in place that reduce risk of head injury as much as possible."

https://www.sciencedaily.com/releases/2023/01/230130213948.htm

More steps, moderate physical activity cuts dementia, cognitive impairment risk

January 25, 2023

Science Daily/University of California - San Diego

Senior women were less likely to develop mild cognitive impairment or dementia if they did more daily walking and moderate-to-vigorous physical activity, according to a new study led by the Herbert Wertheim School of Public Health and Human Longevity Science at University of California San Diego.

In the Jan. 25, 2023 online edition of Alzheimer's & Dementia: The Journal of the Alzheimer's Association, the team reported that, among women aged 65 or older, each additional 31 minutes per day of moderate-to-vigorous physical activity was associated with a 21 percent lower risk of developing mild cognitive impairment or dementia. Risk was also 33 percent lower with each additional 1,865 daily steps.

"Given that the onset of dementia begins 20 years or more before symptoms show, the early intervention for delaying or preventing cognitive decline and dementia among older adults is essential," said senior author Andrea LaCroix, Ph.D., M.P.H., Distinguished Professor at the Herbert Wertheim School of Public Health and Human Longevity Science at UC San Diego.

While there are several types, dementias are a debilitating neurological condition that can cause loss of memory, the ability to think, problem solve or reason. Mild cognitive impairment is an early stage of memory loss or thinking problems that is not as severe as dementias.

According to the United States Department of Health and Human Services, dementia affects more than 5 million people in this country. That number is expected to double by 2050.

More women live with and are at higher risk of developing dementia than men.

"Physical activity has been identified as one of the three most promising ways to reduce risk of dementia and Alzheimer's disease. Prevention is important because once dementia is diagnosed, it is very difficult to slow or reverse. There is no cure," said LaCroix.

However, because few large studies have examined device measures of movement and sitting in relation to mild cognitive impairment and dementia, much of the published research on the associations of physical activity and sedentary behavior with cognitive decline and dementia is based on self-reported measures, said first author, Steven Nguyen, Ph.D., M.P.H., postdoctoral scholar at the Herbert Wertheim School of Public Health.

For this study, the researchers sampled data from 1,277 women as part of two Women's Health Initiative (WHI) ancillary studies -- the WHI Memory Study (WHIMS) and the Objective Physical Activity and Cardiovascular Health (OPACH) study. The women wore research-grade accelerometers and went about their daily activities for up to seven days to obtain accurate measures of physical activity and sitting.

The activity trackers showed the women averaged 3,216 steps, 276 minutes in light physical activities, 45.5 minutes of moderate-to-vigorous physical activity and 10.5 hours of sitting per day. Examples of light physical activity could include housework, gardening or walking. Moderate-to-vigorous physical activity could include brisk walking.

The study findings also showed that higher amounts of sitting and prolonged sitting were not associated with higher risk of mild cognitive impairment or dementia.

Together, this information has clinical and public health importance as there is little published information on the amount and intensity of physical activity needed for a lower dementia risk, said Nguyen.

"Older adults can be encouraged to increase movement of at least moderate intensity and take more steps each day for a lower risk of mild cognitive impairment and dementia," said Nguyen.

"The findings for steps per day are particularly noteworthy because steps are recorded by a variety of wearable devices increasingly worn by individuals and could be readily adopted."

The authors said further research is needed among large diverse populations that include men.

https://www.sciencedaily.com/releases/2023/01/230125085831.htm

Traffic pollution impairs brain function

First-in-the-world study suggests that even brief exposure to air pollution has rapid impacts on the brain

January 24, 2023

Science Daily/University of British Columbia

A new study by researchers at the University of British Columbia and the University of Victoria has shown that common levels of traffic pollution can impair human brain function in only a matter of hours.

The peer-reviewed findings, published in the journal Environmental Health, show that just two hours of exposure to diesel exhaust causes a decrease in the brain's functional connectivity -- a measure of how The study provides the first evidence in humans, from a controlled experiment, of altered brain network connectivity induced by air pollution.

"For many decades, scientists thought the brain may be protected from the harmful effects of air pollution," said senior study author Dr. Chris Carlsten, professor and head of respiratory medicine and the Canada Research Chair in occupational and environmental lung disease at UBC. "This study, which is the first of its kind in the world, provides fresh evidence supporting a connection between air pollution and cognition."

For the study, the researchers briefly exposed 25 healthy adults to diesel exhaust and filtered air at different times in a laboratory setting. Brain activity was measured before and after each exposure using functional magnetic resonance imaging (fMRI).

The researchers analyzed changes in the brain's default mode network (DMN), a set of inter-connected brain regions that play an important role in memory and internal thought. The fMRI revealed that participants had decreased functional connectivity in widespread regions of the DMN after exposure to diesel exhaust, compared to filtered air.

"We know that altered functional connectivity in the DMN has been associated with reduced cognitive performance and symptoms of depression, so it's concerning to see traffic pollution interrupting these same networks," said Dr. Jodie Gawryluk, a psychology professor at the University of Victoria and the study's first author. "While more research is needed to fully understand the functional impacts of these changes, it's possible that they may impair people's thinking or ability to work."

Taking steps to protect yourself

Notably, the changes in the brain were temporary and participants' connectivity returned to normal after the exposure. Dr. Carlsten speculated that the effects could be long lasting where exposure is continuous. He said that people should be mindful of the air they're breathing and take appropriate steps to minimize their exposure to potentially harmful air pollutants like car exhaust.

"People may want to think twice the next time they're stuck in traffic with the windows rolled down," said Dr. Carlsten. "It's important to ensure that your car's air filter is in good working order, and if you're walking or biking down a busy street, consider diverting to a less busy route."

While the current study only looked at the cognitive impacts of traffic-derived pollution, Dr. Carlsten said that other products of combustion are likely a concern.

"Air pollution is now recognized as the largest environmental threat to human health and we are increasingly seeing the impacts across all major organ systems," says Dr. Carlsten. "I expect we would see similar impacts on the brain from exposure to other air pollutants, like forest fire smoke. With the increasing incidence of neurocognitive disorders, it's an important consideration for public health officials and policymakers."

The study was conducted at UBC's Air Pollution Exposure Laboratory, located at Vancouver General Hospital, which is equipped with a state-of-the-art exposure booth that can mimic what it is like to breathe a variety of air pollutants. In this study, which was carefully designed and approved for safety, the researchers used freshly-generated exhaust that was diluted and aged to reflect real-world conditions.

https://www.sciencedaily.com/releases/2023/01/230124112731.htm

Music education benefits youth wellbeing

January 18, 2023

Science Daily/University of Southern California

The latest USC research on the impact of music education shows that for adolescents, the benefits appear to extend beyond a surge in neural connections in their brains. It actually boosts their wellbeing.

The study published Wednesday by the journal Frontiers In Psychology comes just weeks after voters statewide approved Prop. 28 to increase funding for arts and music education in California public schools.

A USC Thornton School of Music researcher said the results are especially meaningful amid a nationwide mental health crisis.

"We know that the pandemic has taken a toll on student mental health. The many narratives of learning loss that have emerged since the start of the pandemic paint a grim picture of what some call a 'lost generation'," said Beatriz Ilari, an associate professor of music education at the USC Thornton School of Music and corresponding author of the study. "Music might be an activity to help students develop skills and competencies, work out their emotions, engage in identity work and strengthen connections to the school and community."

The work was supported by grants including one from the Fender Play Foundation, a nonprofit organization that places instruments in the hands of youth who aspire to play and reap the powerful benefits of music education.

Evidence of those benefits continues to mount, although many states and school districts have reduced the amount of class time, faculty and curriculum dedicated to the arts amid budget crunches and changes in curriculum standards.

Ilari contributed to prior studies, including a longitudinal one by the USC Brain and Creativity Institute, that demonstrated children who learn a musical instrument have enhanced cognitive function. Other research also has shown music education contributes to improved creativity and confidence, better mental health and emotional stability, and student performance, according to a paper published last year by the International Journal of Environmental Research and Public Health.

Greater hope for the future

For the study, researchers examined the impact of music on "positive youth development," a measure of the strengths of adolescents and their potential to contribute to society developed by scholars from Tufts University. Researchers also included measures for school connectedness and hopeful future expectations.

The researchers administered anonymous, online surveys to 120 students from 52 Los Angeles Unified School District middle schools. The survey questions covered the key domains of positive youth development including competence and confidence. Past research shows that adolescents who manifest these attributes are more likely to make positive contributions to society and less likely to engage in risky behaviors later in life.

Ilari and her fellow researchers, including USC Thornton alumna Eun Cho, found many positive effects. They found that students who started music education before age 8 were more hopeful about the future, and younger students receiving musical training scored higher in key measures of positive youth development.

The research team also found that younger students scored higher in key development measures than their older peers. Sixth-grade students, for example, scored higher for overall positive youth development than -- eighth-graders, and scored higher in the confidence domain than both seventh and eighth-graders. Seventh-grade students also scored higher in overall positive youth development than eighth-graders.

In completing the study's survey questions, students were invited to choose from multiple gender categories beyond the usual binary gender options, including "non-binary" and "prefer not to answer," to identify themselves. Non-binary students scored lower in overall positive youth development and connection than girls. They also scored lower in confidence and connection than boys.

"Given the high levels of depression and suicide ideation among LGBTQ+ and non-gender conforming students, it is crucial that research examining adolescent well-being move beyond the gender binary," Ilari said. "In addition to filling critical gaps in the existing literature, results from our study can be used to inform the development of programs and policy for all young people."

The study included students of diverse backgrounds. However, students participating in a virtual music education program primarily came from poor neighborhoods, indicating disparities in access to formal music education.

In addition, the study explored students' engagement in different music programs, including the Virtual Middle School Music Enrichment (VMSME), a tuition-free, extracurricular program that focuses on popular music education and virtual learning. The program is available through a school district partnership with the Fender Play Foundation. Researchers found that students participating in multiple forms of music education and for longer periods of time scored higher in measures for competence and hopeful future expectations. Some participants in these groups were also enrolled in private lessons and/or playing in small ensembles that offer more individual attention than large group classes. In contrast, students in the extracurricular VMSME program came from low-income neighborhoods and participated in fewer extracurricular activities.

"By expanding access to instruments and music classes for students from low socioeconomic areas -- a population that is often left out of school music programs -- VMSME contributed to the democratization of music education," Ilari said. "Throughout the pandemic, students in public schools, especially in urban areas, were disproportionately impacted by the lockdowns that deprived them of physical and social contact with peers. VMSME brought together students from different neighborhoods and at a time when forming peer groups is essential to social identity development."

More research is needed to better understand disparities in access to formal music education, Ilari said, but she said programs that give student agency in their learning and allow them to engage with peers from other schools, like VMSME, have the potential to promote learning and wellbeing.

https://www.sciencedaily.com/releases/2023/01/230118195730.htm

Study explores effects of dietary choline deficiency on neurologic and system-wide health

Reaching adequate dietary choline intake is critical to offset organ pathologies and may help protect the brain against Alzheimer's disease

January 17, 2023

Science Daily/Arizona State University

Choline, an essential nutrient produced in small amounts in the liver and found in foods including eggs, broccoli, beans, meat and poultry, is a vital ingredient for human health. A new study explores deficiency in dietary choline adversely affects the body and may be a missing piece in the puzzle of Alzheimer's disease.

It's estimated that more than 90% of Americans are not meeting the recommended daily intake of choline. The current research, conducted in mice, suggests that dietary choline deficiency can have profound negative effects on the heart, liver and other organs.

Lack of adequate choline is also linked with profound changes in the brain associated with Alzheimer's disease. These include pathologies implicated in the development of two classic hallmarks of the illness, amyloid plaques, which aggregate in the intercellular spaces between neurons, and tau tangles, which condense within the bodies of neurons.

The new research, led by scientists at Arizona State University, describes pathologies in normal mice deprived of dietary choline as well as choline deficient transgenic mice, which already exhibit symptoms associated with the disease. In both cases, dietary choline deficiency results in liver damage, enlargement of the heart and neurologic alterations in the AD mice typically accompanying Alzheimer's disease, including increased levels of plaque-forming amyloid-beta protein and disease-linked alterations in tau protein.

Further, the study illustrates that choline deficiency in mice causes significant weight gain, and alterations in glucose metabolism, (which are tied to conditions such as diabetes), and deficits in motor skills.

In the case of humans, "it's a twofold problem," according to Ramon Velazquez, senior author of the study and Assistant professor with the ASU-Banner Neurodegenerative Disease Research Center. "First, people don't reach the adequate daily intake of choline established by the Institute of Medicine in 1998. And secondly, there is vast literature showing that the recommended daily intake amounts are not optimal for brain-related functions."

Ramon Velazquez led the new study on the importance of dietary choline for the brain and other organs. He is a researcher in the ASU-Banner Neurodegereative Disease Research Center.

The research highlights a constellation of physical and neurological changes linked to choline deficiency. Sufficient choline in the diet reduces levels of the amino acid homocysteine, which has been recognized as a neurotoxin contributing to neurodegeneration and is important for mediating functions such as learning and memory, through the production of acetylcholine.

The growing awareness of choline's importance should encourage all adults to ensure proper choline intake. This is particularly true for those on plant-based diets, which may be low in naturally occurring choline, given that foods high in choline are eggs, meats, and poultry.

Plant-based, choline-rich foods, including soybeans, Brussel sprouts and toast can help boost choline in these cases. Further, inexpensive, over-the-counter choline supplements are encouraged to ensure system-wide health and guard the brain from the effects of neurodegeneration.

Brain-boosting nutrient

Choline is needed to produce acetylcholine, a neurotransmitter that plays an essential role in memory, muscle control and mood. Choline also builds cell membranes and helps regulate gene expression. The established recommendations set forth by the Institute of Medicine were based on evidence preventing fatty liver disease in men. New lines of evidence imply that the established recommended daily intake of dietary choline for adult women (425mg/day) and adult men (550mg/day) may not be optimal for proper brain health and cognition. Additionally, ~90% of Americans are not meeting the recommendation levels and may not even be aware that dietary choline is required on a daily basis.

Despite decades of research and billions of dollars invested since the discovery of the devastating ailment over a century ago, there remains no therapy capable of slowing the advance of the illness. Yet, new research findings suggest that environmental and lifestyle changes, including adequate choline, may help protect the brain from Alzheimer's disease as well as improving overall health.

Velazquez is joined on the study by co-lead authors Nikhil Dave and Jessica Judd. The work is highly interdisciplinary, including researchers from the ASU Biosciences Mass spectrometry facility, and the Translational Cardiovascular Research Center at the University of Arizona College of Medicine in Phoenix, AZ.

"This collaborative work, spanning multiple institutions and surveying the molecular processes of aging at the systems level, adds to the body of evidence produced around the importance of dietary choline in healthy aging," said Nikhil Dave.

"What I found particularly compelling about this project was that multiple organs, whose malfunction can have implications for brain health, were negatively impacted by a choline deficient diet," said Jessica Judd.

The research appears in the current issue of the journal Aging Cell.

A prolific and mysterious killer

Alzheimer's disease is the leading cause of dementia and the fifth leading cause of death among Americans aged 65 and older. Today, Alzheimer's affects 6.5 million in the U.S. alone and is projected to strike close to 14 million Americans by 2060. By this time, the costs of managing Alzheimer's are expected to exceed a $20 trillion, threatening the healthcare infrastructure while causing immense suffering.

The accumulation of sticky protein fragments outside neurons, (which form amyloid-beta plaques), and the buildup of an abnormal form of the protein tau within the bodies of neurons (tau tangles) have long been recognized signposts of Alzheimer's disease. These brain alterations are typically followed by neurodegeneration, involving the damage and destruction of neurons. Plaques are believed to damage cell-to-cell communications in the brain while tangles block the transport of vital nutrients essential for proper cell function and survival.

In addition to amyloid-beta plaques and neurofibrillary tangles, the disease causes cell death in the brain and increasing cognitive impairment. The current work also found dysregulation of proteins in the hippocampus, a key structure affected in Alzheimer's disease, tied to learning and memory. Both normal and AD mice showed dysregulated proteins in the hippocampus with a choline deficient diet, with the AD model showing severe effects.

Gathering storm

The recent, dramatic increase in Alzheimer's disease incidence is of grave concern. Although deaths from stroke, heart disease and HIV decreased between 2000 and 2019, deaths from Alzheimer's increased more than 145%. In addition to the toll on patients caused by the disease, Alzheimer's has placed an immense burden on those caring for the sick. In 2021 alone, 16 billion hours of care were provided by over 11 million family members and other unpaid caregivers.

The first outward symptoms of the disease are usually related to language, memory, and thinking problems, as brain regions associated with these tasks tend to be among the first affected. Yet researchers now know that by the time the disease causes observable symptoms, it has been quietly ravaging the brain for 20 years or more.

Many factors contribute to the development of Alzheimer's disease, from genetic predisposition to age, lifestyle and environmental influences. For reasons that remain murky, females face an increased risk of developing the disease.

Recent studies have identified diet as a significant factor associated with preventing cognitive decline. In earlier research, Velazquez and his colleagues demonstrated that when mice were fed a high choline diet, their offspring showed improvements in spatial memory, compared with a normal choline regimen in the womb. Intriguingly, the beneficial effects of choline supplementation are transgenerational, not only protecting mice receiving choline supplementation during gestation and lactation, but also the subsequent offspring of these mice, suggesting inherited modifications in their genes.

Subsequent studies in the Velazquez lab showed that choline administered to female mice throughout life yielded improvements in spatial memory, compared with those receiving a normal choline regimen.

Multifaceted effects

The new study examines mice at 3-12 months or early to late adulthood, (roughly equivalent to 20-60 years of age for humans). In the case of both normal and transgenic mice displaying symptoms of Alzheimer's, those exposed to a deficient choline diet exhibited weight gain and adverse effects to their metabolism. Damage to the liver was observed through tissue analysis, as well as enlargement of the heart. Elevated soluble, oligomeric and insoluble amyloid-beta protein were detected as well as modifications to tau protein characteristic of those leading to neurofibrillary tangles in the brain.

Further, choline deficient mice performed poorly in a test of motor skills, when compared with mice receiving adequate choline in their diet. These adverse effects were heightened in the transgenic mice. Translating these findings to humans, this implies that people who are predisposed to Alzheimer's disease or in the throes of the illness should ensure they are getting enough choline.

The study also involved a detailed exploration of proteins in the hippocampus, an area of the brain acutely affected by Alzheimer's disease, as well as proteins detected in blood. Dietary choline deficiency altered important hippocampal networks. These pathologies include disruption of pathways associated with microtubule function and postsynaptic membrane regulation -- both essential for proper brain function. In blood, proteins produced in the liver that play a role in metabolic function were particularly dysregulated with the choline deficient diet.

"Our work provides further support that dietary choline should be consumed on a daily basis given the need throughout the body," Velazquez says.

Ultimately, controlled human clinical trials will be essential for establishing the effectiveness and appropriate dosages of choline, before encouraging lifelong choline supplementation. Nevertheless, the powerful new findings offer hope that choline may be one tool in the arsenal needed to defend the brain from neurodegeneration and age-related cognitive decline.

https://www.sciencedaily.com/releases/2023/01/230117193006.htm

Gut bacteria affect brain health

Findings suggest new approach to treating Alzheimer's, other neurodegenerative diseases

January 12, 2023

Science Daily/Washington University School of Medicine

A growing pile of evidence indicates that the tens of trillions of microbes that normally live in our intestines -- the so-called gut microbiome -- have far-reaching effects on how our bodies function. Members of this microbial community produce vitamins, help us digest food, prevent the overgrowth of harmful bacteria and regulate the immune system, among other benefits. Now, a new study suggests that the gut microbiome also plays a key role in the health of our brains, according to researchers from Washington University School of Medicine in St. Louis.

The study, in mice, found that gut bacteria -- partly by producing compounds such as short chain fatty acids -- affect the behavior of immune cells throughout the body, including ones in the brain that can damage brain tissue and exacerbate neurodegeneration in conditions such as Alzheimer's disease. The findings, published Jan. 13 in the journal Science, open up the possibility of reshaping the gut microbiome as a way to prevent or treat neurodegeneration.

"We gave young mice antibiotics for just a week, and we saw a permanent change in their gut microbiomes, their immune responses, and how much neurodegeneration related to a protein called tau they experienced with age," said senior author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology. "What's exciting is that manipulating the gut microbiome could be a way to have an effect on the brain without putting anything directly into the brain."

Evidence is accumulating that the gut microbiomes in people with Alzheimer's disease can differ from those of healthy people. But it isn't clear whether these differences are the cause or the result of the disease -- or both -- and what effect altering the microbiome might have on the course of the disease.

To determine whether the gut microbiome may be playing a causal role, the researchers altered the gut microbiomes of mice predisposed to develop Alzheimer's-like brain damage and cognitive impairment. The mice were genetically modified to express a mutant form of the human brain protein tau, which builds up and causes damage to neurons and atrophy of their brains by 9 months of age. They also carried a variant of the human APOEgene, a major genetic risk factor for Alzheimer's. People with one copy of the APOE4 variant are three to four times more likely to develop the disease than people with the more common APOE3variant.

Along with Holtzman, the research team included gut microbiome expert and co-author Jeffrey I. Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor and director of the Edison Family Center for Genome Sciences & Systems Biology; first author Dong-Oh Seo, PhD, an instructor in neurology; and co-author Sangram S. Sisodia, PhD, a professor of neurobiology at the University of Chicago.

When such genetically modified mice were raised under sterile conditions from birth, they did not acquire gut microbiomes, and their brains showed much less damage at 40 weeks of age than the brains of mice harboring normal mouse microbiomes.

When such mice were raised under normal, nonsterile conditions, they developed normal microbiomes. A course of antibiotics at 2 weeks of age, however, permanently changed the composition of bacteria in their microbiomes. For male mice, it also reduced the amount of brain damage evident at 40 weeks of age. The protective effects of the microbiome shifts were more pronounced in male mice carrying the APOE3 variant than in those with the high-risk APOE4variant, possibly because the deleterious effects of APOE4canceled out some of the protection, the researchers said. Antibiotic treatment had no significant effect on neurodegeneration in female mice.

"We already know, from studies of brain tumors, normal brain development and related topics, that immune cells in male and female brains respond very differently to stimuli," Holtzman said. "So it's not terribly surprising that when we manipulated the microbiome we saw a sex difference in response, although it is hard to say what exactly this means for men and women living with Alzheimer's disease and related disorders."

Further experiments linked three specific short-chain fatty acids -- compounds produced by certain types of gut bacteria as products of their metabolism -- to neurodegeneration. All three of these fatty acids were scarce in mice with gut microbiomes altered by antibiotic treatment, and undetectable in mice without gut microbiomes.

These short-chain fatty acids appeared to trigger neurodegeneration by activating immune cells in the bloodstream, which in turn somehow activated immune cells in the brain to damage brain tissue. When middle-aged mice without microbiomes were fed the three short-chain fatty acids, their brain immune cells became more reactive, and their brains showed more signs of tau-linked damage.

"This study may offer important insights into how the microbiome influences tau-mediated neurodegeneration, and suggests therapies that alter gut microbes may affect the onset or progression of neurodegenerative disorders," said Linda McGavern, PhD, program director at the National Institute of Neurological Disorders and Stroke (NINDS), which provided some of the funding for the study.

The findings suggest a new approach to preventing and treating neurodegenerative diseases by modifying the gut microbiome with antibiotics, probiotics, specialized diets or other means.

"What I want to know is, if you took mice genetically destined to develop neurodegenerative disease, and you manipulated the microbiome just before the animals start showing signs of damage, could you slow or prevent neurodegeneration?" Holtzman asked. "That would be the equivalent of starting treatment in a person in late middle age who is still cognitively normal but on the verge of developing impairments. If we could start a treatment in these types of genetically sensitized adult animal models before neurodegeneration first becomes apparent, and show that it worked, that could be the kind of thing we could test in people."

https://www.sciencedaily.com/releases/2023/01/230112155812.htm