Social isolation is a risk factor for dementia in older adults, point to ways to reduce risk

January 12, 2023

Science Daily/Johns Hopkins Medicine

In two studies using nationally representative data from the National Health and Aging Trends Study gathered on thousands of Americans, researchers from the Johns Hopkins University School of Medicine and Bloomberg School of Public Health have significantly added to evidence that social isolation is a substantial risk factor for dementia in community-dwelling (noninstitutionalized) older adults, and identified technology as an effective way to intervene.

Collectively, the studies do not establish a direct cause and effect between dementia and social isolation, defined as lack of social contact and interactions with people on a regular basis. But, the researchers say, the studies strengthen observations that such isolation increases the risk of dementia, and suggest that relatively simple efforts to increase social support of older adults -- such as texting and use of email -- may reduce that risk. In the United States, an estimated 1 in 4 people over age 65 experience social isolation, according to the National Institute on Aging.

"Social connections matter for our cognitive health, and it is potentially easily modifiable for older adults without the use of medication," says Thomas Cudjoe, M.D., M.P.H., assistant professor of medicine at the Johns Hopkins University School of Medicine and senior author of both of the new studies.

The first study, described Jan. 11 in the Journal of the American Geriatrics Society, used data collected on a group of 5,022 Medicare beneficiaries for a long-term study known as the National Health and Aging Trends, which began in 2011. All participants were 65 or older, and were asked to complete an annual two-hour, in-person interview to assess cognitive function, health status and overall well-being.

At the initial interview, 23% of the 5,022 participants were socially isolated and showed no signs of dementia. However, by the end of this nine-year study, 21% of the total sample of participants had developed dementia. The researchers concluded that risk of developing dementia over nine years was 27% higher among socially isolated older adults compared with older adults who were not socially isolated.

"Socially isolated older adults have smaller social networks, live alone and have limited participation in social activities," says Alison Huang, Ph.D., M.P.H., senior research associate at the Johns Hopkins Bloomberg School of Public Health. "One possible explanation is that having fewer opportunities to socialize with others decreases cognitive engagement as well, potentially contributing to increased risk of dementia."

Interventions to reduce that risk are possible, according to results of the second study, published Dec. 15 in the Journal of the American Geriatrics Society. Specifically, researchers found the use of communications technology such as telephone and email lowered the risk for social isolation.

Researchers for the second study used data from participants in the same National Health and Aging Trends study, and found that more than 70% of people age 65 and up who were not socially isolated at their initial appointment had a working cellphone and/or computer, and regularly used email or texting to initiate and respond to others. Over the four-year research period for this second study, older adults who had access to such technology consistently showed a 31% lower risk for social isolation than the rest of the cohort.

"Basic communications technology is a great tool to combat social isolation," says Mfon Umoh, M.D., Ph.D., postdoctoral fellow in geriatric medicine at the Johns Hopkins University School of Medicine. "This study shows that access and use of simple technologies are important factors that protect older adults against social isolation, which is associated with significant health risks. This is encouraging because it means simple interventions may be meaningful."

Social isolation has gained significant attention in the past decade, especially due to restrictions implemented for the COVID-19 pandemic, but more work needs to be done to identify at-risk populations and create tools for providers and caregivers to minimize risk, the researchers say. Future research in this area should focus on increased risks based on biological sex, physical limitations, race and income level.

https://www.sciencedaily.com/releases/2023/01/230112113224.htm

Fall rate nearly 50% among older Americans with dementia

Targeting specific fall-risk factors could improve fall screening and prevention strategies

January 12, 2023

Science Daily/Drexel University

With falls causing millions of injuries in older adults each year, it is an increasingly important public health concern. Older adults living with dementia have twice the risk of falling and three times the risk of incurring serious fall-related injuries, like fractures, compared to those without dementia. For older adults with dementia, even minor fall-related injuries can lead to hospitalization and nursing home admission. A new study from researchers in Drexel University's College of Nursing and Health Professions, has shed light on the many and varied fall-risk factors facing older adults in community-living environments.

Recently published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, the research led by Safiyyah Okoye, PhD, an assistant professor at Drexel, and Jennifer L. Wolff, PhD, a professor at Johns Hopkins Bloomberg School of Public Health, examined a comprehensive set of potential fall-risk factors -- including environmental factors, in addition to health and function -- in older community-living adults in the United States, both with and without dementia.

"Examining the multiple factors, including environmental ones like a person's home or neighborhood, is necessary to inform fall-risk screening, caregiver education and support, and prevention strategies for this high-risk population of older adults," said Okoye.

Despite awareness of this elevated risk, there are very few studies that have examined fall-risk factors among people with dementia living in a community setting (not nursing homes or other residential facilities). The studies that do exist, overwhelmingly focus on health and function factors. According to the authors, this is the first nationally representative study to compare a comprehensive set of potential risk factors for falls for older Americans living with dementia to those without dementia.

The research team examined data from the 2015 and 2016 National Health and Aging Trends Study (NHATS), a population-based survey of health and disability trends and trajectories of adults 65 and older in the U.S. They were able to obtain potential sociodemographic, health and function predictors of falls, as well as potential social and physical environmental predictors.

Data from NHATS showed that nearly half (45.5%) of older adults with dementia had experienced one or more falls in 2016, compared to less than one third (30.9%) of older adults without dementia.

Among older adults living with dementia, three characteristics stood out as significantly associated with a greater likelihood of falls: a history of falling the previous year; impaired vision; and living with others (versus alone). For older adults without dementia, financial hardship, a history of falling, fear of falling, poor lower extremity performance, depressive symptoms and home disrepair were strongly associated with increased risk of falls.

While prior history of falling and vision impairment are well-known risk factors for falls among older adults in general; the researchers' findings indicate that these were strong risk factors for falls among people living with dementia. According to the team, this suggests that people living with dementia should be assessed for presence of these characteristics. If they're present, the individuals should receive further assessment and treatment, including examining their feet and footwear, assessing their environment and ability to carry out daily living activities, among other items.

The finding that older adults living with dementia who lived with a spouse or with non-spousal others had higher odds of experiencing a fall, compared to those who lived alone, highlights that caregiver support and education are understudied components of fall prevention programs for older adults with dementia who live with family caregivers, and deserve greater attention from clinicians, researchers and policy makers.

"Overall, our findings demonstrate the importance of understanding and addressing fall-risk among older adults living with dementia," said Okoye. "It confirms that fall-risk is multidimensional and influenced by environmental context in addition to health and function factors."

The results of the study indicate the need to further investigate and design fall-prevention interventions, specifically for people living with dementia.

https://www.sciencedaily.com/releases/2023/01/230112090936.htm

Six minutes of high-intensity exercise could delay the onset of Alzheimer's disease

January 12, 2023

Science Daily/The Physiological Society 

Six minutes of high-intensity exercise could extend the lifespan of a healthy brain and delay the onset of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. New research published in The Journal of Physiology shows that a short but intense bout of cycling increases the production of a specialised protein that is essential for brain formation, learning and memory, and could protect the brain from age-related cognitive decline. This insight on exercise is part of the drive to develop accessible, equitable and affordable non-pharmacological approaches that anyone can adopt to promote healthy ageing.  

The specialised protein named brain-derived neurotrophic factor (BDNF) promotes neuroplasticity (the ability of the brain to form new connections and pathways) and the survival of neurons. Animal studies have shown that increasing the availability of BDNF encourages the formation and storage of memories, enhances learning and overall boosts cognitive performance. These key roles and its apparent neuroprotective qualities have led to the interest in BDNF for ageing research.

Lead author Travis Gibbons from University of Otago, New Zealand said: “BDNF has shown great promise in animal models, but pharmaceutical interventions have thus far failed to safely harness the protective power of BDNF in humans. We saw the need to explore non-pharmacological approaches that can preserve the brain’s capacity which humans can use to naturally increase BDNF to help with healthy ageing.”

To tease apart the influence of fasting and exercise on BDNF production the researchers, from the University of Otago, New Zealand, compared the following factors to study the isolated and interactive effects:

• Fasting for 20 hours,

• Light exercise (90-minute low intensity cycling),

• High-intensity exercise (six-minute bout of vigorous cycling),

• Combined fasting and exercise.

They found that brief but vigorous exercise was the most efficient way to increase BDNF compared to one day of fasting with or without a lengthy session of light exercise. BDNF increased by four to five-fold (396 pg L-1 to 1170 pg L-1) more compared to fasting (no change in BDNF concentration) or prolonged activity (slight increase in BDNF concentration, 336 pg L-1 to 390 pg L-1).

The cause for these differences is not yet known and more research is needed to understand the mechanisms involved. One hypothesis is related to the cerebral substrate switch and glucose metabolism, the brain’s primary fuel source. The cerebral substrate switch is when the brain switches its favoured fuel source for another to ensure the body’s energy demands are met, for example metabolising lactate rather than glucose during exercise. The brain’s transition from consuming glucose to lactate initiates pathways that result in elevated levels of BDNF in the blood.

The observed increase in BDNF during exercise could be due to the increased number of platelets (the smallest blood cell) which store large amounts of BDNF. The concentration of platelets circulating in the blood is more heavily influenced by exercise than fasting and increases by 20%.

12 physically active participants (six males, six females aged between 18 and 56 years) took part in the study. The balanced ratio of male and female participants was to provide a better representation of the population rather than indicate sex differences.

Further research is underway to delve deeper into the effects of calorie restriction and exercise to distinguish the influence on BDNF and the cognitive benefits.

Travis Gibbons said: “We are now studying how fasting for longer durations, for example up to three days, influences BDNF. We are curious whether exercising hard at the start of a fast accelerates the beneficial effects of fasting. Fasting and exercise are rarely studied together. We think fasting and exercise can be used in conjunction to optimise BDNF production in the human brain.”

https://www.sciencedaily.com/releases/2023/01/230112090919.htm

New study links hearing loss with dementia in older adults

Findings highlight potential benefit of hearing aid

January 10, 2023

Science Daily/Johns Hopkins Bloomberg School of Public Health

A new study led by researchers at the Johns Hopkins Bloomberg School of Public Health found that older adults with greater severity of hearing loss were more likely to have dementia, but the likelihood of dementia was lower among hearing aid users compared to non-users.

The findings, from a nationally representative sample of more than 2,400 older adults, are consistent with prior studies showing that hearing loss might be a contributing factor to dementia risk over time, and that treating hearing loss may lower dementia risk.

The findings are highlighted in a research letter published online January 10 in the Journal of the American Medical Association.

"This study refines what we've observed about the link between hearing loss and dementia, and builds support for public health action to improve hearing care access," says lead author Alison Huang, PhD, MPH, a senior research associate in the Bloomberg School's Department of Epidemiology and at the Cochlear Center for Hearing and Public Health, also at the Bloomberg School.

Hearing loss is a critical public health issue affecting two-thirds of Americans over 70. The growing understanding that hearing loss might be linked to the risk of dementia, which impacts millions, and other adverse outcomes has called attention to implementing possible strategies to treat hearing loss.

For the new study, Huang and colleagues analyzed a nationally representative dataset from the National Health and Aging Trends Study (NHATS). Funded by the National Institute on Aging, the NHATS has been ongoing since 2011, and uses a nationwide sample of Medicare beneficiaries over age 65, with a focus on the 90-and-over group as well as Black individuals.

The analysis covered 2,413 individuals, about half of whom were over 80 and showed a clear association between severity of hearing loss and dementia. Prevalence of dementia among the participants with moderate/severe hearing loss was 61 percent higher than prevalence among participants who had normal hearing. Hearing aid use was associated with a 32 percent lower prevalence of dementia in the 853 participants who had moderate/severe hearing loss.

The authors note that many past studies were limited in that they relied on in-clinic data collection, leaving out vulnerable populations that did not have the means or capacity to get to a clinic. For their study, the researchers collected data from participants through in-home testing and interviews.

How hearing loss is linked to dementia isn't yet clear, and studies point to several possible mechanisms. Huang's research adds to a body of work by the Cochlear Center for Hearing and Public Health examining the relationship between hearing loss and dementia.

The study authors expect to have a fuller picture of the effect of hearing loss treatment on cognition and dementia from their Aging and Cognitive Health Evaluation in Elders (ACHIEVE) Study. Results from the three-year randomized trial are expected this year.

https://www.sciencedaily.com/releases/2023/01/230110150943.htm

Smoking increases chances of mid-life memory loss, confusion

Study findings support quitting for brain benefits, researchers say

December 21, 2022

Science Daily/Ohio State University

Middle-aged smokers are far more likely to report having memory loss and confusion than nonsmokers, and the likelihood of cognitive decline is lower for those who have quit, even recently, a new study has found.

The research from The Ohio State University is the first to examine the relationship between smoking and cognitive decline using a one-question self-assessment asking people if they've experienced worsening or more frequent memory loss and/or confusion.

The findings build on previous research that established relationships between smoking and Alzheimer's Disease and other forms of dementia, and could point to an opportunity to identify signs of trouble earlier in life, said Jenna Rajczyk, lead author of the study, which appears in the Journal of Alzheimer's Disease.

It's also one more piece of evidence that quitting smoking is good not just for respiratory and cardiovascular reasons -- but to preserve neurological health, said Rajczyk, a PhD student in Ohio State's College of Public Health, and senior author Jeffrey Wing, assistant professor of epidemiology.

"The association we saw was most significant in the 45-59 age group, suggesting that quitting at that stage of life may have a benefit for cognitive health," Wing said. A similar difference wasn't found in the oldest group in the study, which could mean that quitting earlier affords people greater benefits, he said.

Data for the study came from the national 2019 Behavioral Risk Factor Surveillance System

Survey and allowed the research team to compare subjective cognitive decline (SCD) measures for current smokers, recent former smokers, and those who had quit years earlier. The analysis included 136,018 people 45 and older, and about 11% reported SCD.

The prevalence of SCD among smokers in the study was almost 1.9 times that of nonsmokers. The prevalence among those who had quit less than 10 years ago was 1.5 times that of nonsmokers. Those who quit more than a decade before the survey had an SCD prevalence just slightly above the nonsmoking group.

"These findings could imply that the time since smoking cessation does matter, and may be linked to cognitive outcomes," Rajczyk said.

The simplicity of SCD, a relatively new measure, could lend itself to wider applications, she said.

"This is a simple assessment that could be easily done routinely, and at younger ages than we typically start to see cognitive declines that rise to the level of a diagnosis of Alzheimer's Disease or dementia," Rajczyk said. "It's not an intensive battery of questions. It's more a personal reflection of your cognitive status to determine if you're feeling like you're not as sharp as you once were."

Many people don't have access to more in-depth screenings, or to specialists -- making the potential applications for measuring SCD even greater, she said.

Wing said it's important to note that these self-reported experiences don't amount to a diagnosis, nor do they confirm independently that a person is experiencing decline out of the normal aging process. But, he said, they could be a low-cost, simple tool to consider employing more broadly.

https://www.sciencedaily.com/releases/2022/12/221221121301.htm

During sleep, brain regions synchronize to create motor memory

December 19, 2022

Science Daily/University of California - San Francisco

When the Golden State Warriors' Steph Curry makes a free throw, his brain draws on motor memory. Now researchers at UC San Francisco (UCSF) have shown how this type of memory is consolidated during sleep, when the brain processes the day's learning to make the physical act of doing something subconscious.

The study, published Dec. 14, 2022, in Nature, shows the brain does this by reviewing the trials and errors of a given action. In the analogy, that means sorting through all the free throws Curry has ever thrown, weeding out the memory of all the actions except those that hit the mark, or that the brain decided were "good enough." The result is the ability to make the free throw with a high degree of accuracy without having to think about the physical movements involved.

"Even elite athletes makes errors, and that's what makes the game interesting," said Karunesh Ganguly, MD, PhD, a professor of neurology and member of the UCSF Weill Institute for Neurosciences. "Motor memory isn't about perfect performance. It's about predictable errors and predictable successes. As long as the errors are stable from day to day, the brain says, 'Let's just lock this memory in.'"

Ganguly and his team found that the "locking in" process involves some surprisingly complex communication between different parts of the brain and takes place during the deep restorative slumber known as non-REM sleep.

Sleep is important because our conscious brains tend to focus on the failures, said Ganguly, who previously identified the sleep-associated brain waves that influence skill retention.

"During sleep, the brain is able to sift through all the instances it's taken in and bring forward the patterns that were successful," he said.

Earthbound Motor Skills Wouldn't Work on Avatar's Planet Pandora

It was once thought that learning motor skills only required the motor cortex. But in recent years a more complex picture has emerged.

To look into this process more closely, Ganguly set rats on a task to reach for pellets. Then, the team looked at their brain activity in three regions during NREM sleep: the hippocampus, which is the region responsible for memory and navigation, the motor cortex and the prefrontal cortex (PFC).

Over the course of 13 days, a pattern emerged.

First, in a process called "fast learning," the PFC coordinated with the hippocampus, likely enabling the animal to perceive its motion with respect to the space around it and its location in that space. In this phase, the brain seemed to be exploring and comparing all the actions and patterns created while practicing the task.

Second, in a process called slow learning, the PFC appeared to make value judgements, likely driven by reward centers that were activated when the task was successful. It engaged in crosstalk with the motor cortex and the hippocampus, turning down the signals related to failures and turning up the ones related to successes.

Finally, as the electrical activity of the regions became synchronized, the role of the hippocampus diminished and the instances the brain had noted as rewarding came to the fore, where they were stored in what we call "motor memory."

While the rats were initially learning the task, their brain signals were noisy and disorganized. As time went on, Ganguly could see the signals synchronizing, until the rats were succeeding about 70 percent of the time. After that point, the brain seemed to ignore mistakes and maintained the motor memory as long as the level of success was stable. In other words, the brain starts to expect a certain level of error and does not update the motor memory.

Just like NBA players, the rats mastered a skill based on a mental model of how the world works, which they created from their physical experience with gravity, space and other cues. But this kind of motor learning wouldn't easily transfer to a situation where the cues and physical environment were different.

"If all that changed, for example, if Steph Curry was in the world of Avatar, he might not look as skilled initially," Ganguly said.

The Best Way to Break a Habit

What if Curry hurt a finger and had to learn to shoot baskets a little differently? The study offered an answer.

"It's possible to unlearn a task, but to do that, you have to stress the situation to a point where you're making mistakes," Ganguly said.

When the researchers made a slight change to the rats' pellet procurement task, the rats would make more mistakes and the researchers saw more noise in the rats' brain activity.

The change was small enough that the rats didn't have to go all the way back to the beginning of their learning, only to the "breaking point," and relearn the task from there.

But because motor memory gets ingrained as a set of motions that follow each other in time, Ganguly said, changing motor memory in a complex motion like free throwing a basketball might require changing a motion that is used to initiate the whole sequence.

If Curry usually bounces a basketball twice before he throws, Ganguly said, "It might be best to retrain the brain by bouncing it only once, or three times. That way, you'd start with a clean slate."

https://www.sciencedaily.com/releases/2022/12/221219164831.htm

Patterns of lifespan weight gain/loss may predict dementia risk

Monitoring risk indicators such as weight patterns offer opportunities for early intervention

December 15, 2022

Science Daily/Boston University School of Medicine

Dementia is a growing global public health concern currently affecting 50 million people and is expected to rise dramatically to more than 150 million cases worldwide by 2050. Obesity, commonly measured by body mass index (BMI), continues to be a global epidemic and earlier studies suggested that obesity at midlife may lead to increased risk for dementia. But the association between BMI and the risk of dementia remains unclear.

Now, researchers from Boston University Chobanian & Avedisian School of Medicine and Chinese Academy of Medical Sciences & Peking Union Medical College, have found that different patterns of BMI changes over one's life course may be an indicator of a person's risk for dementia.

"These findings are important because previous studies that looked at weight trajectories didn't consider how patterns of weight gain/stability/loss might help signal that dementia is potentially imminent," explained corresponding author Rhoda Au, PhD, professor of anatomy and neurobiology.

Through the Framingham Heart Study, a group of participants was followed for 39 years and their weight was measured approximately every 2-4 years. The researchers compared different weight patterns (stable, gain, loss) among those who did and did not become demented.

They found the overall trend of declining BMI was associated with a higher risk of developing dementia. However, after further exploration, they found a subgroup with a pattern of initial increasing BMI followed by declining BMI, both occurring within midlife, which appeared to be central to the declining BMI-dementia association.

Au points out that for individuals, family members, and primary care physicians, it is relatively easy to monitor weight. "If after a steady increase in weight that is common as one gets older, there is an unexpected shift to losing weight post midlife, it might be good to consult with one's healthcare provider and pinpoint why. There are some potential treatments emerging where early detection might be critical in the effectiveness of any of these treatments as they are approved and become available," she adds.

The researchers hope this study will illustrate that the seeds for dementia risk are being sowed across many years, likely even across the entire lifespan. "Dementia is not necessarily inevitable and monitoring risk indicators such as something as easy to notice as weight patterns, might offer opportunities for early intervention that can change the trajectory of disease onset and progression."

https://www.sciencedaily.com/releases/2022/12/221215104559.htm

Discovery could explain why women are more likely to get Alzheimer's

December 14, 2022

Science Daily/Scripps Research Institute

Scientists at Scripps Research and Massachusetts Institute of Technology (MIT) have found a clue to the molecular cause of Alzheimer's -- a clue that may also explain why women are at greater risk for the disease.

In the study, reported on December 14, 2022, in Science Advances, the researchers found that a particularly harmful, chemically modified form of an inflammatory immune protein called complement C3 was present at much higher levels in the brains of women who had died with the disease, compared to men who had died with the disease. They also showed that estrogen -- which drops in production during menopause -- normally protects against the creation of this form of complement C3.

"Our new findings suggest that chemical modification of a component of the complement system helps drive Alzheimer's, and may explain, at least in part, why the disease predominantly affects women," says study senior author Stuart Lipton, MD, PhD, professor and Step Family Foundation Endowed Chair in the Department of Molecular Medicine at Scripps Research and a clinical neurologist in La Jolla, California.

The study was a collaboration with a team led by Steven Tannenbaum, PhD, Post Tenure Underwood-Prescott Professor of Biological Engineering, Chemistry and Toxicology at MIT.

Alzheimer's, the most common form of dementia that occurs with aging, currently afflicts about six million people in the U.S. alone. It is always fatal, usually within a decade of onset, and there is no approved treatment that can halt the disease process, let alone reverse it. The shortcomings of treatments reflect the fact that scientists have never fully understood how Alzheimer's develops. Scientists also don't know fully why women account for nearly two-thirds of cases.

Lipton's lab studies biochemical and molecular events that may underlie neurodegenerative diseases, including the chemical reaction that forms a modified type of complement C3 -- a process called protein S-nitrosylation. Lipton and his colleagues previously discovered this chemical reaction, which happens when a nitric oxide (NO)-related molecule binds tightly to a sulfur atom (S) on a particular amino acid building-block of proteins to form a modified "SNO-protein." Protein modifications by small clusters of atoms such as NO are common in cells and typically activate or deactivate a target protein's functions. For technical reasons, S-nitrosylation has been more difficult to study than other protein modifications, but Lipton suspects that "SNO-storms" of these proteins could be a key contributor to Alzheimer's and other neurodegenerative disorders.

For the new study, the researchers used novel methods for detecting S-nitrosylation to quantify proteins modified in 40 postmortem human brains. Half of the brains were from people who had died of Alzheimer's, and half were from people who hadn't -- and each group was divided equally between males and females.

In these brains, the scientists found 1,449 different proteins that had been S-nitrosylated. Among the proteins most often modified in this way, there were several that have already been tied to Alzheimer's, including complement C3. Strikingly, the levels of S-nitrosylated C3 (SNO-C3) were more than six-fold higher in female Alzheimer's brains compared to male Alzheimer's brains.

The complement system is an evolutionarily older part of the human immune system. It consists of a family of proteins, including C3, that can activate one another to drive inflammation in what is called the "complement cascade." Scientists have known for more than 30 years that Alzheimer's brains have higher levels of complement proteins and other markers of inflammation, compared to neurologically normal brains. More recent research has shown specifically that complement proteins can trigger brain-resident immune cells called microglia to destroy synapses -- the connection points through which neurons send signals to one another. Many researchers now suspect that this synapse-destroying mechanism at least partly underlies the Alzheimer's disease process, and loss of synapses has been demonstrated to be a significant correlate of cognitive decline in Alzheimer's brains.

Why would SNO-C3 be more common in female brains with Alzheimer's? There has long been evidence that the female hormone estrogen can have brain-protective effects under some conditions; thus, the researchers hypothesized that estrogen specifically protects women's brains from C3 S-nitrosylation -- and this protection is lost when estrogen levels fall sharply with menopause. Experiments with cultured human brain cells supported this hypothesis, revealing that SNO-C3 increases as estrogen (?-estradiol) levels fall, due to the activation of an enzyme that makes NO in brain cells. This increase in SNO-C3 activates microglial destruction of synapses.

"Why women are more likely to get Alzheimer's has long been a mystery, but I think our results represent an important piece of the puzzle that mechanistically explains the increased vulnerability of women as they age," Lipton says.

He and his colleagues now hope to conduct further experiments with de-nitrosylating compounds -- which remove the SNO modification -- to see if they can reduce pathology in animal models of Alzheimer's and eventually in humans.

https://www.sciencedaily.com/releases/2022/12/221214180658.htm

Playing the piano boosts brain processing power and helps lift the blues

December 2, 2022

Science Daily/University of Bath

A new study published by researchers at the University of Bath demonstrates the positive impact learning to play a musical instrument has on the brain's ability to process sights and sounds, and shows how it can also help to lift a blue mood.

Publishing their findings in the academic journal Nature Scientific Reports, the team behind the study shows how beginners who undertook piano lessons for just one hour a week over 11 weeks reported significant improvements in recognising audio-visual changes in the environment and reported less depression, stress and anxiety.

In the randomised control study, 31 adults were assigned into either a music training, music listening, or a control group. Individuals with no prior musical experiences or training were instructed to complete weekly one-hour sessions. Whilst the intervention groups played music, the control groups either listened to music or used the time to complete homework.

The researchers found that within just a few weeks of starting lessons*, people's ability to process multisensory information -- i.e., sight and sound -- was enhanced. Improved 'multisensory process' has benefits for almost every activity we participate in -- from driving a car and crossing a road, to finding someone in a crowd or watching TV.

These multisensory improvements extended beyond musical abilities. With musical training, people's audio-visual processing became more accurate across other tasks. Those who received piano lessons showed greater accuracy in tests where participants were asked to determine whether sound and vision 'events' occurred at the same time.

This was true both for simple displays presenting flashes and beeps, and for more complex displays showing a person talking. Such fine-tuning of individuals' cognitive abilities was not present for the music listening group (where participants listened to the same music as played by the music group), or for the non-music group (where members studied or read).

In addition, the findings went beyond improvements in cognitive abilities, showing that participants also had reduced depression, anxiety and stress scores after the training compared to before it. The authors suggest that music training could be beneficial for people with mental health difficulties, and further research is currently underway to test this.

Cognitive psychologist and music specialist Dr Karin Petrini from the University of Bath's Department of Psychology, explained: "We know that playing and listening to music often brings joy to our lives, but with this study we were interested in learning more about the direct effects a short period of music learning can have on our cognitive abilities.

"Learning to play an instrument like the piano is a complex task: it requires a musician to read a score, generate movements and monitor the auditory and tactile feedback to adjust their further actions. In scientific terms, the process couples visual with auditory cues and results in a multisensory training for individuals.

"The findings from our study suggest that this has a significant, positive impact on how the brain processes audio-visual information even in adulthood when brain plasticity is reduced."

Notes

·       Each music training session included two segments. The first 20-minute segment was dedicated to finger exercise. The second segment consisted of learning songs from the ABRSM 2017-2018 piano grade one exam list for 40 minutes. All training sessions were carried out on a one-to-one basis. Participants learned these pieces in the order presented below. They proceeded to the next song once they could play the former one correctly and fluently:

·       William Gillock A Stately Sarabande. Classic Piano Repertoire (Elementary).

·       Johann Christian Bach Aria in F, BWV Anh. II 131.

·       Giuseppe Verdi La donna è mobile (from Rigoletto).

·       Bryan Kelly Gypsy Song: No. 6 from A Baker's Dozen.

·       Traditional American Folk Song: When the saints go marching in.

https://www.sciencedaily.com/releases/2022/12/221202124841.htm

Small studies of 40Hz sensory stimulation confirm safety, suggest Alzheimer's benefits

December 1, 2022

Science Daily/Picower Institute at MIT

Researchers report early stage clinical study results of tests with non-invasive 40Hz light and sound treatment.

A pair of early stage clinical studies testing the safety and efficacy of 40Hz sensory stimulation to treat Alzheimer's disease has found that the potential therapy was well tolerated, produced no serious adverse effects and was associated with some significant neurological and behavioral benefits among a small cohort of participants.

"In these clinical studies we were pleased to see that volunteers did not experience any safety issues and used our experimental light and sound devices in their homes consistently," said Li-Huei Tsai, Picower Professor in the The Picower Institute for Learning and Memory at MIT and senior author of the paper describing the studies in PLOS ONE Dec. 1. "While we are also encouraged to see some significant positive effects on the brain and behavior, we are interpreting them cautiously given our study's small sample size and brief duration. These results are not sufficient evidence of efficacy, but we believe they clearly support proceeding with more extensive study of 40Hz sensory stimulation as a potential non-invasive therapeutic for Alzheimer's disease."

In three studies spanning 2016-2019, Tsai's lab discovered that exposing mice to light flickering or sound clicking at the gamma-band brain rhythm frequency of 40Hz -- or employing the light and sound together -- produced widespread beneficial effects. Treated mice modeling Alzheimer's disease pathology experienced improvements in learning and memory; reduced brain atrophy, neuron and synapse loss; and showed lower levels of the hallmark Alzheimer's proteins amyloid beta and phosphorylated tau compared to untreated controls. The stimulation appears to produce these effects by increasing the power and synchrony of the 40Hz brain rhythm, which the lab has shown profoundly affects the activity of several types of brain cells, including the brain's vasculature.

Study designs

Based on those encouraging results, Diane Chan, a neurologist at Massachusetts General Hospital and a postdoctoral clinical fellow in Tsai's lab, led the two new clinical studies at MIT. One set of tests, a "Phase 1" study, enrolled 43 volunteers of various ages including 16 people with early stage Alzheimer's to confirm that exposure to 40Hz light and sound was safe and test whether it increased 40Hz rhythm and synchrony after a few minutes of exposure, as measured with EEG electrodes. The study also included two patients with epilepsy at the University of Iowa who consented to having measurements taken in deeper brain structures during exposure to 40Hz sensory stimulation while undergoing epilepsy-related surgery.

The second set of tests, a "Phase 2A" pilot study, enrolled 15 people with early stage Alzheimer's disease in a single-blinded, randomized, controlled study to receive exposure to 40Hz light and sound (or non-40Hz "sham" stimulation for experimental controls) for an hour a day for at least three months. They underwent baseline and follow-up visits including EEG measurements during stimulation, MRI scans of brain volume, and cognitive testing. The stimulation device the volunteers used in their homes (a light panel synchronized with a speaker) was equipped with video cameras to monitor device usage. Participants also wore sleep-monitoring bracelets during their participation in the trial.

The Phase 2A trial launched just before the onset of the Covid-19 pandemic in 2020, causing some participants to become unable to undergo follow ups after three months. The study therefore only reports results through a four-month period.

Study results

In the Phase 1 study volunteers filled out a questionnaire on side effects, reporting a few minor but no major adverse effects. The most common was feeling "sleepy or drowsy." Meanwhile, measurements taken with EEG scalp electrodes clustered at frontal and occipital sites showed significant increases in 40Hz rhythm power at each cortical site among cognitively normal younger and older participants as well as volunteers with mild Alzheimer's. The readings also demonstrated significant increase in coherence at the 40Hz frequency between the two sites. Between the two volunteers with epilepsy, measurements showed significant increases in 40Hz power in deeper brain regions such as the gyrus rectus, amygdala, hippocampus and insula with no adverse events including seizures.

In the Phase 2A study, neither treated nor control volunteers reported serious adverse events. Both groups used their devices 90 percent of the time. The eight volunteers treated with 40Hz stimulation experienced several beneficial effects that reached statistical significance compared to the seven volunteers in the control condition. Control participants exhibited two signs of brain atrophy as expected with disease progression: reduced volume of the hippocampus and increased volume of open spaces, or ventricles. Treated patients did not experience significant changes in these measures. Treated patients also exhibited better connectivity across brain regions involved in the brain's default mode and medial visual networks, which are related to cognition and visual processing respectively. Treated patients also exhibited more consistent sleep patterns than controls.

Neither the treatment and control groups showed any differences after just three months on most cognitive tests, but the treatment group did perform significantly better on a face-name association test, a memory task with a strong visual component. The two groups, which were evenly matched by age, gender, APOE risk gene status, and cognitive scores, differed by years of education but that difference had no relationship to the results, the researchers wrote.

"After such a short time we didn't expect to see significant effects on cognitive measures so it was encouraging to see that at least on face-name association the treatment group did perform significantly better," Chan said.

In PLOS ONE the researchers concluded: "Overall, these findings suggest that 40Hz GENUS has positive effects on AD-related pathology and symptoms and should be studied more extensively to evaluate its potential as a disease-modifying intervention for AD."

After the study ended all participants were permitted to continue using the devices set to provide the 40Hz stimulation.

The MIT team is now planning new clinical studies to test whether 40Hz sensory stimulation may be effective in preventing the onset of Alzheimer's in high-risk volunteers and is launching preliminary studies to determine its therapeutic potential for Parkinson's disease and Down syndrome. Cognito Therapeutics, an MIT spin-off company co-founded by Tsai and co-author Ed Boyden, Y. Eva Tan Professor of Neurotechnology at MIT, has launched Phase 3 trials of 40Hz sensory stimulation as an Alzheimer's treatment using a different device.

Tsai, Boyden and co-author Emery N. Brown, Edward Hood Taplin Professor of Computational Neuroscience and Medical Engineering at MIT, are among the co-founders of MIT's Aging Brain Initiative, which has advanced this collaboration and other neurodegeneration research at MIT.

In addition to Tsai, Chan, Boyden and Brown, the study's other authors are Ho-Jun Suk, Brennan Jackson, Noah Milman, Danielle Stark, Elizabeth Klerman, Erin Kitchener, Vanesa S. Fernandez Avalos, Gabrielle de Weck, Arit Banerjee, Sara D. Beach, Joel Blanchard, Colton Stearns, Aaron D. Boes, Brandt Uitermarkt, Phillip Gander, Matthew Howard III, Eliezer J. Sternberg, Alfonso Nieto-Castanon, Sheeba Anteraper, Susan Whitfield-Gabrieli, and Bradford C. Dickerson.

Funding for the study came from sources including the Robert A. and Renee E. Belfer Family Foundation, Ludwig Family Foundation, JPB Foundation, Eleanor Schwartz Charitable Foundation, the Degroof-VM Foundation, Halis Family Foundation, and David B Emmes, Gary Hua and Li Chen, the Ko Han Family, Lester Gimpelson, Elizabeth K. and Russell L. Siegelman, Joseph P. DiSabato and Nancy E. Sakamoto, Alan and Susan Patricof, Jay L. and Carroll D Miller, Donald A. and Glenda G. Mattes, the Marc Haas Foundation, Alan Alda, and Dave Wargo.

https://www.sciencedaily.com/releases/2022/12/221201163449.htm

Nightmares in middle age linked to dementia risk

September 21, 2022

Science Daily/University of Birmingham

People who experience frequent bad dreams in middle age are more likely to be diagnosed with dementia later in life, according to research at the University of Birmingham.

A new study, published in The Lancet journal, eClinicalMedicine, suggests nightmares may become prevalent several years or even decades before the characteristic memory and thinking problems of dementia set in.

Dr Abidemi Otaiku, of the University of Birmingham's Centre for Human Brain Health, said: "We've demonstrated for the first time that distressing dreams, or nightmares, can be linked to dementia risk and cognitive decline among healthy adults in the general population.

"This is important because there are very few risk indicators for dementia that can be identified as early as middle age. While more work needs to be done to confirm these links, we believe bad dreams could be a useful way to identify individuals at high risk of developing dementia, and put in place strategies to slow down the onset of disease."

In the study, Dr Otaiku examined data from three community-based cohorts in the USA. These included more than 600 adult men and women aged between 35 and 64; and 2,600 adults aged 79 and older. All the participants were dementia-free at the start of the study and followed up for an average of nine years for the younger group and five years for the older participants.

The study started collecting data between 2002 and 2012. Participants completed a range of questionnaires, including the Pittsburgh Sleep Quality Index, which includes a question on how often individuals experienced bad dreams.

This data was analysed using statistical software to find out whether participants with a higher frequency of nightmares were more likely to go on to experience cognitive decline and be diagnosed with dementia.

The research shows that middle-aged people (35-64) who experience bad dreams on a weekly basis are four times more likely to experience cognitive decline over the following decade, while older people were twice as likely to be diagnosed with dementia.

Interestingly, the study found that the associations were much stronger for men than for women. For example, older men experiencing nightmares on a weekly basis were five times more likely to develop dementia than older men reporting no bad dreams. In women, however, the increase in risk was only 41 per cent.

Next steps for the research will include investigating whether nightmares among young people could be associated with future dementia risk, and whether other dream characteristics, such as how often we remember dreams and how vivid they are, could also be used to identify dementia risk. Using electroencephalography (EEG) and magnetic resonance imaging (MRI), the researchers also plan to investigate the biological basis of bad dreams in both healthy people and people with dementia.

https://www.sciencedaily.com/releases/2022/09/220921093009.htm

New method could aid Alzheimer's research by predicting risk before symptoms start

Researchers demonstrate how DNA-based method enables nomination of key proteins linked to Alzheimer's

Science Daily/September 1, 2022

PLOS

Researchers have developed a new method to identify people who are at greater genetic risk of developing Alzheimer's disease before any symptoms appear -- which could help speed creation of novel treatments. Manish Paranjpe of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, United States, and colleagues present these findings in the open-access journal PLOS Genetics on September 1.

People with Alzheimer's disease experience gradual loss of memory and other cognitive functions. While some treatments can ease symptoms, it has been challenging to develop treatments to prevent or slow disease progression. Some clinical trials investigating potential treatments may have been unsuccessful because they involved patients whose disease was too advanced to be treated. Better methods to identify people at high risk of developing Alzheimer's could aid treatment research.

To help meet that need, Paranjpe and colleagues analyzed data on 7.1 million common DNA variants -- alterations to the standard DNA sequence -- from an earlier study that included tens of thousands of people with or without Alzheimer's. They used this data to develop a novel method that predicts a person's risk of Alzheimer's, depending on which DNA variants the person has. Then, they refined and validated the method with data from more than 300,000 additional people.

The researchers note that their DNA-based method is unlikely to be suitable for doctors to predict a patient's risk of Alzheimer's because it may be less accurate for non-European populations, it could impact insurance, and it could cause anxiety without the relief of reliable preventive treatments. However, it could be applied to speed Alzheimer's research.

To demonstrate the potential of the new method, the researchers applied it to determine the risk of Alzheimer's for each of 636 blood donors and examined whether blood levels of any of 3,000 proteins were higher or lower than normal for those identified as being high-risk. The analysis surfaced 28 proteins that could be linked to Alzheimer's risk, including several that have never been studied in Alzheimer's research. Studying these proteins could uncover new directions for drug development.

Future research could help replicate and confirm these findings and expand on them, such as by considering populations with non-European ancestry.

Senior author Dr. Amit V. Khera adds, "We developed a genetic predictor of Alzheimer's disease associated with both clinical diagnosis and age-dependent cognitive decline. By studying the circulating proteome of healthy individuals with very high versus low inherited risk, our team nominated new biomarkers of neurocognitive disease."

https://www.sciencedaily.com/releases/2022/09/220901151607.htm

Music helps patients with dementia connect with loved ones

Novel music intervention sparks emotional connection between patients and caregivers

August 29, 2022

Science Daily/Northwestern University

People with dementia often lose their ability to communicate verbally with loved ones in later stages of the disease. But a Northwestern Medicine study, in collaboration with Institute for Therapy through the Arts (ITA), shows how that gap can be bridged with a new music intervention.

In the intervention -- developed at ITA and called "Musical Bridges to Memory" -- a live ensemble plays music from a patient's youth such as songs from the musicals "Oklahoma" or "The Sound of Music." This creates an emotional connection between a patient and their caregiver by allowing them to interact with the music together via singing, dancing and playing simple instruments, the study authors said.

The program also enhanced patients' social engagement and reduced neuropsychiatric symptoms such as agitation, anxiety and depression in both patients and caregivers.

More than 6 million people in the U.S. have Alzheimer's disease.

The study is unusual because it targeted patients with dementia and their caregivers, said lead study author Dr. Borna Bonakdarpour. Most prior studies using music for dementia patients have focused only on the patients.

"Patients were able to connect with partners through music, a connection that was not available to them verbally," said Bonakdarpour, an associate professor of neurology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine neurologist. "The family and friends of people with dementia also are affected by it. It's painful for them when they can't connect with a loved one. When language is no longer possible, music gives them a bridge to each other."

The study was published Aug. 25 in Alzheimer Disease and Associated Disorders.

Musical memory, processing not as affected by Alzheimer's

Music memories often remain in the brain even as language and other memories disappear in dementia, Bonakdarpour said. This is because regions of the brain that are involved in musical memory and processing (e.g., the cerebellum) are not as affected by Alzheimer's or dementia until much later in the disease course. Thus, patients can retain the ability to dance and sing long after their ability to talk has diminished.

How the study worked

In the study, individuals with dementia -- residents of Silverado Memory Care (in a suburb of Chicago) -- and their care partners were recorded on video conversing and interacting for 10 minutes before and 10 minutes after the intervention. Before playing the music, each patient/caregiver pair had training on how to interact more effectively during the music.

During the 45-minute musical intervention, an ensemble of chamber musicians and a singer performed songs that appealed to the patients from their younger days. The patients and their caregivers received simple instruments such as tambourines and shakers to accompany the music. Specially trained music therapists interacted with patients during performances, getting them to beat on drums, sing and dance.

A group conversation followed the music. Patients were more socially engaged as evidenced by more eye contact, less distraction, less agitation and an elevated mood. In comparison, the control group, which did not receive the intervention and were exposed to usual daily care and programs, did not show such changes within the same time frame.

The program included 12 sessions over three months.

'All could relate to their loved one'

Before the intervention, some individuals would not communicate much with their partners. However, during the intervention, they started to play, sing and dance together, which was a significant change for the family. These changes generalized to their behavior outside the sessions as well.

"As the program progressed, caregivers invited multiple family members," said Jeffrey Wolfe, a neurologic music therapist-fellow at ITA and leader of the Musical Bridges to Memory program. "It became a normalizing experience for the whole family. All could relate to their loved one despite their degree of dementia."

The next step in the research is to conduct the study on a larger group of patients. ITA and Northwestern have been funded by a three-year grant through the National Endowment for the Arts to expand this study.

https://www.sciencedaily.com/releases/2022/08/220829143926.htm

Poor heart health predicts premature brain aging

August 22, 2022

Science Daily/University College London

By estimating people's brain age from MRI scans using machine learning, a team led by UCL researchers has identified multiple risk factors for a prematurely ageing brain.

They found that worse cardiovascular health at age 36 predicted a higher brain age later in life, while men also tended to have older brains than women of the same age, as they report in The Lancet Healthy Longevity.

A higher brain age was associated with slightly worse scores on cognitive tests, and also predicted increased brain shrinkage (atrophy) over the following two years, suggesting it could be an important clinical marker for people at risk of cognitive decline or other brain-related ill health.

Lead author Professor Jonathan Schott (UCL Dementia Research Centre, UCL Queen Square Institute of Neurology) said: "We found that despite people in this study all being of very similar real ages, there was a very wide variation in how old the computer model predicted their brains to be. We hope this technique could one day be a useful tool for identifying people at risk of accelerated ageing, so that they may be offered early, targeted prevention strategies to improve their brain health."

The researchers applied an established MRI based machine learning model to estimate the brain age of members of the Alzheimer's Research UK-funded Insight 46 study, led by Professor Schott. Insight 46 study members are drawn from the Medical Research Council National Survey of Health and Development (NSHD) 1946 British Birth Cohort. As the participants had been a part of the study throughout their lives, the researchers were able to compare their current brain ages to various factors from across the life course.

The participants were all between 69 and 72 years old, but their estimated brain ages ranged from 46 to 93.

The researchers were able to explain roughly one third of the variability in brain age by reviewing various factors from across the life course.

People with worse cardiovascular health at age 36 or 69 had worse brain health, as did those with increased cerebrovascular disease on MRI (relating to blood flow and blood vessels in the brain). This aligns with a previous study led by Professor Schott finding that high blood pressure at age 36 predicted poorer brain health late in life.

The study did not identify any associations between childhood cognitive function, education level or socioeconomic status, and a prematurely ageing brain.

The researchers also found that higher brain age was associated with higher concentration of neurofilament light protein (NfL) in the blood. NfL elevation is thought to arise due to nerve cell damage and is increasingly being recognised as a useful marker of neurodegeneration.

Dr Sara Imarisio, Head of Research at Alzheimer's Research UK, said: "The Insight 46 study is helping reveal more about the complex relationship between the different factors influencing people's brain health throughout their life. Using machine learning, researchers in this study have uncovered yet more evidence that poorer heart health in midlife is linked to greater brain shrinkage in later life. We're incredibly grateful to the dedicated group of individuals who have contributed to research their entire lives making this work possible."

https://www.sciencedaily.com/releases/2022/08/220822184219.htm

What older adults do while they sit affects dementia risk

August 22, 2022

Science Daily/University of Southern California

Adults aged 60 and older who sit for long periods watching TV or other such passive, sedentary behaviors may be at increased risk of developing dementia, according to a new study by USC and University of Arizona researchers.

Their study also showed that the risk is lower for those who are active while sitting, such as when they read or use computers.

The study was published today in the journal Proceedings of the National Academy of Sciences. It also revealed that the link between sedentary behavior and dementia risk persisted even among participants who were physically active.

"It isn't the time spent sitting, per se, but the type of sedentary activity performed during leisure time that impacts dementia risk," said study author David Raichlen, professor of biological sciences and anthropology at the USC Dornsife College of Letters, Arts and Sciences.

"We know from past studies that watching TV involves low levels of muscle activity and energy use compared with using a computer or reading," he said. "And while research has shown that uninterrupted sitting for long periods is linked with reduced blood flow in the brain, the relatively greater intellectual stimulation that occurs during computer use may counteract the negative effects of sitting."

Researchers used self-reported data from the U.K. Biobank, a large-scale biomedical database of more than 500,000 participants across the United Kingdom, to investigate possible correlations between sedentary leisure activity and dementia in older adults.

More than 145,000 participants aged 60 and older -- all of whom did not have a diagnosis of dementia at the start of the project -- used touchscreen questionnaires to self-report information about their levels of sedentary behavior during the 2006-2010 baseline examination period.

After an average of nearly 12 years of follow-up, the researchers used hospital inpatient records to determine dementia diagnosis. They found 3,507 positive cases.

Then, the team adjusted for certain demographics (e.g., age, sex, race/ethnicity, employment type) and lifestyle characteristics (e.g., exercise, smoking and alcohol use, time spent sleeping and engaging in social contact) that could affect brain health.

The impact of physical activity, mental activity on risk

The results remained the same even after the scientists accounted for levels of physical activity. Even in individuals who are highly physically active, time spent watching TV was associated with increased risk of dementia, and leisure-time spent using a computer was associated with a reduced risk of developing dementia.

"Although we know that physical activity is good for our brain health, many of us think that if we are just more physically active during the day, we can counter the negative effects of time spent sitting," said study author Gene Alexander, professor of Psychology and Evelyn F. McKnight Brain Institute at the University of Arizona.

"Our findings suggest that the brain impacts of sitting during our leisure activities are really separate from how physically active we are," said Alexander, "and that being more mentally active, like when using computers, may be a key way to help counter the increased risk of dementia related to more passive sedentary behaviors, like watching TV."

Knowing how sedentary activities impact human health could lead to some improvements.

"What we do while we're sitting matters, " Raichlen added. "This knowledge is critical when it comes to designing targeted public health interventions aimed at reducing the risk of neurodegenerative disease from sedentary activities through positive behavior change."

https://www.sciencedaily.com/releases/2022/08/220822174914.htm

Reprogramming the brain's cleaning crew to mop up Alzheimer's disease

August 11, 2022

Science Daily/University of California - San Francisco

The discovery of how to shift damaged brain cells from a diseased state into a healthy one presents a potential new path to treating Alzheimer's and other forms of dementia, according to a new study from researchers at UC San Francisco.

The research focuses on microglia, cells that stabilize the brain by clearing out damaged neurons and the protein plaques often associated with dementia and other brain diseases.

These cells are understudied, despite the fact that changes in them are known to play a significant role Alzheimer's and other brain diseases, said Martin Kampmann, PhD, senior author on the study, which appears Aug. 11 in Nature Neuroscience.

"Now, using a new CRISPR method we developed, we can uncover how to actually control these microglia, to get them to stop doing toxic things and go back to carrying out their vitally important cleaning jobs," he said. "This capability presents the opportunity for an entirely new type of therapeutic approach."

Leveraging the Brain's Immune System

Most of the genes known to increase the risk for Alzheimer's disease act through microglial cells. Thus, these cells have a significant impact on how such neurodegenerative diseases play out, said Kampmann.

Microglia act as the brain's immune system. Ordinary immune cells can't cross the blood-brain barrier, so it's the task of healthy microglia to clear out waste and toxins, keeping neurons functioning at their best. When microglia start losing their way, the result can be brain inflammation and damage to neurons and the networks they form.

Under some conditions, for example, microglia will start removing synapses between neurons. While this is a normal part of brain development in a person's childhood and adolescent years, it can have disastrous effects in the adult brain.

Over the past five years or so, many studies have observed and profiled these varying microglial states but haven't been able to characterize the genetics behind them.

Kampmann and his team wanted to identify exactly which genes are involved in specific states of microglial activity, and how each of those states are regulated. With that knowledge, they could then flip genes on and off, setting wayward cells back on the right track.

From Advanced Genomics to a Holy Grail

Accomplishing that task required surmount fundamental obstacles that have prevented researchers from controlling gene expression in these cells. For example, microglia are very resistant to the most common CRISPR technique, which involves getting the desired genetic material into the cell by using a virus to deliver it.

To overcome this, Kampmann's team coaxed stem cells donated by human volunteers to become microglia and confirmed that these cells function like their ordinary human counterparts. The team then developed a new platform that combines a form of CRISPR, which enables researchers to turn individual genes on and off -- and which Kampmann had a significant hand in developing -- with readouts of data that indicate functions and states of individual microglia cells.

Through this analysis, Kampmann and his team pinpointed genes that effect the cell's ability to survive and proliferate, how actively a cell produces inflammatory substances, and how aggressively a cell prunes synapses.

And because the scientists had determined which genes control those activities, they were able to reset the genes and flip the diseased cell to a healthy state.

Armed with this new technique, Kampmann plans to investigate how to control the relevant states of microglia, by targeting the cells with existing pharmaceutical molecules and testing them in preclinical models. He hopes to find specific molecules that act on the genes necessary to nudge diseased cells back to a healthy state.

Kampmann said that once the right genes are flipped, it's likely that the "repaired," microglia will resume their responsibilities, removing plaques associated with neurodegenerative disease and protecting synapses rather than taking them apart.

"Our study provides a blueprint for a new approach to treatment," he said. "It's a bit of a holy grail."

https://www.sciencedaily.com/releases/2022/08/220811135415.htm

Why thinking hard makes you tired

August 11, 2022

Science Daily/Cell Press

It's no surprise that hard physical labor wears you out, but what about hard mental labor? Sitting around thinking hard for hours makes one feel worn out, too. Now, researchers have new evidence to explain why this is, and, based on their findings, the reason you feel mentally exhausted (as opposed to drowsy) from intense thinking isn't all in your head.

Their studies, reported in Current Biology on August 11, show that when intense cognitive work is prolonged for several hours, it causes potentially toxic byproducts to build up in the part of the brain known as the prefrontal cortex. This in turn alters your control over decisions, so you shift toward low-cost actions requiring no effort or waiting as cognitive fatigue sets in, the researchers explain.

"Influential theories suggested that fatigue is a sort of illusion cooked up by the brain to make us stop whatever we are doing and turn to a more gratifying activity," says Mathias Pessiglione of Pitié-Salpêtrière University in Paris, France. "But our findings show that cognitive work results in a true functional alteration -- accumulation of noxious substances -- so fatigue would indeed be a signal that makes us stop working but for a different purpose: to preserve the integrity of brain functioning."

Pessiglione and colleagues including first author of the study Antonius Wiehler wanted to understand what mental fatigue really is. While machines can compute continuously, the brain can't. They wanted to find out why. They suspected the reason had to do with the need to recycle potentially toxic substances that arise from neural activity.

To look for evidence of this, they used magnetic resonance spectroscopy (MRS) to monitor brain chemistry over the course of a workday. They looked at two groups of people: those who needed to think hard and those who had relatively easier cognitive tasks.

They saw signs of fatigue, including reduced pupil dilation, only in the group doing hard work. Those in that group also showed in their choices a shift toward options proposing rewards at short delay with little effort. Critically, they also had higher levels of glutamate in synapses of the brain's prefrontal cortex. Together with earlier evidence, the authors say it supports the notion that glutamate accumulation makes further activation of the prefrontal cortex more costly, such that cognitive control is more difficult after a mentally tough workday.

So, is there some way around this limitation of our brain's ability to think hard?

"Not really, I'm afraid," Pessiglione said. "I would employ good old recipes: rest and sleep! There is good evidence that glutamate is eliminated from synapses during sleep."

There may be other practical implications. For example, the researchers say, monitoring of prefrontal metabolites could help to detect severe mental fatigue. Such an ability may help adjust work agendas to avoid burnout. He also advises people to avoid making important decisions when they're tired.

In future studies, they hope to learn why the prefrontal cortex seems especially susceptible to glutamate accumulation and fatigue. They're also curious to learn whether the same markers of fatigue in the brain may predict recovery from health conditions, such as depression or cancer.

https://www.sciencedaily.com/releases/2022/08/220811135344.htm

Non-invasive stimulation of the eye for depression and dementia

August 11, 2022

Science Daily/The University of Hong Kong

A joint research team from the LKS Faculty of Medicine, The University of Hong Kong (HKUMed) and City University of Hong Kong (CityU) has discovered that the electrical stimulation of the eye surface can alleviate depression-like symptoms and improve cognitive function in animal models. These significant findings were recently published in Brain Stimulation and the Annals of the New York Academy of Sciences.

Background

Major depression is the most common and severe psychiatric disorder across the world. Recently, the World Health Organization reported that the COVID-19 pandemic had triggered a massive increase in the number of people with anxiety and depression. About a quarter of patients do not respond adequately to the treatments available.

Dr Lim Lee Wei, Assistant Professor in the School of Biomedical Sciences, HKUMed and a former Lee Kuan Yew Research Fellow in Singapore, reported in 2015 that deep brain stimulation of the prefrontal cortex in the brains of animals could improve memory function and relieve depressive symptoms. These therapeutic effects were attributed to the growth of brain cells in the hippocampus, a region of the brain known to be involved in learning and memory function. However, this technique, also known as deep brain stimulation, is invasive and requires surgery to implant electrodes in the brain, which may cause side effects such as infections and other post-operative complications.

Research findings and significance

A team of Hong Kong researchers headed by Dr Lim Lee Wei; Dr Leanne Chan Lai-hang, Associate Professor in the Department of Electrical Engineering, CityU; Professor Chan Ying-shing, Dexter H C Man Family Professor in Medical Science, Professor of the School of Biomedical Sciences, Associate Dean (Development and Infrastructure), HKUMed, and Director of the Neuroscience Research Centre, HKU, have been looking for alternative ways to treat neuropsychiatric diseases. They discovered that the non-invasive stimulation of the corneal surface of the eye (known as transcorneal electrical stimulation, or TES) that activates brain pathways, resulted in remarkable antidepressant-like effects and reduced stress hormones in an animal model for depression. Furthermore, this technique induced the expression of genes involved in the development and growth of brain cells in the hippocampus.

In related experiments, Yu Wing-shan, PhD student, and other research members from the School of Biomedical Sciences, HKUMed, investigated whether this approach could be used to treat Alzheimer's disease, a common type of dementia with no definitive cure. They found that this non-invasive stimulation in mice drastically improved memory performance and reduced beta-amyloid deposits in the hippocampus, which is one of the hallmarks of Alzheimer's disease.

Dr Leanne Chan Lai-hang, an expert on the electrical stimulation of visual and non-visual brain targets, described this research, 'Transcorneal electrical stimulation is a non-invasive method initially developed to treat eye diseases, and it would be a major scientific breakthrough if it could be applied to treat neuropsychiatric diseases.'

'These research findings pave the way for new therapeutic opportunities to develop novel treatment for patients suffering from treatment-resistant depression and dementia. Nevertheless, clinical trials must be conducted to validate the efficacy and safety,' remarked Professor Chan Ying-shing.

https://www.sciencedaily.com/releases/2022/08/220811143013.htm

Which leisure activities are linked to lower risk of dementia?

August 10, 2022

Science Daily/American Academy of Neurology

Leisure activities, such as reading a book, doing yoga and spending time with family and friends, may help lower the risk of dementia, according to a new meta-analysis published in the August 10, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology. The meta-analysis reviewed available studies on the effects of cognitive activities, physical activities, and social activities and the risk of dementia.

"Previous studies have shown that leisure activities were associated with various health benefits, such as a lower cancer risk, a reduction of atrial fibrillation, and a person's perception of their own well-being," said study author Lin Lu, PhD, of Peking University Sixth Hospital in Beijing, China. "However, there is conflicting evidence of the role of leisure activities in the prevention of dementia. Our research found that leisure activities like making crafts, playing sports or volunteering were linked to a reduced risk of dementia."

The meta-analysis involved a review of 38 studies from around the world involving a total of more than 2 million people who did not have dementia. The participants were followed for at least three years.

Participants provided information on their leisure activities through questionnaires or interviews. Leisure activities were defined as those in which people engaged for enjoyment or well-being and were divided into mental, physical and social activities.

During the studies, 74,700 people developed dementia.

After adjusting for factors such as age, sex and education, researchers found that leisure activities overall were linked to a reduced risk of dementia. Those who engaged in leisure activities had a 17% lower risk of developing dementia than those who did not engage in leisure activities.

Mental activity mainly consisted of intellectual activities and included reading or writing for pleasure, watching television, listening to the radio, playing games or musical instruments, using a computer and making crafts. Researchers found that people who participated in these activities had a 23% lower risk of dementia.

Physical activities included walking, running, swimming, bicycling, using exercise machines, playing sports, yoga, and dancing. Researchers found that people who participated in these activities had a 17% lower risk of dementia.

Social activities mainly referred to activities that involved communication with others and included attending a class, joining a social club, volunteering, visiting with relatives or friends, or attending religious activities. Researchers found that people who participated in these activities had a 7% lower risk of dementia.

"This meta-analysis suggests that being active has benefits, and there are plenty of activities that are easy to incorporate into daily life that may be beneficial to the brain," Lu said. "Our research found that leisure activities may reduce the risk of dementia. Future studies should include larger sample sizes and longer follow-up time to reveal more links between leisure activities and dementia."

A limitation of the study was that people reported their own physical and mental activity, so they may not have remembered and reported the activities correctly.

https://www.sciencedaily.com/releases/2022/08/220810161200.htm

Researchers gain insights into the genetic and molecular machinery that predisposes individuals to Alzheimer's disease

August 5, 2022

Science Daily/The Mount Sinai Hospital / Mount Sinai School of Medicine

Mount Sinai researchers have achieved an unprecedented understanding of the genetic and molecular machinery in human microglia -- immune cells that reside in the brain -- that could provide valuable insights into how they contribute to the development and progression of Alzheimer's disease (AD). The team's findings were published in Nature Genetics.

Working with fresh human brain tissue harvested via biopsy or autopsy from 150 donors, researchers identified 21 candidate risk genes and highlighted one, SPI1, as a potential key regulator of microglia and AD risk.

"Our study is the largest human fresh-tissue microglia analysis to date of genetic risk factors that might predispose someone to Alzheimer's disease," says senior author Panos Roussos, MD, PhD, Professor of Psychiatry, and Genetic and Genomic Sciences, at the Icahn School of Medicine at Mount Sinai and Director of the Center for Disease Neurogenomics. "By better understanding the molecular and genetic mechanisms involved in microglia function, we're in a much better position to unravel the regulatory landscape that controls that function and contributes to AD. That knowledge could, in turn, pave the way for novel therapeutic interventions for a disease that currently has no effective treatments."

Microglia are primarily responsible for the immune response in the brain, and are also critical to the development and maintenance of neurons. While previous studies, including some at Mount Sinai, have identified microglia as playing a key role in the genetic risk and development of Alzheimer's disease, little is known about the epigenetic mechanics of how that occurs. Because microglia are challenging to isolate within the human brain, most previous studies have used either animal- or cell-line-based models which do not reflect the true complexity of microglia function in the brain. Another challenge has been relating AD genetic risk variation to specific molecular function because these risk factors are frequently found in the non-coding part of the genome (what used to be called "junk DNA"), which is more difficult to study.

The Mount Sinai team's solution was to access fresh brain tissue from biopsies or autopsies made possible by a collaboration between four brain bio-depositories, three at Mount Sinai and the other from Rush University Medical Center/Rush Alzheimer's Disease Center. "Using a total of 150 samples from these sources, we were able to isolate high-quality microglia, which provided unprecedented insights into genetic regulation by reflecting the entire set of regulatory components of microglia in both healthy and neurodegenerative patients," explains Dr. Roussos.

That process -- comparing epigenetic, gene expression, and genetic information from the samples of both AD and healthy aged patients -- allowed researchers to comprehensively describe how microglia functions are genetically regulated in humans. As part of their statistical analysis, they expanded the findings of prior genome-wide association studies to link identified AD-predisposing genetic variants to specific DNA regulatory sequences and genes whose dysregulation is known to directly contribute to the development of the disease. They further described the cell-wide regulatory mechanisms as a way of identifying genetic regions involved in specific aspects of the microglial activity.

From their investigation emerged new knowledge about the SPI1gene, already known to scientists, as the main microglial transcription factor regulating a network of other transcription factors and genes that are genetically linked to AD. Data the team is generating could also be important to deciphering the molecular and genetic mysteries behind other neurodegenerative diseases in which microglia play a role, including Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis.

Dr. Roussos concedes that much work remains for his team to fully understand how the identified genes contribute to the development and progression of Alzheimer's disease, and how they could be targeted with new therapeutics. He is greatly encouraged, though, by the results of single-cell analysis by his lab of microglia using highly sophisticated instruments that are uncovering the unique interactions between different types of immune cells in the brain and its periphery that are related to neurodegenerative disease. "We're seeing very exciting results through our single-cell data," Dr. Roussos reports, "and that's bringing us ever closer to understanding the genetically driven variations and cell-specific interactions of inheritable diseases like Alzheimer's."

https://www.sciencedaily.com/releases/2022/08/220805154359.htm