Tooth loss associated with increased cognitive impairment, dementia

Good oral health, including dentures, may protect against cognitive decline

July 8, 2021

Science Daily/New York University

Tooth loss is a risk factor for cognitive impairment and dementia -- and with each tooth lost, the risk of cognitive decline grows, according to a new analysis led by researchers at NYU Rory Meyers College of Nursing and published in JAMDA: The Journal of Post-Acute and Long-Term Care Medicine. However, this risk was not significant among older adults with dentures, suggesting that timely treatment with dentures may protect against cognitive decline.

About one in six adults aged 65 or older have lost all of their teeth, according to the Centers for Disease Control and Prevention. Prior studies show a connection between tooth loss and diminished cognitive function, with researchers offering a range of possible explanations for this link. For one, missing teeth can lead to difficulty chewing, which may contribute to nutritional deficiencies or promote changes in the brain. A growing body of research also points to a connection between gum disease -- a leading cause of tooth loss -- and cognitive decline. In addition, tooth loss may reflect life-long socioeconomic disadvantages that are also risk factors for cognitive decline.

"Given the staggering number of people diagnosed with Alzheimer's disease and dementia each year, and the opportunity to improve oral health across the lifespan, it's important to gain a deeper understanding of the connection between poor oral health and cognitive decline," said Bei Wu, PhD, Dean's Professor in Global Health at NYU Rory Meyers College of Nursing and co-director of the NYU Aging Incubator, as well as the study's senior author.

Wu and her colleagues conducted a meta-analysis using longitudinal studies of tooth loss and cognitive impairment. The 14 studies included in their analysis involved a total of 34,074 adults and 4,689 cases of people with diminished cognitive function.

The researchers found that adults with more tooth loss had a 1.48 times higher risk of developing cognitive impairment and 1.28 times higher risk of being diagnosed with dementia, even after controlling for other factors.

However, adults missing teeth were more likely to have cognitive impairment if they did not have dentures (23.8 percent) compared to those with dentures (16.9 percent); a further analysis revealed that the association between tooth loss and cognitive impairment was not significant when participants had dentures.

The researchers also conducted an analysis using a subset of eight studies to determine if there was a "dose-response" association between tooth loss and cognitive impairment -- in other words, if a greater number of missing teeth was linked to a higher risk for cognitive decline. Their findings confirmed this relationship: each additional missing tooth was associated with a 1.4 percent increased risk of cognitive impairment and 1.1 percent increased risk of being diagnosed with dementia.

"This 'dose-response' relationship between the number of missing teeth and risk of diminished cognitive function substantially strengthens the evidence linking tooth loss to cognitive impairment, and provides some evidence that tooth loss may predict cognitive decline," said Xiang Qi, a doctoral candidate from NYU Meyers.

"Our findings underscore the importance of maintaining good oral health and its role in helping to preserve cognitive function," said Wu.

https://www.sciencedaily.com/releases/2021/07/210708083904.htm

Faulty memories of our past whereabouts: The fallacy of an airtight alibi

July 7, 2021

Science Daily/Association for Psychological Science

When someone is suspected of criminal activity, one of the most important questions they are asked is if they have a credible alibi. Playing back past events in our minds, however, is not like playing back a video recording. Recollections of locations, dates, and companions can become muddled with the passage of time. If a suspect's memories are out of line with documented events, a once-plausible alibi can crumble and may be seen as evidence of guilt.

To put people's memories of past whereabouts to the test, a team of researchers tracked the locations of 51 volunteers for one month and found that their recollections were wrong approximately 36% of the time.

"This is the first study to examine memory for where an event happened," said Simon J. Dennis, director of the Complex Human Data Hub at the University of Melbourne's School of Psychological Sciences and lead author of the study, which was published in the journal Psychological Science. "We were able to use experience-sampling methods to actually examine people's memories and analyze what is affecting memory error in their everyday life."

In the study, an app on the participants' smartphones continuously (and securely) recorded their locations and surroundings via GPS. The app also made sound recordings of the environment every 10 minutes. Participants had the freedom to turn off the app or to delete events -- a mechanism designed to protect privacy.

At the end of the month, the participants received a memory test in which they were given a time and date and then asked to select one of four markers on Google Maps to show where they had been at that moment.

The results revealed that participants tended to confuse days across weeks. They also often confused weeks in general and hours across days. The participants had the poorest recall when memories of one event become entwined with memories of a similar experience, such as filling up a car with gas at a different location of the same gas-station chain.

Additionally, the researchers found that people tended to confuse places they had visited at similar times or locations, such as multiple bars visited in one evening. People also made mistakes -- although less frequently -- when events involved similar sounds or movement patterns, such as when they had walked through town on different days while listening to their favorite music.

"This has implications for alibi generation, as jurors tend to assume that a suspect who is wrong is lying," said Dennis. "These results can alert investigators to the questions they should ask in order to catch the memory errors that suspects are likely to make."

https://www.sciencedaily.com/releases/2021/07/210707160527.htm

Could ketogenic diet be helpful with brain cancer?

July 7, 2021

Science Daily/American Academy of Neurology

A modified ketogenic diet may be worth exploring for people with brain tumors, according to a new study published in the July 7, 2021, online issue of Neurology®, the medical journal of the American Academy of Neurology. The diet is high in fat and low in carbohydrates.

The small study found that the diet was safe and feasible for people with brain tumors called astrocytomas. All of the people had completed radiation treatment and chemotherapy. The diet led to changes in the metabolism in the body and the brain. The study was not designed to determine whether the diet could slow down tumor growth or improve survival.

"There are not a lot of effective treatments for these types of brain tumors, and survival rates are low, so any new advances are very welcome," said study author Roy E. Strowd, MD, MS, MEd, of Wake Forest School of Medicine in Winston-Salem, N.C., and a Fellow of the American Academy of Neurology.

"These cancer cells rely on glucose, or sugar, to divide and grow. Since the ketogenic diet is low in sugar, the body changes what it uses for energy -- instead of carbohydrates, it uses what are called ketones. Normal brain cells can survive on ketones, but the theory is that cancer cells cannot use ketones for energy."

The study involved 25 people with astrocytomas. They followed a type of ketogenic diet, the modified Atkins diet with intermittent fasting, for eight weeks. The diet includes foods such as bacon, eggs, heavy cream, butter, leafy green vegetables and fish. Participants met with a dietician at the start of the study and then every two weeks. Five days a week they followed the modified Atkins diet, which combined carbohydrate restriction with high amounts of fats. Two days a week they fasted, eating up to 20% of their recommended daily calorie amount.

The main goal of the study was to see if people were able to follow the diet with no serious side effects. A total of 21 people completed the study, and 48% followed the diet completely, according to their food records. But urine tests showed that 80% of the people reached the level where their body was primarily using fats and protein for fuel, rather than carbohydrates.

The diet was well-tolerated. Two people had serious side effects during the study -- one was not related to the diet and one was possibly related.

By the end of the study, changes in the metabolism in the body and the brain were seen. Hemoglobin A1c levels, insulin levels, and fat body mass all decreased. Lean body mass increased. Specialized brain scans that detect changes in brain metabolites showed an increase in concentrations of ketones and metabolic changes in the tumor.

"Of course more studies are needed to determine whether this diet can prevent the growth of brain tumors and help people live longer, but these results show that the diet can be safe for people with brain tumors and successfully produce changes in the metabolism of the body and the brain," Strowd said.

A limitation of the study is that study team members provided a high amount of contact with participants, which may not be feasible in a larger study or in routine clinical care.

https://www.sciencedaily.com/releases/2021/07/210707160516.htm

Source of remarkable memory of 'superagers' revealed

July 6, 2021

Science Daily/Massachusetts General Hospital

'Superagers' who performed a challenging memory task in an MRI scanner were able to learn and recall new information as well as 25-year-old participants. Neurons in the visual cortex of brains of superaging older adults retain their selective and efficient ability to process visual stimuli and create a distinct memory of the images. In the future, interventions to train specific areas of the brain to be more efficient may enable normal aging adults to enhance memory and other cognitive functions.

As we age, our brains typically undergo a slow process of atrophy, causing less robust communication between various brain regions, which leads to declining memory and other cognitive functions. But a rare group of older individuals called "superagers" have been shown to learn and recall novel information as well as a 25-year-old. Investigators from Massachusetts General Hospital (MGH) have now identified the brain activity that underlies superagers' superior memory. "This is the first time we have images of the function of superagers' brains as they actively learn and remember new information," says Alexandra Touroutoglou, PhD, director of Imaging Operations at MGH's Frontotemporal Disorders Unit and senior author of the paper published in Cerebral Cortex.

In 2016, Touroutoglou and her fellow researchers identified a group of adults older than 65 with remarkable performance on memory tests. The superagers are participants in an ongoing longitudinal study of aging at MGH led by Bradford Dickerson, MD, director of the Frontotemporal Disorders Unit at MGH, and Lisa Feldman Barrett, PhD, a research scientist in Psychiatry at MGH. "Using MRI, we found that the structure of superagers' brains and the connectivity of their neural networks more closely resemble the brains of young adults; superagers had avoided the brain atrophy typically seen in older adults," says Touroutoglou.

In the new study, the investigators gave 40 adults with a mean age of 67 a very challenging memory test while their brains were imaged using functional magnetic resonance imaging (fMRI), which, unlike typical MRI, shows the activity of different brain areas during tasks. Forty-one young adults (mean age of 25) also took the same memory test while their brains were imaged. The participants first viewed 80 pictures of faces or scenes that were each paired with an adjective, such as a cityscape paired with the word "industrial" or a male face paired with the word "average." Their first task was to determine whether the word matched the image, a process called encoding. After 10 minutes, participants were presented with the 80 image-word pairs they had just learned, an additional 40 pairs of new words and images, and 40 rearranged pairs consisting of words and images they had previously seen. Their second task was to recall whether they had previously seen each specific word-picture pair, or whether they were looking at a new or rearranged pair.

While the participants were in the scanner, the researchers paid close attention to the visual cortex, which is the area of the brain that processes what you see and is particularly sensitive to aging. "In the visual cortex, there are populations of neurons that are selectively involved in processing different categories of images, such as faces, houses or scenes," says lead author Yuta Katsumi, PhD, a postdoctoral fellow in Psychiatry at MGH. "This selective function of each group of neurons makes them more efficient at processing what you see and creating a distinct memory of those images, which can then easily be retrieved."

During aging, this selectivity, called neural differentiation, diminishes and the group of neurons that once responded primarily to faces now activates for other images. The brain now has difficulty creating unique neural activation patterns for different types of images, which means it is making less distinctive mental representations of what the person is seeing. That's one reason older individuals have trouble remembering when they may have seen a television show, read an article, or eaten a specific meal.

But in the fMRI study, the superagers' memory performance was indistinguishable from the 25-year-olds', and their brains' visual cortex maintained youthful activity patterns. "The superagers had maintained the same high level of neural differentiation, or selectivity, as a young adult," says Katsumi. "Their brains enabled them to create distinct representations of the different categories of visual information so that they could accurately remember the image-word pairs."

An important question that researchers still must answer is whether "superagers' brains were always more efficient than their peers, or whether, over time, they developed mechanisms to compensate for the decline of the aging brain," says Touroutoglou.

Previous studies have shown that training can increase the selectivity of brain regions, which may be a potential intervention to delay or prevent the decline in neural differentiation in normal aging adults and make their brains more like those of superagers. Currently the researchers are conducting a clinical trial to evaluate whether noninvasive electromagnetic stimulation, which delivers an electrical current to targeted areas of the brain, can improve memory in older adults. The researchers also plan to study different brain regions to further understand how superagers learn and remember, and they will examine lifestyle and other factors that might contribute to superagers' amazing memory.

Major funding for this study was provided by the National Institute on Aging.

Touroutoglou is an assistant professor of Neurology at Harvard Medical School (HMS). Dickerson is professor of Neurology at HMS. Barrett is distinguished professor of Psychology at Northeastern University. The other co-author is Joseph Andreano, PhD, an investigator in the Department of Psychiatry at MGH and an instructor of Psychiatry at HMS.

https://www.sciencedaily.com/releases/2021/07/210706133136.htm

Scientists rejuvenate mouse brains with ketamine or flickering light

July 6, 2021

Science Daily/Institute of Science and Technology Austria

Can you remember the smell of flowers in your grandmother's garden or the tune your grandpa always used to whistle? Some childhood memories are seemingly ingrained into your brain. In fact, there are critical periods in which the brain learns and saves profound cognitive routines and memories. The structure responsible for saving them is called the perineuronal net.

This extracellular structure envelops certain neurons, thereby stabilizes existing connections -- the synapses -- between them and prevents new ones from forming. But what if we could remove the perineuronal net and restore the adaptability of a young brain? The neuroscientist Sandra Siegert and her research group at IST Austria now published two promising techniques to do so.

In defining periods of development, the brain re-organizes connections between its neurons more freely than in its adult form. Researchers have now discovered two methods to reopen such plasticity: repeated ketamine anesthesia and non-invasive 60 hertz light flickering. The  findings may have the potential to become a therapeutic tool applicable to humans.

Taking Ketamine or Flashing Lights 

It all began four years ago when the researchers at IST Austria found that microglia cells in mice become very reactive after they had anesthetized animals with the drug ketamine. Microglia are typically seen as the brain's immune cells. However, recent studies have shown that they also interact with the neurons. The reactive microglia have the ability to eat synapses and even entire neurons, which is often seen in the late phases of Alzheimer's disease.

"The strong response of the microglia upon ketamine anesthesia surprised us," explains Alessandro Venturino, leading author in the study and member of the Siegert group. "But we did not see any synapses or dead neurons vanishing. So, we were puzzled, what the microglia were actually eating." It turned out to be the perineuronal net that protects and stabilizes the connections between neurons.

"Alessandro came to my office and told me that the perineuronal net was gone. I could not believe it," Siegert remembers. They had applied repeated anesthetic dosages of ketamine to mice. Ketamine is an essential drug for human surgery and was also recently approved for treating psychiatric symptoms. "After just three treatments, we could see a considerable loss in the perineuronal net, which lasted for seven days before being rebuilt."

When Siegert shared the results with Mark Bear, collaborating neuroscientist at the Massachusetts Institute of Technology (MIT), he was equally amazed and intrigued by the potential of this discovery. "In biology, you rarely witness such a black-and-white situation," Siegert continues. "Yet, the cherry on top was the effect of the 60-hertz light flickering."

Neurons communicate by sending electric impulses to each other. These are coordinated to create waves of signals -- so-called brainwaves -- which can be influenced by external sensory information, for example, light shining into the eyes. "It had been previously shown that light flickering 40 times a second -- at 40 hertz -- can promote microglia to remove plaques in Alzheimer disease. But it did not remove the perineuronal net," Venturino explains. But when the scientists then put mice in boxes with light flickering 60 times a second, it had a similar effect as the ketamine treatments. "This fine-tuning between distinct brainwaves and the microglia action is the most fascinating and might be a new way of thinking about brainwaves."

Caution and Possibilities 

Previously established strategies to remove the perineuronal net are long-lasting and extremely invasive. The high-dosage ketamine treatment but even more so the 60-hertz light flickering are minimally invasive. Therefore, they could open new therapeutic approaches in humans.

Once the blocking of the perineuronal net in the brain is lessened, neurons are again sensitive to new input, and new synapses can be formed. "But it is not like you take ketamine as a drug and become smart," Venturino emphasizes. By re-establishing plasticity, one could potentially overwrite traumatic experiences and treat post-traumatic stress disorder. "But we are very cautious because in this formative window also something traumatic could happen," Siegert says. "It is probably also not a good idea to blast yourself with flickering light."

There are various possible applications for these treatments, one being amblyopia, also known as the lazy eye. This sight disorder is caused by an unbalanced visual input during a child's development and, if untreated, leads to permanent loss of vision. Another topic the researchers want to investigate is the molecular mechanisms behind their discovery which are still not fully understood. Venturino puts it in a nutshell: "There is a lot to explore."

https://www.sciencedaily.com/releases/2021/07/210706115323.htm

Non-invasive potential treatment for Alzheimer's disease

June 24, 2021

Science Daily/University of Queensland

Ultrasound can overcome some of the detrimental effects of ageing and dementia without the need to cross the blood-brain barrier, Queensland Brain Institute researchers have found.

Professor Jürgen Götz led a multidisciplinary team at QBI's Clem Jones Centre for Ageing Dementia Research who showed low-intensity ultrasound effectively restored cognition without opening the barrier in mice models.

The findings provide a potential new avenue for the non-invasive technology and will help clinicians tailor medical treatments that consider an individual's disease progression and cognitive decline.

"Historically, we have been using ultrasound together with small gas-filled bubbles to open the almost-impenetrable blood-brain barrier and get therapeutics from the bloodstream into the brain," Professor Götz said.

The new research involved a designated control group who received ultrasound without the barrier-opening microbubbles.

"The entire research team was surprised by the remarkable restoration in cognition," he said.

"We conclude therapeutic ultrasound is a non-invasive way to enhance cognition in the elderly."

Ageing is associated with impaired cognition and a reduction in the learning induced plasticity of the signalling between neurons called long-term potentiation (LTP).

Dr Daniel Blackmore, senior postdoctoral researcher on the team, said the new research aimed to use ultrasound to restore LTP and improved spatial learning in aged mice.

Professor Götz said the brain was "not particularly accessible," but ultrasound provided a tool for overcoming challenges like the blood-brain barrier.

"Using ultrasound could enhance cognition independently of clearing amyloid and tau, which form plaques and tangles in people with Alzheimer's disease," he said.

"Microbubbles will continue to be used in combination with ultrasound in ongoing Alzheimer's research."

About 400,000 people in Australia have dementia and numbers are projected to increase to one million by 2050, with ageing the single biggest risk factor.

Previous research has shown the long-term safety of ultrasound technology and that pathological changes and cognitive deficits could be improved by using ultrasound to treat Alzheimer's disease.

Professor Götz said there were still questions about the differences between normal "physiological" ageing and the "pathological" ageing that happens in Alzheimer's disease.

''We believe there may be some overlap between physiological and pathological ageing in the brain and the potential for this to be corrected with ultrasound is meaningful for those living with Alzheimer's disease," he said.

''We are taking these findings and implementing them in our Alzheimer's research as we go forward to clinical trials.''

Professor Götz's research team aims to understand how brain diseases begin and their progression at molecular and cellular levels in the hope of ultimately developing therapies.

https://www.sciencedaily.com/releases/2021/06/210624114329.htm

Self-reported declines in cognition may be linked to changes in brain connectivity

June 22, 2021

Science Daily/Wayne State University - Office of the Vice President for Research

Jessica Damoiseaux, Ph.D., an associate professor with the Institute of Gerontology at Wayne State University, recently published the results of a three-year study of cognitive changes in older adults. The team followed 69 primarily African American females, ages 50 to 85, who complained that their cognitive ability was worsening though clinical assessments showed no impairments. Three magnetic resonance imaging scans (MRIs) at 18-month intervals showed significant changes in functional connectivity in two areas of the brain.

"An older adult's perceived cognitive decline could be an important precursor to dementia," Damoiseaux said. "Brain alterations that underlie the experience of decline could reflect the progression of incipient dementia and may emerge before cognitive assessment is sensitive enough to detect a deficit."

The resulting paper, "Longitudinal change in hippocampal and dorsal anterior insulae functional connectivity in subjective cognitive decline," appeared in the May 31 issue of Alzheimer's Research & Therapy. Damoiseaux conducted the study with graduate student Raymond Viviano, Ph.D., who is first author.

Subjective cognitive decline, defined as a perceived worsening of cognitive ability not noted on clinical assessment, may be an early indicator of dementia. Previous cross-sectional research has demonstrated aberrant brain functional connectivity in subjective cognitive decline, but longitudinal evaluation has been limited.

Viviano and Damoiseaux's three-year study found that persons reporting more subjective cognitive decline showed a larger decrease in connectivity between components of the default mode network and a larger increase in connectivity between salience and default mode network components. The functional connectivity changed in the absence of a change in cognitive performance.

Since these brain changes occurred without concomitant cognitive changes, they could indicate that brain changes underlie the perception of decline. These changes could be a sensitive marker for nascent dementia months or years before assessments detect any cognitive deficit.

https://www.sciencedaily.com/releases/2021/06/210622132311.htm

Protein linked to heart health, disease a potential therapeutic target for dementia

Brain protein reduces Alzheimer's-like brain damage in mice

June 23, 2021

Science Daily/Washington University School of Medicine

By the time people with Alzheimer's disease start exhibiting difficulty remembering and thinking, the disease has been developing in their brains for two decades or more, and their brain tissue already has sustained damage. As the disease progresses, the damage accumulates, and their symptoms worsen.

Researchers at Washington University School of Medicine in St. Louis have found that high levels of a normal protein associated with reduced heart disease also protect against Alzheimer's-like brain damage -- at least in mice. The findings, published June 21 in Neuron, suggest that raising levels of the protein -- known as low-density lipoprotein receptor (LDL receptor) -- could potentially be a way to slow or stop cognitive decline.

The discovery of LDL receptor as a potential therapeutic target for dementia is surprising since the protein is much better known for its role in cholesterol metabolism. Statins and PCSK9 inhibitors, two groups of drugs widely prescribed for cardiovascular disease, work in part by increasing levels of LDL receptor in the liver and some other tissues. It is not known whether they affect LDL receptor levels in the brain.

"There are not yet clearly effective therapies to preserve cognitive function in people with Alzheimer's disease," said senior author David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. "We found that increasing LDL receptor in the brain strongly decreases neurodegeneration and protects against brain injury in mice. If you could increase LDL receptor in the brain with a small molecule or other approach, it could be a very attractive treatment strategy."

The key to the importance of LDL receptor lies in a different protein, APOE, that also is linked to both cholesterol metabolism and Alzheimer's disease. High cholesterol in the blood is associated with increased risk of Alzheimer's disease, although the exact nature of the association is unclear.

During the long, slow development of Alzheimer's disease, plaques of a protein called amyloid gradually accumulate in the brain. After many years, another brain protein called tau starts forming tangles that become detectable just before Alzheimer's symptoms arise. The tangles are thought to be toxic to neurons, and their spread through the brain foretells the death of brain tissue and cognitive decline. First author Yang Shi, PhD, a postdoctoral researcher, and Holtzman previously showed that APOE drives tau-mediated degeneration in the brain by activating microglia, the brain's cellular janitorial crew. Once activated, microglia can injure neural tissue in their zeal to clean up molecular debris.

Higher levels of LDL receptor limit the damage APOE can do in part by binding to APOE and degrading it. Higher levels of LDL receptor in the brain, therefore, should pull more APOE out of the fluid surrounding brain cells and mitigate damage even further, the researchers reasoned.

As part of this study, Shi, Holtzman and colleagues including co-senior author Jason Ulrich, PhD, an associate professor of neurology, studied mice predisposed to develop Alzheimer's-like neurodegeneration because they had been genetically modified to develop tau buildup in the brain, much like people with Alzheimer's disease and other forms of dementia. The researchers bred the tau mice with mice genetically modified to express high levels of LDL receptor in their brains. The resulting offspring had high levels of LDL receptor and a propensity to develop Alzheimer's-like brain damage by the time they were 9 months old, which is similar to middle age in a person.

Then, the researchers compared the four groups: normal mice, tau mice, mice with high levels of LDL receptor, and tau mice with high levels of LDL receptor. At 9 months, the normal mice and the mice with high levels of LDL receptor had healthy looking brains. The tau mice had severe brain atrophy and neurological damage. In comparison, the tau mice with high levels of LDL receptor were in much better shape. They had significantly less brain shrinkage and damage, their levels of certain forms of tau and APOE were significantly lower, and their microglia were shifted toward a less damaging pattern of activation.

"Alzheimer's develops slowly through multiple phases, and the degeneration phase when tau is building up is when the symptoms arise and worsen," Holtzman said. "In terms of quality of life for people with Alzheimer's, this is a phase in which it would be great if we could intervene. I think this LDL receptor pathway is a good candidate because it has a strong effect, and we know it can be targeted in other parts of the body. This has motivated us over the last few years to try to develop programs to modulate the receptor in other ways."

https://www.sciencedaily.com/releases/2021/06/210623095247.htm

Some blood pressure-lowering meds linked to less memory decline in older adults

June 21, 2021

Science Daily/American Heart Association

Older adults taking blood pressure-lowering medications known to cross the blood-brain barrier had better memory recall over time compared to those taking other types of medicines to treat high blood pressure, according to new research published today in the American Heart Association journal Hypertension.

High blood pressure, or hypertension, is a risk factor for cognitive decline and dementia in older adults. Nearly half of American adults have elevated blood pressure. Treating high blood pressure with blood pressure-lowering medicines reduced the cases of mild cognitive impairment by 19% in one large trial (SPRINT MIND).

ACE inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers and diuretics are different classes of blood pressure-lowering medicines. Each class acts in a different way to reduce blood pressure, and some cross the blood-brain barrier, thereby impacting cognitive function.

"Research has been mixed on which medicines have the most benefit to cognition," said study author Daniel A. Nation, Ph.D., an associate professor of psychological science in the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine. "Studies of angiotensin II receptor blockers and angiotensin-converting-enzyme (ACE) inhibitors have suggested these medicines may confer the greatest benefit to long-term cognition, while other studies have shown the benefits of calcium channel blockers and diuretics on reducing dementia risk."

This is the first meta-analysis to compare the potential impact over time of blood pressure lowering medicines that do vs. those that do not cross the blood-brain barrier. The medicines were evaluated for their effects on several cognitive domains, including attention, language, verbal memory, learning and recall.

"Hypertension occurs decades prior to the onset of dementia symptoms, affecting blood flow not only in the body but also to the brain," Nation said . "Treating hypertension is likely to have long-term beneficial effects on brain health and cognitive function later."

Researchers gathered information from 14 studies of nearly 12,900 adults ages 50 years and older. These included studies done in the United States, Australia, Canada, Germany, Ireland and Japan. The meta-analysis found:

• Older adults taking blood pressure-lowering medicines that cross the blood-brain barrier had better memory recall for up to 3 years of follow-up compared to those taking medicines that do not cross the blood-brain barrier even though they had a higher level of vascular risk.

• Adults taking hypertension medications that did not cross the blood-brain barrier had better attention for up to 3 years of follow-up.

"These findings represent the most powerful evidence to-date linking brain-penetrant ACE-inhibitors and angiotensin receptor blockers to better memory. It suggests that people who are being treated for hypertension may be protected from cognitive decline if they medications that cross the blood-brain barrier," said study co-author Jean K. Ho, Ph.D., a postdoctoral fellow at the University of California, Irvine.

Blood pressure is considered elevated at 120/80 mm Hg and higher. The current American Heart Association/American College of Cardiology guidelines for treating high blood pressure suggest changes to diet and activity levels to lower blood pressure and adding blood pressure-lowering medication for people with levels of 130/80 mm Hg or higher depending on their risk status. If blood pressure reaches 140/90 mm Hg, blood pressure-lowering medication is recommended.

Limitations of this analysis are that the authors could not account for differences in racial/ethnic background based on the available studies, and there is a higher proportion of men vs. women in the group who took medications that cross the blood-brain barrier. This is an important area of future research since previous studies have shown that people from various racial/ethnic backgrounds may respond differently to different blood pressure medications.

https://www.sciencedaily.com/releases/2021/06/210621084105.htm

Link found between gut microbes and stroke

Findings lay the groundwork for new stroke treatments, prevention strategies

June 16, 2021

Science Daily/Cleveland Clinic

New findings from Cleveland Clinic researchers show for the first time that the gut microbiome impacts stroke severity and functional impairment following stroke. The results, published in Cell Host & Microbe, lay the groundwork for potential new interventions to help treat or prevent stroke.

The research was led by Weifei Zhu, Ph.D., and Stanley Hazen, M.D., Ph.D., of Cleveland Clinic's Lerner Research Institute. The study builds on more than a decade of research spearheaded by Dr. Hazen and his team related to the gut microbiome's role in cardiovascular health and disease, including the adverse effects of TMAO (trimethylamine N-oxide) -- a byproduct produced when gut bacteria digest certain nutrients abundant in red meat and other animal products.

"In this study we found that dietary choline and TMAO produced greater stroke size and severity, and poorer outcomes in animal models," said Dr. Hazen, chair of the Department of Cardiovascular & Metabolic Sciences and director of Cleveland Clinic's Center for Microbiome & Human Health. "Remarkably, simply transplanting gut microbes capable of making TMAO was enough to cause a profound change in stroke severity."

Previously, Dr. Hazen and his team discovered that elevated TMAO levels can lead to the development of cardiovascular disease. In clinical studies involving thousands of patients, they have shown that blood levels of TMAO predict future risk of heart attack, stroke and death -findings that have been replicated around the world. Earlier studies, also led by Drs. Zhu and Hazen, were the first to show a link between TMAO and enhanced risk for blood clotting.

"This new study expands on these findings, and for the first time provides proof that gut microbes in general -- and through TMAO specifically -- can directly impact stroke severity or post-stroke functional impairment," said Dr. Hazen.

The researchers compared brain damage in preclinical stroke models between those with elevated or reduced TMAO levels. Over time, those with higher levels of TMAO had more extensive brain damage and a greater degree of motor and cognitive functional deficits following stroke. The researchers also found that dietary changes that alter TMAO levels, such as eating less red meat and eggs, impacted stroke severity.

"Functionality after a stroke -- which occurs when blood flow to the brain is blocked -- is a major concern for patients," said Dr. Hazen, who is also co-section head of Preventive Cardiology & Cardiac Rehabilitation in Cleveland Clinic's Miller Heart, Vascular & Thoracic Institute. "To understand if choline and TMAO affect post-stroke functionality, in addition to stroke severity, we compared performance on various tasks pre-stroke, and then both in the short- and long-term following stroke."

The team found that a gut microbe enzyme critical to TMAO production called CutC drove heightened stroke severity and worsened outcomes.

According to Dr. Zhu, targeting this gut microbe enzyme may be a promising approach to prevent stroke. "When we genetically silenced the gut microbe gene that encodes CutC, stroke severity significantly diminished," she said. "Ongoing research is exploring this treatment approach, as well as the potential for dietary interventions to help reduce TMAO levels and stroke risk, since both a Western diet and a diet rich in red meat are known to elevate TMAO levels. Switching to plant-based protein sources helps to lower TMAO."

https://www.sciencedaily.com/releases/2021/06/210616113816.htm

Forget me not: Novel target shows promise in treating Alzheimer's and related dementias

June 10, 2021

Science Daily/Medical University of South Carolina

Researchers remain perplexed as to what causes dementia and how to treat and reverse the cognitive decline seen in patients. In a first-of-its-kind study, researchers at the Medical University of South Carolina (MUSC) and Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School discovered that cis P-tau, a toxic, non-degradable version of a healthy brain protein, is an early marker of vascular dementia (VaD) and Alzheimer's disease (AD). Their results, published on June 2 in Science Translational Medicine, define the molecular mechanism that causes an accumulation of this toxic protein. Furthermore, they showed that a monoclonal antibody (mAb) that targets this toxic protein was able to prevent disease pathology and memory loss in AD- and VaD-like preclinical models. Additionally, this treatment was even capable of reversing cognitive impairment in an AD-like preclinical model.

"We believe our findings have not only discovered cis P-tau as a previously unrecognized major early driver of VaD and AD but also identified a highly effective and specific immunotherapy to target this common disease driver for treating and preventing AD and VaD at early stages," said Onder Albayram, Ph.D., co-lead author and assistant professor in the Division of Cardiology in the Department of Medicine at MUSC.

Aging is a normal part of life -- we experience weakening of our bones and muscles, stiffening of our blood vessels and some memory lapses. But for around 50 million people worldwide, these memory lapses become progressively more severe, ultimately leading to a diagnosis of dementia.

Dementia is an umbrella term that covers AD, which accounts for 60% to 80% of cases; VaD, the second most common cause; and other less common pathologies. Currently, there are no effective treatments for AD. Interestingly, most AD cases have a vascular component, suggesting a broader relationship between cognitive function and healthy brain vasculature. A better understanding of that relationship could provide a platform to discover novel therapeutic targets.

"Our work provides evidence that cis P-tau may be a pathogenic factor that explains VaD, which is not generally linked to other dementias," added Chenxi Qiu, Ph.D., co-lead author and a postdoctoral research fellow at BIDMC, Harvard Medical School.

In a preclinical model of VaD, young mice showed signs of brain inflammation and memory loss within one month. However, treating these mice with the cis P-tau mAb prevented neural degradation and cognitive decline out to six months. In a separate preclinical model of AD, old mice showed severe cognitive impairment. Excitingly, this severe impairment was significantly reversed when mice were given the cis P-tau mAb.

"These data show that cis P-tau could be an early upstream pathogenic factor common to both diseases," said Albayram.

Translating information gained from preclinical models to humans is often difficult, but this study offers reasons to be optimistic. Accumulation of cis P-tau caused dramatic changes in the genetic architecture of affected cells in a VaD model; these changes were consistent with those seen in human AD patients. The researchers went on to show that treatment with the cis P-tau mAb reversed 85% to 90 % of those changes suggesting the power of this potential therapy.

"The genomic landscape really adapts after the silencing of this toxic protein," said Albayram. "That was a big discovery."

Not only are Albayram and Qiu excited about these findings, but colleagues at MUSC are already quite enthusiastic about this work.

"I can go on and on about this paper," said Adviye Ergul, M.D., Ph.D., professor in the College of Medicine, Department of Pathology and Laboratory Medicine at MUSC. "They provide robust evidence that there is accumulation of a specific form of the tau protein -- cis P-tau -- that highlights a different tau protein pathology in VaD research."

This groundbreaking research has opened the door for new potential immunotherapies and highlighted several new areas of research that need to be explored. While the researchers delineated a pathway that leads to the accumulation of cis P-tau, the underlying linkage between vascular abnormalities and activation of the pathway needs to be identified. A better understanding of how toxic cis P-tau interacts with the healthy trans P-tau could provide further insights into the progression of AD disease.

AD and VaD might not be the only diseases affected by high levels of cis P-tau. Other brain disorders with a vascular component might also arise from this toxic protein, but further study will be required to establish such a link.

"Cis P-tau may be a common, early and pathogenic factor underlying traumatic brain injury, VaD and AD," said Qiu.

As we get older and our memory begins to lapse -- misplacing our car keys or forgetting the name of a new acquaintance -- we fear the possibility that these are the first signs of dementia. And while there is currently no approved treatment to reverse the physiological effects of dementia, this new research may provide hope that new therapies are around the corner.

https://www.sciencedaily.com/releases/2021/06/210610162350.htm

Memory biomarkers confirm aerobic exercise helps cognitive function in older adults

Study conducted on older adults with familial and genetic risk for Alzheimer's disease

June 10, 2021

Science Daily/Florida Atlantic University

Increasing evidence shows that physical activity and exercise training may delay or prevent the onset of Alzheimer's disease (AD). In aging humans, aerobic exercise training increases gray and white matter volume, enhances blood flow, and improves memory function. The ability to measure the effects of exercise on systemic biomarkers associated with risk for AD and relating them to key metabolomic alterations may further prevention, monitoring, and treatment efforts. However, systemic biomarkers that can measure exercise effects on brain function and that link to relevant metabolic responses are lacking.

To address this issue, Henriette van Praag, Ph.D., from Florida Atlantic University's Schmidt College of Medicine and Brain Institute and Ozioma Okonkwo, Ph.D., Wisconsin Alzheimer's Disease Research Center and Department of Medicine at the University of Wisconsin-Madison and their collaborators, tested the hypotheses that three specific biomarkers, which are implicated in learning and memory, would increase in older adults following exercise training and correlate with cognition and metabolomics markers of brain health. They examined myokine Cathepsin B (CTSB), brain derived neurotrophic factor (BDNF), and klotho, as well as metabolomics, which have become increasingly utilized to understand biochemical pathways that may be affected by AD.

Researchers performed a metabolomics analysis in blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50 percent female) who participated in the "aeRobic Exercise And Cognitive Health (REACH) Pilot Study" (NCT02384993) at the University of Wisconsin. The participants were divided into two groups: usual physical activity (UPA) and enhanced physical activity (EPA). The EPA group underwent 26 weeks of supervised treadmill training. Blood samples for both groups were taken at baseline and after 26 weeks.

Results of the study, published in the journal Frontiers in Endocrinology, showed that plasma CTSB levels were increased following this 26-week structured aerobic exercise training in older adults at risk for AD. Verbal learning and memory correlated positively with change in CTSB but was not related to BDNF or klotho. The present correlation between CTSB and verbal learning and memory suggests that CTSB may be useful as a marker for cognitive changes relevant to hippocampal function after exercise in a population at risk for dementia.

Plasma BDNF levels decreased in conjunction with metabolomic changes, including reductions in ceramides, sphingo- and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis. Indeed, multiple lipid metabolites relevant to AD were modified by exercise in a manner that may be neuroprotective. Serum klotho was unchanged but was associated with cardiorespiratory fitness.

"Our findings position CTSB, BDNF, and klotho as exercise biomarkers for evaluating the effect of lifestyle interventions on brain function," said van Praag, corresponding author, an associate professor of biomedical science, FAU's Schmidt College of Medicine, and a member of the FAU Brain Institute and the FAU Institute for Human Health & Disease Intervention (I-HEALTH). "Human studies often utilize expensive and low throughput brain imaging analyses that are not practical for large population-wide studies. Systemic biomarkers that can measure the effect of exercise interventions on Alzheimer's-related outcomes quickly and at low-cost could be used to inform disease progression and to develop novel therapeutic targets."

CTSB, a lysosomal enzyme, is secreted from muscle into circulation after exercise and is associated with memory function and adult hippocampal neurogenesis. Older adults with cognitive impairment have lower serum and brain CTSB levels. BDNF is a protein that is upregulated in the rodent hippocampus and cortex by running and is important for adult neurogenesis, synaptic plasticity, and memory function. Klotho is a circulating protein that can enhance cognition and synaptic function and is associated with resilience to neurodegenerative disease, possibly by supporting brain structures responsible for memory and learning.

"The positive association between CTSB and cognition, and the substantial modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function and brain health in asymptomatic individuals at risk for Alzheimer's disease," said van Praag.

https://www.sciencedaily.com/releases/2021/06/210610135527.htm

Largescale brain epigenetics study provides new insights into dementia

June 10, 2021

Science Daily/University of Exeter

The largest study of its kind has unveiled new insights into how genes are regulated in dementia, including discovering 84 new genes linked to the disease.

Led by the University of Exeter, the international collaboration combined and analysed data from more than 1,400 people across six different studies, in a meta-analysis published in Nature Communications. These studies had used brain samples from people who had died with Alzheimer's disease. The project, funded by Alzheimer's Society and supported by the Medical Research Council and the National Institutes for Health, looked at an epigenetic mark called DNA methylation at nearly half a million sites in the genome. Epigenetic processes control the extent to which genes are switched on and off, meaning they behave differently as needed across the different cell-types and tissues that make up a human body. Importantly, unlike our genes, epigenetic processes can be influenced by environmental factors, making them potentially reversible and a possible route to new treatments.

The study looked at epigenetic patterns across the genome, in a number of different regions of the brain. The team then related the amount of DNA methylation to the amount of neurofibrillary tangles within the brain, which is an important hallmark of the severity of Alzheimer's disease.

The team looked in different regions of the brain, which are affected in Alzheimer's disease before looking for common changes across these cortical regions. They identified 220 sites in the genome, including 84 new genes, which showed different levels of DNA methylation in the cortex in individuals with more severe Alzheimer's disease, which weren't seen in another area of the brain called the cerebellum.

The team went on to show that a subset of 110 of these sites could distinguish in two independent datasets whether a brain sample had high or low levels of disease, with more than 70 per cent accuracy. This suggests that epigenetic changes in the brain in Alzheimer's disease are very consistent. The findings were subsequently confirmed in an independent set of brain samples from the Brains for Dementia Research cohort funded by the Alzheimer's Society and Alzheimer's Research UK.

Professor Katie Lunnon, of the University of Exeter, who led the research, said: "Our study is the largest of its kind, giving important insights into genomic areas that could one day provide the key to new treatments. The next step for this work is to explore whether these epigenetic changes lead to measurable changes in the levels of genes and proteins being expressed. This will then allow us to explore whether we could repurpose existing drugs that are known to alter the expression levels of these genes and proteins, to effectively treat dementia"

The study included a number of international collaborators from the US (Columbia University and Mount Sinai School of Medicine in New York, Rush University Center in Chicago, Arizona State University), and Europe (Maastricht University in Netherlands, University of Saardland, Germany). The paper is titled 'A meta-analysis of epigenome-wide association studies in Alzheimer's disease highlights novel differentially methylated loci across cortex', published in Nature Communications.

Dr Richard Oakley, Head of Research, Alzheimer's Society said: "Epigenetics is a flourishing area of dementia research. Work like this, led by the University of Exeter, is another step forward in our understanding of the incredibly complex role our genes play in Alzheimer's disease.

"It's now important to delve into the specific impact of these epigenetic changes and the associated genes on the changes in the brains of people with Alzheimer's disease. This work is in early stages but breakthroughs in research begins with work like this, and it brings us a step closer to developing new treatments for Alzheimer's disease.

"Alzheimer's Society is delighted to have part-funded this work and 'Brains for Dementia Research', which provided the tissue samples to this research team. Without the support of charities, this work simply would not be possible -- we are committed to investing in, and accelerating, dementia research. However, dementia research remains hugely underfunded. We need public support now more than ever to help us continue our ground-breaking research to make a world without dementia a reality."

https://www.sciencedaily.com/releases/2021/06/210610091050.htm

Taking short breaks may help our brains learn new skills

Scientists discover that the resting brain repeatedly replays compressed memories of what was just practiced

June 8, 2021

Science Daily/NIH/National Institute of Neurological Disorders and Stroke

In a study of healthy volunteers, National Institutes of Health researchers have mapped out the brain activity that flows when we learn a new skill, such as playing a new song on the piano, and discovered why taking short breaks from practice is a key to learning. The researchers found that during rest the volunteers' brains rapidly and repeatedly replayed faster versions of the activity seen while they practiced typing a code. The more a volunteer replayed the activity the better they performed during subsequent practice sessions, suggesting rest strengthened memories.

"Our results support the idea that wakeful rest plays just as important a role as practice in learning a new skill. It appears to be the period when our brains compress and consolidate memories of what we just practiced," said Leonardo G. Cohen, M.D., senior investigator at the NIH's National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study published in Cell Reports. "Understanding this role of neural replay may not only help shape how we learn new skills but also how we help patients recover skills lost after neurological injury like stroke."

The study was conducted at the NIH Clinical Center. Dr. Cohen's team used a highly sensitive scanning technique, called magnetoencephalography, to record the brain waves of 33 healthy, right-handed volunteers as they learned to type a five-digit test code with their left hands. The subjects sat in a chair and under the scanner's long, cone-shaped cap. An experiment began when a subject was shown the code "41234" on a screen and asked to type it out as many times as possible for 10 seconds and then take a 10 second break. Subjects were asked to repeat this cycle of alternating practice and rest sessions a total of 35 times.

During the first few trials, the speed at which subjects correctly typed the code improved dramatically and then leveled off around the 11th cycle. In a previous study, led by former NIH postdoctoral fellow Marlene Bönstrup, M.D., Dr. Cohen's team showed that most of these gains happened during short rests, and not when the subjects were typing. Moreover, the gains were greater than those made after a night's sleep and were correlated with a decrease in the size of brain waves, called beta rhythms. In this new report, the researchers searched for something different in the subjects' brain waves.

"We wanted to explore the mechanisms behind memory strengthening seen during wakeful rest. Several forms of memory appear to rely on the replaying of neural activity, so we decided to test this idea out for procedural skill learning," said Ethan R. Buch, Ph.D., a staff scientist on Dr. Cohen's team and leader of the study.

To do this, Leonardo Claudino, Ph.D., a former postdoctoral fellow in Dr. Cohen's lab, helped Dr. Buch develop a computer program which allowed the team to decipher the brain wave activity associated with typing each number in the test code.

The program helped them discover that a much faster version -- about 20 times faster -- of the brain activity seen during typing was replayed during the rest periods. Over the course of the first eleven practice trials, these compressed versions of the activity were replayed many times -- about 25 times -- per rest period. This was two to three times more often than the activity seen during later rest periods or after the experiments had ended.

Interestingly, they found that the frequency of replay during rest predicted memory strengthening. In other words, the subjects whose brains replayed the typing activity more often showed greater jumps in performance after each trial than those who replayed it less often.

"During the early part of the learning curve we saw that wakeful rest replay was compressed in time, frequent, and a good predictor of variability in learning a new skill across individuals," said Dr. Buch. "This suggests that during wakeful rest the brain binds together the memories required to learn a new skill."

As expected, the team discovered that the replay activity often happened in the sensorimotor regions of the brain, which are responsible for controlling movements. However, they also saw activity in other brain regions, namely the hippocampus and entorhinal cortex.

"We were a bit surprised by these last results. Traditionally, it was thought that the hippocampus and entorhinal cortex may not play such a substantive role in procedural memory. In contrast, our results suggest that these regions are rapidly chattering with the sensorimotor cortex when learning these types of skills," said Dr. Cohen. "Overall, our results support the idea that manipulating replay activity during waking rest may be a powerful tool that researchers can use to help individuals learn new skills faster and possibly facilitate rehabilitation from stroke."

https://www.sciencedaily.com/releases/2021/06/210608154506.htm

Weak brain waves may warn of age-related neurodegenerative disease

June 8, 2021

Science Daily/eLife

Weakened electrical signals in the brain may be an early warning sign of age-related neurodegenerative diseases such as Alzheimer's disease, suggests a study published today in eLife.

The findings hint at new ways to identify early on patients who may have an age-related brain disease. They also provide new insights on the changes that occur in the brain as these diseases develop.

"As tools for detecting Alzheimer's disease early are limited, there is a need to develop a reliable, non-invasive test that would enable early diagnosis," says first author Murty Dinavahi, who was a PhD Research Scholar at the Centre for Neuroscience, Indian Institute of Science (IISc), Bengaluru, India, at the time the study was carried out, and is now a Postdoctoral Associate at the University of Maryland, US.

Previous studies in mice with a condition similar to Alzheimer's disease had suggested that weakened gamma brain waves may be an early sign of disease. Based on these findings, Murty and colleagues conducted a community-based study on around 250 elderly subjects. They compared gamma wave activity in 12 people diagnosed with mild cognitive impairment, and five with Alzheimer's disease, with their healthy peers.

The researchers used a technique called electroencephalography to measure electrical activity in the participants' brains while they viewed black and white patterns on a screen. These patterns are known to induce gamma oscillations in the part of the brain that processes visual information. The team also monitored the participants' eye movements during the experiments.

Their results showed that people who had been diagnosed with mild cognitive impairment or Alzheimer's disease had weaker gamma waves in their brain than healthy individuals of the same age.

"We observed reductions in the strength of gamma waves in early stages of age-related cognitive decline," Murty says. "Changes in these electrical signals could provide an early warning sign of an impending disease." He adds that an early diagnosis could help individuals put care plans in place or allow them to begin treatments sooner.

"Our work provides a low-cost and non-invasive way to detect early signs of Alzheimer's disease," concludes senior author Supratim Ray, Associate Professor at the Centre for Neuroscience, IISc. "This could be useful for clinicians and scientists studying early changes that take place in the brain during age-related neurodegenerative diseases, and potentially lead to new ways to diagnose and treat these conditions."

https://www.sciencedaily.com/releases/2021/06/210608113213.htm

Studies reveal skull as unexpected source of brain immunity

Immune cells from skull bone marrow guard the brain, spinal cord

June 3, 2021

Science Daily/Washington University School of Medicine

The immune system is the brain's best frenemy. It protects the brain from infection and helps injured tissues heal, but it also causes autoimmune diseases and creates inflammation that drives neurodegeneration.

Two new studies in mice suggest that the double-edged nature of the relationship between the immune system and the brain may come down to the origins of the immune cells that patrol the meninges, the tissues that surround the brain and spinal cord. In complementary studies published June 3 in the journal Science, two teams of researchers at Washington University School of Medicine in St. Louis unexpectedly found that many of the immune cells in the meninges come from bone marrow in the skull and migrate to the brain through special channels without passing through the blood.

These skull-derived immune cells are peacekeepers, dedicated to maintaining a healthy status quo. It's the other immune cells, the ones that arrive from the bloodstream, that seem to be the troublemakers. They carry genetic signatures that mark them as likely to promote autoimmunity and inflammation, and they become more abundant with aging or under conditions of disease or injury. Taken together, the findings reveal a key aspect of the connection between the brain and the immune system that could inform our understanding of a wide range of brain disorders.

"There has been this gap in our knowledge that applies to almost every neurological disease: neuro-COVID, Alzheimer's disease, multiple sclerosis, brain injury, you name it," said Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology and a BJC Investigator. Kipnis is the senior author on one of the papers. "We knew immune cells were involved in neurological conditions, but where were they coming from? What we've found is that there's a new source that hasn't been described before for these cells."

Earlier this year, Kipnis showed that immune cells stationed in the meninges keep tabs on the brain. As part of these new studies, Kipnis and Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology and the senior author on the other paper, independently launched projects to find where such cells come from. Kipnis focused on the innate arm of the immune system and Colonna on the adaptive arm. Innate immune cells are responsible for inflammation, which helps defend against infection and heal injuries, but also can damage tissues and contribute to degenerative conditions such as Alzheimer's and Parkinson's disease. Adaptive immune cells are capable of specifically targeting undesirables such as viruses and tumors, but they also can mistakenly home in on the body's own healthy tissues, resulting in autoimmune diseases such as multiple sclerosis.

Colonna and colleagues -- including co-first authors Simone Brioschi, PhD, a postdoctoral researcher, Wei-Le Wang, PhD, a postdoctoral researcher, and Vincent Peng, a graduate student -- traced the development of B cells, antibody-producing members of the adaptive immune system. They found that most B cells in the meninges arose and matured in the skull bone marrow. As B cells mature, they must be taught to distinguish between normal proteins from the body, which pose no threat, and foreign proteins that signal infection or disease and require a response. For B cells destined for a life patrolling the boundaries of the central nervous system, the skull is a convenient site for this education.

"B cells in the bone marrow of the skull come into contact with the central nervous system and are educated by the central nervous system," said Colonna, who is also a professor of medicine. "That would not happen if they were released into the blood. Because they are directly in contact with the brain, they learn to be tolerant of brain proteins."

Along with the tolerant B cells derived from the skull, the researchers also discovered a population of B cells that come into the meninges from the blood. These blood-derived B cells are not trained to ignore normal central nervous system proteins. Some of these cells may wrongly recognize harmless central nervous system proteins as foreign and produce antibodies against them, Colonna said. Moreover, the number of these blood-derived B cells increases with age, providing a clue to why the risk of neuro-immune conditions is higher in older people.

Meanwhile, Kipnis' team -- led by co-first authors Andrea Cugurra, a graduate student, Tornike Mamuladze, MD, a visiting researcher, and Justin Rustenhoven, PhD, a postdoctoral researcher -- was searching for the source of meningeal myeloid cells, a group of innate immune cells. They found that myeloid cells arose in the bone marrow of the skull and spinal vertebrae and entered the meninges via direct channels through the bone.

Using mouse models of multiple sclerosis and of brain and spinal cord injuries, Kipnis and colleagues found that myeloid cells swarm into the brain and spinal cord in response to injury or disease. Most of the entering cells are drawn from the resident population of myeloid cells in the meninges. These are biased toward regulating and modulating the immune response. But some myeloid cells come in from the blood, and these are more inflammatory, capable of causing damage if not properly controlled.

"Understanding where these cells come from and how they behave is a critical part of understanding the basic mechanisms of neuro-immune interactions, so we can design new therapeutic approaches for neurological conditions associated with inflammation," said Kipnis, who is also a professor of neurosurgery, of neurology and of neuroscience. "The location of these cells in the skull makes them relatively accessible, and opens up the possibility of designing therapies to alter the behavior of these cells and treat neuro-immune conditions."

https://www.sciencedaily.com/releases/2021/06/210603171058.htm

Secondary infections inflame the brain, worsening cognition in Alzheimer's disease

June 3, 2021

Science Daily/Trinity College Dublin

New research into Alzheimer's disease (AD) suggests that secondary infections and new inflammatory events amplify the brain's immune response and affect memory in mice and in humans -- even when these secondary events occur outside the brain.

Scientists believe that key brain cells (astrocytes and microglia) are already in an active state due to inflammation caused by AD and this new research shows that secondary infections can then trigger an over-the-top response in those cells, which has knock-on effects on brain rhythms and on cognition.

In the study, just published in Alzheimer's & Dementia, the journal of the Alzheimer's Association, mice engineered to show features of AD were exposed to acute inflammatory events to observe the downstream effects on brain inflammation, neuronal network function and memory.

These mice showed new shifts in the output of astrocytes and microglia and displayed new cognitive impairment and disturbed 'brain rhythms' that did not occur in healthy, age-matched, mice. These new onset cognitive changes are similar to acute and distressing psychiatric disturbances like delirium, that frequently occur in elderly patients.

Although it is difficult to replicate these findings in patients, the study additionally showed that AD patients who died with acute systemic infection showed heighted brain levels of IL-1β -- a pro-inflammatory molecule that was important in causing the heightened immune response and the new onset disruptions seen in the AD mice.

Colm Cunningham, Associate Professor in Trinity's School of Biochemistry and Immunology, and the Trinity Biomedical Sciences Institute, led the research. He said:

"Alzheimer's disease is the most common form of dementia, affecting more than 5% of those over 60 and this distressing, debilitating condition causes difficulties for a huge number of people across the globe. The more we know about the disease and its progression the better chance we have of treating those living with it. We believe our work adds to this knowledge base in a few ways. Primarily, we show that the Alzheimer's-affected brain has a greater vulnerability to acute inflammatory events, even if they occur outside the brain.

Placing this within the context of the slowly evolving progression of AD, we propose that these hypersensitive responses, now seen in multiple cell populations, may contribute to the negative outcomes that follow acute illness in older patients, including episodes of delirium and the accelerated cognitive trajectory that has been observed in patients who experience delirium before or during their dementia."

The research was supported by the US National Institutes of Health (NIH) and by the Wellcome Trust.

https://www.sciencedaily.com/releases/2021/06/210603083545.htm

Healthy lifestyle linked to better cognition for oldest adults -- regardless of genetic risk

New study suggests importance of maintaining healthy lifestyle even after age 80

June 1, 2021

Science Daily/PLOS

A new analysis of adults aged 80 years and older shows that a healthier lifestyle is associated with a lower risk of cognitive impairment, and that this link does not depend on whether a person carries a particular form of the gene APOE. Xurui Jin of Duke Kunshan University in Jiangsu, China, and colleagues present these findings in the open-access journal PLOS Medicine.

The APOE gene comes in several different forms, and people with a form known as APOE ε4 have an increased risk of cognitive impairment and Alzheimer's disease. Previous research has also linked cognitive function to lifestyle factors, such as smoking, exercise, and diet. However, it has been unclear whether the benefits of a healthy lifestyle are affected by APOE ε4, particularly for adults over 80 years of age.

To clarify the relationship between APOE ε4 and lifestyle, Jin and colleagues examined data from 6,160 adults aged 80 or older who had participated in a larger, ongoing study known as the Chinese Longitudinal Healthy Longevity Survey. The researchers statistically analyzed the data to investigate links between APOE ε4, lifestyle, and cognition. They also accounted for sociodemographics and other factors that could impact cognition.

The analysis confirmed that participants with healthy lifestyles or intermediately healthy lifestyles were significantly less likely to have cognitive impairment than those with an unhealthy lifestyle, by 55 and 28 percent, respectively. In addition, participants with APOE ε4 were 17 percent more likely to have cognitive impairment than those with other forms of APOE.

A previous study suggested that in individuals at low and intermediate genetic risk, favorable lifestyle profiles are related to a lower risk of dementia compared to unfavorable profiles. But these protective associations were not found in those at high genetic risk. However, the investigation showed the link between lifestyle and cognitive impairment did not vary significantly based on APOE ε4 status which represented the genetic dementia risk. This suggests that maintaining a healthier lifestyle could be important for maintaining cognitive function in adults over 80 years of age, regardless of genetic risk.

This cross-sectional study emphasized the importance of a healthy lifestyle on cognitive health. While further research will be needed to validate these findings among different population, this study could help inform efforts to boost cognitive function for the oldest of adults.

In the next step, the team will explore this association using the AD polygenetic risk score (AD-PRS) and explore the interactive relationship between AD-PRS and lifestyle on cognition with the longitudinal data.

https://www.sciencedaily.com/releases/2021/06/210601152005.htm

Role of sleep-related brain activity in clearing toxic proteins and preventing Alzheimer's disease

June 1, 2021

Science Daily/PLOS

Evidence of sleep-dependent low-frequency (<0.1 Hz) global brain activity in the clearance of Alzheimer's disease-related toxin buildup is presented in research published on 1st June 2021 in the open access journal PLOS Biology by Xiao Liu and colleagues at The Pennsylvania State University. This neuronal activity was more strongly linked with cerebrospinal fluid flow in healthy controls than higher risk groups and patients, and the findings could serve as a potential imaging marker for clinicians in evaluating patients.

The development of Alzheimer's disease is believed to be driven by the buildup of the toxic proteins amyloid-β and tau in the brain. The brain's glymphatic system plays a crucial role in clearing these toxins and previous work has shown a possible relationship between sleep-dependent global brain activity and the glymphatic system by showing this activity is coupled by cerebrospinal fluid flow essential for the glymphatic system.

Using 118 subjects in the Alzheimer's Disease Neuroimaging Initiative project, the researchers measured this global brain activity and cerebrospinal fluid flow as well as looking at behavioral data. Individuals underwent resting-state fMRI sessions two years apart, and the team compared their findings with neurobiological and neuropsychological markers related to Alzheimer's disease, such as levels of the toxic protein amyloid-β.

The strength of the connection between brain activity and cerebrospinal fluid flow was weaker in individuals at a higher risk or who had already developed Alzheimer's disease. Additionally, this weaker connection was associated with higher levels of amyloid-β and disease-related behavioral measures two years later. This suggests an important role for sleep-dependent global brain activity in the clearance of brain waste, and its connection to cerebrospinal fluid flow could be helpful as a future marker for clinical evaluation.

Dr. Liu adds, "The study linked the coupling between the resting-state global brain activity and cerebrospinal fluid flow to Alzheimer's disease pathology. The finding highlights the potential role of low-frequency (<0.1 Hz) resting-state neural and physiological dynamics in the neurodegenerative diseases, presumably due to their sleep-dependent driving of cerebrospinal fluid flow to wash out brain toxins. Future studies are warranted to fully understand the global brain activity and associated physiological modulations and their role in glymphatic clearance and neurodegenerative diseases."

https://www.sciencedaily.com/releases/2021/06/210601152018.htm

Memory details fade over time, with only the main gist preserved

May 26, 2021

Science Daily/University of Birmingham

What information is retained in a memory over time, and which parts get lost? These questions have led to many scientific theories over the years, and now a team of researchers at the Universities of Glasgow and Birmingham have been able to provide some answers.

Their new study, which is published today in Nature Communications, demonstrates that our memories become less vibrant and detailed over time, with only the central gist eventually preserved. Moreover, this 'gistification' of our memories is boosted when we frequently recall our recent experiences.

The work could have implications in a number of areas, including the nature of memories in post-traumatic stress disorder, the repeated questioning of eye-witness testimonies and even in best practice for exam studying.

While memories are not exact carbon copies of the past -- remembering is understood to be a highly reconstructive process -- experts have suggested that the contents of a memory could change each time we bring it back to mind.

However, exactly how our memories differ from the original experiences, and how they are transformed over time, has until now proven difficult to measure in laboratory settings.

For this study the researchers developed a simple computerised task that measures how fast people can recover certain characteristics of visual memories when prompted to do so. Participants learned word-image pairs and were later required to recollect different elements of the image when cued with the word. For example, participants were asked to indicate, as fast as possible, if the image was coloured or greyscale (a perceptual detail), or whether it showed an animate or inanimate object (a semantic element).

These tests, probing the quality of the visual memories, happened immediately after learning and also after a two-day delay. Reaction time patterns showed that participants were faster to recollect meaningful, semantic elements than surface, perceptual ones.

Julia Lifanov, lead author of the study from the University of Birmingham, said: "Many memory theories assume that over time, and as people re-tell their stories, they tend to forget the surface details but retain the meaningful, semantic content of an event.

"Imagine reminiscing about a pre-COVID dinner with a friend -- you realize that you cannot recall the table décor but know exactly what you ordered; or you remember the conversation with the bartender, but not the colour of his shirt. Memory experts call this phenomenon 'semanticization'."

Prof Maria Wimber, senior author on the study from the University of Glasgow, said: "The pattern towards recollection of meaningful semantic elements we demonstrate in this study indicates that memories are biased towards meaningful content in the first place -- and we have shown in previous studies that this bias is clearly reflected in brain signals too.

"Our memories change with time and use and that is a good and adaptive thing. We want our memories to retain the information that is most likely to be useful in the future, when we encounter similar situations."

The researchers found that the bias towards semantic memory content becomes significantly stronger with the passage of time, and with repeated remembering. When participants came back to the lab two days later, they were much slower at answering the perceptual-detailed questions, but they show relatively preserved memory for the semantic content of the images. However, the shift from detail-rich to more concept-based memories was far less pronounced in a group of subjects who repeatedly viewed the images, rather than being asked to actively bringing them back to mind.

The study has implications for probing the nature of memories in health and disease. It provides a tool to study maladaptive changes, for example in post-traumatic stress disorder where patients often suffer from intrusive, traumatic memories, and tend to over-generalize these experiences to novel situations. The findings are also highly relevant for understanding how eyewitness memories may be biased by frequent interviews and repeatedly recalling the same event.

The findings also demonstrate that testing yourself prior to an exam (for example, by using flashcards) will make the meaningful information stick for longer, especially when followed by periods of rest and sleep.

https://www.sciencedaily.com/releases/2021/05/210526085058.htm