Nanoplastics promote conditions for Parkinson's across various lab models

Nanoplastics interact with a particular protein that is naturally found in the brain, creating changes linked to Parkinson's disease and some types of dementia.

In a Duke-led study appearing Nov. 17 in Science Advances, the researchers report that the findings create a foundation for a new area of investigation, fueled by the timely impact of environmental factors on human biology.

"Parkinson's disease has been called the fastest growing neurological disorder in the world," said principal investigator, Andrew West, Ph.D., professor in the Department of Pharmacology and Cancer Biology at Duke University School of Medicine. "Numerous lines of data suggest environmental factors might play a prominent role in Parkinson's disease, but such factors have for the most part not been identified."

Improperly disposed plastics have been shown to break into very small pieces and accumulate in water and food supplies, and were found in the blood of most adults in a recent study.

"Our study suggests that the emergence of micro and nanoplastics in the environment might represent a new toxin challenge with respect to Parkinson's disease risk and progression," West said. "This is especially concerning given the predicted increase in concentrations of these contaminants in our water and food supplies."

West and colleagues in Duke's Nicholas School of the Environment and the Department of Chemistry at Trinity College of Arts and Sciences found that nanoparticles of the plastic polystyrene -- typically found in single use items such as disposable drinking cups and cutlery -- attract the accumulation of the protein known as alpha-synuclein. West said the study's most surprising findings are the tight bonds formed between the plastic and the protein within the area of the neuron where these accumulations are congregating, the lysosome.

Researchers said the plastic-protein accumulations happened across three different models performed in the study -- in test tubes, cultured neurons, and mouse models of Parkinson's disease. West said questions remain about how such interactions might be happening within humans and whether the type of plastic might play a role.

"While microplastic and nanoplastic contaminants are being closely evaluated for their potential impact in cancer and autoimmune diseases, the striking nature of the interactions we could observe in our models suggest a need for evaluating increasing nanoplastic contaminants on Parkinson's disease and dementia risk and progression," West said.

"The technology needed to monitor nanoplastics is still at the earliest possible stages and not ready yet to answer all the questions we have," he said. "But hopefully efforts in this area will increase rapidly, as we see what these particles can do in our models. If we know what to look out for, we can take the necessary steps to protect ourselves, without compromising all the benefits we reap every day from plastics."

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Wildfires and farming activities may be top sources of air pollution linked to increased risk, cases of dementia

No amount of air pollution is good for the brain, but wildfires and the emissions resulting from agriculture and farming in particular may pose especially toxic threats to cognitive health, according to new research from the University of Michigan.

Increasingly, evidence shows exposure to air pollution makes the brain susceptible to dementia. And now the findings of Boya Zhang and Sara Adar, environmental epidemiology researchers in U-M's School of Public Health, point to a strong likelihood that agriculture and wildfires, with their release of a range of harmful emissions at high concentrations, need to be more closely studied and monitored for their risks to public health, specifically dementia.

"We saw in our research that all airborne particles increased the risk of dementia but those generated by agricultural settings and wildfires seemed to be especially toxic for the brain," said Adar, associate chair of the Department of Epidemiology in the School of Public Health. She currently leads several large cohort studies on the impacts of exposures on cognitive aging and dementia.

"Our findings indicate that lowering levels of particulate matter air pollution, even in a relatively clean country like the United States, may reduce the number of people developing dementia in late life," Adar said.

Adar and Zhang's paper, "Comparison of Particulate Air Pollution From Different Emission Sources and Incident Dementia in the U.S.," appears today in the Journal of the American Medical Association's Internal Medicine.

Zhang, a research fellow who focuses on the effects of air pollution on cardiopulmonary disease and cognitive aging, said: "This work suggests that particulate matter air pollution from agriculture and wildfires might be more neurotoxic compared with other sources. However, more research is needed to confirm these effects, especially for these two sources which have received less attention in prior research."

"Given that the development of dementia could take a long time, this study mainly aimed to provide evidence for policymakers to reduce exposures to these sources of emissions," Zhang said.

The findings come as unusually poor air quality is regularly triggering alerts in the U.S. The alerts are aimed at protecting the public from the unseen, swirling mix of microscopic toxins in air pollution, specifically fine particulate matter or PM2.5. It is one of the most concerning elements of air pollution. At less than 2.5 microns in size, PM2.5 is less than the width of a human hair. Because it's so small, it can enter the brain through the nose directly or cross the blood-brain barrier in other ways. PM2.5 is also known to affect the lungs, heart, and in emerging research, the brain and cognitive function.

"These findings are quite timely given the increasing frequency of wildfire smoke in our

communities," Adar said. "Our data suggest that in addition to some of the more obvious health impacts of wildfire smoke like irritation to our throats and eyes along with breathing difficulties, high smoke days might also be taking a toll on our brains."

The record number of air quality alerts in the U.S. this year are due in large part to smoke from wildfires burning in Canada since May. The effect of wildfire is not new in the U.S., especially given the fires in the western part of the country.

Adar, a long-time environmental epidemiologist, said that wildfire smoke is becoming a more widespread stressor with many cities experiencing 30-plus days each year impacted by smoke. Given the extremely high levels of exposure to the public, wildfires are thought to contribute up to 25% of fine particulate matter exposures over a year across the U.S. and as much as 50% in some western regions of the country, Adar said.

"While individual wildfires may be short-lived, these events are becoming more frequent in our communities due to warmer temperatures, drier conditions, and longer fire seasons. As we've seen, wildfire smoke can also travel very far distances," Adar said.

Their findings are based on research into the development of dementia among nearly 30,000 adults from across the U.S. over an 18-year period. The data comes from the Health and Retirement Study, a nationally-representative collection of cohorts of older adults who have been followed since 1992. Pollution estimates in Adar and Zhang's study were based on home addresses of participants. Participants have been interviewed biennially about their cognition, overall health, and health behaviors until death or loss of contact for the survey.

They observed that higher levels of particulate matter air pollution, especially from agriculture and wildfires, were associated with greater risks of dementia. The findings could not be explained by other factors such as individual, neighborhood, socioeconomic status, occupation, or hometown or region of the country.

"With the knowledge of which sources are more toxic than others, it may be possible to design interventions for specific sources as a more effective way to decrease the burden of dementia," Zhang said.

Dementia is currently the seventh leading cause of death and one of the major causes of disability and dependency for older people, according to the World Health Organization.

The research specifically sought to test the hypothesis that a variation in emission sources could explain which are most toxic, but measuring the emissions with their distinct physical and chemical characteristics is challenging.

Past studies analyzing exposures to source specific fine particulate matter meant researchers mainly investigated relationships with the total mass of fine particulate matter in the air.

"In our study, we used a sophisticated prediction model that includes information about the chemical transformations and dispersion of pollution from different sources to estimate the levels of source-specific particulate matter air pollution at participants' residential addresses," Zhang said. "This approach is beneficial because it not only accounts for pollution directly emitted by a source but also pollution generated through reactions with other chemicals in the air."

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Regular napping linked to larger brain volume

Daytime napping may help to preserve brain health by slowing the rate at which our brains shrink as we age, suggests a new study led by researchers at UCL and the University of the Republic in Uruguay.

The study, published in the journal Sleep Health, analysed data from people aged 40 to 69 and found a causal link between habitual napping and larger total brain volume -- a marker of good brain health linked to a lower risk of dementia and other diseases.

Senior author Dr Victoria Garfield (MRC Unit for Lifelong Health & Ageing at UCL) said: "Our findings suggest that, for some people, short daytime naps may be a part of the puzzle that could help preserve the health of the brain as we get older."

Previous research has shown that napping has cognitive benefits, with people who have had a short nap performing better in cognitive tests in the hours afterwards than counterparts who did not nap.

The new study aimed to establish if there was a causal relationship between daytime napping and brain health.

Using a technique called Mendelian randomisation, they looked at 97 snippets of DNA thought to determine people's likelihood of habitual napping. They compared measures of brain health and cognition of people who are more genetically "programmed" to nap with counterparts who did not have these genetic variants, using data from 378,932 people from the UK Biobank study, and found that, overall, people predetermined to nap had a larger total brain volume.

The research team estimated that the average difference in brain volume between people programmed to be habitual nappers and those who were not was equivalent to 2.6 to 6.5 years of ageing.

But the researchers did not find a difference in how well those programmed to be habitual nappers performed on three other measures of brain health and cognitive function -- hippocampal volume, reaction time and visual processing.

Lead author and PhD candidate Valentina Paz (University of the Republic (Uruguay) and MRC Unit for Lifelong Health & Ageing at UCL) said: "This is the first study to attempt to untangle the causal relationship between habitual daytime napping and cognitive and structural brain outcomes. By looking at genes set at birth, Mendelian randomisation avoids confounding factors occurring throughout life that may influence associations between napping and health outcomes. Our study points to a causal link between habitual napping and larger total brain volume."

Dr Garfield added: "I hope studies such as this one showing the health benefits of short naps can help to reduce any stigma that still exists around daytime napping."

The genetic variants influencing our likelihood to nap were identified in an earlier study looking at data from 452,633 UK Biobank participants. The study, led by Dr Hassan Dashti (Harvard University and Massachusetts General Hospital), also an author on the new study, identified the variants on the basis of self-reported napping, and this was supported by objective measurements of physical activity recorded by a wrist-worn accelerometer.

In the new study, researchers analysed health and cognition outcomes for people with these genetic variants as well as several different subsets of these variants, adjusted to avoid potential bias, for instance avoiding variants linked to excessive daytime sleepiness.

Genetic data and magnetic resonance imaging (MRI) scans of the brain were available for 35,080 individuals drawn from the larger UK Biobank sample.

In terms of study limitations, the authors noted that all of the participants were of white European ancestry, so the findings might not be immediately generalisable to other ethnicities.

While the researchers did not have information on nap duration, earlier studies suggest that naps of 30 minutes or less provide the best short-term cognitive benefits, and napping earlier in the day is less likely to disrupt night-time sleep.

Previous research looking at the UK and the Netherlands found that nearly a third of adults aged 65 or over had a regular nap.

Read more at Science Daily

How the brain's 'internal compass' works

Scientists have gained new insights into the part of the brain that gives us a sense of direction, by tracking neural activity with the latest advances in brain imaging techniques. The findings shed light on how the brain orients itself in changing environments -- and even the processes that can go wrong with degenerative diseases like dementia, that leave people feeling lost and confused.

"Neuroscience research has witnessed a technology revolution in the last decade allowing us to ask and answer questions that could only be dreamed of just years ago," says Mark Brandon, an Associate Professor of psychiatry at McGill University and researcher at the Douglas Research Centre, who co-led the research with Zaki Ajabi, a former student at McGill University and now a postdoctoral research fellow at Harvard University.

Reading the brain's internal compass

To understand how visual information impacts the brain's internal compass, the researchers exposed mice to a disorienting virtual world while recording the brain's neural activity. The team recorded the brain's internal compass with unprecedented precision using the latest advances in neuronal recording technology.

This ability to accurately decode the animal's internal head direction allowed the researchers to explore how the Head-Direction cells, which make up the brain's internal compass, support the brain's ability to re-orient itself in changing surroundings. Specifically, the research team identified a phenomenon they term 'network gain' that allowed the brain's internal compass to reorient after the mice were disoriented. "It's as if the brain has a mechanism to implement a 'reset button' allowing for rapid reorientation of its internal compass in confusing situations," says Ajabi.

Although the animals in this study were exposed to unnatural visual experiences, the authors argue that such scenarios are already relevant to the modern human experience, especially with the rapid spread of virtual reality technology. These findings "may eventually explain how virtual reality systems can easily take control over our sense of orientation," adds Ajabi.

The results inspired the research team to develop new models to better understand the underlying mechanisms. "This work is a beautiful example of how experimental and computational approaches together can advance our understanding of brain activity that drives behaviour," says co-author Xue-Xin Wei, a computational neuroscientist and an Assistant Professor at The University of Texas at Austin.

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New studies suggest social isolation is a risk factor for dementia in older adults, point to ways to reduce risk

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.

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Fall rate nearly 50% among older Americans with dementia

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.

Read more at Science Daily

Chores, exercise, and social visits linked to lower risk of dementia

Physical and mental activities, such as household chores, exercise, and visiting with family and friends, may help lower the risk of dementia, according to a new study published in the July 27, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study looked at the effects of these activities, as well as mental activities and use of electronic devices in people both with and without higher genetic risk for dementia.

"Many studies have identified potential risk factors for dementia, but we wanted to know more about a wide variety of lifestyle habits and their potential role in the prevention of dementia," said study author Huan Song, MD, PhD, of Sichuan University in Chengdu, China. "Our study found that exercise, household chores, and social visits were linked to a reduced risk of various types of dementia."

The study involved 501,376 people from a UK database without dementia with an average age of 56.

Participants filled out questionnaires at the beginning of the study, including one on physical activities. They were asked how often they participated in activities such as climbing a flight of stairs, walking, and participating in strenuous sports. They were also asked about household chores, job-related activities, and what kind of transportation they used, including walking or biking to work.

Participants completed another questionnaire on mental activities. They were asked about their education level, whether they attend adult education classes, how often they visit with friends and family, visit pubs or social clubs or religious groups, and how often they use electronic devices such as playing computer games, watching TV, and talking on the phone.

Additionally, participants reported whether they had any immediate family members with dementia. This helped researchers determine if they had a genetic risk for Alzheimer's disease. Study participants were followed an average of 11 years. At the end of the study, 5,185 people had developed dementia.

After adjusting for multiple factors such as age, income, and smoking, researchers found that most physical and mental activities studied showed links to the risk of dementia. Importantly, the findings remain after considering the high correlations and interactions of these activities. People who were highly engaged in activity patterns including frequent exercises, household chores, and daily visits of family and friends had 35%, 21%, and 15% lower risk of dementia, respectively, compared to people who were the least engaged in these activity patterns.

Researchers also looked at dementia incidence rates by identified activity patterns. The rate in people who exercised frequently was 0.45 cases for every 1,000 person-years compared to 1.59 for people who rarely exercised. Person-years take into account the number of people in a study as well as the amount of time spent in the study. Those who frequently did household chores had a rate of 0.86 cases for every 1,000 person-years compared to 1.02 for people who rarely did household chores. People who visited family daily had a rate of 0.62 cases for every 1,000 person-years compared to 0.8 cases for those who only visited friends and family once every few months.

"Our study has found that by engaging more frequently in healthy physical and mental activities people may reduce their risk of dementia," Song said. "More research is needed to confirm our findings. However, our results are encouraging that making these simple lifestyle changes may be beneficial."

The researchers found that all participants benefited from the protective effect of physical and mental activities, whether or not they had a family history of dementia.

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

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Do benefits of physical, mental activity on thinking differ for men and women?

Studies have shown that physical and mental activity help preserve thinking skills and delay dementia. A new study suggests that these benefits may vary for men and women. The study is published in the July 20, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology.

The study looked at the effects of physical and mental activities, such as reading, going to classes, or playing cards or games, on cognitive reserve in the areas of thinking speed and memory. Cognitive reserve is the buffer that occurs when people have strong thinking skills even when their brains show signs of the underlying changes associated with cognitive impairment and dementia.

"We found that greater physical activity was associated with greater thinking speed reserve in women, but not in men," said study author Judy Pa, PhD, of the University of California, San Diego. "Taking part in more mental activities was associated with greater thinking speed reserve for both men and women."

Greater physical activity was not associated with memory reserve in men or women.

The study involved 758 people with an average age of 76. Some had no thinking or memory problems, some had mild cognitive impairment, and some had dementia. The participants had brain scans and took thinking speed and memory tests. To calculate cognitive reserve, people's thinking tests scores were compared against the changes in the brain associated with dementia, such as the total volume of the hippocampus, a key brain region impacted by Alzheimer's disease.

People were also asked about their usual weekly physical activity. For mental activity, they were asked whether they participated in three types of activities in the past 13 months: reading magazines, newspapers or books; going to classes; and playing cards, games or bingo. They were given one point for each type of activity, for a maximum of three points.

For mental activity, participants averaged 1.4 points. For physical activity, participants took part in an average of at least 15 minutes per week of activities that elevate heart rates such as brisk walking and biking.

Pa said that each additional mental activity people participated in corresponded to 13 fewer years of aging in their processing speed in their thinking skills -- 17 years among men and 10 years among women.

"As we have arguably few-to-no effective treatments for Alzheimer's disease, prevention is crucial. An ounce of prevention is worth a pound of treatment," Pa said. "To know that people could potentially improve their cognitive reserve by taking simple steps such as going to classes at the community center, playing bingo with their friends or spending more time walking or gardening is very exciting."

Pa said that based on the effect sizes seen in the study, a doubling of the amount of physical activity would be equivalent to an estimated 2.75 fewer years of aging when it comes to women's processing speed in their thinking skills.

Researchers also looked at whether the relationship between physical and mental activities and cognitive reserve was affected by the gene that carries the strongest risk for Alzheimer's, called APOE e4. They found that for women, having the gene lessens the effects of the beneficial relationship between physical and mental activities and cognitive reserve.

The study does not prove that physical and mental activities help improve cognitive reserve. It only shows an association.

A limitation of the study was that people reported their own physical and mental activity, so they may not have remembered correctly. Also, structural and societal factors that affect cognitive reserve, such as education, were not measured in the study.

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Scientists identify how the brain links memories

Our brains rarely record single memories -- instead, they store memories into groups so that the recollection of one significant memory triggers the recall of others connected by time. As we age, however, our brains gradually lose this ability to link related memories.

Now UCLA researchers have discovered a key molecular mechanism behind memory linking. They've also identified a way to restore this brain function in middle-aged mice -- and an FDA-approved drug that achieves the same thing.

Published in Nature, the findings suggest a new method for strengthening human memory in middle age and a possible early intervention for dementia.

"Our memories are a huge part of who we are," explained Alcino Silva, a distinguished professor of neurobiology and psychiatry at the David Geffen School of Medicine at UCLA. "The ability to link related experiences teaches how to stay safe and operate successfully in the world."

A bit of Biology 101: cells are studded with receptors. To enter a cell, a molecule must latch onto its matching receptor, which operates like a doorknob to provide access inside.

The UCLA team focused on a gene called CCR5 that encodes the CCR5 receptor -- the same one that HIV hitches a ride on to infect the brain cell and cause memory loss in AIDS patients.

Silva's lab demonstrated in earlier research that CCR5 expression reduced memory recall.

In the current study, Silva and his colleagues discovered a central mechanism underlying mice's ability to link their memories of two different cages. A tiny microscope opened a window into the animals' brains, enabling the scientists to observe neurons firing and creating new memories.

Boosting CCR5 gene expression in the brains of middle-aged mice interfered with memory linking. The animals forgot the connection between the two cages.

When the scientists deleted the CCR5 gene in the animals, the mice were able to link memories that normal mice could not.

Silva had previously studied the drug, maraviroc, which the U.S. Food and Drug Administration approved in 2007 for the treatment of HIV infection. His lab discovered that maraviroc also suppressed CCR5 in the brains of mice.

"When we gave maraviroc to older mice, the drug duplicated the effect of genetically deleting CCR5 from their DNA," said Silva, a member of the UCLA Brain Research Institute. "The older animals were able to link memories again."

The finding suggests that maraviroc could be used off-label to help restore middle-aged memory loss, as well as reverse the cognitive deficits caused by HIV infection.

"Our next step will be to organize a clinical trial to test maraviroc's influence on early memory loss with the goal of early intervention," said Silva. "Once we fully understand how memory declines, we possess the potential to slow down the process."

Which begs the question: why does the brain need a gene that interferes with its ability to link memories?

Read more at Science Daily

Promising treatment for dementia

A Monash University led study has found a promising new treatment for patients with behavioural variant frontotemporal dementia, the second most common form of dementia in the under 60s -- resulting in a stabilising of what would normally be escalating behavioural issues, and a slowing of brain shrinkage due to the disease. It is the second clinical trial to show that the drug, sodium selenate, may slow cognitive decline and neurodegenerative damage that is the hallmark of many dementias including Alzheimer's Disease.

Behavioural variant frontotemporal dementia (bvFTD) is a rapidly progressing destructive disease and can occur in people as young as 35 years of age. It is characterised by behavioural disturbances and personality changes and can be highly disruptive and distressing for both patients and their families. Currently there are no treatments or cures for bvFTD and typical survival is 5-7 years from diagnosis.

The Phase 1 trial run in conjunction with the Royal Melbourne Hospital, the only one in Australia targeting non-genetic bvFTD, and one of a handful worldwide, showed that the drug, sodium selenate is safe and well-tolerated in patients with bvFTD over a period of 12 months. Importantly, the majority of patients receiving sodium selenate showed no change in their cognitive or behavioural symptoms, and reduced rates of brain atrophy over the trial period. The results from the trial, led by Dr Lucy Vivash, from the Monash University's Department of Neuroscience, have just been published in the journal, Alzheimer's and Dementia: Translational Research and Clinical Interventions.

In almost half of the cases with bvFTD, the damage to the neurons in the brain is caused by the build-up of a protein called tau. This protein is a major target for research in the prevention and treatment of Alzheimer's and other dementias, as a way to reverse the neurodegeneration caused by this tau accumulation.

According to Dr Vivash, sodium selenate upregulates an enzyme in the brain that effectively breaks down the tau protein. "We have previously shown, in a Phase 2 trial, that sodium selenate given to patients with mild to moderate Alzheimer's Disease resulted in less neurodegeneration than in those who did not," she said. Importantly those patients in the trial with higher levels of selenium, a breakdown product of sodium selenate, in their bloodstream showed less cognitive decline.

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Cases of cognitive decline in older people more than doubles in ten years

The researchers set out to see if there had been an increase in the numbers of older people who were reporting their first concerns about memory loss or cognitive decline to their doctor and what their chances of developing dementia were after consultation.

The study, published today in Clinical Epidemiology, looked at data from more than 1.3m adults aged between 65 and 99 years old, taken between 2009 and the end of 2018. The researchers identified 55,941 adults who had spoken to their GP about memory concerns and 14,869 people who had a record of cognitive decline.

For every 1,000 people that were observed for one year in 2009, there was one new case of cognitive decline being recorded. By 2018, for every 1,000 people that were observed for one year, there were three new cases of cognitive decline being recorded.

Lead author and PhD candidate Brendan Hallam (UCL Epidemiology & Health Care) said: "This is an important study which sheds new light on how prevalent memory concerns and cognitive decline are among the older generation in the UK and how likely these symptoms might progress to a dementia diagnosis.

"The study showed that while memory concern rates had remained stable, incidence of cognitive decline, a step beyond memory concern, had more than doubled between 2009 and 2018.

"There has been a drive in the past decade to encourage people to seek help earlier from their doctors if they are worried about their memory and we found that among those over 80, women and people living in more deprived areas were more likely to have a record of memory concern or cognitive decline, and their symptoms were more likely to progress to dementia diagnosis."

The study also showed that within three years of following up a person from the date when the doctor reported a memory concern, 46% of people would go on to develop dementia. For people with cognitive decline, 52% would go on to develop dementia.

Co-author, Professor Kate Walters (UCL Epidemiology & Health Care) explained: "People who have been noted in their health records as having concerns about their memory are at just under 50% chance of developing dementia within the next three years."

Brendan Hallam also outlined "Memory concerns and cognitive decline are not only hallmark symptoms of dementia, but they also predict a high risk of developing dementia. It is important for GPs to identify people with memory concerns as soon as possible to deliver recommendations to improve memory and allow timely diagnosis of dementia."

The authors note one potential limitation of the present study is the potential variations in which GPs record memory concerns and memory decline. They also say more research is needed to better understand the discrepancy between rates of memory symptoms and cognitive decline in the general population and those recorded in primary care.

Read more at Science Daily

Extended napping in seniors may signal dementia

Daytime napping among older people is a normal part of aging -- but it may also foreshadow Alzheimer's disease and other dementias. And once dementia or its usual precursor, mild cognitive impairment, are diagnosed, the frequency and/or duration of napping accelerates rapidly, according to a new study.

The study, led by UC San Francisco and Harvard Medical School together with Brigham and Women's Hospital, its teaching affiliate, departs from the theory that daytime napping in older people serves merely to compensate for poor nighttime sleep. Instead, it points to work by other UCSF researchers suggesting that dementia may affect the wake-promoting neurons in key areas of the brain, the researchers state in their paper publishing March 17, 2022, in Alzheimer's and Dementia: The Journal of the Alzheimer's Association.

"We found the association between excessive daytime napping and dementia remained after adjusting for nighttime quantity and quality of sleep," said co-senior author Yue Leng, MD, PhD, of the UCSF Department of Psychiatry and Behavioral Sciences.

"This suggested that the role of daytime napping is important itself and is independent of nighttime sleep," said Leng, who partnered with Kun Hu, PhD, of Harvard Medical School, in senior-authoring the paper.

Watch-Like Devices, Annual Evaluations Used to Measure Naps, Cognition

In the study, the researchers tracked data from 1,401 seniors, who had been followed for up to 14 years by the Rush Memory and Aging Project at the Rush Alzheimer's Disease Center in Chicago. The participants, whose average age was 81 and of whom approximately three-quarters were female, wore a watch-like device that tracked mobility. Each prolonged period of non-activity from 9 a.m. to 7 p.m. was interpreted as a nap.

The device was worn every year continuously for up to 14 days, and once a year each participant underwent a battery of neuropsychological tests to evaluate cognition. At the start of the study 75.7% of participants had no cognitive impairment, while 19.5% had mild cognitive impairment and 4.1% had Alzheimer's disease.

For participants who did not develop cognitive impairment, daily daytime napping increased by an average 11 minutes per year. The rate of increase doubled after a diagnosis of mild cognitive impairment to a total of 24 minutes and nearly tripled to a total of 68 minutes after a diagnosis of Alzheimer's disease.

When the researchers looked at the 24% of participants who had normal cognition at the start of the study but developed Alzheimer's six years later, and compared them with those whose cognition remained stable, they found differences in napping habits. Participants who napped more than an hour a day had a 40% higher risk of developing Alzheimer's than those who napped less than an hour a day; and participants who napped at least once a day had a 40% higher risk of developing Alzheimer's than those who napped less than once a day.

The research confirms the results of a 2019 study, of which Leng was the first author, that found older men who napped two hours a day had higher odds of developing cognitive impairment that those who napped less than 30 minutes a day. The current study builds on these findings by evaluating both daytime napping and cognition each year, hence addressing directionality, Leng notes.

Loss of Wake-Promoting Neurons May Account for Longer Naps

According to the researchers, increase in napping may be explained by a further 2019 study, by other UCSF researchers, comparing the postmortem brains of people with Alzheimer's disease to those without cognitive impairment. Those with Alzheimer's disease were found to have fewer wake-promoting neurons in three brain regions. These neuronal changes appear to be linked to tau tangles -- a hallmark of Alzheimer's, characterized by increased activity of enzymes causing the protein to misfold and clump.

"It is plausible that our observed associations of excessive daytime napping at baseline, and increased risk for Alzheimer's disease during follow-up, may reflect the effect of Alzheimer's disease pathology at preclinical stages," the authors noted.

The study shows for the first time that napping and Alzheimer's disease "seem to be driving each other's changes in a bi-directional way," said Leng, who is also affiliated with the UCSF Weill Institute for Neurosciences. "I don't think we have enough evidence to draw conclusions about a causal relationship, that it's the napping itself that caused cognitive aging, but excessive daytime napping might be a signal of accelerated aging or cognitive aging process," she said.

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How does the brain make memories?

Researchers have discovered two types of brain cells that play a key role in dividing continuous human experience into distinct segments that can be recalled later. The discovery provides new promise as a path toward development of novel treatments for memory disorders such as dementia and Alzheimer's disease.

In a study led by Cedars-Sinai, researchers have discovered two types of brain cells that play a key role in dividing continuous human experience into distinct segments that can be recalled later. The discovery provides new promise as a path toward development of novel treatments for memory disorders such as dementia and Alzheimer's disease.

The study, part of a multi-institutional BRAIN Initiative consortium funded by the National Institutes of Health and led by Cedars-Sinai, was published in the peer-reviewed journal Nature Neuroscience. As part of ongoing research into how memory works, Ueli Rutishauser, PhD, professor of Neurosurgery, Neurology, and Biomedical Sciences at Cedars-Sinai, and co-investigators looked at how brain cells react as memories are formed.

"One of the reasons we can't offer significant help for somebody who suffers from a memory disorder is that we don't know enough about how the memory system works," said Rutishauser, senior author of the study, adding that memory is foundational to us as human beings.

Human experience is continuous, but psychologists believe, based on observations of people's behavior, that memories are divided by the brain into distinct events, a concept known as event segmentation. Working with 19 patients with drug-resistant epilepsy, Rutishauser and his team were able to study how neurons perform during this process.

Patients participating in the study had electrodes surgically inserted into their brains to help locate the focus of their epileptic seizures, allowing investigators to record the activity of individual neurons while the patients viewed film clips that included cognitive boundaries.

While these boundaries in daily life are nuanced, for research purposes, the investigators focused on "hard" and "soft" boundaries.

"An example of a soft boundary would be a scene with two people walking down a hallway and talking, and in the next scene, a third person joins them, but it is still part of the same overall narrative," said Rutishauser, interim director of the Center for Neural Science and Medicine and the Board of Governors Chair in Neurosciences at Cedars-Sinai.

In the case of a hard boundary, the second scene might involve a completely different set of people riding in a car. "The difference between hard and soft boundaries is in the size of the deviation from the ongoing narrative," Rutishauser said. "Is it a totally different story, or like a new scene from the same story?"

When study participants watched film clips, investigators noted that certain neurons in the brain, which they labeled "boundary cells," increased their activity after both hard and soft boundaries. Another group of neurons, labeled "event cells," increased their activity only in response to hard boundaries, but not soft boundaries.

Rutishauser and his co-investigators theorize that peaks in the activity of boundary and event cells -- which are highest after hard boundaries, when both types of cells fire -- send the brain into the proper state for initiating a new memory.

"A boundary response is kind of like creating a new folder on your computer," said Rutishauser. "You can then deposit files in there. And when another boundary comes around, you close the first folder and create another one."

To retrieve memories, the brain uses boundary peaks as what Rutishauser calls "anchors for mental time travel."

"When you try to remember something, it causes brain cells to fire," Rutishauser said. "The memory system then compares this pattern of activity to all the previous firing peaks that happened shortly after boundaries. If it finds one that is similar, it opens that folder. You go back for a few seconds to that point in time, and things that happened then come into focus."

To test their theory, investigators gave study participants two memory tests.

They first showed participants a series of still images and asked them whether or not they had seen them in the film clips they had viewed. Study participants were more likely to remember images that closely followed a hard or soft boundary, when a new "memory folder" would have been created.

Investigators also showed participants pairs of images from film clips they had viewed and asked which of the images appeared first. Participants had difficulty remembering the correct order of images that appeared on opposite sides of a hard boundary, possibly because the brain had segmented those images into separate memory folders.

Rutishauser said that therapies that improve event segmentation could help patients with memory disorders. Even something as simple as a change in atmosphere can amplify event boundaries, he explained.

"The effect of context is actually quite strong," Rutishauser said. "If you study in a new place, where you have never been before, instead of on your couch where everything is familiar, you will create a much stronger memory of the material."

The research team included postdoctoral fellow Jie Zheng, PhD, and neuroscientist Gabriel Kreiman, PhD, from Boston Children's Hospital; neurosurgeon Taufik A. Valiante, MD, PhD, of the University of Toronto; and Adam Mamelak, MD, professor of Neurosurgery and director of the Functional Neurosurgery Program at Cedars-Sinai.

In follow-up studies, the team plans to test the theory that boundary and event cells activate dopamine neurons when they fire, and that dopamine, a chemical that sends messages between cells, might be used as a therapy to strengthen memory formation.

Rutishauser and his team also noted during this study that when event cells fired in time with one of the brain's internal rhythms, the theta rhythm -- a repetitive pattern of activity linked to learning, memory and navigation -- subjects were better able to remember the order of images they had seen. This is an important new insight because it shows that deep brain stimulation that adjusts theta rhythms could prove therapeutic for memory disorders.

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Higher education and language skills may help ward off dementia

New research has found that people with mild cognitive impairment may not inevitably develop dementia and, in fact, having higher education and advanced language skills more than doubles their chances of returning to normal.

The study, led by researchers at the University of Waterloo, may reassure those with mild cognitive impairment as it contradicts a common assumption that the condition is simply an early stage of dementia. People with mild cognitive impairment show signs of cognitive decline, but not enough to prevent them from performing typical daily tasks. They have been considered at higher risk of progressing to the more severe cognitive decline seen in dementia.

"Possessing high cognitive reserve -- based on education, high academic grades, and written language skills -- may predict what happens years after someone receives a diagnosis of mild cognitive impairment," said Suzanne Tyas, a professor in the School of Public Health Sciences at Waterloo and lead author. "Even after considering age and genetics -- established risk factors for dementia -- we found that higher levels of education more than doubled the chances that people with mild cognitive impairment would return to normal cognition instead of progressing to dementia."

The study also found that language skills, whether reflected in high grades in English in school or in strong writing that was grammatically complex and full of ideas, were also protective.

The researchers discovered that almost one-third of 472 women diagnosed with mild cognitive impairment reverted to normal cognition at least once over an average of eight-and-a-half years following their diagnosis, with more than 80 per cent of them never developing dementia.

Almost another third of the total number progressed to dementia without ever reverting to normal cognition, while three per cent stayed in the mild cognitive impairment stage, and 36 per cent died. None of the participants reverted from dementia to mild cognitive impairment.

The researchers also highlighted that reverse transitions are much more common than progressing to dementia in relatively younger individuals who didn't carry a certain genetic risk factor and had high levels of education and language skills.

"We can't do much about age and genetics, so it's encouraging that our findings show that there are other ways to reduce the risk of dementia, such as building cognitive reserve through education and language skills earlier in life," Tyas said.

The study's findings have implications for treatment and research in people with mild cognitive impairment.

"If individuals with higher cognitive reserve are more likely to improve even without treatment, then this needs to be taken into consideration when recruiting participants for clinical trials of prospective treatments and when interpreting the results of these trials," Tyas said, adding there's no cure for most causes of dementia, so prevention is key.

For the analysis, researchers used complex modelling with data drawn from a longitudinal study called the Nun Study, which looked at older, highly educated religious sisters. The participants were mostly homogeneous, with similar socioeconomic status and marital and reproductive history, strengthening the conclusions of this work.

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Neuroscientists explore mysterious 'events' in the brain that open new avenues for understanding brain injuries and disorders

Using a new model of brain activity, Indiana University computational neuroscientists Maria Pope, Richard Betzel and Olaf Sporns are exploring striking bursts of activity in the human brain that have not been examined before. These bursts may have potential to serve as biomarkers for brain disease and conditions such as depression, schizophrenia, dementia, and ADHD.

While analyzing human neuroimaging data, the IU research team discovered short bursts of activity that form ongoing "events" in the brain and are always taking place no matter the activity or state of the brain. In the course of a 10-minute brain scan, these events will occur roughly 10 to 20 times, each lasting for just a few seconds, the researchers found.

"What people had not seen is that how brain regions talk to each other is punctuated by these brief moments that are just a few seconds long during which there's a lot happening," said Olaf Sporns, who is Distinguished Professor and Robert H. Shaffer Chair in the College of Arts and Sciences Department of Psychological and Brain Sciences at IU Bloomington.

"Now that we see them, we've focused on those moments to get a picture of how specific brain regions link up and talk to each other during these events."

To begin investigating the workings of these mysterious events, the team built a computational model. Led by Maria Pope, a graduate student in Sporns' lab and a dual Ph.D. candidate in neuroscience and informatics, the group used neuroimaging data of a human brain to build a model replicating its connections. The model was then simulated in a state similar to the resting brain to create synthetic MRI signals, using mathematical equations that reenact neuronal activity.

The model showed burst-like events just like those seen in human brain recordings.

The paper outlining the model and describing how it compares to the real brain was published in the November 16 issue of the Proceedings of the National Academy of Sciences.

"The model shows us that these events are guided by the brain's structural network," Pope said. "They are tied to the physical structure of brain."

More specifically, the events originate in clusters of neurons and brain regions that are densely interconnected and momentarily light up together. Sporns compared the pattern to an orchestra playing a piece of music.

"There are moments when the orchestra comes together and there's a theme. They are not just playing a single note for 10 minutes. There are brief moments in which coordinated activity dominates and at other times there might be much less," Sporns said. "This ebb and flow of coordination is something we also see in the brain, and our model can reproduce it. Clusters of brain regions combine in different ways. It's not just one pattern, but multiple variations on a theme."

The new model's outcome, Sporns suggested, is a potential game changer.

"Functional connectivity has been a strong focus in research as a potential biomarker for brain disorders and has been related to conditions such as depression, schizophrenia, dementia, and ADHD. And researchers have tried for years to use brain simulations in clinical applications for modeling lesions or diseases," Sporns said. "This new model gives us a better lens through which to look at the brain, to see more clearly what goes on under both normal and abnormal conditions."

The researchers are now delving further into why the human brain employs these brief bursts of activity.

"Perhaps the brain has developed this type of activity because it's beneficial. Something about the structure of events may be useful to the brain," Pope said. "For example, many kinds of networked systems have to do occasional system updates or resets, taking some kind of globally useful information and communicating it to the rest of the system."

Answers to these questions may have implications not only for understanding the brain, but also for the study of neural networks and artificial intelligence.

"A clearer mapping of structure and function at the individual level could have implications for how we diagnose neurological disease and lead to personalized treatment and intervention," said Betzel, professor in the College of Arts and Sciences Department of Psychological and Brain Sciences.

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Researchers find warning signs for dementia in the blood

Researchers at the DZNE and the University Medical Center Göttingen (UMG) have identified molecules in the blood that can indicate impending dementia. Their findings, which are presented in the scientific journal EMBO Molecular Medicine, are based on human studies and laboratory experiments. Various university hospitals across Germany were also involved in the investigations. The biomarker described by the team led by Prof. André Fischer is based on measuring levels of so-called microRNAs. The technique is not yet suitable for practical use; the scientists therefore aim to develop a simple blood test that can be applied in routine medical care to assess dementia risk. According to the study data, microRNAs could potentially also be targets for dementia therapy.

"When symptoms of dementia manifest, the brain has already been massively damaged. Presently, diagnosis happens far too late to even have a chance for effective treatment. If dementia is detected early, the odds of positively influencing the course of the disease increase," says André Fischer, research group leader and spokesperson at the DZNE site in Göttingen and professor at the Department of Psychiatry and Psychotherapy at UMG. "We need tests that ideally respond before the onset of dementia and reliably estimate the risk of later disease. In other words, tests that give an early warning. We are confident that our current study results pave the way for such tests."

Molecular Signature

The biomarker that Fischer and his colleagues have found is based on measuring so-called microRNAs in the blood. MicroRNAs are molecules with regulatory properties: they influence the production of proteins and thus a key process in the metabolism of every living being. "There are many different microRNAs and each of them can regulate entire networks of interdependent proteins and thus influence complex processes in the organism. So, microRNAs have a broad impact. We wanted to find out whether there are specific microRNAs whose presence in the blood correlates with mental fitness," Fischer says.

Through extensive studies in humans, mice and cell cultures, the researchers ultimately identified three microRNAs whose levels were associated with mental performance. For this, they analyzed data from both young, cognitively normal individuals and from elderly people with mild cognitive impairment (MCI). For the data from healthy individuals, the Göttingen scientists cooperated with Munich University Hospital. The data from MCI patients came from a DZNE study that has been running for years and involves university clinics throughout Germany.

Omens of Dementia

In the end, the various findings came together like pieces of a puzzle: In healthy individuals, levels of microRNAs correlated with mental fitness. The lower the blood level, the better the subjects performed in cognition tests. In mice, in turn, this score increased even before the rodents started to show mental decline -- regardless of whether this was due to age or because they developed symptoms similar to those of Alzheimer's dementia. Further evidence came from patients with MCI: Of those in whom the blood marker was highly elevated, about 90 percent developed Alzheimer's disease within two years. "We therefore see an increased blood level of these three microRNAs as a harbinger of dementia," Fischer says. "We estimate that in humans this biomarker indicates a development that is about two to five years in the future."

Potential Targets for Therapy

In their studies on mice and cell cultures, the researchers also found that the three identified microRNAs influence inflammatory processes in the brain and "neuroplasticity" which includes the ability of neurons to establish connections with each other. This suggests that the three microRNAs are more than warning signals. "In our view, they are not only markers, but also have an active impact on pathological processes. This makes them potential targets for therapy," Fischer says. "Indeed, we see in mice that learning ability improves when these microRNAs are blocked with drugs. We've observed this in mice with age-related mental deficits, as well as in mice with brain damage similar to that occurring in Alzheimer's disease."

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Beige fat 'indispensable' in protecting the brain from dementia

Beige is considered a calming paint color, and scientists have new evidence that beige fat has a similar impact on the brain, bringing down the inflammation associated with the more common white fat and providing protection from dementia.

They have found that beige fat cells, which are typically intermingled with white fat cells in the subcutaneous fat present on "pear shaped" people, mediate subcutaneous fat's brain protection, Dr. Alexis M. Stranahan and her colleagues report in the journal Nature Communications.

Pear-shaped people, whose weight is generally distributed more evenly, rather than "apple shaped" individuals with fat clustered around their middle and often around internal organs like the liver in the abdominal cavity, are considered less at risk for cardiometabolic problems like heart disease and diabetes, as well as cognitive decline, says Stranahan, neuroscientist at the Medical College of Georgia at Augusta University.

Now the scientists have shown that beige fat cells, or adipocytes, are "indispensable" to the neuroprotective and anti-inflammatory effects of subcutaneous fat, says Stranahan, the study's corresponding author.

In fact without beige adipocytes, in the face of a high-fat diet, they saw subcutaneous fat start acting more like dangerous visceral fat, says Stranahan who reported last year in The Journal of Clinical Investigation that visceral adiposity sends a message to resident immune cells in the brain to fire up the inflammation, which ultimately damages cognition. "It's a very different signature," she says.

Visceral fat around the organs is mostly white fat cells, which store energy as triglycerides, which are yet another fat type found in the blood, and a risk factor for heart disease and stroke at high levels. Particularly in younger people, subcutaneous fat is a mixture of white and beige fat cells, and these beige cells are more like brown fat cells, which are packed with powerhouses called mitochondria and are efficient at using fat and sugars to produce heat in a process called thermogenesis. Exercise and cold exposure are said to enable the so-called "beiging" of white fat cells.

For some of their studies, the scientists used male mice with a specific gene knocked out that prevents adipocytes in the subcutaneous fat from beiging or browning, effectively resulting in subcutaneous fat that is more like visceral fat.

On a high-fat diet, it's already been shown that these mice develop diabetes more rapidly than those with normal amounts of beige fat. It's also known that transplanting subcutaneous fat into an obese mouse will improve their metabolic profile in a few weeks, and she wanted to know about potential impact on cognitive problems.

While both the normal and knockout mice gained about the same amount of weight over four weeks, mice without functional beige fat displayed accelerated cognitive dysfunction on testing, and their brains and bodies indicated a strong, rapid inflammatory response to the high-fat diet that included activation of microglial cells, those resident immune cells in the brain, which can further heighten inflammation and contribute to dementia and other brain problems.

Before they ever developed diabetes, the microglia of the mice, whose ages were comparable to a 20-something-year-old, had already turned on numerous inflammatory markers. Interestingly normal mice they studied as controls also turned on these markers but turned on anti-inflammatory markers as well apparently to minimize any response.

Normally it takes mice about three months on a high-fat diet to show the kind of responses they saw in the beige-fat knockouts in a single month.

To further explore the impact of beige fat, they also transplanted subcutaneous fat from young, lean healthy mice into the visceral compartment of otherwise normal but now-obese mice who had developed dementia-like behavior after remaining on a high-fat diet for 10 to 12 weeks.

Transplanting the subcutaneous fat resulted in improved memory, restoring essentially normal synaptic plasticity -- the ability of the connections between neurons to adapt so they can communicate -- in the hippocampus, the center of learning and memory deep in the brain. These positive changes were dependent on the beige adipocytes in the donor subcutaneous fat, Stranahan and her colleagues write.

Transplants from the beige-fat knockouts on the other hand did not improve cognition in the obese mice, including by strictly objective measures like any increased electrical activity between neurons.

"If we can figure out what it is about beige fat that limits inflammation and maybe what it is about beige fat that improves brain plasticity, then maybe we can mimic that somehow with a drug or with cold-stimulated beiging or even taking out some of your subcutaneous fat when you are young, freezing it and giving it back to you when you are older," Stranahan says.

All fat tends to be packed with immune cells, which can both promote and calm inflammation. They found beige fat interacts continuously with those immune cells, inducing the anti-inflammatory cytokine IL-4 in the subcutaneous fat. IL-4 in turn is required for cold to stimulate the "beiging" of fat, she notes.

Also in turn, the fat induced IL-4 in microglia and T cells, key drivers of the immune response, in the meninges, a sort of multilayer cap that fits over the brain to help protect it. They also found T cells in the choroid plexus, where cerebrospinal fluid is produced, had calming IL-4 induced.

Their findings suggest IL-4 is directly involved in communication between beige adipocytes and neurons in the hippocampus, the scientists write.

"It's kind of like "Whisper Down the Lane" if you ever played that at camp," Stranahan says of what appears to be a calming chain of communication.

When Stranahan and her team looked further they found it was the recipient's own T cells in the meninges that were called to positive, protective action by the transplanted beige fat cells, not immune cells from the transplanted fat itself.

There is evidence that in chronic obesity, your own immune cells can reach the brain, and there was no evidence in this case that it was the donor's immune cells making the journey.

"It's exciting because we have a way for peripheral immune cells to interact with the brain in a way that promotes cognition," Stranahan says, noting that there also are many bad things immune cells could do in the brain like contribute to stroke and Alzheimer's.

Her many next goals include learning more about how much it matters where you put the transplanted fat, like whether transferring subcutaneous fat to a subcutaneous area might work even better to protect against cognitive decline; whether transplanting visceral fat to a subcutaneous area decreases its damaging effect; and better understanding how subcutaneous fat sends what appears to be an active anti-inflammatory message. She also wants to explore these issues in female mice since the current studies were limited to males.

But what they and others already are finding underscores the importance of inherent fat distribution, which could be a biomarker for those most at risk for cognitive decline, she says.

The stage of obesity may be another factor, because she also has early evidence suggesting that the longer a high-fat diet is maintained and the more subcutaneous fat increases, its protective powers decrease and visceral fat increases.

Even in a healthy, non-obese young person visceral fat is going to produce higher levels of basal inflammation, Stranahan notes.

Stranahan emphasizes that she does not want her findings to cause excessive concern in overweight individuals or generate more prejudice against them, rather the work is about better identifying risk factors and different points and methods of intervention to fit the needs of individuals.

Stranahan and her colleagues reported in 2015 in the journal Brain, Behavior, and Immunity that a high-fat diet prompts microglia to become uncharacteristically sedentary and to start eating the connections between neurons.

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Scientists discover early signs of frontotemporal dementia in personalized cerebral organoids

Frontotemporal dementias are a group of fatal and debilitating brain disorders for which there are no cures. In an article published July 26 in Cell, Mount Sinai researchers describe how they were able to recreate much of the damage seen in a widely studied form of the disease by growing special types of cerebral organoids in petri dishes. This form of the disease is caused by a genetic mutation in tau, a protein that is a hallmark of Alzheimer's disease and other dementias. By studying these organoids, the scientists discovered how the mutated tau protein may trigger the death of a specific class of neurons known to be vulnerable in frontotemporal dementia. They also showed that they could prevent the death of these neurons by treating the organoids with an experimental drug, originally designed to combat Crohn's disease.

"Frontotemporal dementia is a devastating disease for patients and their loved ones. Understanding the causes of dementia can be difficult, as most of the damage to the brain occurs well before any symptoms appear. It's like trying to unravel the events that created a crime scene. In this study, we were able to model many aspects of the pathology seen in the brains of patients who carry the V337M mutation in tau," said Alison M. Goate, DPhil, Director, Ronald M. Loeb Center for Alzheimer's Disease at Mount Sinai, and a senior author of the study. "Our results identified several very early transcriptomic and proteomic changes that lead to the formation of tau pathology and neuronal death. Our goal is to help researchers develop novel treatments against frontotemporal dementias and prevent the suffering experienced by patients and their families."

Frontotemporal dementia is a rare form of dementia that usually begins between ages 40 and 60. It affects the front and side (temporal) areas of the brain, leading to behavior changes and difficulty with speaking and thinking.

The study was led by Kathryn Bowles, PhD, an instructor in Dr. Goate's lab at Mount Sinai. Working with scientists at the Neural Stem Cell Institute (NSCI) in Rensselaer, New York, Washington University in St. Louis, Missouri, Massachusetts General Hospital in Boston, and the University of Southern California, Los Angeles, the researchers created thousands of cerebral organoids from induced pluripotent stem cells (iPSCs).

Induced pluripotent stem cells are created by genetically and chemically reprogramming a person's skin or blood cells into newborn stem cells, which have the potential to become any cell in the body. From these stem cells, the NSCI created thousands of tiny, 3D cerebral organoids, which mimic the early growth and development of the cerebral cortex for intensive study by collaborating scientific groups.

"Induced pluripotent stem cells are powerful tools. They allow researchers to study each patient's personalized disease in a petri dish," said Sally Temple, PhD, Scientific Director of the NSCI and a senior author of the study. "In this study we were able to take this idea to the next level. By combining iPSC-organoid technology with high-throughput, single cell gene activity analysis, we were able to get a better look at what might be going on in a patient's brain at early stages of disease development, even before symptoms emerge."

In this study, the researchers examined the growth and development of organoids derived from the stem cells of three patients, all of whom carried the V337M mutation in tau. They then compared their results with those observed in "isogenic," control organoids. The controls were derived from patient stem cells in which the disease-causing mutation was genetically corrected.

After six months of growth, signs of neurodegeneration were seen in the organoids. Most notably, the patient-derived organoids had fewer excitatory neurons than those derived from the control cells, demonstrating that the tau mutation was sufficient to cause higher levels of cell death of this specific class of neurons. Excitatory neurons usually fire in response to the neurochemical glutamate and are known to die at abnormally high levels in frontotemporal dementia. The patient-derived organoids also had higher levels of harmful versions of tau protein and elevated levels of inflammation.

"Excitatory neuron cell death, tau protein deposits, and inflammation are classic hallmarks of the kind of damage seen in many forms of frontotemporal dementia," said Dr. Bowles. "What we wanted to know next was: what are the cellular and molecular processes that occur before the appearance of these disease hallmarks?"

The researchers found clues by examining two- and four-month-old organoids.

For instance, two-month-old mutant organoids appeared to be undergoing elevated levels of cellular stress, whereas four-month-old ones developed problems with autophagy, or the recycling of proteins. The results also suggested that during these early months the excitatory neurons matured faster in the mutant organoids than in the controls.

Other experiments suggested that many of these changes may have been the by-product of a complex interaction between mutant tau, excitatory neuronal genes, and ELAVL4, a protein that controls gene activity by binding to ribonucleic acid (RNA) molecules.

"Our results suggest that the V337M mutant tau sets off a vicious cycle in the brain that puts excitatory neurons under great stress. It hastens the production of new proteins needed for maturation but prevents disposal of the proteins that are being replaced," Dr. Bowles said.

Further experiments supported this idea. For example, excitatory neurons in mutant organoids were less likely to survive in the presence of toxic levels of glutamate than those in control organoids. The researchers then found that this could be prevented by apilimod, an experimental drug designed to alter a cell's protein recycling system. In other words, the researchers saw no difference in levels of glutamate-induced cell death between mutant and control organoids when they treated samples with apilimod.

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Think about this: Keeping your brain active may delay Alzheimer's dementia 5 years

Keeping your brain active in old age has always been a smart idea, but a new study suggests that reading, writing letters and playing card games or puzzles in later life may delay the onset of Alzheimer's dementia by up to five years. The research is published in the July 14, 2021, online issue of Neurology, the medical journal of the American Academy of Neurology.

"The good news is that it's never too late to start doing the kinds of inexpensive, accessible activities we looked at in our study," said study author Robert S. Wilson, PhD, of Rush University Medical Center in Chicago. "Our findings suggest it may be beneficial to start doing these things, even in your 80s, to delay the onset of Alzheimer's dementia."

The study looked at 1,978 people with an average age of 80 who did not have dementia at the start of the study. The people were followed for an average of seven years. To determine if they had developed dementia, participants were given annual examinations, which included a number of cognitive tests.

When the study began, people rated their participation in seven activities on a five-point scale. The questions included: "During the past year, how often did you read books?" and "During the past year, how often did you play games like checkers, board games, cards or puzzles?"

Participants also answered questions about cognitive activity in childhood, adulthood and middle age.

Researchers then averaged each person's responses, with a score of one meaning once a year or less and score of five meaning every day or almost every day. People in the group with high cognitive activity scored an average of 4.0 which meant activities several times per week, compared to an average score of 2.1 for those with low cognitive activity, which meant activities several times per year.

During the study follow-up period, 457 people with an average age of 89 were diagnosed with Alzheimer's dementia. People with the highest levels of activity, on average, developed dementia at age 94. The people with the lowest cognitive activity, on average, developed dementia at age 89, a difference of five years. The results were similar when researchers adjusted for other factors that could affect dementia risk, such as education level and sex.

To test the idea that low cognitive activity may be an early sign of dementia, not the other way around, researchers also looked at the brains of 695 people who died during the study. Brain tissue was examined for markers of Alzheimer's like amyloid and tau protein deposits, but researchers found no association between how active they were cognitively and markers of Alzheimer's disease and related disorders in their brains.

"Our study shows that people who engage in more cognitively stimulating activities may be delaying the age at which they develop dementia," Wilson said. "It is important to note, after we accounted for late life level of cognitive activity, neither education nor early life cognitive activity were associated with the age at which a person developed Alzheimer's dementia. Our research suggests that the link between cognitive activity and the age at which a person developed dementia is mainly driven by the activities you do later in life."

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Success in reversing dementia in mice sets the stage for human clinical trials

Researchers have identified a new treatment candidate that appears to not only halt neurodegenerative symptoms in mouse models of dementia and Alzheimer's disease, but also reverse the effects of the disorders.

The team, based at Tohoku University, published their results on June 8 in the International Journal of Molecular Sciences. The treatment candidate has been declared safe by Japan's governing board, and the researchers plan to begin clinical trials in humans in the next year.

"There are currently no disease-modifying therapeutics for neurodegenerative disorders such as Alzheimer's disease, Lewy body dementia, Huntington disease and frontotemporal dementia in the world," said paper author Kohji Fukunaga, professor emeritus in Tohoku University's Graduate School of Pharmaceutical Sciences. "We discovered the novel, disease-modifying therapeutic candidate SAK3, which, in our studies, rescued neurons in most protein-misfolding, neurodegenerative diseases."

In a previous study, the team found that the SAK3 molecule - the base structure of which is found in the enhancement of T-type Ca2+ channel activity - appeared to help improve memory and learning in a mouse model of Alzheimer's disease.

According to previous studies, SAK3 enhances the function of a cell membrane channel thereby promoting neuronal activity in the brain. Typically, SAK3 promotes neurotransmitter releases of acetylcholine and dopamine that are significantly reduced in Alzheimer's disease and Lewy body dementia. The Ca2+ channel enhancement is thought to trigger a change from resting to active in neuronal activity. When the Ca2+ channel is dysregulated in the brain, the acetylcholine and dopamine releases are reduced. The result is a dysregulated system that a person experiences as cognitive confusion and uncoordinated motor function.

SAK3 directly binds to the subunit of this channel, resulting in the enhancement of neurotransmission thereby improving cognitive deficits. The researchers found that the same process also appeared to work in a mouse model of Lewy body dementia, which is characterized by a build-up of proteins known as Lewy bodies.

"Even after the onset of cognitive impairment, SAK3 administration significantly prevented the progression of neurodegenerative behaviors in both motor dysfunction and cognition," Fukunaga said.

In comparison, Aduhelm, the Alzheimer's drug recently approved by the U.S. Food and Drug Administration, reduces the number of amyloid plaques in the brain, but it is not yet known if the amyloid reduction actually prevents further cognitive or motor decline in patients. According to Fukunaga, SAK3 helps destroy amyloid plaque - at least in mice.

SAK3 also helps manage the destruction of misfolded alpha-synuclein. Normal alpha-synuclein helps regulate neurotransmitter transmission in the brain. The protein can misfold and aggregate, contributing to what researchers suspect may be an underlying cause of neurodegenerative symptoms. This aggregation can also lead to the loss of dopamine neurons, which help with learning and memory.

"We found that chronic administration of SAK3 significantly inhibited the accumulation of alpha-synuclein in the mice," Fukunaga said, noting that the mice received a daily oral dose of SAK3.

According to Fukunaga, SAK3 enhances the activity of the system that identifies and destroys misfolded proteins. In neurodegenerative diseases, this system is often dysfunctional, leaving misfolded proteins to muck up the cell's machinery.

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