Living near major roads linked to risk of dementia, Parkinson's, Alzheimer's and MS

January 23, 2020

Science Daily/University of British Columbia

Living near major roads or highways is linked to higher incidence of dementia, Parkinson's disease, Alzheimer's disease and multiple sclerosis (MS), suggests new research published this week in the journal Environmental Health.

Researchers from the University of British Columbia analyzed data for 678,000 adults in Metro Vancouver. They found that living less than 50 metres from a major road or less than 150 metres from a highway is associated with a higher risk of developing dementia, Parkinson's, Alzheimer's and MS -- likely due to increased exposure to air pollution.

The researchers also found that living near green spaces, like parks, has protective effects against developing these neurological disorders.

"For the first time, we have confirmed a link between air pollution and traffic proximity with a higher risk of dementia, Parkinson's, Alzheimer's and MS at the population level," says Weiran Yuchi, the study's lead author and a PhD candidate in the UBC school of population and public health. "The good news is that green spaces appear to have some protective effects in reducing the risk of developing one or more of these disorders. More research is needed, but our findings do suggest that urban planning efforts to increase accessibility to green spaces and to reduce motor vehicle traffic would be beneficial for neurological health."

Neurological disorders -- a term that describes a range of disorders, including Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis and motor neuron diseases -- are increasingly recognized as one of the leading causes of death and disability worldwide. Little is known about the risk factors associated with neurological disorders, the majority of which are incurable and typically worsen over time.

For the study, researchers analyzed data for 678,000 adults between the ages of 45 and 84 who lived in Metro Vancouver from 1994 to 1998 and during a follow-up period from 1999 to 2003. They estimated individual exposures to road proximity, air pollution, noise and greenness at each person's residence using postal code data. During the follow-up period, the researchers identified 13,170 cases of non-Alzheimer's dementia, 4,201 cases of Parkinson's disease, 1,277 cases of Alzheimer's disease and 658 cases of MS.

For non-Alzheimer's dementia and Parkinson's disease specifically, living near major roads or a highway was associated with 14 per cent and seven per cent increased risk of both conditions, respectively. Due to relatively low numbers of Alzheimer's and MS cases in Metro Vancouver compared to non-Alzheimer's dementia and Parkinson's disease, the researchers did not identify associations between air pollution and increased risk of these two disorders. However, they are now analyzing Canada-wide data and are hopeful the larger dataset will provide more information on the effects of air pollution on Alzheimer's disease and MS.

When the researchers accounted for green space, they found the effect of air pollution on the neurological disorders was mitigated. The researchers suggest that this protective effect could be due to several factors.

"For people who are exposed to a higher level of green space, they are more likely to be physically active and may also have more social interactions," said Michael Brauer, the study's senior author and professor in the UBC school of population and public health. "There may even be benefits from just the visual aspects of vegetation."

Brauer added that the findings underscore the importance for city planners to ensure they incorporate greenery and parks when planning and developing residential neighbourhoods.

https://www.sciencedaily.com/releases/2020/01/200123152616.htm

Possible Alzheimer's breakthrough suggested

January 22, 2020

Science Daily/Case Western Reserve University

Researchers at the Case Western University School of Medicine say they have identified a previously unknown gene and associated protein which could potentially be suppressed to slow the advance of Alzheimer's disease.

"Based on the data we have, this protein can be an unrecognized new risk factor for Alzheimer's disease (AD)," said Xinglong Wang, an associate professor of pathology at the School of Medicine. "We also see this as a potential novel therapeutic target for this devastating disease."

Wang said proving the latter assertion, which has not yet been tested in humans, would require additional research to corroborate the function of the protein they have dubbed "aggregatin." Eventually, that would someday mean clinical trials with Alzheimer's patients, he said.

"This protein characteristically accumulates, or aggregates, within the center of plaque in AD patients, like the yolk of an egg -- which is part of the reason we named it "aggregatin," Wang said.

A research team led by Wang and Xiaofeng Zhu, a professor of Population and Quantitative Health Sciences at the School of Medicine, has filed for a patent through the university's Office of Research and Technology Management for "novel Alzheimer's disease treatments and diagnosis based on this and related study," Wang said.

"We're very excited about this because our study is likely the first systematic work combining the identification from a genome-wide association study of high dimensional brain-imaging data and experimental validation so perfectly in Alzheimer's disease," Zhu said.

Their research was published this month by the scientific journal Nature Communications and supported by grants from the National Institutes of Health (NIH) and the Alzheimer's Association. Genomic and brain imaging data was obtained from the Alzheimer's Disease Neuroimaging Initiative, which is supported by the NIH.

Alzheimer's Disease affects millions

More than 5.7 million Americans have Alzheimer's disease, which is the primary cause of dementia and sixth-leading cause of death in the United States. That population is predicted to reach 14 million by the year 2050, according to the Alzheimer's Association.

The relationship between Alzheimer's (and subsequent brain atrophy) and amyloid plaques -- the hard accumulations of beta amyloid proteins that clump together between the nerve cells (neurons) in the brains of Alzheimer's patients -- has been well-established among researchers.

Less understood is precisely how that amyloid-beta actually leads to plaque formation -- and where this new work appears to have broken new ground, Wang said.

Further, while there has been much research into what genes might influence whether or not someone gets Alzheimer's, there is less understanding of genes that might be linked to the progression of the disease, meaning the formation of plaque and subsequent atrophy in the brain.

The role of 'aggregatin' protein

In the new work, the researchers began by correlating roughly a million genetic markers (called single-nucleotide polymorphisms, or SNPs) with brain images. They were able to identify a specific SNP in the FAM222, a gene linked to different patterns of regional brain atrophy.

Further experiments then suggested that the protein encoded by gene FAM222A is not only associated with AD patient-related beta-amyloid plaques and regional brain atrophy, but that "aggregatin" attaches to amyloid beta peptide -- the major component of plaque and facilitates the plaque formation.

So when researchers injected mouse models with the "aggregatin" protein (made from the FAM222A gene), plaque (amyloid deposits) formation accelerated in the brain, resulting in more neuroinflammation and cognitive dysfunction. This happened, they report, because the protein was found to bind directly the amyloid beta peptide, thus facilitating the aggregation and placque formation, Wang said.

Conversely, when they suppressed the protein, the plaques were reduced and neuroinflammation and cognitive impairment alleviated.

Their findings indicate that reducing levels of this protein and inhibition of its interaction with amyloid beta peptide could potentially be therapeutic -- not necessarily to prevent Alzheimer's but to slow its progression.

https://www.sciencedaily.com/releases/2020/01/200122080532.htm

Blue light triggers memory and emphatic fear in mice via a non-invasive approach

January 21, 2020

Science Daily/Institute for Basic Science

Researchers at the Center for Cognition and Sociality, within the Institute for Basic Science (IBS) in South Korea, have engineered an improved biological tool that controls calcium (Ca2+) levels in the brain via blue light. Published in Nature Communications, this optogenetic construct, called monster-OptoSTIM1 or monSTIM1 for short, causes a change in mice's fear learning behavior without the need of optic fiber implants in the brain.

The brain utilizes Ca2+ signaling to regulate a variety of functions, including memory, emotion, and movement. Several evidences show correlation between abnormally regulated Ca2+ levels in certain brain cells and neurodegenerative diseases, but the details still remain obscure. For understanding the precise role of Ca2+ signaling, the IBS team is studying Ca2+-specific modulators that can be triggered in different parts of the brain at a designated time.

Optogenetics uses light to control Ca2+ signaling in the mouse brain. Since the brain is surrounded by hair, skin and skull, which prevent light from reaching deep tissues, optic fiber insertion in the brain used to be the norm in optogenetics. However, these implants can cause inflammation, morphological changes of neurons and disconnection of neural circuits. In this study, the research team improved their optogenetic tool so that it works with an external source of blue light, shone from the ceiling of the mouse cage, and without the need of brain implants.

MonSTIM1 is made of a part (CRY2) that responds to blue light and another part (STIM1) that activates calcium channels. Compared to the previously developed optogenetic techniques, the researchers were able to enhance CRY2's light-sensitivity approximately 55-fold and also avoid the increase of basal Ca2+ levels. The monSTIM1 construct was injected into the mouse brain through a virus, and was shown to activate Ca2+ signals in the cortex as well as in the deeper hippocampus and thalamus regions.

The team observed behavioral changes in mice with monSTIM1 expressed in excitatory neurons in the anterior cingulate cortex, a brain region that has a central function in empathic emotions. Mice with activated monSTIM1 froze with fear by looking at other mice, which experienced a mild electric foot shock. Twenty-four hours later the same mice remembered about it and showed again an enhanced fear response, indicating that Ca2+ signaling contributed to both short- and long-term social fear responses.

"MonSTIM1 can be applied to a wide range of brain calcium research and brain cognitive science research, because it allows easy manipulation of intracellular calcium signals without damaging the brain," says Won Do Heo (KAIST professor), leading author of this research.

https://www.sciencedaily.com/releases/2020/01/200121123953.htm

America's most widely consumed oil causes genetic changes in the brain

Soybean oil linked to metabolic and neurological changes in mice

January 17, 2020

Science Daily/University of California - Riverside

New UC Riverside research shows soybean oil not only leads to obesity and diabetes, but could also affect neurological conditions like autism, Alzheimer's disease, anxiety, and depression.

Used for fast food frying, added to packaged foods, and fed to livestock, soybean oil is by far the most widely produced and consumed edible oil in the U.S., according to the U.S. Department of Agriculture. In all likelihood, it is not healthy for humans.

It certainly is not good for mice. The new study, published this month in the journal Endocrinology, compared mice fed three different diets high in fat: soybean oil, soybean oil modified to be low in linoleic acid, and coconut oil.

The same UCR research team found in 2015 that soybean oil induces obesity, diabetes, insulin resistance, and fatty liver in mice. Then in a 2017 study, the same group learned that if soybean oil is engineered to be low in linoleic acid, it induces less obesity and insulin resistance.

However, in the study released this month, researchers did not find any difference between the modified and unmodified soybean oil's effects on the brain. Specifically, the scientists found pronounced effects of the oil on the hypothalamus, where a number of critical processes take place.

"The hypothalamus regulates body weight via your metabolism, maintains body temperature, is critical for reproduction and physical growth as well as your response to stress," said Margarita Curras-Collazo, a UCR associate professor of neuroscience and lead author on the study.

The team determined a number of genes in mice fed soybean oil were not functioning correctly. One such gene produces the "love" hormone, oxytocin. In soybean oil-fed mice, levels of oxytocin in the hypothalamus went down.

The research team discovered roughly 100 other genes also affected by the soybean oil diet. They believe this discovery could have ramifications not just for energy metabolism, but also for proper brain function and diseases such as autism or Parkinson's disease. However, it is important to note there is no proof the oil causes these diseases.

Additionally, the team notes the findings only apply to soybean oil -- not to other soy products or to other vegetable oils.

"Do not throw out your tofu, soymilk, edamame, or soy sauce," said Frances Sladek, a UCR toxicologist and professor of cell biology. "Many soy products only contain small amounts of the oil, and large amounts of healthful compounds such as essential fatty acids and proteins."

A caveat for readers concerned about their most recent meal is that this study was conducted on mice, and mouse studies do not always translate to the same results in humans.

Also, this study utilized male mice. Because oxytocin is so important for maternal health and promotes mother-child bonding, similar studies need to be performed using female mice.

One additional note on this study -- the research team has not yet isolated which chemicals in the oil are responsible for the changes they found in the hypothalamus. But they have ruled out two candidates. It is not linoleic acid, since the modified oil also produced genetic disruptions; nor is it stigmasterol, a cholesterol-like chemical found naturally in soybean oil.

Identifying the compounds responsible for the negative effects is an important area for the team's future research.

"This could help design healthier dietary oils in the future," said Poonamjot Deol, an assistant project scientist in Sladek's laboratory and first author on the study.

"The dogma is that saturated fat is bad and unsaturated fat is good. Soybean oil is a polyunsaturated fat, but the idea that it's good for you is just not proven," Sladek said.

Indeed, coconut oil, which contains saturated fats, produced very few changes in the hypothalamic genes.

"If there's one message I want people to take away, it's this: reduce consumption of soybean oil," Deol said about the most recent study.

https://www.sciencedaily.com/releases/2020/01/200117080827.htm

Exosomes promote remarkable recovery in stroke

January 14, 2020

Science Daily/University of Georgia

Scientists present brain-imaging data for a new stroke treatment that supported full recovery in swine, modeled with the same pattern of neurodegeneration as seen in humans with severe stroke.

It's been almost a quarter century since the first drug was approved for stroke. But what's even more striking is that only a single drug remains approved today.

In a publication appearing this month in the journal Translational Stroke Research, animal scientists, funded by the National Institutes of Health, present brain-imaging data for a new stroke treatment that supported full recovery in swine, modeled with the same pattern of neurodegeneration as seen in humans with severe stroke.

"It was eye opening and unexpected that you would see such a benefit after having had such a severe stroke," said Steven Stice, Georgia Research Alliance Eminent Scholar and D.W. Brooks Distinguished Professor in the University of Georgia's College of Agricultural and Environmental Sciences. "Perhaps the most formidable discovery was that one could recover and do so well after the exosome treatment."

Stice and his colleagues at UGA's Regenerative Bioscience Center report the first observational evidence during a midline shift -- when the brain is being pushed to one side -- to suggest that a minimally invasive and non-operative exosome treatment can now influence the repair and damage that follow a severe stroke.

Exosomes are considered to be powerful mediators of long-distance cell-to-cell communication that can change the behavior of tumor and neighboring cells. The results of the study echo findings from other recent RBC studies using the same licensed exosome technology.

Many patients who suffer stroke exhibit a shift of the brain past its center line -- the valley between the left and right part of the brain. Lesions or tumors will induce pressure or inflammation in the brain, causing what typically appears as a straight line to shift.

"Based on results of the exosome treatment in swine, it doesn't look like lesion volume or the effects of a midline shift matter nearly as much as one would think," said Franklin West, associate professor of animal and dairy science in the UGA College of Agricultural and Environmental Sciences. "This suggests that, even in some extremely severe cases caused by stroke, you're still going to recover just as well."

Trauma from an acute stroke can happen quickly and can cause irreversible damage almost immediately. "Time is brain," a phrase coined by stroke advocacy organizations in the late 1990s, captures the importance of acting on the first signs of stroke. In less than 60 seconds, warns the Stroke Awareness Foundation, an ischemic stroke kills 1.9 million brain cells.

Data from the team's research showed that non-treated brain cells near the site of the stroke injury quickly starved from lack of oxygen and died -- triggering a lethal action of damage signals throughout the brain network and potentially compromising millions of healthy cells.

However, in brain areas treated with exosomes that were taken directly from cold storage and administered intravenously, these cells were able to penetrate the brain and interrupt the process of cell death.

"Basically, during a stroke, these really destructive free radicals are all over the place destroying things," said Stice, director of the RBC. "What the exosome technology does is communicate with jeopardized cells and work like an anti-inflammatory agent to interrupt and stop further damage."

According to the team's results, neuroimaging is an essential tool for evaluating brain tissue and managing stroke recovery.

In this observational study, the team analyzed brain images taken 24 hours after stroke. They then applied recovery scores, commonly used in human practice, based on swine gait, cadence, walking speed and stride length. By recording the relationship between brain measurements and functional outcomes, the new assessment scales can better help physicians predict how quickly a person will recover in real time.

"What I'm trying to do with this assessment data is come up with something that we can implement in the clinics right now -- today -- to help with predicting patient outcomes," said Samantha Spellicy, a neuroscience graduate student and first author on the publication.

Spellicy, who is currently training under Stice, began her first two years at the Medical College of Georgia at Augusta University and has plans to return to MCG after completing her Ph.D. She anticipates a return to stroke care and one day using the same outcome assessments presented in the study with human patients.

"When a patient arrives in emergency with a stroke, the available clinician would not be left crunching an arbitrary number based on some standardized scale assessment," Spellicy said. "Instead, the clinician could take more of a personalized approach based on the patient's midline shift measurement, and, say for instance, 'OK, in three months you're going to get better, but you're going to have issues with your gait. Let's talk to a specialist now to target that exact condition.'"

As for the future of the exosome treatment, Spellicy and the RBC team anticipate that the patented neural exosome technology, called AB126, will be filed for clinical trials by 2021.

https://www.sciencedaily.com/releases/2020/01/200114125924.htm

Long-term memory performance depends upon gating system

Suppression of genetic switch boosts hardwired memory in Drosophila

January 13, 2020

Science Daily/Scripps Research Institute

Why do we remember some experiences for our entire lives but quickly forget others? The brain is constantly deciding which events are important enough for long-term storage. A new study sheds light on one element of that process.

Storing and retrieving memories is among the most important tasks our intricate brains must perform, yet how that happens at a molecular level remains incompletely understood. A new study from the lab of Neuroscience Professor Ronald Davis, PhD, at Scripps Research, Florida, sheds light on one element of that memory storage process, namely the storage and retrieval of a type of hardwired long-term memory.

The Davis team found that moving memories to long-term storage involves the interplay of multiple genes, a known group whose activity must be upregulated, and, unexpectedly, another gatekeeping gene set, Ras, and its downstream connecting molecules, which are down-regulated. If either Ras or its downstream connector Raf are silenced, long-term memory storage is eliminated, the team writes in the Proceedings of the National Academies of Sciences, published the week of Jan. 13.

The type of memory they studied, ironically has a rather difficult-to-remember name: "protein-synthesis dependent long-term memory," or PSD-LTM for short. To study how it and other types of memory form, scientists rely upon the fruit fly, Drosophila melanogaster, as a model organism. The genetic underpinnings of memory storage are mostly conserved across species types, Davis explains.

To assess how the flies' memory consolidation process works at a molecular level, they used a process called RNA interference to lower expression of several candidate genes in several areas of the fly brain. Doing so with both the Ras gene and its downstream molecule Raf in the fly brain's mushroom body, its memory-storage area, had a two-pronged effect. It dramatically enhanced intermediate-term memories while completely eliminating PSD long-term memory of an aversive experience, Davis says.

The team's experiments involved exposing flies to certain odors in one section of a glass tube while simultaneously administering a foot-shock. Flies' subsequent avoidant behavior on exposure to that odor indicated their recollection of the unpleasant shock. Regardless of how many times the flies were "trained," lowering expression of Ras and Raf reduced their PSD long-term memory performance, explains first author Nathaniel Noyes, PhD, a research associate in the Davis lab.

While the Ras enzyme, Ras85D, was already known for its roles in organ development and cancer, the studies showed that in the adult brain, it apparently plays memory gatekeeper, helping direct whether experiences should be remembered as intermediate memory that dissipates after a time, or as long-term "protein-synthesis dependent" memory that persists.

Gating off the memory from the intermediate storage process shifted it over to PSD long-term memory storage, indicates that it's an either-or situation. Intermediate storage appears to be the fly brain's preferential, default pathway, Noyes says. He expects that the neurotransmitter dopamine will prove to play a key signaling role.

"We believe that dopamine signals to the brain that this memory is important enough to be stored long-term. We speculate that Ras and Raf receive this dopamine signal and thereby block intermediate memory and promote PSD long-term memory," Noyes says.

How this "intermediate" memory system works in humans requires further study as well, he adds.

"It's becoming apparent that many of the same genes involved in intermediate memory storage also play a role in mammalian memory and plasticity," he notes.

https://www.sciencedaily.com/releases/2020/01/200113153330.htm

Environmental light triggers production of memory proteins in fruit flies

January 13, 2020

Science Daily/Society for Neuroscience

Maintaining long-term memories requires environmental light, according to research in fruit flies recently published in JNeurosci.

Memories begin in a temporary form, which are converted into long term memories as protein expression and brain circuits change. But, long term memories require active maintenance in order to survive the changing molecular landscape of the brain. Previous research indicates exposure to different colors of light alters memory function in humans and animals, but the role of natural lighting conditions in memory maintenance remains unknown.

Inami et al. explored this question by testing the ability of male fruit flies to learn that their proposal is not accepted by females through their courtship toward unreceptive females. After the learning period, the male fruit flies were either exposed to constant darkness, constant light, or a 12-hour light/dark cycle. The flies experiencing a light/dark cycle recognized the ready-to-mate females for five days, whereas flies in constant darkness couldn't maintain the memory. The researchers found environmental light exposure activates light-sensitive neurons, triggering the production of memory maintenance proteins. Darkness during the learning period did not affect memory formation, indicating that light is required for the maintenance, but not creation, of long-term memories.

https://www.sciencedaily.com/releases/2020/01/200113131644.htm

Lifestyle choices could slow familial frontotemporal dementia

Patients can influence outcomes despite a genetic diagnosis, study suggests

January 8, 2020

Science Daily/University of California - San Francisco

A physically and mentally active lifestyle confers resilience to frontotemporal dementia (FTD), even in people whose genetic profile makes the eventual development of the disease virtually inevitable, according to new research by scientists at the UC San Francisco Memory and Aging Center.

The research aligns with long-standing findings that exercise and cognitive fitness are one of the best ways to prevent or slow Alzheimer's disease, but is the first study to show that the same types of behaviors can benefit people with FTD, which is caused by a distinct form of brain degeneration.

FTD is a neurodegenerative disease that can disrupt personality, decision-making, language, or movement abilities, and typically begins between the ages of 45 and 65. It is the most common form of dementia in people under 65 (accounting for 5 to 15 percent of dementia cases overall) and typically results in rapid cognitive and physical decline and death in less than 10 years. There are currently no drugs to treat FTD, though numerous clinical trials for the disease are underway at UCSF Memory and Aging Center and elsewhere.

"This is devastating disease without good medical treatments, but our results suggest that even people with a genetic predisposition for FTD can still take actions to increase their chances of living a long and productive life. Their fate may not be set in stone," said Kaitlin Casaletto, PhD, assistant professor of neurology at the UCSF Memory and Aging Center and corresponding author of the new study, published January 8, 2020 in Alzheimer's and Dementia.

'If This Were a Drug, We Would Be Giving it to All Our Patients'

About 40 percent of people with FTD have a family history of the disease, and scientists have identified specific dominant genetic mutations that drive the development of the disease in roughly half of these cases. But even in these individuals, the disease can have very different courses and severity.

"There's incredible variability in FTD, even among people with the same genetic mutations driving their disease. Some people are just more resilient than others for reasons we still don't understand," said, Casaletto, a member of the UCSF Weill Institute for Neurosciences. "Our hypothesis was that the activities people engage in each day of their lives may contribute to the very different trajectories we see in clinic, including when the disease develops and how it progresses."

To test this hypothesis, Casaletto and colleagues studied how lifestyle differences affected FTD progression in 105 people with dominant, disease-causing genetic mutations who were mostly asymptomatic or had experienced only mild, early-stage symptoms. The research participants were drawn from two large multisite studies, called ARTFL and LEFFTDS (recently combined into a study known as ALLFTD), led by co-authors Adam Boxer, MD, PhD, and Howie Rosen, MD, also of the UCSF Memory and Aging Center.

As part of these larger studies, all participants underwent initial MRI scans to measure the extent of brain degeneration caused by the disease, completed tests of thinking and memory, and reported on their current levels of cognitive and physical activity in their daily lives (e.g., reading, spending time with friends, jogging). At the same time, their family members completed regular gold-standard assessments of how well the study participants were functioning in their lives -- managing finances, medications, bathing themselves, and so on. All of these measures were repeated at annual follow-up visits to track the long-term progression of participants' disease.

Even after only two to three visits (one to two years into the ongoing study), Casaletto and her team have already begun to see significant differences in the speed and severity of FTD between the most and least mentally and physically active individuals in the study, with mentally and physically active lifestyles showing similar effects across participants.

Specifically, the researchers found that functional decline, as assessed by participants' family members, was 55 percent slower in the most active 25 percent of participants compared to the least active five percent. "This was a remarkable effect to see so early on," Casaletto said. "If this were a drug, we would be giving it to all of our patients."

The researchers found that participants' lifestyles did not significantly alter the inexorable degeneration of brain tissue associated with FTD, as measured by follow-up MRI scans a year into the study. But even among participants whose brain scans revealed signs of atrophy, the most mentally and physically active participants continued to perform twice as well as the least active participants on cognitive tests. These results suggest that active lifestyles may slow FTD symptoms by providing some form of cognitive resilience to the consequences of brain degeneration.

Findings Could Illuminate Biology of Brain Resilience Across Dementias

The researchers anticipate seeing even larger differences in cognitive decline between more and less active groups as the merged ALLFTD study continues to follow these participants over time. "We've seen such significant effects in just the first year or two in people with very mild disease -- if these results hold, we may see that an active lifestyle sets individuals on a different trajectory for the coming years," Casaletto said.

The next step for the research is to include more detailed and objective assessments of participants' physical and mental activity -- including fitting them with wearable FitBit activity sensors -- to begin to estimate exactly how much activity is needed to promote cognitive resilience.

Casaletto cautions that the results, though exciting, so far only report a correlation: "It is possible that some participants have less active lifestyles because they have a more severe or aggressive form of FTD, which is already impacting their ability to be active. Clinical trials that manipulate cognitive and physical activity levels in people with FTD mutations are needed to prove that lifestyle changes can alter the course of the disease."

With this caveat in mind, Casaletto hopes the findings will not only encourage care teams and individuals with family histories of FTD to adopt lifestyle changes that could provide more productive years of life, but also that the ongoing study will lead to a better biological understanding of the drivers of resilience in people with FTD.

"We can see that lifestyle differences impact people's resilience to FTD despite very penetrant genetics, so now we can start to ask more fundamental questions, like how these behaviors actually affect the brain's biology to confer that resilience." Casaletto said. "Is that biological effect something we could replicate pharmacologically to help slow the progression of this terrible disease for everyone?"

https://www.sciencedaily.com/releases/2020/01/200108074801.htm

Alzheimer 'tau' protein far surpasses amyloid in predicting toll on brain tissue

Tau PET brain imaging could launch precision medicine era for Alzheimer's disease

January 1, 2020

Science Daily/University of California - San Francisco

The results support researchers' growing recognition that tau drives brain degeneration in Alzheimer's disease more directly than amyloid protein, and at the same time demonstrates the potential of recently developed tau-based PET (positron emission tomography) brain imaging technology to accelerate Alzheimer's clinical trials and improve individualized patient care.

Brain imaging of pathological tau-protein "tangles" reliably predicts the location of future brain atrophy in Alzheimer's patients a year or more in advance, according to a new study by scientists at the UC San Francisco Memory and Aging Center. In contrast, the location of amyloid "plaques," which have been the focus of Alzheimer's research and drug development for decades, was found to be of little utility in predicting how damage would unfold as the disease progressed.

The results, published January 1, 2020 in Science Translational Medicine, support researchers' growing recognition that tau drives brain degeneration in Alzheimer's disease more directly than amyloid protein, and at the same time demonstrates the potential of recently developed tau-based PET (positron emission tomography) brain imaging technology to accelerate Alzheimer's clinical trials and improve individualized patient care.

"The match between the spread of tau and what happened to the brain in the following year was really striking," said neurologist Gil Rabinovici, MD, the Edward Fein and Pearl Landrith Distinguished Professor in Memory and Aging and leader of the PET imaging program at the UCSF Memory and Aging Center. "Tau PET imaging predicted not only how much atrophy we would see, but also where it would happen. These predictions were much more powerful than anything we've been able to do with other imaging tools, and add to evidence that tau is a major driver of the disease."

Interest in Tau Growing as Amyloid-Based Therapies Stumble

Alzheimer's researchers have long debated the relative importance of amyloid plaques and tau tangles -- two kinds of misfolded protein clusters seen in postmortem studies of patients' brains, both first identified by Alois Alzheimer in the early 20th century. For decades, the "amyloid camp" has dominated, leading to multiple high-profile efforts to slow Alzheimer's with amyloid-targeting drugs, all with disappointing or mixed results.

Many researchers are now taking a second look at tau protein, once dismissed as simply a "tombstone" marking dying cells, and investigating whether tau may in fact be an important biological driver of the disease. In contrast to amyloid, which accumulates widely across the brain, sometimes even in people with no symptoms, autopsies of Alzheimer's patients have revealed that tau is concentrated precisely where brain atrophy is most severe, and in locations that help explain differences in patients' symptoms (in language-related areas vs. memory-related regions, for example).

"No one doubts that amyloid plays a role in Alzheimer's disease, but more and more tau findings are beginning to shift how people think about what is actually driving the disease," explained Renaud La Joie, PhD, a postdoctoral researcher in Rabinovici's In Vivo Molecular Neuroimaging Lab, and lead author of the new study. "Still, just looking at postmortem brain tissue, it has been hard to prove that tau tangles cause brain degeneration and not the other way around. One of our group's key goals has been to develop non-invasive brain imaging tools that would let us see whether the location of tau buildup early in the disease predicts later brain degeneration."

Tau PET Scans Predict Locations of Future Brain Atrophy in Individual Patients

Despite early misgivings that tau might be impossible to measure in the living brain, scientists recently developed an injectable molecule called flortaucipir -- currently under review by the FDA -- which binds to misfolded tau in the brain and emits a mild radioactive signal that can be picked up by PET scans.

Rabinovici and collaborator William Jagust, MD, of UC Berkeley and Lawrence Berkeley National Laboratory, have been among the first to adopt tau PET imaging to study the distribution of tau tangles in the normally aging brain and in a smaller cross-sectional study of Alzheimer's patients. Their new study represents the first attempt to test whether tau levels in Alzheimer's patients can predict future brain degeneration.

La Joie recruited 32 participants with early clinical stage Alzheimer's disease through the UCSF Memory and Aging Center, all of whom received PET scans using two different tracers to measure levels of amyloid protein and tau protein in their brains. The participants also received MRI scans to measure their brain's structural integrity, both at the start of the study, and again in follow-up visits one to two years later.

The researchers found that overall tau levels in participants' brains at the start of the study predicted how much degeneration would occur by the time of their follow up visit (on average 15 months later). Moreover, local patterns of tau buildup predicted subsequent atrophy in the same locations with more than 40 percent accuracy. In contrast, baseline amyloid-PET scans correctly predicted only 3 percent of future brain degeneration.

"Seeing that tau buildup predicts where degeneration will occur supports our hypothesis that tau is a key driver of neurodegeneration in Alzheimer's disease," La Joie said.

Notably, PET scans revealed that younger study participants had higher overall levels of tau in their brains, as well as a stronger link between baseline tau and subsequent brain atrophy, compared to older participants. This suggests that other factors -- likely other abnormal proteins or vascular injuries -- may play a larger role in late-onset Alzheimer's, the researchers say.

Ability to Predict Brain Atrophy a 'Valuable Precision Medicine Tool'

The results add to hopes that tau-targeting drugs currently under study at the UCSF Memory and Aging Center and elsewhere may provide clinical benefits to patients by blocking this key driver of neurodegeneration in the disease. At the same time, the ability to use tau PET to predict later brain degeneration could enable more personalized dementia care and speed ongoing clinical trials, the authors say.

"One of the first things people want to know when they hear a diagnosis of Alzheimer's disease is simply what the future holds for themselves or their loved ones. Will it be a long fading of memory, or a quick decline into dementia? How long will the patient be able to live independently? Will they lose the ability to speak or get around on their own? These are questions we can't currently answer, except in the most general terms," Rabinovici said. "Now, for the first time, this tool could let us give patients a sense of what to expect by revealing the biological process underlying their disease."

Rabinovici and his team also anticipate that the ability to predict future brain atrophy based on tau PET imaging will allow Alzheimer's clinical trials to quickly assess whether an experimental treatment can alter the specific trajectory predicted for an individual patient, which is currently impossible due to the wide variability in how the disease progresses from individual to individual. Such insights could make it possible to adjust dosage or switch to a different experimental compound if the first treatment is not affecting tau levels or altering a patient's predicted trajectory of brain atrophy.

"Tau PET could be an extremely valuable precision medicine tool for future clinical trials," Rabinovici said. "The ability to sensitively track tau accumulation in living patients would for the first time let clinical researchers seek out treatments that can slow down or even prevent the specific pattern of brain atrophy predicted for each patient."

https://www.sciencedaily.com/releases/2020/01/200101144012.htm

Possible dementia vaccine closer after mice studies

Human trials tipped within two years

December 31, 2019

Science Daily/Flinders University

A vaccine to ward off dementia may proceed to clinical trials after successful animal testing. The research is looking to develop effective immunotherapy via a dual vaccine to remove 'brain plaque' and tau protein aggregates linked to Alzheimer's disease. It is showing success in begenic mice models, supports progression to human trials in years to come.

A preventive treatment for dementia may proceed to clinical trials after successful animal testing.

The US-led research is looking to develop effective immunotherapy via a new vaccine to remove 'brain plaque' and tau protein aggregates linked to Alzheimer's disease.

Recent success in bigenic mice models supports progression to human trials in years to come, the researchers say.

A new paper in the journal Alzheimer's Research & Therapy paves the way for more work in 2020, with medical researchers at the Institute for Molecular Medicine and University of California, Irvine (UCI) working with a successful vaccine formulated on adjuvant developed by Flinders University Professor Nikolai Petrovsky in South Australia.

The latest research aims to come up with a new treatment to remove accumulated beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline in Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of age-related dementia, affecting about 5.7 million people in the US. Major challenges in AD include the lack of effective treatments, reliable biomarkers, or preventive strategies.

Professor of the Institute for Molecular Medicine Anahit Ghochikyan and colleagues, Associate Professors Hvat Davtyan and Mathew Blurton-Jones from UCI, and other co-authors tested the universal MultiTEP platform-based vaccines formulated in the adjuvant developed at Professor Petrovsky's Australian lab.

The possible new therapies were tested in bigenic mice with mix Aβ and tau pathologies.

"Taken together, these findings warrant further development of this dual vaccination strategy based on the MultiTEP technology for ultimate testing in human Alzheimer's disease," the lead authors Professor Ghochikyan and Blurton-Jones conclude.

Professor Petrovsky says the Advax adjuvant method is a pivotal system to help take the combination MultiTEP-based Aβ/tau vaccines therapy, as well as separate vaccines targeting these pathological molecules, to clinical trials -- perhaps within two years.

"Our approach is looking to cover all bases and get past previous roadblocks in finding a therapy to slow the accumulation of Aβ/tau molecules and delay AD progression in a the rising number of people around the world," says Professor Petrovsky, who will work in the US for the next three months.

Several promising drug candidates have failed in clinical trials so the search for new preventions or therapies continues.

A recent report on human monoclonal antibody, aducanumab, showed that high dose of this antibody reduced clinical decline in patients with early AD as measured by primary and secondary endpoints.

However, it is obvious that it could not be used as a preventive measure in healthy subjects due to the need for frequent (monthly) administration of high concentrations of immunotherapeutic.

Professor Ghochikyan says there is a pressing need to keep searching for new preventive vaccine to delay AD and slow down progression of this devastating disease.

The new combined vaccination approach could potentially be used to induce strong immune responses to both of the hallmark pathologies of AD in a broad population base of vaccinated subjects with high MHC (major histocompatibility complex) class II gene polymorphisms, the new paper concludes.

https://www.sciencedaily.com/releases/2019/12/191231111835.htm

Objective subtle cognitive difficulties predict amyloid accumulation and neurodegeneration

December 31, 2019

Science Daily/University of California - San Diego

Writing in the December 30, 2019 online issue of Neurology, researchers at University of California San Diego School of Medicine and Veterans Affairs San Diego Healthcare System report that accumulating amyloid -- an abnormal protein linked to neurodegenerative conditions such as Alzheimer's disease (AD) -- occurred faster among persons deemed to have "objectively-defined subtle cognitive difficulties" (Obj-SCD) than among persons considered to be "cognitively normal."

Classification of Obj-SCD, which has been previously shown to predict progression to mild cognitive impairment (MCI) and dementia, is determined using non-invasive but sensitive neuropsychological measures, including measures of how efficiently someone learns and retains new information or makes certain types of errors.

The new findings, say authors, suggest that Obj-SCD can be detected during the preclinical state of AD when amyloid plaques are accumulating in the brain, neurodegeneration is just starting, but symptoms of impairment on total scores on thinking and memory tests have not yet been recorded.

"The scientific community has long thought that amyloid drives the neurodegeneration and cognitive impairment associated with Alzheimer's disease," said senior author Mark W. Bondi, PhD, professor of psychiatry at UC San Diego School of Medicine and the VA San Diego Healthcare System. "These findings, in addition to other work in our lab, suggest that this is likely not the case for everyone and that sensitive neuropsychological measurement strategies capture subtle cognitive changes much earlier in the disease process than previously thought possible.

"This work, led by Dr. Kelsey Thomas, has important implications for research on treatment targets for AD, as it suggests that cognitive changes may be occurring before significant levels of amyloid have accumulated. It seems like we may need to focus on treatment targets of pathologies other than amyloid, such as tau, that are more highly associated with the thinking and memory difficulties that impact people's lives."

Study participants were enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI), an on-going effort (launched in 2003) to test whether regular, repeated brain imaging, combined with other biological markers and clinical assessments, can measure the progression of MCI and early AD. Seven hundred and forty-seven persons were involved in this study: 305 deemed cognitively normal, 153 with Obj-SCD and 289 MCI. All underwent neuropsychological testing and both PET and MRI scans.

The research team found that amyloid accumulation was faster in persons classified with Obj-SCD than in the cognitively normal group. Those classified as Obj-SCD also experienced selective thinning of the entorhinal cortex, a region of the brain impacted very early in Alzheimer's disease and associated with memory, navigation and perception of time. Persons with MCI had more amyloid in their brain at the start of the study, but they did not have faster accumulation of amyloid compared to those with normal cognition. However, those with MCI had more widespread temporal lobe atrophy, including the hippocampus.

Broadly speaking, scientists believe that for most people, AD is likely caused by a combination of genetic, lifestyle and environmental factors. Increasing age is a primary, known risk factor. The amyloid hypothesis or amyloid cascade model posits that accumulating amyloid protein plaques in the brain kill neurons and gradually impair specific cognitive functions, such as memory, resulting in AD dementia. However, many scientists are now questioning the amyloid hypothesis given the large number of clinical trials in which drugs targeted and successfully cleared amyloid from the brain but did not impact the trajectory of cognitive decline.

The ability to identify those at risk for AD before significant impairment and before or during the phase of faster amyloid accumulation would be a clinical boon, said authors, providing both a way to monitor disease progression and a window of opportunity to apply potential preventive or treatment strategies.

Currently, both approaches are limited. Some risk factors for Alzheimer's can be minimized, such as not smoking, managing vascular risk factors such as hypertension or following a healthy diet with regular exercise. There are a handful of medications approved for treating symptoms of AD, but as yet, there is no cure.

"While the emergence of biomarkers of Alzheimer's disease has revolutionized research and our understanding of how the disease progresses, many of these biomarkers continue to be highly expensive, inaccessible for clinical use or not available to those with certain medical conditions," said first author Thomas, PhD, assistant professor of psychiatry at UC San Diego School of Medicine and research health scientist at the VA San Diego Healthcare System.

"A method of identifying individuals at risk for progression to AD using neuropsychological measures has the potential to improve early detection in those who may otherwise not be eligible for more expensive or invasive screening."

https://www.sciencedaily.com/releases/2019/12/191231111811.htm

Alzheimer's study shows promise in protecting brain from tau

Researchers discover impact of MSUT2 gene and binding protein, offering others a starting point for new therapeutics

December 18, 2019

Science Daily/University of Washington Health Sciences/UW Medicine

In the wake of recent disappointments over clinical trials targeting amyloid plaque build-up in Alzheimer's disease, researchers are focusing more attention on misfolded tau protein, another culprit in brain diseases that cause dementia.

New research published in Science Translational Medicine finds that targeting abnormal tau through the suppression of a gene called MSUT2 (mammalian suppressor of tauopathy 2) shows promise.

Tau, like amyloid protein, is another substance that builds up in Alzheimer's disease and damages brain cells.

However, clinical trials targeting tau have been far less numerous in part because tau-targeted drugs have been hard to find.

In this study, researchers concluded that suppressing MSUT2 might protect people from Alzheimer's disease as long as the RNA binding protein PolyA Binding Protein Nuclear 1 (PABPN1) is not depleted. MSUT2 and PABPNI normally work together closely to regulate the biology of tau in the brain.

"If you inhibit MSUT2 and don't affect PABN1, that protects against the effects of tau pathology," said senior author Brian Kraemer, a research associate professor of medicine, Division of Gerontology and Geriatric Medicine at the University of Washington School of Medicine. He is also a scientist at the Veterans Affairs Puget Sound Health Care System.

Kraemer said his team sees their role as the person kicking the ball down field to provide other researchers and drug companies an opportunity to move the ball towards the ultimate goal: A treatment or cure for Alzheimer's disease.

"Pharmaceutical companies have heavily invested in going after amyloid but so far these efforts haven't moved the needle on dementia treatments," he said. "I think the field needs to think about targeting amyloid and tau together because both amyloid and tau act together to kill neurons in Alzheimer's disease."

Senior author Jeanna Wheeler, a research scientist at the Seattle Institute for Biomedical and Clinical Research and the VA, said what's novel about the study is the discovery of the role of the MSUT2 gene.

"We discovered MSUT2 originally in a completely unbiased way by looking for anything that could make worms resistant to pathological tau protein. Now we have shown that this gene can also affect tau toxicity in mice, and also that there are differences in MSUT2 in human Alzheimer's patients," she said. "If we can use MSUT2 in the future as a drug target, this would be a completely novel approach for treating Alzheimer's and other related disorders."

The study also brings more attention to the role of tau pathology in Alzheimer's disease.

The healthy human brain contains tens of billions of specialized cells or neurons that process and transmit information. By disrupting communication among these cells, Alzheimer's disease results in loss of neuron function and cell death.

Previous studies have shown that abnormal tau burden correlates strongly with cognitive decline in Alzheimer's disease patients, but amyloid does not. Some dementia disorders, such as frontotemporal lobar degeneration, may have only abnormal tau with no amyloid deposits.

"If you could protect the brain from tau alone, you may provide substantial benefit for people with Alzheimer's disease," Kraemer said. "Likewise, targeting tau in tangle-only Alzheimer's disease-related dementia disorders, like frontotemporal lobar degeneration, will almost certainly be beneficial for patients."

This study follows previous work by these researchers that showed very similar results using the worm C. elegans. Worms go from egg to adult in three days so it was easier to do experiments on the biology of aging rapidly. Although worms don't have complex cognitive functions, their movement is affected by tau buildup. Researchers found that they could cure the worm by knocking out the worm sut-2 gene.

The more recent study applied the experiment to mice, whose evolutionary distance to humans is much smaller than the distance between worms and humans.

The researchers knocked out the MSUT2 gene in mice, thereby, preventing the formation of the tau tangles that kill off brain cells. This lessened learning and memory problems as well.

While examining autopsy brain samples from Alzheimer's patients, the researchers found that cases with more severe disease lacked both MSUT2 protein, and its partner protein, PABPN1. This finding suggests that neurons that lose the MSUT2 -PABPN1 protein partnership may simply die during a patient's life.

Moreover, mice lacking MSUT2 but possessing a normal complement of PABPN1 were strongly protected against abnormal tau and the resulting brain degeneration. Therefore, the researchers concluded that the key to helping people with abnormal tau buildup is blocking MSUT2 while preserving PABPN1 activity.

https://www.sciencedaily.com/releases/2019/12/191218153505.htm

Are herpes virus infections linked to Alzheimer's disease?

December 18, 2019

Science Daily/Baylor College of Medicine

Researchers at Baylor College of Medicine report today in the journal Neuron evidence that refutes the link between increased levels of herpes virus and Alzheimer's disease. In addition, the researchers provide a new statistical and computational framework for the analysis of large-scale sequencing data.

About 50 million people worldwide are affected by Alzheimer's disease, a type of progressive dementia that results in the loss of memory, cognitive abilities and verbal skills, and the numbers are growing rapidly. Currently available medications temporarily ease the symptoms or slow the rate of decline, which maximizes the time patients can live and function independently. However, there are no treatments to halt progression of Alzheimer's disease.

"Like all types of dementia, Alzheimer's disease is characterized by massive death of brain cells, the neurons. Identifying the reason why neurons begin and continue to die in the brains of Alzheimer's disease patients is an active area of research," said corresponding author Dr. Zhandong Liu, associate professor of pediatrics at Baylor and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.

One theory that has gained traction in the past year is that certain microbial infections, such as those caused by viruses, can trigger Alzheimer's disease. A 2018 study reported increased levels of human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) in the postmortem brain tissues of more than 1,000 patients with Alzheimer's disease when compared to the brain tissues of healthy-aging subjects or those suffering from a different neurodegenerative condition.

Presence of elevated levels of genetic material of herpes viruses indicated active infections, which were linked to Alzheimer's disease. In less than a year, this study generated a flurry of excitement and led to the initiation of several studies to better understand the link between viral infections and Alzheimer's disease.

Surprisingly, when co-author Dr. Hyun-Hwan Jeong, a postdoctoral fellow in Dr. Liu's group and others, reanalyzed the data sets from the 2018 study using the identical statistical methods with rigorous filtering, as well as four commonly used statistical tools, they were unable to produce the same results.

The team was motivated to reanalyze the data from the previous study because they observed that while the p-values (a statistical parameter that predicts the probability of obtaining the observed results of a test, assuming that other conditions are correct) were highly significant, they were being ascribed to data in which the differences were not visually appreciable.

Moreover, the p-values did not fit with simple logistic regression -- a statistical analysis that predicts the outcome of the data as one of two defined states. In fact, after several types of rigorous statistical tests, they found no link between the abundance of herpes viral DNA or RNA and likelihood of Alzheimer's disease in this cohort.

"As high-throughput 'omics' technologies, which include those for genomics, proteomics, metabolomics and others, become affordable and easily available, there is a rising trend toward 'big data' in basic biomedical research. In these situations, given the massive amounts of data that have to be mined and extracted in a short time, researchers may be tempted to rely solely on p-values to interpret results and arrive at conclusions," Liu said.

"Our study highlights one of the potential pitfalls of over-reliance on p-values. While p-values are a very valuable statistical parameter, they cannot be used as a stand-alone measure of statistical correlation -- data sets from high-throughput procedures still need to be carefully plotted to visualize the spread of the data," Jeong said. "Data sets also have to be used in conjunction with accurately calculated p-values to make gene-disease associations that are statistically correct and biologically meaningful."

"Our goal in pursuing and publishing this study was to generate tools and guidelines for big data analysis, so the scientific community can identify treatment strategies that will likely benefit patients," Liu said.

https://www.sciencedaily.com/releases/2019/12/191218153350.htm

Changes in the immune system explain why belly fat is bad for thinking

December 17, 2019

Science Daily/Iowa State University

Researchers have found for the first time that less muscle and more body fat may affect how flexible our thinking gets as we become older, and changes in parts of the immune system could be responsible.

These findings could lead to new treatments that help maintain mental flexibility in aging adults with obesity, sedentary lifestyles, or muscle loss that naturally happens with aging.

The study, led by Auriel Willette, assistant professor of food science and human nutrition, and Brandon Klinedinst, a PhD student in neuroscience, looked at data from more than 4,000 middle-aged to older UK Biobank participants, both men and women. The researchers examined direct measurements of lean muscle mass, abdominal fat, and subcutaneous fat, and how they were related to changes in fluid intelligence over six years.

Willette and Klinedinst discovered people mostly in their 40s and 50s who had higher amounts of fat in their mid-section had worse fluid intelligence as they got older. Greater muscle mass, by contrast, appeared to be a protective factor. These relationships stayed the same even after taking into account chronological age, level of education, and socioeconomic status.

"Chronological age doesn't seem to be a factor in fluid intelligence decreasing over time," Willette said. "It appears to be biological age, which here is the amount of fat and muscle."

Generally, people begin to gain fat and lose lean muscle once they hit middle age, a trend that continues as they get older. To overcome this, implementing exercise routines to maintain lean muscle becomes more important. Klinedinst said exercising, especially resistance training, is essential for middle-aged women, who naturally tend to have less muscle mass than men.

The study also looked at whether or not changes in immune system activity could explain links between fat or muscle and fluid intelligence. Previous studies have shown that people with a higher body mass index (BMI) have more immune system activity in their blood, which activates the immune system in the brain and causes problems with cognition. BMI only takes into account total body mass, so it has not been clear whether fat, muscle, or both jump-start the immune system.

In this study, in women, the entire link between more abdominal fat and worse fluid intelligence was explained by changes in two types of white blood cells: lymphocytes and eosinophils. In men, a completely different type of white blood cell, basophils, explained roughly half of the fat and fluid intelligence link. While muscle mass was protective, the immune system did not seem to play a role.

While the study found correlations between body fat and decreased fluid intelligence, it is unknown at this time if it could increase the risk of Alzheimer's disease.

"Further studies would be needed to see if people with less muscle mass and more fat mass are more likely to develop Alzheimer's disease, and what the role of the immune system is," Klinedinst said.

Starting a New Year's resolution now to work out more and eat healthier may be a good idea, not only for your overall health, but to maintain healthy brain function.

"If you eat alright and do at least brisk walking some of the time, it might help you with mentally staying quick on your feet," Willette said.

https://www.sciencedaily.com/releases/2019/12/191217141531.htm

How a protein in your brain could protect against Alzheimer's disease

New research sets the stage for new therapeutic strategies for Alzheimer's disease

December 13, 2019

University of Alberta

Research shows that white blood cells in the human brain are regulated by a protein called CD33--a finding with important implications in the fight against Alzheimer's disease, according to a new study.

 "Immune cells in the brain, called microglia, play a critical role in Alzheimer's disease," explained Matthew Macauley, assistant professor in theDepartment of Chemistry and co-author on the paper. "They can be harmful or protective. Swaying microglia from a harmful to protective state could be the key to treating the disease."

Scientists have identified the CD33 protein as a factor that may decrease a person's likelihood of Alzheimer's disease. Less than 10 percent of the population have a version of CD33 that makes them less likely to get Alzheimer's disease. "The fact that CD33 is found on microglia suggests that immune cells can protect the brain from Alzheimer's disease under the right circumstances," said Abhishek Bhattacherjee, first author and postdoctoral fellow in the Macauley lab.

Now, Macauley's research shows that the most common type of CD33 protein plays a crucial role in modulating the function of microglia.

"These findings set the stage for future testing of a causal relationship between CD33 and Alzheimer's Disease, as well as testing therapeutic strategies to sway microglia from harmful to protecting against the disease -- by targeting CD33," said Macauley. "Microglia have the potential to 'clean up' the neurodegenerative plaques, through a process called phagocytosis -- so a therapy to harness this ability to slow down or reverse Alzheimer's disease can be envisioned."

Macauley is an investigator with GlycoNet, a Canada-wide network of researchers based at the University of Alberta that is working to further our understanding of biological roles for sugars. GlycoNet provided key funding to get this project off the ground in the Macauley lab and continues to support the ongoing applications of the project.

According to the Alzheimer's Association, 747,000 Canadians are currently living with Alzheimer's or another form of dementia. The disease affects more than 44 million people around the world.

https://www.sciencedaily.com/releases/2019/12/191213124921.htm

Dementia study reveals how proteins interact to stop brain signals

December 10, 2019

University of Edinburgh

Fresh insights into damaging proteins that build up in the brains of people with Alzheimer's disease could aid the quest for treatments.

A study in mice reveals how the two proteins work together to disrupt communication between brain cells.

Scientists observed how proteins -- called amyloid beta and tau -- team up to hamper key genes responsible for brain messaging. By changing how genes are expressed in the brain, the proteins can affect its normal function.

These changes in brain function were completely reversed when genetic tools were used to reduce the presence of tau, researchers at the University of Edinburgh found.

The study focused on the connection points between brain cells -- known as synapses -- that allow chemical and electrical messages to flow and are vital to healthy brain function.

Stopping the damage that the two proteins cause to synapses could help scientists prevent or reverse dementia symptoms, the researchers say.

In both the mouse model and in brain tissue from people with Alzheimer's disease, the team found clumps of amyloid beta and tau proteins in synapses.

When both amyloid beta and tau were present in the brain, genes that control the function of synapses were less active. And some of the genes that control the immune system in the brain were more active.

Related to increased immune system activity, the scientists observed immune cells called microglia containing synapses in the brains of mice. This adds to findings from recent studies suggesting that these immune cells consume synapses during Alzheimer's disease.

Alzheimer's disease is the most common form of dementia, affecting some 850,000 people in the UK -- a figure predicted to rise to more than one million by 2025. It can cause severe memory loss and there is currently no cure.

Lead researcher, Professor Tara-Spires Jones of the UK Dementia Research Institute at the University of Edinburgh, said: "More work is needed to take what we've learned in this study and find therapeutics -- but this is a step in the right direction, giving us new targets to work towards."

The study is published in the journal Cell Reports. It was funded by the European Research Council, and the UK Dementia Research Institute which is funded by the UK Medical Research Council, Alzheimer' Society and Alzheimer's Research UK.

https://www.sciencedaily.com/releases/2019/12/191210111726.htm

Community factors influence how long you'll live

March 10, 2020

Science Daily/Penn State

While lifestyle choices and genetics go a long way toward predicting longevity, a new study shows that certain community characteristics also play important roles. American communities with more fast food restaurants, a larger share of extraction industry-based jobs, or higher population density have shorter life expectancies, according to researchers from Penn State, West Virginia, and Michigan State Universities. Their findings can help communities identify and implement changes that may promote longer lifespans among their residents.

"American life expectancy recently declined for the first time in decades, and we wanted to explore the factors contributing to this decline. Because of regional variation in life expectancy, we knew community-level factors must matter," said Elizabeth Dobis, a postdoctoral scholar at the Penn State-based Northeast Regional Center for Rural Development (NERCRD), and lead author of the study. "By analyzing place-based factors alongside personal factors, we were able to draw several conclusions about which community characteristics contribute most strongly to this variation in life expectancy."

Life expectancy refers to the length of time a person born in a given year can expect to live. Dobis and her colleagues analyzed on a county-by-county basis how life expectancy in 2014 has changed from a 1980 baseline, using data from more than 3,000 U.S. counties.

They developed a statistical model to determine the relationship between a dozen community variables and each county's 2014 life expectancy, while controlling for personal variables that are known to be important, such as sex, race, education, single-parent status, obesity, and alcohol use.

The community variables they examined included health care access, population growth and density, fast food restaurants, healthy food access, employment by sector, urbanization, and social capital, which measures the networks and bonds providing social cohesion among residents. They looked at each variable in isolation while holding others constant, allowing them to determine which variables independently exert the strongest effect on life expectancy.

The researchers found that a county's 1980 life expectancy value strongly predicted variations in the 2014 value, but it didn't account for all of the variation.

"When we controlled for historical life expectancy, we found three additional community factors that each exert a significant negative effect -- a greater number of fast food restaurants, higher population density, and a greater share of jobs in mining, quarrying, and oil and gas extraction," Dobis said. "For example, for every one percentage point increase in the number of fast food restaurants in a county, life expectancy declined by .004 years for men and .006 years for women."

This represents a 15-20 days shorter life span for every man, woman and child in a community, for each 10 percentage point increase in fast food restaurants in a community -- or a 150-200 day shorter life span if the number of fast food restaurants were to double.

Similarly, a one percent increase in a county's share of jobs in the mining, quarrying, oil and gas sectors was found to decrease average life expectancy by .04 years for men (or 15 days) and .06 years (22 days) for women.

The research, which was published recently in Social Science and Medicine, also revealed several community factors that are positively related to life expectancy, including a growing population, good access to physicians, and a greater level of social cohesion.

"We were surprised by the strong positive contribution of social capital to life expectancy within communities," said NERCRD Director Stephan Goetz, professor of agricultural economics and regional economics at Penn State and a co-author on the study. "Places with residents who stick together more on a community or social level also appear to do a better of job of helping people in general live longer."

"Another interesting finding was that lower population density, or living in more rural areas, is associated with higher life expectancy," Goetz said. "This suggests that living in large, densely-settled metropolitan areas, with all of their amenities and other advantages, comes at the expense of lower life expectancy, at least in a statistical sense."

In addition to being the first life-expectancy study to include community variables in a county-level analysis, this also was the first study to statistically analyze the extent to which disparities in life expectancy are geographically clustered. This analysis revealed some striking patterns.

"We found exceptionally low life expectancies in the areas of the Pine Ridge and Rosebud Reservations in South Dakota," Dobis said. "We found similar 'cold spots' of low life expectancy in the arctic and interior portions of Alaska, the Deep South surrounding the Mississippi River, and in the Appalachian regions of Kentucky and West Virginia."

The research also revealed four "hot spots" of high life expectancy: a section of the Northeast spanning from Philadelphia to New England, southern Minnesota and the eastern Dakotas into Nebraska, an area in Colorado, and an area spanning central Idaho into the upper Rocky Mountains.

The team's findings have important policy implications, as they suggest that certain aspects of the built environment can be changed to enhance life expectancy. For example, public places that promote social interaction could increase a community's social capital levels, which in turn promote longer lifespans.

https://www.sciencedaily.com/releases/2020/03/200310124706.htm

For older adults, more physical activity could mean longer, healthier lives

March 5, 2020

Science Daily/American Heart Association

Older adults were 67% less likely to die of any cause if they were moderately or vigorously physically active for at least 150 minutes per week, compared to people who exercised less. Women with an average age of 79 who walked 2,100 to 4,500 steps daily reduced their risk of dying from heart attacks, heart failure, stroke and other cardiovascular diseases by up to 38%, compared to women who walked less than 2,100 daily steps.

Two studies demonstrate that older adults may be able to live longer, healthier lives by increasing physical activity that doesn't have to be strenuous to be effective, according to preliminary research presented at the American Heart Association's Epidemiology and Prevention | Lifestyle and Cardiometabolic Health Scientific Sessions 2020. The EPI Scientific Sessions, March 3-6 in Phoenix, is a premier global exchange of the latest advances in population-based cardiovascular science for researchers and clinicians.

"Finding a way to physically move more in an activity that suits your capabilities and is pleasurable is extremely important for all people, and especially for older people who may have risk factors for cardiovascular diseases. Physical activities such as brisk walking can help manage high blood pressure and high cholesterol, improve glucose control among many benefits," said Barry A. Franklin, Ph.D., past chair of both the American Heart Association's Council on Physical Activity and Metabolism and the National Advocacy Committee, director of preventive cardiology and cardiac rehabilitation at Beaumont Health in Royal Oak, Michigan and professor of internal medicine at Oakland University William Beaumont School of Medicine in Rochester, Michigan.

Higher levels of light physical activity are associated with lower risk of death from any cause

Older adults were 67% less likely to die of any cause if they spent at least 150 minutes per week in moderate to vigorous physical activity -- a goal recommended by the American Heart Association -- compared to those who did not engage in more than 150 minutes per week of moderate to vigorous physical activity.

However, this investigation observed that, among the participants with an average age of 69, physical activity doesn't have to be strenuous to be effective. The researchers observed that each 30-minute interval of light-intensity physical activities -- such as doing household chores or casual walking -- was associated with a 20% lower risk of dying from any cause. Conversely, every additional 30-minutes of being sedentary was related to a 32% higher risk of dying from any cause.

"Promoting light-intensity physical activity and reducing sedentary time may be a more practical alternative among older adults," said Joowon Lee, Ph.D., a researcher at Boston University in Boston.

This investigation evaluated physical activity levels of 1,262 participants from the ongoing Framingham Offspring Study. Participants were an average age of 69 (54% women), and they were instructed to wear a device that objectively measured physical activity for at least 10 hours a day, for at least four days a week between 2011 and 2014.

The strengths of this investigation include its large sample size and the use of a wearable device to objectively measure physical activity. However, the participants of the Framingham Offspring Study are white, so it is unclear if these findings would be consistent for other racial groups.

Co-authors of the study are Nicole L. Spartano, Ph.D.; Ramachandran S. Vasan, M.D. and Vanessa Xanthakis Ph.D. Author disclosures are in the abstract.

This study was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health.

Every step counts in reducing cardiovascular disease deaths among older women

Women who walked 2,100 to 4,500 steps daily reduced their risk of dying from heart attacks, heart failure, stroke and other cardiovascular diseases by up to 38%, compared to women who walked less than 2,100 daily steps. The women who walked more than 4,500 steps per day reduced their risk by 48%, in this study of over 6,000 women with an average age of 79. 2

The cardio-protective effect of more steps per day was present even after the researchers took into consideration heart disease risk factors, such as obesity, elevated cholesterol, blood pressure, triglycerides and/or blood sugar levels, and was not dependent on how fast the women walked.4

"Despite popular beliefs, there is little evidence that people need to aim for 10,000 steps daily to get cardiovascular benefits from walking. Our study showed that getting just over 4,500 steps per day is strongly associated with reduced risk of dying from cardiovascular disease in older women," said lead study author Andrea Z. LaCroix, Ph.D., distinguished professor and chief of epidemiology at the University of California, San Diego.

"Taking more steps per day, even just a few more, is achievable, and step counts are an easy-to-understand way to measure how much we are moving. There are many inexpensive wearable devices to choose from. Our research shows that older women reduce their risk of heart disease by moving more in their daily life, including light activity and taking more steps. Being up and about, instead of sitting, is good for your heart," said LaCroix.

The study included more than 6,000 women enrolled in the Women's Health Initiative with an average age of 79 who wore an accelerometer on their waist to measure physical activity for seven days in a row; participants were followed for up to seven years for heart disease death.

This study was prospective, and half of the participants were African American or Hispanic. The use of an accelerometer to measure movement is a strength of the study. The study did not include men or people younger than 60, so it will be important for future research to examine step counts and other measures of daily activity across the adult age range among both men and women.

https://www.sciencedaily.com/releases/2020/03/200305132217.htm

Low blood pressure linked to high mortality in older adults

March 7, 2020

Science Daily/University of Exeter

A large-scale study analyzed 415,980 electronic medical records of older adults in England. People aged 75 or over with low blood pressure (below 130/80) had increased mortality rates in the follow-up, compared to those with normal blood pressure. This was especially pronounced in 'frail' individuals, who had 62% increased risk of death during the 10-year follow-up.

The research was conducted after some countries have changed blood pressure guidelines to encourage clinicians to take measures to reduce blood pressure in a bid to improve health outcomes. UK blood pressure guidelines are within safe parameters for all. However, previous research has not considered the impact on frail older adults, who are often omitted from trials.

The team found that people aged 75 or over with low blood pressure (below 130 / 80) had increased mortality rates in the follow-up, compared to those with normal blood pressure. This was especially pronounced in 'frail' individuals, who had 62 per cent increased risk of death during the ten year follow-up.

Although high blood pressure increased risk of cardiovascular incidents, such as heart attacks, it was not linked to higher mortality in frail adults over 75. Older people aged 85 and over who had raised blood pressure actually had reduced mortality rates, compared to those with lower blood pressure, regardless of whether they were frail or not.

Jane Masoli, a geriatrician and NIHR Doctoral Research Fellow, who led the study as part of her PhD at the University of Exeter, said: "Internationally, guidelines are moving towards tight blood pressure targets, but our findings indicate that this may not be appropriate in frail older adults. We need more research to ascertain whether aggressive blood pressure control is safe in older adults, and then for which patient groups there may be benefit, so we can move towards more personalised blood pressure management in older adults."

She added: "We know that treating blood pressure helps to prevent strokes and heart attacks and we would not advise anyone to stop taking their medications unless guided by their doctor."

https://www.sciencedaily.com/releases/2020/03/200307170735.htm

The harmful effects of stress during pregnancy can last a lifetime

March 5, 2020

Science Daily/Yale University

Mice exposed to stress in the womb and soon after birth can expect a lifetime of immune system deficiencies that hinder the ability to ward off infections and cancer, Yale University researchers report March 5 in the journal Cell.

In a new study, they tracked a lifetime of physiological changes experienced by mice given a liquid solution containing the stress hormone glucocorticoid while in the womb or soon after birth. Glucocorticoids are naturally occurring hormones that reduce inflammation and are instrumental in helping infants and adults alike adapt quickly to environmental dangers, such as famine or violence. Physicians use them to treat asthma and autoimmune diseases caused by overactive immune systems, for example.

But, the researchers found, early-life exposure to the stress hormone can permanently alter many immune system responses, decreasing the body's ability to ward off bacterial infections and fight tumors.

"Mice for rest of their lives are rewired and reprogrammed in ways fundamentally different from those not exposed to glucocorticoids," said Yale immunobiologist Ruslan Medzhitov, senior author of the study and Howard Hughes Medical Institute investigator.

Medzhitov and first author Jun Young Hun, also of Yale, catalogued a host of physiological changes that occurred in mice given glucocorticoids and that had serious consequences for the rest of their lives. As adults, for instance, the exposed mice were more susceptible to bacterial infections and tumors than mice without exposure. One specific physiological change was decreased activity in a key T cell that responds to pathogens and other threats to the host.

The study helps explain why individuals vary so widely in their ability to ward off infections, the authors said. It also provides an explanation for a social phenomenon found throughout human history: an emphasis on shielding women from stress during pregnancy.

"In all cultures, there are efforts to shelter women from stress during pregnancy," he said. "The effects of early life stress don't just go away."

As more is learned about molecular changes caused by early exposure to stress, the more likely it is that medical science will find a way to minimize its damage, said the authors.

"We aren't there yet," Medzhitov said.

https://www.sciencedaily.com/releases/2020/03/200305132154.htm