Dementia spreads via connected brain networks

Brain maps allow individualized predictions of frontotemporal dementia progression

October 14, 2019

Science Daily/University of California - San Francisco

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Slower walkers have older brains and bodies at 45

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

October 11, 2019

Science Daily/Duke University

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

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

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

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

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

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

The study appears Oct. 11 in JAMA Network Open.

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

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

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

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

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

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

Study pinpoints Alzheimer's plaque emergence early and deep in the brain

October 4, 2019

Science Daily/Picower Institute at MIT

By scanning whole brains of Alzheimer's model mice from an early age, researchers were able to precisely trace the terrible march of amyloid plaques from deep brain structures outward along specific circuits. They also showed that plaque density in a key region in humans scales with disease stage.

Long before symptoms like memory loss even emerge, the underlying pathology of Alzheimer's disease, such as an accumulation of amyloid protein plaques, is well underway in the brain. A longtime goal of the field has been to understand where it starts so that future interventions could begin there. A new study by MIT neuroscientists at The Picower Institute for Learning and Memory could help those efforts by pinpointing the regions with the earliest emergence of amyloid in the brain of a prominent mouse model of the disease. Notably, the study also shows that the degree of amyloid accumulation in one of those same regions of the human brain correlates strongly with the progression of the disease.

"Alzheimer's is a neurodegenerative disease so in the end you can see a lot of neuron loss," said Wen-Chin "Brian" Huang, co-lead author of the study and a postdoc in the lab of co-senior author Li-Huei Tsai, Picower Professor of Neuroscience and director of the Picower Institute. "At that point it would be hard to cure the symptoms. It's really critical to understand what circuits and regions show neuronal dysfunction early in the disease. This will in turn facilitate the development of effective therapeutics."

In addition to Huang, the study's co-lead authors are Rebecca Canter, a former member of the Tsai lab, and Heejin Choi, a former member of the lab of co-senior author Kwanghun Chung, associate professor of chemical engineering and a member of the Picower Institute and the Institute for Medical Engineering and Science.

Tracking plaques

Many research groups have made progress in recent years by tracing amyloid's path in the brain using technologies such as positron emission tomography and by looking at brains post-mortem, but the new study adds substantial new evidence from the 5XFAD mouse model because it presents an unbiased look at the entire brain as early as one month of age. The study reveals that amyloid begins its terrible march in deep brain regions such as the mammillary body, the lateral septum and the subiculum before making its way along specific brain circuits that ultimately lead it to the hippocampus, a key region for memory, and the cortex, a key region for cognition.

The team used SWITCH, a technology developed by Chung, to label amyloid plaques and to clarify the whole brains of 5XFAD mice so that they could be imaged in fine detail at different ages. The team was consistently able to see that plaques first emerged in the deep brain structures and then tracked along circuits such as the Papez memory circuit to spread throughout the brain by 6-12 months (a mouse's lifespan is up to three years).

The findings help to cement an understanding that has been harder to obtain from human brains, Huang said, because post-mortem dissection cannot easily account for how the disease developed over time and PET scans don't offer the kind of resolution the new study provides from the mice.

Key validations

Importantly, the team directly validated a key prediction of their mouse findings in human tissue: If the mammillary body is indeed a very early place that amyloid plaques emerge, then the density of those plaques should increase in proportion with how far advanced the disease is. Sure enough, when the team used SWITCH to examine the mammillary bodies of post-mortem human brains at different stages of the disease, they saw exactly that relationship: The later the stage, the more densely plaque-packed the mammillary body was.

"This suggests that human brain alterations in Alzheimer's disease look similar to what we observe in mouse," the authors wrote. "Thus we propose that amyloid-beta deposits start in susceptible subcortical structures and spread to increasingly complex memory and cognitive networks with age."

The team also performed experiments to determine whether the accumulation of plaques they observed were of real disease-related consequence for neurons in affected regions. One of the hallmarks of Alzheimer's disease is a vicious cycle in which amyloid makes neurons too easily excited and overexcitement causes neurons to produce more amyloid. The team measured the excitability of neurons in the mammillary body of 5XFAD mice and found they were more excitable than otherwise similar mice that did not harbor the 5XFAD set of genetic alterations.

In a preview of a potential future therapeutic strategy, when the researchers used a genetic approach to silence the neurons in the mammillary body of some 5XFAD mice but left neurons in others unaffected, the mice with silenced neurons produced less amyloid.

While the study findings help explain much about how amyloid spreads in the brain over space and time, they also raise new questions, Huang said. How might the mammillary body affect memory and what types of cells are most affected there?

"This study sets a stage for further investigation of how dysfunction in these brain regions and circuits contributes to the symptoms of Alzheimer's disease," he said.

https://www.sciencedaily.com/releases/2019/10/191004074850.htm

Manipulating specific brain waves in sleep shifts balance between learning or forgetting a new skill

October 3, 2019

Science Daily/University of California - San Francisco

Distinct patterns of electrical activity in the sleeping brain may influence whether we remember or forget what we learned the previous day, according to a new study by UC San Francisco researchers. The scientists were able to influence how well rats learned a new skill by tweaking these brainwaves while animals slept, suggesting potential future applications in boosting human memory or forgetting traumatic experiences, the researchers say.

In the new study, published online October 3 in the journal Cell, a research team led by Karunesh Ganguly, MD, PhD, an associate professor of neurology and member of the UCSF Weill Institute for Neurosciences, used a technique called optogenetics to dampen specific types of brain activity in sleeping rats at will.

This allowed the researchers to determine that two distinct types of slow brain waves seen during sleep, called slow oscillations and delta waves, respectively strengthened or weakened the firing of specific brain cells involved in a newly learned skill -- in this case how to operate a water spout that the rats could control with their brains via a neural implant.

"We were astonished to find that we could make learning better or worse by dampening these distinct types of brain waves during sleep," Ganguly said. "In particular, delta waves are a big part of sleep, but they have been less studied, and nobody had ascribed a role to them. We believe these two types of slow waves compete during sleep to determine whether new information is consolidated and stored, or else forgotten."

"Linking a specific type of brain wave to forgetting is a new concept," Ganguly added. "More studies have been done on strengthening of memories, fewer on forgetting, and they tend to be studied in isolation from one another. What our data indicate is that there is a constant competition between the two -- it's the balance between them that determines what we remember."

Some Sleep to Remember, Others to Forget

Over the past two decades the centuries-old human hunch that sleep plays a role in the formation of memories has been increasingly supported by scientific studies. Animal studies show that the same neurons involved in forming the initial memory of a new task or experience are reactivated during sleep to consolidate these memory traces in the brain. Many scientists believe that forgetting is also an important function of sleep -- perhaps as a way of uncluttering the mind by eliminating unimportant information.

Slow oscillations and delta waves are hallmarks of so-called non-REM sleep, which -- in humans, at least -- makes up half or more of a night's sleep. There is evidence that these non-REM sleep stages play a role in consolidating various kinds of memory, including the learning of motor skills. In humans, researchers have found that time spent in the early stages of non-REM sleep is associated with better learning of a simple piano riff, for instance.

Ganguly's team began studying the role of sleep in learning as part of their ongoing efforts to develop neural implants that would allow people with paralysis to more reliably control robotic limbs with their brain. In early experiments in laboratory animals, he had noted that the biggest improvements in the animals' ability to operate these brain-computer interfaces occurred when they slept between training sessions.

"We realized that we needed to understand how learning and forgetting occur during sleep to understand how to truly integrate artificial systems into the brain," Ganguly said.

Brain Waves Compete to Determine Learning During Sleep

In the new study, a dozen rats were implanted with electrodes that monitor firing among a small group of selected neurons in their brains' motor cortex, which is involved in conceiving and executing voluntary movements. Producing a particular pattern of neural firing allowed the rats to control a water-dispensing tube in their cages. In essence, the rats were performing a kind of biofeedback -- each rat learned how to fire a small ensemble of neurons together in a unique new pattern in order to move the spigot and get the water.

Ganguly's team observed the same unique new firing pattern replaying in animals' brains as they slept. The strength of this reactivation during sleep determined how well rats were able to control the water spout the next day. But the researchers wanted to go further -- to understand how the brain controls whether rats learn or forget while they slumber.

To manipulate the effect of brain waves during non-REM sleep, the researchers genetically modified rat neurons to express a light-sensitive optogenetic control switch, allowing the team to use lasers and fiber optics to instantaneously dampen brain activity associated with the transmission of specific brain waves. With precise, millisecond timing of the laser, the scientists in separate experiments specifically dampened either slow oscillating waves or delta waves in a tiny patch of the brain around the new memory circuit.

Disruption of delta waves strengthened reactivation of the task-associated neural activity during sleep and was associated with better performance upon waking. Conversely, disruption of slow oscillations resulted in poor performance upon waking. "Slow oscillations seem to be protecting new patterns of neural firing after learning, while delta waves tend to erase them and promote forgetting," Ganguly said.

Further analysis showed that in order to protect learning, slow oscillations had to occur at the same time as a third, well-studied brain wave phenomenon, called sleep spindles. A sleep spindle is a high-frequency, short-duration burst of activity that originates in a region called the thalamus and then propagates to other parts of the brain. They have been linked to memory consolidation, and a lack of normal sleep spindles is associated with brain maladies including schizophrenia and developmental delay, and also with aging.

"Our work shows that there is a strong drive to forget during sleep," Ganguly said. "Very brief pairings of sleep spindles and slow oscillations can overcome delta wave-driven forgetting and preserve learning, but the balance is very delicate. Even small disturbances in these events lead to forgetting."

It's not yet known what tips the scales between delta wave-driven forgetting and slow oscillation-driven learning, but it's clear that better understanding the process could have profound impacts on the study of human learning and memory, Ganguly said. "Sleep is truly driving profound changes in the brain. Understanding these changes will be critical for brain integration of artificial interfaces and may one day allow us to modify neural circuits to aid in movement rehabilitation, such as after stroke, where previous studies have shown that sleep plays an important role in successful recovery."

Funding: The study was funded by the Department of Veterans Affairs, the National Institutes of Health, the National Research Foundation of Korea, and the Burroughs Wellcome Fund. Ganguly designed the study with postdoctoral fellows Jaekyung Kim and Tanuj Gulati, who conducted the experiments.

https://www.sciencedaily.com/releases/2019/10/191003114039.htm

Chair yoga more effective than music therapy in older adults with advanced dementia

Pilot study first to show adults with advanced dementia can participate in non-pharmacological interventions

October 2, 2019

Science Daily/Florida Atlantic University

Researchers assessed the ability of older adults with advanced dementia to participate in non-pharmacological interventions and compared chair yoga with chair-based exercise and music therapy. Results showed that participants with moderate-to-severe dementia could safely adhere to non-pharmacological interventions; more than 97 percent fully engaged in each session. The chair yoga group reported a higher quality of life score, including physical condition, mood, functional abilities, interpersonal relationships, and ability to participate in meaningful activities.

As dementia progresses, the ability to participate in exercise programs declines. Sticking to a program also becomes challenging because of impaired cognition, mobility issues or risk of falls and fractures -- some exercise regimens are just too complicated or physically demanding. Although studies have shown the benefits of physical activity on dementia, few have included participants with moderate-to-severe dementia or examined the effects of gentle types of exercise on this population.

Researchers from Florida Atlantic University conducted a pilot study that is the first cluster, randomized controlled trial to examine the effects of chair yoga on older adults with moderate to severe dementia who are unable to participate in regular exercise or standing yoga due to cognitive impairment, problems with balance, or fear of falling. The key aim of the study was to assess the likelihood of these individuals' ability to participate in non-pharmacological interventions as well as demonstrate the safety and effects of chair yoga on older adults with all levels of dementia.

For the study, published in the American Journal of Alzheimer's Disease & Other Dementias, researchers compared chair yoga with two other types of non-pharmacological interventions: chair-based exercise and music intervention. Participants in each of the three groups attended 45-minute sessions twice a week for 12 weeks. Researchers collected data at baseline, after six weeks and after completing the 12-week intervention.

Results showed that participants with moderate-to-severe dementia could safely adhere to non-pharmacological interventions. More than 97 percent of the participants fully engaged in each session. Study findings showed that the chair yoga group improved significantly in quality of life compared to the music intervention group. Both the chair yoga and chair-exercise groups showed improvement over time, while the music intervention group declined. In addition, both the chair yoga and chair-based exercise groups showed lower depression across all three time points when compared to the music intervention group.

Researchers examined the effects of chair yoga on physical function, including balance and mobility, and compared the effects with chair-based exercise and music intervention. They also looked at the effects of chair yoga on reducing psychological symptoms like anxiety and depression, behavioral symptoms like agitation or aggression, and improved quality of life. They also explored the effects of chair yoga on sleep problems.

Chair yoga provides a safe environment for stretching, strengthening and flexibility while decreasing the risk of falls by using a chair. It also provides important breathing and relaxation techniques utilizing stationary poses that use isometric contraction and guided relaxation of various muscle groups.

"We think that the physical poses we used in the chair yoga and chair-based exercise groups were an important factor in improving quality of life for the participants in our study," said Juyoung Park, Ph.D., lead author and an associate professor in the Phyllis and Harvey Sandler School of Social Work within FAU's College for Design and Social Inquiry. "It is fascinating that, although some participants showed mild levels of agitation or wandering in the intervention room prior to the yoga session, they became calm and attentive when the yoga interventionist started demonstrating yoga poses. Although they did not understand the interventionist's verbal instructions due to their cognitive impairment associated with advanced dementia, they followed the instructor's poses."

Park and collaborators did not find any differences in the three intervention groups on physical function, with the exception of handgrip strength, which was higher in the chair yoga group compared to the music intervention group. None of the three groups declined significantly in any of the investigated physical functional measures.

Researchers also did not find any significant between-group differences in anxiety at any time point. There were no significant between-group differences in change in depression and anxiety. The researchers also did not find significant differences among the three intervention groups for sleep quality at any of the three time points.

"We did see an increase in agitation in the chair yoga group even though this group reported a higher quality of life score, including physical condition, mood, functional abilities, interpersonal relationships, ability to participate in meaningful activities, and final situations," said Park. "It's important to note that quality of life is a more comprehensive approach to biopsychosocial and behavioral function than a mere measure of agitation. Meditation and the mind-body connection component of the chair yoga program may have increased quality of life for participants in this study. This finding is consistent with our earlier studies that showed a targeted approach was successful in increasing quality of life in patients with dementia."

Study participants were 60 years or older (mean average age was 84 years-old) and diagnosed with dementia including Alzheimer's disease (the largest diagnostic group), Lewy Body dementia and Parkinson disease dementia. There were no significant demographic differences among intervention groups. More than half of the group (67.7 percent) were taking medication(s) to manage symptoms associated with dementia.

https://www.sciencedaily.com/releases/2019/10/191002102800.htm

A brain protein that could put the brakes on Alzheimer's

October 1, 2019

Science Daily/University of California - Irvine

Biologists blazing new approaches to studying Alzheimer's have made a major finding on combating inflammation linked to the disease. The researchers' discovery about the role of a protein called TOM-1 heralds a shift toward examining the molecular underpinnings of Alzheimer's processes.

University of California, Irvine biologists blazing new approaches to studying Alzheimer's have made a major finding on combating inflammation linked to the disease. The School of Biological Sciences researchers' discovery about the role of a protein called TOM-1 heralds a shift toward examining the molecular underpinnings of Alzheimer's processes. Their paper has just been published in Proceedings of the National Academy of Sciences.

"Scientists have known for a long time that inflammation is a driver of Alzheimer's disease, but inflammation is complex and involves many factors," said School of Biological Sciences Dean Frank M. LaFerla, Ph.D., whose laboratory conducted the research. "That's why we decided to look at TOM-1."

The protein helps to regulate a key component of the inflammatory response. "We were interested in TOM-1 because its levels are low in the Alzheimer's brain and in the brains of Alzheimer's rodent models," said Alessandra C. Martini, Ph.D., the paper's first author and a postdoctoral researcher who worked with Dean LaFerla. "However, its specific role in the disease has largely been unexplored."

The scientists discovered that reducing the amount of TOM-1 in Alzheimer's rodent models increased pathology, which included increased inflammation, and exacerbated cognitive problems associated with the disease. Restoring TOM-1 levels reversed those effects.

"You can think of TOM-1 as being like the brakes of a car and the brakes aren't working for people with Alzheimer's," Dean LaFerla said. "This research shows that fixing the brakes at the molecular level could provide an entirely new therapeutic avenue. With millions of people affected by Alzheimers and the numbers growing, we must research a diverse portfolio of approaches so we can one day vanquish this terrible disease."

https://www.sciencedaily.com/releases/2019/10/191001102220.htm

Common nutrient supplementation may hold the answers to combating Alzheimer's disease

September 27, 2019

Science Daily/Arizona State University

In a new study, Biodesign researchers reveal that a lifelong dietary regimen of choline holds the potential to prevent Alzheimer's disease (AD).

Choline is a safe and easy-to-administer nutrient that is naturally present in some foods and can be used as a dietary supplement. Lead author Ramon Velazquez and his colleagues at the ASU-Banner Neurodegenerative Disease Research Center (NDRC) looked into whether this nutrient could alleviate the effects of Alzheimer's.

Earlier this year, Velazquez and colleagues found transgenerational benefits of AD-like symptoms in mice whose mothers were supplemented with choline. The latest work expands this line of research by exploring the effects of choline administered in adulthood rather than in fetal mice.

The study focuses on female mice bred to develop AD-like symptoms. Given the higher prevalence of AD in human females, the study sought to establish the findings in female mice. Results showed that when these mice are given high choline in their diet throughout life, they exhibit improvements in spatial memory, compared with those receiving a normal choline regimen.

Notably, findings published in July 2019 from a group in China found benefits of lifelong choline supplementation in male mice with AD-like symptoms. "Our results nicely replicate findings by this group in females," Velazquez says.

Intriguingly, the beneficial effects of lifelong choline supplementation reduce the activation of microglia. Microglia are specialized cells that rid the brain of deleterious debris. Although they naturally occur to keep the brain healthy, if they are overactivated, brain inflammation and neuronal death, common symptoms of AD, will occur.

The observed reductions in disease-associated microglia, which are present in various neurodegenerative diseases, offer exciting new avenues of research and suggest ways of treating a broad range of disorders, including traumatic brain injuries, multiple sclerosis and Parkinson's disease.

The findings appear in the current issue of the journal Aging Cell.

Supplementing the brain with additional choline

Choline acts to protect the brain from Alzheimer's disease in at least two ways, both of which are explored in the new study. First, choline blocks the production of amyloid-beta plaques. Amyloid-beta plaques are the hallmark pathology observed in Alzheimer's disease.

Secondly, choline supplementation reduces the activation of microglia. Over-activation of microglia causes brain inflammation and can eventually lead to neuronal death, thereby compromising cognitive function. Choline supplementation reduces the activation of microglia, offering further protection from the ravages of AD.

Mechanistically, the reductions in microglia activation are driven by alteration of two key receptors, the alpha7 nicotinic acetylcholine and Sigma-1 receptor. A new report this year found that choline can act as an agonist for Sigma-1 receptors. These results confirm that lifelong choline supplementation can alter the expression of the Sigma-1 receptor, which thereby attenuates microglia activation. (An agonist is a substance that activates a given receptor.)

The devastating decline

In the scientific community, it is well understood that Alzheimer's disease causes harm to the brain long before clinical symptoms are made evident. And once these symptoms are identified, it is too late -- the disease has become irreversible. In addition to causing disorientation and memory loss, the disease causes loss of motor control in those who are afflicted.

Approximately 6 million individuals are living with AD in the U.S. currently, and the disease is projected to afflict 14 million Americans in the next four decades. Economically, the costs associated with managing Alzheimer's are expected to exceed $20 trillion in the same time span.

To develop more effective treatments, we first need to understand the disease itself, which is one of the tallest orders facing modern medicine today.

Women are at a particular increased risk of developing Alzheimer's disease. This study shows that the simple addition of choline in the diet throughout life may reduce AD pathology in those most affected by the disease. Additionally, these results have implications for other neurodegenerative afflictions where activated microglia are rampant says Velazquez.

Guidelines for dietary choline

Prior research concerning Alzheimer's has indicated that there is no one factor at play. Rather, a multitude of factors that are believed to contribute to the development of the disease, including genetics, age and lifestyle. Additionally, studies suggest that diet can have a significant effect in increasing or lowering the risk of cognitive decline.

A recent report suggested that plant-based diets may be determinantal due to the lack of important nutrients, including choline. Another recent report found that the increase in cases of dementia in the United Kingdom may be associated with a lack of recommendations for choline in the diet throughout life. In fact, as of August 2019, AD and other forms of dementia are now the leading cause of death in England and Wales.

The current established adequate intake level of choline for adult women (>19yrs of age) is 425mg/day, and 550mg/day for adult men. A converging line of evidence indicates that even the current recommended daily intake (RDI) may not be optimal for a proper aging process, especially in women. This is relevant, given the higher incidence of AD seen in women. This suggests that additional choline in diet may be beneficial in preventing neuropathological changes associated with the aging brain.

The tolerable upper limit (TUL) of choline unlikely to cause side effects for adult females and males (>19yrs of age) is 3500mg/day, which is 8.24 times higher than the 425mg/day recommendation for females and 6.36 times higher than the 550mg/day recommendation for males. "Our choline supplemented diet regimen was only 4.5 times the RDI, which is well below the TUL and makes this a safe strategy," Velazquez says.

Choline can be found in various foods. According to the United States Department of Agriculture (USDA), high levels of choline are found in chicken liver (3oz; 247mg), eggs (1 large egg with yolk;147mg), beef grass-fed steak (3oz; 55mg), wheat germ (1oz toast; 51mg), milk (8oz; 38mg), and Brussels sprouts (1/2 cup; 32mg). Additionally, vitamin supplements containing choline, for example choline bitartrate and choline chloride, are widely available at affordable costs. The vitamin supplements containing choline are particularly relevant for those who are on plant-based diets.

Effects of choline

All plant and animal cells require choline to maintain their structural integrity. It has long been recognized that choline is particularly important for brain function.

The human body uses choline to produce acetylcholine, a neurotransmitter responsible for functioning memory, muscle control and mood. Choline also is used to build cell membranes and plays a vital role in regulating gene expression. Additionally, a new report in Jan 2019 found that choline acts as an agonist for Sigma-1 receptors, which are implicated in AD pathogenesis.

In this study, researchers used a water maze to determine whether the mice with AD-like symptoms that received lifelong supplemental choline exhibited improvements in spatial memory. It was found that this was indeed the case, and subsequent examination of mouse tissue extracted from the hippocampus, a brain region known to play a central role in memory formation, confirmed changes in toxic amyloid-beta and reductions in microglia activation, which reduces brain inflammation.

Due to alterations of key microglia receptors induced by choline, the improvements in behavior may be attributed to reduced microglia activation. "We found that lifelong choline supplementation altered the alpha7 nicotinic acetylcholine and Sigma-1 receptor, which may have resulted in the reduction of diseased associated activated microglia," Velazquez said. These receptors regulate CNS immune response and their dysregulation contributes to AD pathogenesis.

The study's significance establishes beneficial effects of nutrient supplementation in females throughout life. "Our work nicely complements recent work showing benefits in male AD-mice on a lifelong choline supplementation regimen." "No one has shown lifelong benefits of choline supplementation in female AD-mice." "That's what is novel about our work."

Choline is an attractive candidate for prevention of AD as it is considered a very safe alternative, compared with many pharmaceuticals. "At 4.5 times the RDI (recommended daily intake), we are well under the tolerable upper limit, making this a safe preventive therapeutic strategy."

Although the results improve the understanding of the disease, the authors suggest that clinical trials will be necessary to confirm whether choline can be used as a viable treatment in the future.

https://www.sciencedaily.com/releases/2019/09/190927122526.htm

For the first time walking patterns identify specific types of dementia

September 19, 2019

Science Daily/Newcastle University

Walking may be a key clinical tool in helping medics accurately identify the specific type of dementia a patient has, pioneering research has revealed.

For the first time, scientists at Newcastle University have shown that people with Alzheimer's disease or Lewy body dementia have unique walking patterns that signal subtle differences between the two conditions.

The research, published today in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, shows that people with Lewy body dementia change their walking steps more -- varying step time and length -- and are asymmetric when they move, in comparison to those with Alzheimer's disease.

It is a first significant step towards establishing gait as a clinical biomarker for various subtypes of the disease and could lead to improved treatment plans for patients.

Useful diagnostic tool

Dr Ríona McArdle, Post-Doctoral Researcher at Newcastle University's Faculty of Medical Sciences, led the Alzheimer's Society-funded research.

She said: "The way we walk can reflect changes in thinking and memory that highlight problems in our brain, such as dementia.

"Correctly identifying what type of dementia someone has is important for clinicians and researchers as it allows patients to be given the most appropriate treatment for their needs as soon as possible.

"The results from this study are exciting as they suggest that walking could be a useful tool to add to the diagnostic toolbox for dementia.

"It is a key development as a more accurate diagnosis means that we know that people are getting the right treatment, care and management for the dementia they have."

Current diagnosis of the two types of dementia is made through identifying different symptoms and, when required, a brain scan.

For the study, researchers analysed the walk of 110 people, including 29 older adults whose cognition was intact, 36 with Alzheimer's disease and 45 with Lewy body dementia.

The participants took part in a simple walking test at the Gait Lab of the Clinical Ageing Research Unit, an NIHR-funded research initiative jointly run by Newcastle Hospitals NHS Foundation Trust and Newcastle University.

Participants moved along a walkway -- a mat with thousands of sensors inside -- which captured their footsteps as they walked across it at their normal speed and this revealed their walking patterns.

People with Lewy body dementia had a unique walking pattern in that they changed how long it took to take a step or the length of their steps more frequently than someone with Alzheimer's disease, whose walking patterns rarely changed.

When a person has Lewy body dementia, their steps are more irregular and this is associated with increased falls risk. Their walking is more asymmetric in step time and stride length, meaning their left and right footsteps look different to each other.

Scientists found that analysing both step length variability and step time asymmetry could accurately identify 60% of all dementia subtypes -- which has never been shown before.

Further work will aim to identify how these characteristics enhance current diagnostic procedures, and assess their feasibility as a screening method. It is hoped that this tool will be available on the NHS within five years.

Pioneering study

Dr James Pickett, Head of Research at Alzheimer's Society, said: "In this well conducted study we can see for the first time that the way we walk may provide clues which could help us distinguish between Alzheimer's disease and Lewy body dementia.

"This research -- funded by the Alzheimer's Society -- is pioneering for dementia. It shows promise in helping to establish a novel approach to accurately diagnose different types of dementia.

"We know that research will beat dementia, and provide invaluable support for the 850,000 people living with the condition in the UK today. It's now vital that we continue to support promising research of this kind.

"We look forward to seeing larger, longer studies to validate this approach and shed light on the relationship between a person's gait and dementia diagnosis."

Dementia describes different brain disorders that triggers loss of brain function and these conditions are usually progressive and eventually severe.

It is estimated by the Alzheimer's Society that people living with dementia in the UK will rise to more than one million by 2025.

Future research at Newcastle University will look at alternative methods to assess walking as part of the €50 MOBILISED-D digital monitoring project, which aims to develop a system of small sensors that can be worn on the body during daily routine to assess how well you walk -- a sign of health and wellbeing.

Living with Lewy body dementia

Father-of-four and grandfather-of-two John Tinkler has lived with Lewy body dementia for the past three years.

The 70-year-old, of Langley Park, County Durham, was diagnosed after starting to experience difficulties walking when he began to shuffle his feet and would regularly trip over.

John, his wife, Jenny, 59, and the rest of their family, have learned to cope with the difficult diagnosis and have had to adapt their lifestyles accordingly.

Jenny, a physiotherapist, said: "Since John's diagnosis things have been difficult and, over the years, he has deteriorated to the point where he fatigues easily, which affects his mobility, balance and coordination, and he is now struggling to get out of an armchair. In addition to this, he has joint pain and muscle cramps.

"When we were asked if John would like to take part in the Newcastle University research we didn't hesitate to say 'yes' because it's important that people do their bit to help research.

"The findings of the study are exciting because it can help lead to a definitive diagnosis of the subtype of dementia, which will allow patients to be on the right management programme as early as possible.

"If patients and their families know the specific type of dementia they are dealing with, this enables there to be a greater understanding of the specific needs of the person living with the condition.

"We are extremely lucky to live in an area where research into ageing is among the best there is. It would be fantastic if a screening tool like this was available within the NHS for dementia patients."

https://www.sciencedaily.com/releases/2019/09/190919211806.htm

AAN recommends people 65+ be screened yearly for memory problems

September 19, 2019

Science Daily/American Academy of Neurology

To help physicians provide the highest quality patient-centered neurologic care, the American Academy of Neurology (AAN) is recommending physicians measure how frequently they complete annual assessments of people age 65 and older for thinking and memory problems.

People with mild cognitive impairment have thinking and memory problems but usually do not know it because such problems are not severe enough to affect their daily activities. Yet mild cognitive impairment can be an early sign of Alzheimer's disease or other forms of dementia. It can also be a symptom of sleep problems, medical illness, depression, or a side effect of medications.

To help physicians provide the highest quality patient-centered neurologic care, the American Academy of Neurology (AAN) is recommending physicians measure how frequently they complete annual assessments of people age 65 and older for thinking and memory problems. This metric for yearly cognitive screening tests is part of an AAN quality measurement set published in the September 18, 2019, online issue of Neurology®, the medical journal of the American Academy of Neurology.

A quality measure is a mathematical tool to help physicians and practices understand how often health care services are consistent with current best practices and are based on existing AAN guideline recommendations. Quality measures are intended to drive quality improvement in practice. Physicians are encouraged to start small using one or two quality measures in practice that are meaningful for their patient population, and measure use is voluntary.

"Since thinking skills are the most sensitive indicator of brain function and they can be tested cost-effectively, this creates an enormous opportunity to improve neurologic care," said author Norman L. Foster, MD, of the University of Utah in Salt Lake City and a Fellow of the American Academy of Neurology. "The American Academy of Neurology is recommending the measurement of annual cognitive screenings for everyone age 65 and older because age itself is a significant risk factor for cognitive decline and mild cognitive impairment is increasingly prevalent with older age. The measure complements past American Academy of Neurology quality measures released for Parkinson's disease, multiple sclerosis and stroke, and allows for a doctor to meet the measure with a recommended periodic three-minute cognitive test."

According to the 2018 AAN guideline on mild cognitive impairment, nearly 7 percent of people in their early 60s worldwide have mild cognitive impairment, while 38 percent of people age 85 and older have it.

The new AAN quality measurement set recommends doctors measure how often they conduct annual screenings to improve the recognition of mild cognitive impairment and allow for earlier intervention.

"We cannot expect people to report their own memory and thinking problems because they may not recognize that they are having problems or they may not share them with their doctors," said Foster. "Annual assessments will not only help identify mild cognitive impairment early, it will also help physicians more closely monitor possible worsening of the condition."

The new measurement set states that documenting mild cognitive impairment in a person's medical record can be invaluable in alerting other physicians and medical staff so that the best care is provided to that patient.

Early diagnosis can help identify forms of mild cognitive impairment that may be reversible, including those caused by sleep problems, depression or medications, and lead to treatments that can improve a person's quality of life such as correcting hearing loss and avoiding social isolation.

When mild cognitive impairment is not reversible and could develop into more severe forms of dementia like Alzheimer's disease, the quality measurement set recommends measuring how frequently people are given information about their condition as early as possible, so they can take steps to avoid exploitation, plan for their care and monitor their condition.

It is also important not to forget about family and caregivers. The measurement set also asks doctors to identify care partners to help describe symptoms. Doctors should quantify involvement with family and caregivers and provide them with information so that they too receive support and get access to services to help them cope if person's illness progresses and to improve their well-being.

https://www.sciencedaily.com/releases/2019/09/190919093916.htm

New piece of Alzheimer's puzzle found

September 17, 2019

Science Daily/University of Alberta Faculty of Medicine & Dentistry

Scientists found two short peptides, or strings of amino acids, that when injected into mice with Alzheimer's disease daily for five weeks, significantly improved the mice's memory. The treatment also reduced some of the harmful physical changes in the brain that are associated with the disease.

Two years after discovering a way to neutralize a rogue protein linked to Alzheimer's disease, University of Alberta Distinguished University Professor and neurologist Jack Jhamandas has found a new piece of the Alzheimer's puzzle, bringing him closer to a treatment for the disease.

In a study published in Scientific Reports, Jhamandas and his team found two short peptides, or strings of amino acids, that when injected into mice with Alzheimer's disease daily for five weeks, significantly improved the mice's memory. The treatment also reduced some of the harmful physical changes in the brain that are associated with the disease.

"In the mice that received the drugs, we found less amyloid plaque buildup and a reduction in brain inflammation," said Jhamandas, who is also a member of the Neuroscience and Mental Health Institute.

"So this was very interesting and exciting because it showed us that not only was memory being improved in the mice, but signs of brain pathology in Alzheimer's disease were also greatly improved. That was a bit of a surprise for us."

This discovery builds on previous findings of a compound called AC253 that can block the toxic effects of a protein called amyloid beta, which is believed to be a major contributor to Alzheimer's because it is often found in large quantities in the brains of patients with the disease. AC253 blocks amyloid beta from attaching to certain receptors in brain cells -- a process Jhamandas likens to plugging a keyhole.

However, while AC253 was shown to prevent a buildup of amyloid beta, it isn't very effective at reaching the brain and is quickly metabolized in the bloodstream. As a result, treatment using AC253 requires large amounts of the compound to be effective, which is impractical and increases the chances of the body developing an immune reaction to treatment. Transforming AC253 from an injectable drug into a pill would address the metabolism issues and increase efficacy, but AC253 was too complex to be able to make an effective oral drug.

Jhamandas' solution was to chop AC253 into pieces to see whether he could create smaller peptide strings that blocked amyloid beta in the same way AC253 did. Through a series of tests using mice genetically modified to carry Alzheimer's disease, Jhamandas' team found two shorter pieces of AC253 that replicated the preventative and restorative abilities of the larger peptide.

With the short peptides identified, Jhamandas and his team, which includes virologists Lorne Tyrell and Michael Houghton, used a process of computer modelling and artificial intelligence to discover a small-molecule drug -- similar to medications used to treat high blood pressure or cholesterol -- it's now developing.

The team is focused on manufacturing an optimized and oral version of the drug so human clinical trials can begin, said Jhamandas, who added small-molecule drugs are preferable for treatments, particularly for drug companies, because they are cheaper to make, can be taken orally and can more easily reach the brain through the blood, said Jhamandas.

While Jhamandas is optimistic about the potential of his new drug to change the way Alzheimer's is managed, he is quick to point out the years of research he and other researchers have done to get to this point.

"This has been 15, 20 years of painstaking and incremental work," he said. "And it's like building a house: you put one brick down, then you put another brick on top of that, and pretty soon you have a foundation and then you have a house.

"Occasionally you come across a discovery that has the potential to change the game in a very fundamental way, like hitting a home run, and I'm very excited that we are really on to something here."

https://www.sciencedaily.com/releases/2019/09/190917134359.htm

Exercise could slow withering effects of Alzheimer's

Imaging shows less brain deterioration in physically active people at high risk for dementia

September 17, 2019

Science Daily/UT Southwestern Medical Center

Exercising several times a week may delay brain deterioration in people at high risk for Alzheimer's disease, according to a study that scientists say merits further research to establish whether fitness can affect the progression of dementia.

Research from UT Southwestern found that people who had accumulation of amyloid beta in the brain -- a hallmark of Alzheimer's disease -- experienced slower degeneration in a region of the brain crucial for memory if they exercised regularly for one year.

Although exercise did not prevent the eventual spread of toxic amyloid plaques blamed for killing neurons in the brains of dementia patients, the findings suggest an intriguing possibility that aerobic workouts can at least slow down the effects of the disease if intervention occurs in the early stages.

"What are you supposed to do if you have amyloid clumping together in the brain? Right now doctors can't prescribe anything," said Dr. Rong Zhang, who led the clinical trial that included 70 participants ages 55 and older. "If these findings can be replicated in a larger trial, then maybe one day doctors will be telling high-risk patients to start an exercise plan. In fact, there's no harm in doing so now."

Reduced brain atrophy

The study published in the Journal of Alzheimer's Disease compared cognitive function and brain volume between two groups of sedentary older adults with memory issues: One group did aerobic exercise (at least a half-hour workout four to five times weekly), and another group did only flexibility training.

Both groups maintained similar cognitive abilities during the trial in areas such as memory and problem solving. But brain imaging showed that people from the exercise group who had amyloid buildup experienced slightly less volume reduction in their hippocampus -- a memory-related brain region that progressively deteriorates as dementia takes hold.

"It's interesting that the brains of participants with amyloid responded more to the aerobic exercise than the others," said Dr. Zhang, who conducted the trial at the Institute for Exercise and Environmental Medicine. "Although the interventions didn't stop the hippocampus from getting smaller, even slowing down the rate of atrophy through exercise could be an exciting revelation."

However, Dr. Zhang notes that more research is needed to determine how or if the reduced atrophy rate benefits cognition.

Elusive answers

The search for dementia therapies is becoming increasingly pressing: More than 5 million Americans have Alzheimer's disease, and the number is expected to triple by 2050.

Recent research has helped scientists gain a greater understanding of the molecular genesis of the disease, including a UT Southwestern discovery published last year that is guiding efforts to detect the condition before symptoms arise. Yet the billions of dollars spent on trying to prevent or slow dementia have yielded no proven treatments that would make an early diagnosis actionable for patients.

Fitness and brain health

Dr. Zhang is among a group of scientists across the world trying to determine if exercise may be the first such therapy.

His latest research builds upon numerous studies suggesting links between fitness and brain health. For example, a 2018 study showed that people with lower fitness levels experienced faster deterioration of vital nerve fibers in the brain called white matter. Research in mice has similarly shown exercise correlated with slower deterioration of the hippocampus -- findings that prompted Dr. Zhang to investigate whether the same effects could be found in people.

"I'm excited about the results, but only to a certain degree," Dr. Zhang said. "This is a proof-of-concept study, and we can't yet draw definitive conclusions."

Expanded research

Dr. Zhang is leading a five-year national clinical trial that aims to dig deeper into potential correlations between exercise and dementia.

The trial, which includes six medical centers across the country, involves more than 600 older adults (ages 60-85) at high risk of developing Alzheimer's disease. The study will measure whether aerobic exercise and taking specific medications to reduce high blood pressure and cholesterol can help preserve brain volume and cognitive abilities.

"Understanding the molecular basis for Alzheimer's disease is important," Dr. Zhang said. "But the burning question in my field is, 'Can we translate our growing knowledge of molecular biology into an effective treatment?' We need to keep looking for answers.

https://www.sciencedaily.com/releases/2019/09/190917124832.htm

Drinking tea improves brain health

September 12, 2019

Science Daily/National University of Singapore

A recent study led by researchers from the National University of Singapore (NUS) revealed that regular tea drinkers have better organised brain regions -- and this is associated with healthy cognitive function -- compared to non-tea drinkers. The research team made this discovery after examining neuroimaging data of 36 older adults.

"Our results offer the first evidence of positive contribution of tea drinking to brain structure, and suggest that drinking tea regularly has a protective effect against age-related decline in brain organisation," explained team leader Assistant Professor Feng Lei, who is from the Department of Psychological Medicine at the NUS Yong Loo Lin School of Medicine.

The research was carried out together with collaborators from the University of Essex and University of Cambridge, and the findings were published in scientific journal Aging on 14 June 2019.

Benefits of regular intake of tea

Past studies have demonstrated that tea intake is beneficial to human health, and the positive effects include mood improvement and cardiovascular disease prevention. In fact, results of a longitudinal study led by Asst Prof Feng which was published in 2017 showed that daily consumption of tea can reduce the risk of cognitive decline in older persons by 50 per cent.

Following this discovery, Asst Prof Feng and his team further explored the direct effect of tea on brain networks.

The research team recruited 36 adults aged 60 and above, and gathered data about their health, lifestyle, and psychological well-being. The elderly participants also had to undergo neuropsychological tests and magnetic resonance imaging (MRI). The study was carried out from 2015 to 2018.

Upon analysing the participants' cognitive performance and imaging results, the research team found that individuals who consumed either green tea, oolong tea, or black tea at least four times a week for about 25 years had brain regions that were interconnected in a more efficient way.

"Take the analogy of road traffic as an example -- consider brain regions as destinations, while the connections between brain regions are roads. When a road system is better organised, the movement of vehicles and passengers is more efficient and uses less resources. Similarly, when the connections between brain regions are more structured, information processing can be performed more efficiently," explained Asst Prof Feng.

He added, "We have shown in our previous studies that tea drinkers had better cognitive function as compared to non-tea drinkers. Our current results relating to brain network indirectly support our previous findings by showing that the positive effects of regular tea drinking are the result of improved brain organisation brought about by preventing disruption to interregional connections."

Next step in research

As cognitive performance and brain organisation are intricately related, more research is needed to better understand how functions like memory emerge from brain circuits, and the possible interventions to better preserve cognition during the ageing process. Asst Prof Feng and his team plan to examine the effects of tea as well as the bioactive compounds in tea can have on cognitive decline.

https://www.sciencedaily.com/releases/2019/09/190912100945.htm

Calcium channel blockers may be effective in treating memory loss in Alzheimer's disease

September 11, 2019

Science Daily/University of Bristol

Alzheimer's disease (AD) is the most common cause of dementia but the changes in brain cell function underlying memory loss remains poorly understood. Researchers at the University of Bristol have identified that calcium channel blockers may be effective in treating memory loss.

The team's findings, published in Frontiers in Cellular Neuroscience, found treating a diseased brain cell with a blocker of the L-type channel reduced the number of calcium ions able to flow into the brain cell.

The researchers used fruit flies to study AD, using a fluorescent molecule called GCaMP6f, which reports the amount of calcium ions inside brain cells.

They found that diseased brain cells become overloaded with calcium ions, which at normal levels are important for memory formation. This overload was due to the overproduction of the gene encoding a channel, known as the L-type channel, which allows calcium ions to flow into the cell from outside. More of these channels means more calcium ions are able to flow into the cell, disrupting memory formation. Using a drug to block the L-type channel reversed the effect of disease and reduced the flow of calcium ions to a normal level.

The research team also investigated the memory of fruit flies by testing if they could remember which of two odours had previously been paired with an electric shock -- similar to Pavlov's experiments with dogs.

While healthy flies remembered well, the diseased flies, like humans, displayed impaired memory. However, if the overproduction of L-type channels was corrected in the diseased flies, their brain cells were no longer overloaded with calcium ions and their memory was just as good as healthy flies. This shows that memory loss is likely due to calcium overload because too many L-type channels are made and, if this is corrected, memory impairment is rescued.

Dr James Hodge, Associate Professor in Neuroscience in the School of Physiology, Pharmacology & Neuroscience, said: "Memory loss in Alzheimer's disease (AD) is a highly distressing and difficult to treat symptom. Targeting the early changes in brain cell function -- before they begin to degenerate -- may be effective in treating memory loss.

"L-type channels have been thought to have a role in AD for some time and this study shows a direct link between memory loss and L-type channel overproduction in brain cells."

In humans suffering with AD, blocking these channels may be beneficial in treating memory impairment. The findings show that further work should be carried out to determine the mechanism underlying the recovery of memory and whether or not the team's research will prove effective in humans.

https://www.sciencedaily.com/releases/2019/09/190911101601.htm

How the eyes might be windows to the risk of Alzheimer's disease

Researchers say how quickly a person's pupil dilates while taking cognitive tests

September 10, 2019

Science Daily/University of California - San Diego

Researchers say that measuring how quickly a person's pupil dilates while they are taking cognitive tests may be a low-cost, low-invasive method to aid in screening individuals at increased genetic risk for AD before cognitive decline begins.

Alzheimer's disease (AD) begins to alter and damage the brain years -- even decades -- before symptoms appear, making early identification of AD risk paramount to slowing its progression.

In a new study published online in the September 9, 2019 issue of the Neurobiology of Aging, scientists at University of California San Diego School of Medicine say that, with further developments, measuring how quickly a person's pupil dilates while they are taking cognitive tests may be a low-cost, low-invasive method to aid in screening individuals at increased genetic risk for AD before cognitive decline begins.

In recent years, researchers investigating the pathology of AD have primarily directed their attention at two causative or contributory factors: the accumulation of protein plaques in the brain called amyloid-beta and tangles of a protein called tau. Both have been linked to damaging and killing neurons, resulting in progressive cognitive dysfunction.

The new study focuses on pupillary responses which are driven by the locus coeruleus (LC), a cluster of neurons in the brainstem involved in regulating arousal and also modulating cognitive function. Tau is the earliest occurring known biomarker for AD; it first appears in the LC; and it is more strongly associated with cognition than amyloid-beta. The study was led by first author William S. Kremen, PhD, and senior author Carol E. Franz, PhD, both professors of psychiatry and co-directors of the Center for Behavior Genetics of Aging at UC San Diego School of Medicine.

The LC drives pupillary response -- the changing diameter of the eyes' pupils -- during cognitive tasks. (Pupils get bigger the more difficult the brain task.) In previously published work, the researchers had reported that adults with mild cognitive impairment, often a precursor to AD, displayed greater pupil dilation and cognitive effort than cognitively normal individuals, even if both groups produced equivalent results. Critically, in the latest paper, the scientists link pupillary dilation responses with identified AD risk genes.

"Given the evidence linking pupillary responses, LC and tau and the association between pupillary response and AD polygenic risk scores (an aggregate accounting of factors to determine an individual's inherited AD risk), these results are proof-of-concept that measuring pupillary response during cognitive tasks could be another screening tool to detect Alzheimer's before symptom appear," said Kremen.

https://www.sciencedaily.com/releases/2019/09/190910154659.htm

The fast and the curious: Fitter adults have fitter brains

Large database links fitness to better cognitive performance and healthy white matter in brain

September 9, 2019

Science Daily/European College of Neuropsychopharmacology

In a large study, German scientists have shown that physical fitness is associated with better brain structure and brain functioning in young adults. This opens the possibility that increasing fitness levels may lead to improved cognitive ability, such as memory and problem solving, as well as improved structural changes in the brain. This work is presented for the first time at the ECNP Congress in Copenhagen, with simultaneous publication in the peer-reviewed journal Scientific Reports.

Scientists have previously shown that "exercise is good for the brain," but most studies have not controlled for underlying causes which might give distorted results, such as body weight, blood glucose levels, education status, age and other factors, making it difficult to take an overall view of the benefits. In addition, studies have rarely looked at fitness in relations to both brain structure and mental functioning.

The scientists used a publicly available database of 1206 MRI brain scans from the Human Connectome Project, which had been contributed by volunteers who wanted to contribute to scientific research. The volunteers (average age 30 years old) underwent some additional testing. The first test was a "two-minute walking test," where each person was asked to walk as fast as possible for 2 minutes and the distance was then measured. The volunteers then underwent a series of cognitive tests, to measure such things as memory, sharpness, judgement, and reasoning.

As team leader, Dr Jonathan Repple (University Hospital Muenster, Germany) said "The great strength of this work is the size of the database. Normally when you are dealing with MRI work, a sample of 30 is pretty good, but the existence of this large MRI database allowed us to eliminate possibly misleading factors, and strengthened the analysis considerably."

The tests were able to show two main points: better performance on a 2-minute walking test in young healthy adults is associated with better cognitive performance, and with structural integrity of the white matter in the brain: healthy white matter is known to improve the speed and quality of nerve connections in the brain.

Repple continued, "It surprised us to see that even in a young population cognitive performance decreases as fitness levels drops. We knew how this might be important in an elderly population which does not necessarily have good health, but to see this happening in 30 year olds is surprising. This leads us to believe that a basic level of fitness seems to be a preventable risk factor for brain health.

This type of study raises an important question. We see that fitter people have better brain health, so we now need to ask whether actually making people fitter will improve their brain health. Finding this out is our next step. There are some trials which point in that direction, but if we can prove this using such a large database, this would be very significant."

Commenting, Professor Peter Falkai (University Clinic, Munich, Germany) said:

"This is an important cross-sectional study demonstrating a robust correlation between physical health and cognitive functioning in a large cohort of healthy young adults. This correlation was backed by changes in the white matter status of the brain supporting the notion that better macro-connectivity is related to better brain functioning. It stresses the importance of physical activity at all stages of life and as preliminary recent evidence suggests one can start improving physical health even in later life even if one has never trained before (see reference). These findings however need to be replicated in longitudinal studies and translated for the use in mental illness."

https://www.sciencedaily.com/releases/2019/09/190909121245.htm

High-fat diets affect your brain, not just your physical appearance

September 9, 2019

Science Daily/Yale University

Much research has pointed to how an unhealthy diet correlates to obesity, but has not explored how diet can bring about neurological changes in the brain. A recent Yale study has discovered that high-fat diets contribute to irregularities in the hypothalamus region of the brain, which regulates body weight homeostasis and metabolism.

Led by Sabrina Diano, the Richard Sackler Family Professor of Cellular & Molecular Physiology and professor of neuroscience and comparative medicine, the study evaluated how the consumption of a high-fat diet -- specifically diets that include high amounts of fats and carbohydrates -- stimulates hypothalamic inflammation, a physiological response to obesity and malnutrition.

The researchers reaffirmed that inflammation occurs in the hypothalamus as early as three days after consumption of a high-fat diet, even before the body begins to display signs of obesity. "We were intrigued by the fact that these are very fast changes that occur even before the body weight changes, and we wanted to understand the underlying cellular mechanism," said Diano who is also a member of the Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism.

The researchers observed hypothalamic inflammation in animals on a high fat diet and discovered that changes in physical structure were occurring among the microglial cells of animals. These cells act as the first line of defense in the central nervous system that regulate inflammation. Diano's lab found that the activation of the microglia was due to changes in their mitochondria, organelles that help our bodies derive energy from the food we consume. The mitochondria were substantially smaller in the animals on a high-fat diet. The mitochondria's change in size was due to a protein, Uncoupling Protein 2 (UCP2), which regulates the mitochondria's energy utilization, affecting the hypothalamus' control of energy and glucose homeostasis.

The UCP2-mediated activation of microglia affected neurons in the brain that, when receiving an inflammatory signal due to the high fat diet, stimulated the animals in the high-fat diet group to eat more and become obese. However, when this mechanism was blocked by removing the UCP2 protein from microglia, animals exposed to a high fat diet ate less and were resistant to gain weight.

The study not only illustrates how high-fat diets affect us physically, but conveys how an unhealthy diet can alter our food intake neurologically. "There are specific brain mechanisms that get activated when we expose ourselves to specific type of foods. This is a mechanism that may be important from an evolutionary point of view. However, when food rich in fat and carbs is constantly available it is detrimental."

Diano's long-standing goal is to understand the physiological mechanisms that regulate how much food we consume, and she continues to perform research on how activated microglia can affect various diseases in the brain, including Alzheimer's disease, a neurological disorder that is associated with changes in the brain's microglial cells and has been shown to have higher incidence among obese individuals.

https://www.sciencedaily.com/releases/2019/09/190909121234.htm

Hearing aids linked to lower risk of dementia, depression and falls

September 5, 2019

Science Daily/Michigan Medicine - University of Michigan

Older adults who get a hearing aid for a newly diagnosed hearing loss have a lower risk of being diagnosed with dementia, depression or anxiety for the first time over the next three years, and a lower risk of suffering fall-related injuries, than those who leave their hearing loss uncorrected, a new study finds.

Yet only 12% of those who have a formal diagnosis of hearing loss actually get the devices -- even when they have insurance coverage for at least part of the cost, the study shows. It also reveals gaps in hearing aid use among people of different racial and ethnic backgrounds, geographic locations and genders.

The findings, made by a University of Michigan team using data from nearly 115,000 people over age 66 with hearing loss and insurance coverage through a Medicare HMO between 2008 and 2016, are published in the Journal of the American Geriatrics Society.

Unlike traditional Medicare, Medicare HMOs typically cover some hearing aid costs for members diagnosed with hearing loss by an audiologist.

Elham Mahmoudi, MBA, Ph.D., the U-M Department of Family Medicine health economist who led the study, says the study confirms what other studies have shown among patients studied at a single point in time -- but the new findings show differences emerging as time goes on.

"We already know that people with hearing loss have more adverse health events, and more co-existing conditions, but this study allows us to see the effects of an intervention and look for associations between hearing aids and health outcomes," she says. "Though hearing aids can't be said to prevent these conditions, a delay in the onset of dementia, depression and anxiety, and the risk of serious falls, could be significant both for the patient and for the costs to the Medicare system."

Long-term tracking

Mahmoudi and her colleagues at the U-M Institute for Healthcare Policy and Innovation looked at anonymous insurance data to perform the study, and looked at the data for each person with hearing loss one year before their diagnosis, and three years after, so they could see only newly diagnosed dementia, depression, anxiety and fall injuries.

They intend to keep studying further data from this population, to see if the differences in health outcomes continue beyond three years.

The study shows that men with hearing loss were more likely to receive a hearing aid -- 13.3% compared with 11.3% of women. Only 6.5% of people of Latino heritage received a hearing aid for their hearing loss, compared with 9.8% of African-Americans and 13.6% of whites.

Nearly 37% of people with hearing loss who lived in the north-central part of the country, as designated by the Census Bureau, used a hearing aid, compared with just 5.9% of people in the mountain states.

Differences in diagnosis

When the researchers looked at the path that patients who received hearing aids took over three years, compared with those who didn't get the devices, significant differences emerged.

In all, the relative risk of being diagnosed with dementia, including Alzheimer's disease, within three years of a hearing loss diagnosis was 18% lower for hearing aid users. The risk of being diagnosed with depression or anxiety by the end of three years was 11% lower for hearing aid users, and the risk of being treated for fall-related injuries was 13% lower.

The study also confirms previous studies' findings that people with hearing loss had much higher rates of dementia, depression and fall injuries than the general population.

The reasons for this are complicated, and can include loss of social interaction, loss of independence, loss of balance and less stimulation to the brain. Some researchers also believe that the loss of nerve impulses from the ear to the brain, and loss of cognitive ability leading to dementia, could be part of the same aging process.

What's to come

The study only included individuals who billed their insurance company for part of the cost of their hearing aid, Mahmoudi notes. The coming of FDA-approved over-the-counter hearing aids in 2020 for people with mild to moderate hearing loss could make the devices much more accessible for many people.

But those new devices could also complicate researchers' ability to study the effects of hearing aids on other health outcomes, if people do not use insurance coverage and researchers can't tell if they have one.

"Correcting hearing loss is an intervention that has evidence behind it, and we hope our research will help clinicians and people with hearing loss understand the potential association between getting a hearing aid and other aspects of their health," says Mahmoudi.

She notes that Medicaid in the state of Michigan is now covering hearing aid testing, fitting and purchase, since a policy change in 2018, and that it will be important to study impacts in this population as well.

https://www.sciencedaily.com/releases/2019/09/190905080110.htm

Protein tangles linked with dementia seen in patients after single head injury

September 5, 2019

Science Daily/Imperial College London

Scientists have visualised for the first time protein 'tangles' associated with dementia in the brains of patients who have suffered a single head injury.

This is the finding of a new study led by scientists from Imperial College London, published in the journal Science Translational Medicine.

In the early-stage study, researchers studied 21 patients who had suffered a moderate to severe head injury at least 18 years earlier (mostly from traffic accidents), as well as 11 healthy individuals who had not experienced a head injury.

The research, from scientists at Imperial's Dementia Research Institute as well as the University of Glasgow, showed some of these patients had clumps of protein in their brain called tau tangles.

The team, who recruited patients from the Institute of Health and Wellbeing at the University of Glasgow and from Imperial College Healthcare NHS Trust, say the research may accelerate the development of treatments that breakdown tau tangles, by enabling medics to monitor the amount of the protein.

Tau normally helps provide structural support to nerve cells in the brain - acting as a type of scaffolding, but when brain cells become damaged - for instance during a head injury, the protein may form clumps, or tangles.

Tau tangles are found in Alzheimer's disease and other forms of dementia, and associated with progressive nerve damage.

Scientists have known for some time that repeated head injury - such as those sustained in sports such as boxing, rugby and American Football - can lead to neurodegeneration and dementia in later life - with particularly strong links to a type of brain condition called chronic traumatic encephalopathy.

However, this is the first time scientists have seen the protein tangles in living patients who have suffered a single, severe head injury, explains Dr Nikos Gorgoraptis, author of the paper from Imperial's Department of Brain Sciences.

"Scientists increasingly realise that head injuries have a lasting legacy in the brain - and can continue to cause damage decades after the initial injury. However, up until now most of the research has focussed on the people who have sustained multiple head injuries, such as boxers and American Football players. This is the first time we have seen in these protein tangles in patients who have sustained a single head injury."

Dr Gorgoraptis adds that although these tangles have been detected in the brains of patients in post-mortem examination - where findings suggest around one in three patients with a single head injury develop protein tangles - they have not before been seen in the brains of living patients.

The study used a type of brain scan, called a PET scan, combined with a substance that binds to tau protein, called flortaucipir, to study the amount of tau protein in the brains of head injury patients.

The results revealed that, collectively, patients with head injury were more likely to have tau tangles. The paper also showed that patients with tau tangles had higher levels of nerve damage, particular in the white matter of the brain. None of the healthy individuals had tau tangles.

Interestingly, the results revealed patients with higher levels of tau tangles did not necessarily have any reduction in brain function, such as memory problems, compared to patients with fewer tangles.

However, Dr Gorgoraptis adds these tangles can develop years before a person starts to develop symptoms such as memory loss. He explained there are still many questions to answer about the tau tangles and brain damage.

"This research adds a further piece in the puzzle of head injury and the risk of neurodegeneration. Not all patients with head injury develop these protein tangles, and some patients can have them for many years without developing symptoms. While we know tau tangles are associated with Alzheimer's and other forms of dementia, we are only beginning to understand how brain trauma might lead to their formation. What is exciting about this study is this is the first step towards a scan that can give a clear indication of how much tau is in the brain, and where it is located. As treatments develop over the coming years that might target tau tangles, these scans will help doctors select the patients who may benefit and monitor the effectiveness of these treatments."

https://www.sciencedaily.com/releases/2019/09/190905103013.htm

Poor oral health linked to cognitive decline, perceived stress

Studies examine the role of psychosocial factors in oral health among older Chinese Americans

September 4, 2019

Science Daily/Rutgers University

Two studies explore the relationship between poor oral health and cognitive decline and the effects of perceived stress and social support on dry mouth among older Chinese Americans.

Oral health is an essential part of psychological well-being and overall health in older adults. Poor oral health is associated with decreased quality of life, depression, hypertension, and cognitive decline. Two Rutgers studies, co-authored by Darina Petrovsky, Bei Wu, and Weiyu Mao, and published in the Journal of the American Geriatrics Society, explored the relationship between poor oral health and cognitive decline and the effects of perceived stress and social support on dry mouth among older Chinese Americans.

Researchers interviewed more than 2,700 Chinese Americans aged 60 and older and found that nearly 50 percent of study participants reported experiencing tooth symptoms, 25.5 percent reported dry mouth. In the first study, those who reported tooth symptoms experienced declines in cognition and episodic memory, often precursors to dementia. In the second study, the researchers found that stress increased symptoms of dry mouth, leading to poorer overall oral health.

"Racial and ethnic minorities are particularly vulnerable to the negative consequences of poor oral health," said XinQi Dong, director of Rutgers University's Institute for Health, Health Care Policy and Aging Research. "Minorities have less access to preventive dental care that is further exacerbated by language barriers and low socioeconomic status. Older Chinese Americans are at particular risk for experiencing oral health symptoms due to lack of dental insurance or not visiting a dental clinic regularly."

According to Dong, the increasing oral health disease burdens among older Chinese immigrants point to the need for investigations of psychosocial factors due to the current emphasis on physical diseases and health behaviors in oral health.

"Efforts must be made to increase social support to alleviate stress and the resulting dry mouth issues reported by our study participants," Dong continued. "These efforts can help preserve older adults' health and well-being and limit cognitive decline."

Key findings:

·      47.8 percent of older Chinese Americans reported having teeth symptoms; participants who reported teeth symptoms at baseline experienced their global cognition and episodic memory decline

·      18.9 percent of older Chinese Americans reported gum symptoms.

·      15.6 percent of older Chinese Americans reported teeth and gum symptoms.

·      25.5 percent of older Chinese Americans reported dry mouth.

·      More perceived stress was associated with higher odds of dry mouth.

"These studies demonstrate the importance of examining immigrant oral health outcomes later in life to understand the specific type of outcomes of different cultural groups," said Dong. "The studies further serve as a call to action for policymakers to develop programs aimed at improving oral health preventative and dental care services in this high-risk population. Darina Petrovsky, first author, added, "Examining current oral health practices among older Chinese Americans is crucial for developing culturally-tailored interventions to promote oral health and ultimately mitigate cognitive decline."

"Poor oral health is a top concern among older Chinese Americans. In our study, the prevalence rate of dry mouth is followed by diabetes and heart disease. Our findings demonstrate the importance of studying the linkage between stress and dry mouth in this vulnerable population." said author Weiyu Mao, Assistant Professor, School of Social Work, University of Nevada, Reno.

"Support from family and friends could be protective against dry mouth symptoms in relation to stress; however, the potential overload of such support could be detrimental to oral health outcomes among older Chinese Americans." Mao continued. "Intervention strategies need to expand beyond the common risk factors, such as health conditions and health behaviors, and account for the psychosocial determinants, including stress and social support, to better promote oral health and reduce oral health disparities in this population."

"Our research raises critical awareness for dental and healthcare providers of the role of perceived stress in dry mouth symptoms," added Dong. "Working collaboratively, dental, and healthcare providers can better identify oral health symptoms as risk factors of cognitive decline in this fast-growing vulnerable population. The primary focus should include promoting optimal oral health and improving the quality of life."

https://www.sciencedaily.com/releases/2019/09/190904125333.htm

Promising new target to combat Alzheimer's disease

September 3, 2019

Science Daily/Temple University Health System

In the case of Alzheimer's disease, researchers show that mitochondrial calcium transport remodeling -- what appears to be an attempt by cells to compensate for flagging energy production and metabolic dysfunction -- while initially beneficial, ultimately becomes maladaptive, fueling declines in mitochondrial function, memory, and learning. The new research, published by Nature Communications, is the first to link maladaptive changes in calcium transport by mitochondria -- the energy-generating powerhouses of cells -- to the progression of Alzheimer's disease.

Sometimes the more a person tries to fix a seemingly minor problem, the worse things become. Cells are no different, it turns out, though attempting to compensate for what begins as a minor deficiency or dysfunction can be dire. In the case of Alzheimer's disease, Lewis Katz School of Medicine at Temple University (LKSOM) researchers now show that mitochondrial calcium transport remodeling -- what appears to be an attempt by cells to compensate for flagging energy production and metabolic dysfunction -- while initially beneficial, ultimately becomes maladaptive, fueling declines in mitochondrial function, memory, and learning.

The new research, published online in the journal Nature Communications, is the first to link maladaptive changes in calcium transport by mitochondria -- the energy-generating powerhouses of cells -- to the progression of Alzheimer's disease.

"Amyloid-beta deposition and tau pathology are considered the major contributors to Alzheimer's disease and, as a result, they have been the main focus of therapeutic development," explained John W. Elrod, PhD, Associate Professor in the Center for Translational Medicine at LKSOM and senior investigator on the new study. "Large clinical trials targeting these pathways have universally failed, however."

Altered calcium regulation and metabolic dysfunction have been suspected of contributing to neuronal dysfunction and Alzheimer's development. "But up to now, no one has investigated the impact of altered calcium transport into and out of the mitochondria on the progression of Alzheimer's disease," Dr. Elrod noted. "Our current study provides a missing link between these two hypotheses of Alzheimer's pathogenesis."

Calcium transport into mitochondria plays an important part in many cellular functions and requires the involvement of multiple proteins to be carried out effectively. Among the key regulators of this process is a protein known as NCLX, which previously was discovered by Dr. Elrod's laboratory to mediate calcium efflux from heart cells. NCLX expression is also important in mitochondrial calcium efflux in neurons.

In their new study, Dr. Elrod and colleagues examined the role of mitochondrial calcium uptake by neurons in Alzheimer's disease. To do so, the team used a mouse model of familial Alzheimer's disease in which animals harbored three gene mutations that give rise to age-progressive pathology comparable to Alzheimer's progression in human patients.

As mice carrying the three mutations aged, the researchers observed a steady reduction in NCLX expression. This reduction was accompanied by decreases in the expression of proteins that limit mitochondrial calcium uptake, resulting in damaging calcium overload. NCLX loss was further linked to increases in the production of cell-damaging oxidants.

To better understand the physiological relevance of NCLX loss, Dr. Elrod's team next completely eliminated NCLX expression in the forebrain of Alzheimer's disease mice. In tests for memory and cognitive function, the animals exhibited significant impairments. Analyses of brain tissue from these mice showed that NCLX reduction and the consequent loss of calcium efflux from mitochondria accelerated the development of amyloid beta and tau pathology. When NCLX expression was restored, levels of harmful protein aggregates declined, neuronal mitochondrial calcium homeostasis was reestablished, and mice were rescued from cognitive decline.

"Our findings indicate that maladaptive remodeling of pathways to compensate for abnormalities in calcium regulation, which perhaps are meant to maintain energy production in cells, lead to neuronal dysfunction and Alzheimer's pathology," Dr. Elrod said. "Moreover, our data suggest that amyloid beta and tau pathology actually lie downstream of mitochondrial dysfunction in the progression of Alzheimer's disease, which opens up a new therapeutic angle."

Dr. Elrod and colleagues plan next to carry out a more detailed investigation of metabolic dysfunction that arises before Alzheimer's disease pathology emerges.

https://www.sciencedaily.com/releases/2019/09/190903153827.htm