Women accumulate Alzheimer's-related protein faster

March 25, 2021

Science Daily/Lund University

Alzheimer's disease seems to progress faster in women than in men. The protein tau accumulates at a higher rate in women, according to research from Lund University in Sweden. The study was recently published in Brain.

Over 30 million people suffer from Alzheimer's disease worldwide, making it the most common form of dementia. Tau and beta-amyloid are two proteins known to aggregate and accumulate in the brain in patients with Alzheimer's.

The first protein to aggregate in Alzheimer's is beta-amyloid. Men and women are equally affected by the first disease stages, and the analysis did not show any differences in the accumulation of beta-amyloid. Memory dysfunction arises later, when tau starts to accumulate. More women than men are affected by memory problems due to Alzheimer's, and it was for tau that the researchers found a higher rate of accumulation in women.

"Tau accumulation rates vary greatly between individuals of the same sex, but in the temporal lobe, which is affected in Alzheimer's disease, we found a 75% higher accumulation rate in women as a group compared to men," explains Ruben Smith, first author of the study.

The accumulation of tau is faster in patients who already have a pathological accumulation of beta-amyloid, and are in the early phase of the disease. The discovery that the accumulation rate of tau is higher in women remained even after adjusting for age and the levels of tau they had at the beginning. Together with data from three similar cohorts in the USA, the project contains 209 women and 210 men.

"The next step would be to examine why this accumulation is faster in women," says Sebastian Palmqvist, the researcher responsible for the cognitive assessment of the patients.

The study did not investigate the reasons for the higher rate of tau accumulation in women.

"Our study strongly indicates that the faster spread of tau makes women more prone to develop dementia because of Alzheimer's pathology compared to men. Future experimental studies will be important to understand the reasons behind this," concludes Professor Oskar Hansson.

https://www.sciencedaily.com/releases/2021/03/210325115423.htm

Eating processed meat could increase dementia risk

March 21, 2021

Science Daily/University of Leeds

Scientists from the University's Nutritional Epidemiology Group used data from 500,000 people, discovering that consuming a 25g serving of processed meat a day, the equivalent to one rasher of bacon, is associated with a 44% increased risk of developing the disease.

But their findings also show eating some unprocessed red meat, such as beef, pork or veal, could be protective, as people who consumed 50g a day were 19% less likely to develop dementia. 

The researchers were exploring whether there is a link between consumption of meat and development of dementia, a health condition which affects 5%-8% of over 60s worldwide.

Their results, titled Meat consumption and risk of incident dementia: cohort study of 493,888 UK Biobank participants, are published today in the American Journal of Clinical Nutrition.

Lead researcher Huifeng Zhang, a PhD student from Leeds' School of Food Science and Nutrition, said: "Worldwide, the prevalence of dementia is increasing and diet as a modifiable factor could play a role.

"Our research adds to the growing body of evidence linking processed meat consumption to increased risk of a range of non-transmissible diseases." 

The research was supervised by Professors Janet Cade and Laura Hardie, both at Leeds.

The team studied data provided by UK Biobank, a database containing in-depth genetic and health information from half a million UK participants aged 40 to 69, to investigate associations between consuming different types of meat and risk of developing dementia.  

The data included how often participants consumed different kinds of meat, with six options from never to once or more daily, collected in 2006-2010 by the UK Biobank. The study did not specifically assess the impact of a vegetarian or vegan diet on dementia risk, but it included data from people who said they did not eat red meat. 

Among the participants, 2,896 cases of dementia emerged over an average of eight years of follow up. These people were generally older, more economically deprived, less educated, more likely to smoke, less physically active, more likely to have stroke history and family dementia history, and more likely to be carriers of a gene which is highly associated with dementia. More men than women were diagnosed with dementia in the study population.  

Some people were three to six times more likely to develop dementia due to well established genetic factors, but the findings suggest the risks from eating processed meat were the same whether or not a person was genetically predisposed to developing the disease. 

Those who consumed higher amounts of processed meat were more likely to be male, less educated, smokers, overweight or obese, had lower intakes of vegetables and fruits, and had higher intakes of energy, protein, and fat (including saturated fat). 

Meat consumption has previously been associated with dementia risk, but this is believed to be the first large-scale study of participants over time to examine a link between specific meat types and amounts, and the risk of developing the disease. 

There are around 50 million dementia cases globally, with around 10 million new cases diagnosed every year. Alzheimer's Disease makes up 50% to 70% of cases, and vascular dementia around 25%. Its development and progression are associated with both genetic and environmental factors, including diet and lifestyle.  

Ms Zhang said: "Further confirmation is needed, but the direction of effect is linked to current healthy eating guidelines suggesting lower intakes of unprocessed red meat could be beneficial for health."

Professor Cade said: "Anything we can do to explore potential risk factors for dementia may help us to reduce rates of this debilitating condition. This analysis is a first step towards understanding whether what we eat could influence that risk."

https://www.sciencedaily.com/releases/2021/03/210321215434.htm

CBD reduces plaque, improves cognition in model of familial Alzheimer's

March 9, 2021

Science Daily/Medical College of Georgia at Augusta University

A two-week course of high doses of CBD helps restore the function of two proteins key to reducing the accumulation of beta-amyloid plaque, a hallmark of Alzheimer's disease, and improves cognition in an experimental model of early onset familial Alzheimer's, investigators report.

The proteins TREM2 and IL-33 are important to the ability of the brain's immune cells to literally consume dead cells and other debris like the beta-amyloid plaque that piles up in patients' brains, and levels of both are decreased in Alzheimer's.

The investigators report for the first time that CBD normalizes levels and function, improving cognition as it also reduces levels of the immune protein IL-6, which is associated with the high inflammation levels found in Alzheimer's, says Dr. Babak Baban, immunologist and associate dean for research in the Dental College of Georgia and the study's corresponding author.

There is a dire need for novel therapies to improve outcomes for patients with this condition, which is considered one of the fastest-growing health threats in the United States, DCG and Medical College of Georgia investigators write in the Journal of Alzheimer's Disease.

"Right now we have two classes of drugs to treat Alzheimer's," says Dr. John Morgan, neurologist and director of the Movement and Memory Disorder Programs in the MCG Department of Neurology. One class increases levels of the neurotransmitter acetylcholine, which also are decreased in Alzheimer's, and another works through the NMDA receptors involved in communication between neurons and important to memory. "But we have nothing that gets to the pathophysiology of the disease," says Morgan, a study coauthor.

The DCG and MCG investigators decided to look at CBD's ability to address some of the key brain systems that go awry in Alzheimer's.

They found CBD appears to normalize levels of IL-33, a protein whose highest expression in humans is normally in the brain, where it helps sound the alarm that there is an invader like the beta-amyloid accumulation. There is emerging evidence of its role as a regulatory protein as well, whose function of either turning up or down the immune response depends on the environment, Baban says. In Alzheimer's, that includes turning down inflammation and trying to restore balance to the immune system, he says.

That up and down expression in health and disease could make IL-33 both a good biomarker and treatment target for disease, the investigators say.

CBD also improved expression of triggering receptor expressed on myeloid cells 2, or TREM2, which is found on the cell surface where it combines with another protein to transmit signals that activate cells, including immune cells. In the brain, its expression is on the microglial cells, a special population of immune cells found only in the brain where they are key to eliminating invaders like a virus and irrevocably damaged neurons.

Low levels of TREM2 and rare variations in TREM2 are associated with Alzheimer's, and in their mouse model TREM2 and IL-33 were both low.

Both are essential to a natural, ongoing housekeeping process in the brain called phagocytosis, in which microglial cells regularly consume beta amyloid, which is regularly produced in the brain, the result of the breakdown of amyloid-beta precursor protein, which is important to the synapses, or connection points, between neurons, and which the plaque interrupts.

They found CBD treatment increased levels of IL-33 and TREM2 -- sevenfold and tenfold respectively.

CBD's impact on brain function in the mouse model of early onset Alzheimer's was assessed by methods like the ability to differentiate between a familiar item and a new one, as well as observing the rodents' movement.

People with Alzheimer's may experience movement problems like stiffness and an impaired gait, says Dr. Hesam Khodadadi, a graduate student working in Baban's lab. Mice with the disease run in an endless tight circle, behavior which stopped with CBD treatment, says Khodadadi, the study's first author.

Next steps include determining optimal doses and giving CBD earlier in the disease process. The compound was given in the late stages for the published study, and now the investigators are using it at the first signs of cognitive decline, Khodadadi says. They also are exploring delivery systems including the use of an inhaler that should help deliver the CBD more directly to the brain. For the published studies, CBD was put into the belly of the mice every other day for two weeks.

A company has developed both animal and human inhalers for the investigators who also have been exploring CBD's effect on adult respiratory distress syndrome, or ARDS, a buildup of fluid in the lungs that is a major and deadly complication of COVID-19, as well as other serious illnesses like sepsis and major trauma. The CBD doses used for the Alzheimer's study were the same the investigators successfully used to reduce the "cytokine storm" of ARDS, which can irrevocably damage the lungs.

Familial disease is an inherited version of Alzheimer's in which symptoms typically surface in the 30s and 40s and occurs in about 10-15% of patients.

CBD should be at least equally effective in the more common, nonfamilial type Alzheimer's, which likely have more targets for CBD, Baban notes. They already are looking at its potential in a model of this more common type and moving forward to establish a clinical trial.

Plaques as well as neurofibrillary tangles, a collection of the protein tau inside neurons, are the main components of Alzheimer's, Morgan says. Beta-amyloid generally appears in the brain 15-20 years or more before dementia, he says, and the appearance of tau tangles, which can occur up to 10 years afterward, correlates with the onset of dementia. There is some interplay between beta amyloid and tau that decrease the dysfunction of each, Morgan notes.

The Food and Drug Administration is scheduled to make a ruling by early June on a new drug aducanumab, which would be the first to attack and help clear beta amyloid, Morgan says.

https://www.sciencedaily.com/releases/2021/03/210309192548.htm

Head injury 25 years later: Study finds increased risk of dementia

March 9, 2021

Science Daily/University of Pennsylvania School of Medicine

Head injury in the United States is common, with over 23 million adults age 40 or older reporting a history of head injury with loss of consciousness. Many head injuries can be caused by a host of different situations -- from car and motorcycle accidents to sports injuries. What's more, it has become increasingly recognized that the effects from head injuries are long-lasting. New research led by the Perelman School of Medicine at the University of Pennsylvania shows that a single head injury could lead to dementia later in life. This risk further increases as the number of head injuries sustained by an individual increases. The findings also suggest stronger associations of head injury with risk of dementia among women compared to among men and among white as compared to among Black populations.

The researchers, whose findings were published today in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, conducted the investigation using data from the Atherosclerosis Risk in Communities (ARIC) Study, which aimed to uncover associations between head injury and dementia over the span of 25 years in a diverse population in the United States. Previously, data on traumatic brain injury has been limited to select populations, such as military and medical claims databases. These are among the first findings to specifically investigate head injury and dementia risk in both Black and white populations, as well as among both males and females, in a community-based setting.

"Head injury is a significant risk factor for dementia, but it's one that can be prevented. Our findings show that the number of head injuries matter -- more head injuries are associated with greater risk for dementia," said lead investigator, Andrea L.C. Schneider, MD, PhD, an assistant professor of Neurology at Penn. "The dose-dependence of this association suggests that prevention of head injury could mitigate some risk of dementia later in life. While head injury is not the only risk factor for dementia, it is one risk factor for dementia that is modifiable by behavior changes such as wearing helmets and seat belts."

The findings show that compared to participants who never experienced a head injury, a history of a single prior head injury was associated with a 1.25 times increased risk of dementia, and a history of two or more prior head injuries was associated with over 2 times increased risk of dementia compared to individuals without a history of head injury. Overall, 9.5 percent of all dementia cases in the study population could be attributed to at least one prior head injury.

To illustrate the relationship between dementia and head injuries, the authors gathered data from a diverse cohort with a mean baseline age of 54 years, comprised of 56 percent female and 27 percent Black participants from four different communities across the United States. Participants were followed for a median of 25 years through up to six in-person visits and semi-annual telephone follow-ups. Data on head injuries of participants was drawn from hospital records, as well as self-reporting from some participants.

Previous research on dementia and traumatic brain injuries suggests that women are at higher risk for dementia compared to men. Additionally, Black populations overall are at higher risk for dementia compared to people who are white. However, few prior studies have evaluated for possible differences in associations of head injury with dementia risk by sex and race.

This data from the ARIC study found evidence that females were more likely to experience dementia as a result of head injury than males. Further, the study showed that although there is increased dementia risk associated with head injury among both White and Black participants, White participants were at higher risk for dementia after head injury compared to Black participants. The authors conclude that more research is needed to better understand reasons for these observed sex and race differences in the association of head injury with dementia risk.

"Given the strong association of head injury with dementia, there is an important need for future research focused on prevention and intervention strategies aimed at reducing dementia after head injury," Schneider said. "The results of this study have already led to several ongoing research projects, including efforts to uncover the causes of head injury-related dementia as well as investigations into reasons underlying the observed sex and race differences in the risk of dementia associated with head injury."

https://www.sciencedaily.com/releases/2021/03/210309091257.htm

Why odors trigger powerful memories

Smell travels on superhighway to hippocampus in the brain

March 8, 2021

Science Daily/Northwestern University

A new Northwestern Medicine paper is the first to identify a neural basis for how the brain enables odors to so powerfully elicit those memories. The paper shows unique connectivity between the hippocampus -- the seat of memory in the brain -- and olfactory areas in humans.

This new research suggests a neurobiological basis for privileged access by olfaction to memory areas in the brain. The study compares connections between primary sensory areas -- including visual, auditory, touch and smell -- and the hippocampus. It found olfaction has the strongest connectivity. It's like a superhighway from smell to the hippocampus.

"During evolution, humans experienced a profound expansion of the neocortex that re-organized access to memory networks," said lead investigator Christina Zelano, assistant professor of neurology at Northwestern University Feinberg School of Medicine. "Vision, hearing and touch all re-routed in the brain as the neocortex expanded, connecting with the hippocampus through an intermediary -- association cortex -- rather than directly. Our data suggests olfaction did not undergo this re-routing, and instead retained direct access to the hippocampus."

The paper, "Human hippocampal connectivity is stronger in olfaction than other sensory systems" was published March 4 in the journal Progress in Neurobiology.

Epidemic loss of smell in COVID-19 makes research more urgent In COVID-19, smell loss has become epidemic, and understanding the way odors affect our brains -- memories, cognition and more -- is more important than ever, Zelano noted.

"There is an urgent need to better understand the olfactory system in order to better understand the reason for COVID-related smell loss, diagnose the severity of the loss and to develop treatments," said first author Guangyu Zhou, research assistant professor of neurology at Northwestern. "Our study is an example of the basic research science that our understanding of smell, smell loss and future treatments is built on."

Below is a Q & A with Zelano about the importance of the sense of smell, olfactory research and the link to COVID-19.

Why do smells evoke such vivid memories? 

"This has been an enduring mystery of human experience. Nearly everyone has been transported by a whiff of an odor to another time and place, an experience that sights or sounds rarely evoke. Yet, we haven't known why. The study found the offactory parts of the brain connect more strongly to the memory parts than other senses. This is a major piece of the puzzle, a striking finding in humans. We believe our results will help future research solve this mystery.'

How does smell research relate to COVID-19?

"The COVID-19 epidemic has brought a renewed focus and urgency to olfactory research. While our study doesn't address COVID smell loss directly, it does speak to an important aspect of why olfaction is important to our lives: smells are a profound part of memory, and odors connect us to especially important memories in our lives, often connected to loved ones. The smell of fresh chopped parsley may evoke a grandmother's cooking, or a whiff of a cigar may evoke a grandfather's presence. Odors connect us to important memories that transport us back to the presence of those people."

Loss of smell linked to depression and poor quality of life

"Loss of the sense of smell is underestimated in its impact. It has profound negative effects of quality of life, and many people underestimate that until they experience it. Smell loss is highly correlated with depression and poor quality of life.

"Most people who lose their smell to COVID regain it, but the time frame varies widely, and some have had what appears to be permanent loss. Understanding smell loss, in turn, requires research into the basic neural operations of this under-studied sensory system.

"Research like ours moves understanding of the olfactory parts of the brain forward, with the goal of providing the foundation for translational work on, ultimately, interventions."

https://www.sciencedaily.com/releases/2021/03/210308140743.htm

A weak heart makes a suffering brain

Evidence of disturbed gene activity in the brain as a result of heart problems

February 26, 2021

Science Daily/DZNE - German Center for Neurodegenerative Diseases

Heart problems cause disturbed gene activity in the brain's memory center, from which cognitive deficits arise. Researchers at the German Center for Neurodegenerative Diseases (DZNE), the University Medical Center Göttingen (UMG) and the German Center for Cardiovascular Research (DZHK) come to this conclusion based on laboratory studies. They consider that they have found a possible cause for the increased risk of dementia in people with heart problems. In mice, a specific drug which is known to affect gene activity alleviated the mental deficits. The involved experts see these results as potential approaches for therapies. The study data are published in the scientific journal EMBO Molecular Medicine.

In Germany, about four million people are affected by what is called "heart failure": Their heart muscle is too weak to pump enough blood through the body and is therefore abnormally enlarged. Physical fitness and quality of life suffer as a result. Moreover, affected individuals have an increased risk of developing dementia. "People with cardiological problems and heart failure in particular may experience noticeable cognitive deficits and increased risk of developing Alzheimer's disease. Possible reasons include impaired blood supply to the brain and dysfunction of the hippocampus, which is the memory's control center," explained André Fischer, research group leader at the DZNE's Göttingen site and professor at the Department of Psychiatry and Psychotherapy at UMG. "Yet, there is a lack of therapies to effectively treat cognitive deficits in people with heart problems. This is because it is completely unclear which deficiencies are triggered in neurons. There was no data on this so far."

Stressed Cells

Now, a team led by Prof. André Fischer and Prof. Karl Toischer (Clinic of Cardiology and Pneumology at UMG and DZHK's Göttingen site) is presenting findings on this subject for the first time. The researchers observed in mice that impaired gene activity developed in the hippocampus as a result of heart problems. "In memory tests, mice with heart failure performed significantly worse than their healthy mates," Fischer explained. "We then examined the neurons of the hippocampus. In the mice with heart failure, we found increased cellular stress pathways and altered gene activity in neurons."

Tight Windings

The genome of a mouse -- and also of humans -- comprises around 20,000 genes. In any given cell, however, only a part of them is active, switched on, so to speak. This is not a mere on or off state: the activity can be strong or less strong. This depends, among other things, on how tightly the DNA (the thread-like molecule that carries the genome) is wound and how accessible the genes on it are. In both mice and humans, the DNA is more than a meter long. But in a cell, the molecule is so tightly packed that it fits into the nucleus. "Genes can only be active if they are accessible to the cell's machinery. To this end, the DNA needs to be wound a little more loosely at the relevant sites. This is similar to a ball of yarn with loops sticking out of it," said Fischer. In the current study, the DNA was found to be more tightly wound in neurons of mice with heart problems than in healthy mates. Various genes important for hippocampal function were therefore less active than in healthy mice.

A Drug Improved Memory

The scientists identified chemical changes in the histones as the cause of the tight winding. Histones are special proteins: The DNA wraps around them, much like yarn around a spool of thread. Fischer's research group has been studying histones and other players that influence gene activity for quite some time -- in technical jargon they are called "epigenetic mechanisms." In this context, the researchers are also investigating drugs. In previous studies, they were able to show that the cancer drug "vorinostat" can alleviate genetically driven as well as age-related memory problems in mice. Currently, vorinostat is being investigated for the therapy of people with Alzheimer's in a clinical trial of the DZNE. In the current study, the scientists treated mice with heart failure with this drug. They found that the heart's pumping capacity did not change significantly, but memory performance improved.

Interdisciplinary Cooperation

"Vorinostat has been shown to act on histones and thus on gene activity. Our study thereby provides initial clues about the molecular processes that contribute to cognitive dysfunction following heart problems, and it indicates potential approaches for therapy," Fischer commented on the results. "Fact is, however, that we do not yet understand why, as a result of heart failure, gene activity in the hippocampus is disturbed. What is the role of the deficient blood supply to the brain? Does the troubled heart release substances that affect the histones? We intend to investigate this in patients with heart problems. As with our current study, which involved experts from neuroscience and cardiac research, we aim to address these questions in an interdisciplinary way."

https://www.sciencedaily.com/releases/2021/02/210226121252.htm

Sleep is vital to associating emotion with memory

February 22, 2021

Science Daily/University of Michigan

When you slip into sleep, it's easy to imagine that your brain shuts down, but University of Michigan research suggests that groups of neurons activated during prior learning keep humming, tattooing memories into your brain.

U-M researchers have been studying how memories associated with a specific sensory event are formed and stored in mice. In a study conducted prior to the coronavirus pandemic and recently published in Nature Communications, the researchers examined how a fearful memory formed in relation to a specific visual stimulus.

They found that not only did the neurons activated by the visual stimulus keep more active during subsequent sleep, sleep is vital to their ability to connect the fear memory to the sensory event.

Previous research has shown that regions of the brain that are highly active during intensive learning tend to show more activity during subsequent sleep. But what was unclear was whether this "reactivation" of memories during sleep needs to occur in order to fully store the memory of newly learned material.

"Part of what we wanted to understand was whether there is communication between parts of the brain that are mediating the fear memory and the specific neurons mediating the sensory memory that the fear is being tied to. How do they talk together, and must they do so during sleep? We would really like to know what's facilitating that process of making a new association, like a particular set of neurons, or a particular stage of sleep," said Sara Aton, senior author of the study and a professor in the U-M Department of Molecular, Cellular and Developmental Biology. "But for the longest time, there was really no way to test this experimentally."

Now, researchers have the tools to genetically tag cells that are activated by an experience during a specific window of time. Focusing on a specific set of neurons in the primary visual cortex, Aton and the study's lead author, graduate student Brittany Clawson, created a visual memory test. They showed a group of mice a neutral image, and expressed genes in the visual cortex neurons activated by the image.

To verify that these neurons registered the neutral image, Aton and her team tested whether they could instigate the memory of the image stimulus by selectively activating the neurons without showing them the image. When they activated the neurons and paired that activation with a mild foot shock, they found that their subjects would subsequently be afraid of visual stimuli that looked similar to the image those cells encode. They found the reverse also to be true: after pairing the visual stimulus with a foot shock, their subjects would subsequently respond with fear to reactivating the neurons.

"Basically, the precept of the visual stimulus and the precept of this completely artificial activation of the neurons generated the same response," Aton said.

The researchers found that when they disrupted sleep after they showed the subjects an image and had given them a mild foot shock, there was no fear associated with the visual stimulus. Those with unmanipulated sleep learned to fear the specific visual stimulus that had been paired with the foot shock.

"We found that these mice actually became afraid of every visual stimulus we showed them," Aton said. "From the time they go to the chamber where the visual stimuli are presented, they seem to know there's a reason to feel fear, but they don't know what specifically they're afraid of."

This likely shows that, in order for them to make an accurate fear association with a visual stimulus, they have to have sleep-associated reactivation of the neurons encoding that stimulus in the sensory cortex, according to Aton. This allows a memory specific to that visual cue to be generated.The researchers think that at the same time, that sensory cortical area must communicate with other brain structures, to marry the sensory aspect of the memory to the emotional aspect.

Aton says their findings could have implications for how anxiety and post-traumatic stress disorder are understood.

"To me this is kind of a clue that says, if you're linking fear to some very specific event during sleep, sleep disruption may affect this process. In the absence of sleep, the brain seems to manage processing the fact that you are afraid, but you may be unable to link that to what specifically you should be afraid of," Aton said. "That specification process may be one that goes awry with PTSD or generalized anxiety."

https://www.sciencedaily.com/releases/2021/02/210222164216.htm

How the 'noise' in our brain influences our behavior

Neural variability provides an essential basis for how we perceive the world and react to it

February 17, 2021

Science Daily/Max Planck Institute for Human Development

The brain's neural activity is irregular, changing from one moment to the next. To date, this apparent "noise" has been thought to be due to random natural variations or measurement error. However, researchers at the Max Planck Institute for Human Development have shown that this neural variability may provide a unique window into brain function. In a new Perspective article out now in the journal Neuron, the authors argue that researchers need to focus more on neural variability to fully understand how behavior emerges from the brain.

When neuroscientists investigate the brain, its activity seems to vary all the time. Sometimes activity is higher or lower, rhythmic or irregular. Whereas averaging brain activity has served as a standard way of visualizing how the brain "works," the irregular, seemingly random patterns in neural signals have often been disregarded. Strikingly, such irregularities in neural activity appear regardless of whether single neurons or entire brain regions are assessed. Brains simply always appear "noisy," prompting the question of what such moment-to-moment neural variability may reveal about brain function.

Across a host of studies over the past 10 years, researchers from the Lifespan Neural Dynamics Group (LNDG) at the Max Planck Institute for Human Development and the Max Planck UCL Centre for Computational Psychiatry and Ageing Research have systematically examined the brain's "noise," showing that neural variability has a direct influence on behavior. In a new Perspective article published in the journal Neuron, the LNDG in collaboration with the University of Lübeck highlights what is now substantial evidence supporting the idea that neural variability represents a key, yet under-valued dimension for understanding brain-behavior relationships. "Animals and humans can indeed adapt successfully to environmental demands, but how can such behavioral success emerge in the face of neural variability? We argue that neuroscientists must grapple with the possibility that behavior may emerge because of neural variability, not in spite of it," says Leonhard Waschke, first author of the article and LNDG postdoctoral fellow.

A recent LNDG study published in the journal eLife exemplifies the direct link between neural variability and behavior. Participants' brain activity was measured via electroencephalography (EEG) while they responded to faint visual targets. When people were told to detect as many visual targets as possible, neural variability generally increased, whereas it was downregulated when participants were asked to avoid mistakes. Crucially, those who were better able to adapt their neural variability to these task demands performed better on the task. "The better a brain can regulate its 'noise,' the better it can process unknown information and react to it. Traditional ways of analyzing brain activity simply disregard this entire phenomenon." says LNDG postdoctoral fellow Niels Kloosterman, first author of this study and co-author of the article in Neuron.

The LNDG continues to demonstrate the importance of neural variability for successful human behavior in an ongoing series of studies. Whether one is asked to process a face, remember an object, or solve a complex task, the ability to modulate moment-to-moment variability seems to be required for optimal cognitive performance. "Neuroscientists have seen this 'noise' in the brain for decades but haven't understood what it means. A growing body of work by our group and others highlights that neural variability may indeed serve as an indispensable signal of behavioral success in its own right. With the increasing availability of tools and approaches to measure neural variability, we are excited that such a hypothesis is now immediately testable," says Douglas Garrett, Senior Research Scientist and LNDG group leader. In the next phases of their research, the group plans to examine whether neural variability and behavior can be optimized through brain stimulation, behavioral training, or medication.

https://www.sciencedaily.com/releases/2021/02/210217134848.htm

Study identifies potential link between Soldiers exposed to blasts, Alzheimer's

February 25, 2021

Science Daily/U.S. Army Research Laboratory

Research shows that Soldiers exposed to shockwaves from military explosives are at a higher risk for developing Alzheimer's disease -- even those that don't have traumatic brain injuries from those blasts. A new Army-funded study identifies how those blasts affect the brain.

Researchers at the University of North Carolina at Pembroke in collaboration with the U.S. Army Combat Capabilities Development Command, now known as DEVCOM, the Army Research Laboratory, and the National Institutes of Health found that the mystery behind blast-induced neurological complications when traumatic damage is undetected may be rooted in distinct alterations to the tiny connections between neurons in the hippocampus, the part of the brain particularly involved in memory encoding and social behavior.

The research published in Brain Pathology, the medical journal of the International Society of Neuropathology, was funded by the lab's Army Research Office.

"Blasts can lead to debilitating neurological and psychological damage but the underlying injury mechanisms are not well understood," said Dr. Frederick Gregory, program manager, ARO. "Understanding the molecular pathophysiology of blast-induced brain injury and potential impacts on long-term brain health is extremely important to understand in order to protect the lifelong health and well-being of our service members."

The research team tested slices of rat hippocampus by exposing the healthy tissue to controlled military blast waves. In the experimental brain explants (tissue slices maintained alive in culture dishes), the rapid blast waves produced by the detonated military explosives led to selective reductions in components of brain connections needed for memory, and the distinct electrical activity from those neuronal connections was sharply diminished.

The research showed that the blast-induced effects were evident among healthy neurons with subtle synaptic pathology, which may be an early indicator of Alzheimer's-type pathogenesis occurring independent of overt brain damage.

"This finding may explain those many blast-exposed individuals returning from war zones with no detectable brain injury, but who still suffer from persistent neurological symptoms, including depression, headaches, irritability and memory problems," said Dr. Ben Bahr, the William C. Friday distinguished professor of Molecular Biology and Biochemistry at UNC-Pembroke.

The researchers believe that the increased risk of developing Alzheimer's disease is likely rooted in the disruption of neuronal communication instigated by blast exposures.

"Early detection of this measurable deterioration could improve diagnoses and treatment of recurring neuropsychiatric impediments, and reduce the risk of developing dementia and Alzheimer's disease later in life," Bahr said.

https://www.sciencedaily.com/releases/2021/02/210225112922.htm

Gut microbiome implicated in healthy aging and longevity

Data from over 9,000 people reveal a distinct gut microbiome signature that is associated with healthy aging and survival in the latest decades of life

February 18, 2021

Science Daily/Institute for Systems Biology

The gut microbiome is an integral component of the body, but its importance in the human aging process is unclear. ISB researchers and their collaborators have identified distinct signatures in the gut microbiome that are associated with either healthy or unhealthy aging trajectories, which in turn predict survival in a population of older individuals. The work is set to be published in the journal Nature Metabolism.

The research team analyzed gut microbiome, phenotypic and clinical data from over 9,000 people -- between the ages of 18 and 101 years old -- across three independent cohorts. The team focused, in particular, on longitudinal data from a cohort of over 900 community-dwelling older individuals (78-98 years old), allowing them to track health and survival outcomes.

The data showed that gut microbiomes became increasingly unique (i.e. increasingly divergent from others) as individuals aged, starting in mid-to-late adulthood, which corresponded with a steady decline in the abundance of core bacterial genera (e.g. Bacteroides) that tend to be shared across humans.

Strikingly, while microbiomes became increasingly unique to each individual in healthy aging, the metabolic functions the microbiomes were carrying out shared common traits. This gut uniqueness signature was highly correlated with several microbially-derived metabolites in blood plasma, including one -- tryptophan-derived indole -- that has previously been shown to extend lifespan in mice. Blood levels of another metabolite -- phenylacetylglutamine -- showed the strongest association with uniqueness, and prior work has shown that this metabolite is indeed highly elevated in the blood of centenarians.

"This uniqueness signature can predict patient survival in the latest decades of life," said ISB Research Scientist Dr. Tomasz Wilmanski, who led the study. Healthy individuals around 80 years of age showed continued microbial drift toward a unique compositional state, but this drift was absent in less healthy individuals.

"Interestingly, this uniqueness pattern appears to start in mid-life -- 40-50 years old -- and is associated with a clear blood metabolomic signature, suggesting that these microbiome changes may not simply be diagnostic of healthy aging, but that they may also contribute directly to health as we age," Wilmanski said. For example, indoles are known to reduce inflammation in the gut, and chronic inflammation is thought to be a major driver in the progression of aging-related morbidities.

"Prior results in microbiome-aging research appear inconsistent, with some reports showing a decline in core gut genera in centenarian populations, while others show relative stability of the microbiome up until the onset of aging-related declines in health," said microbiome specialist Dr. Sean Gibbons, co-corresponding author of the paper. "Our work, which is the first to incorporate a detailed analysis of health and survival, may resolve these inconsistencies. Specifically, we show two distinct aging trajectories: 1) a decline in core microbes and an accompanying rise in uniqueness in healthier individuals, consistent with prior results in community-dwelling centenarians, and 2) the maintenance of core microbes in less healthy individuals."

This analysis highlights the fact that the adult gut microbiome continues to develop with advanced age in healthy individuals, but not in unhealthy ones, and that microbiome compositions associated with health in early-to-mid adulthood may not be compatible with health in late adulthood.

"This is exciting work that we think will have major clinical implications for monitoring and modifying gut microbiome health throughout a person's life," said ISB Professor Dr. Nathan Price, co-corresponding author of the paper.

This research project was conducted by ISB and collaborators from Oregon Health and Science University, University of California San Diego, University of Pittsburgh, University of California Davis, Lifestyle Medicine Institute, and University of Washington. It was supported in part by a Catalyst Award in Healthy Longevity from the National Academy of Medicine, and the Longevity Consortium of the National Institute on Aging.

https://www.sciencedaily.com/releases/2021/02/210218142758.htm

Mediterranean-style diet linked to better thinking skills in later life

February 10, 2021

Science Daily/University of Edinburgh

People who eat a Mediterranean-style diet -- particularly one rich in green leafy vegetables and low in meat -- are more likely to stay mentally sharp in later life, a study shows.

Closely adhering to a Mediterranean diet was associated with higher scores on a range of memory and thinking tests among adults in their late 70s, the research found.

The study found no link, however, between the Mediterranean-style diet and better brain health.

Markers of healthy brain ageing -- such as greater grey or white matter volume, or fewer white matter lesions -- did not differ between those regularly eating a Mediterranean diet and those who did not.

These latest findings suggest that this primarily plant-based diet may have benefits for cognitive functioning as we get older, researchers say.

Researchers at the University of Edinburgh tested the thinking skills of more than 500 people aged 79 and without dementia.

The participants completed tests of problem solving, thinking speed, memory, and word knowledge, as well as a questionnaire about their eating habits during the previous year.

More than 350 of the group also underwent a magnetic resonance imaging (MRI) brain scan to gain insights into their brain structure.

The team used statistical models to look for associations between a person's diet and their thinking skills and brain health in later life.

The findings show that, in general, people who most closely adhered to a Mediterranean diet had the highest cognitive function scores, even when accounting for childhood IQ, smoking, physical activity and health factors. The differences were small but statistically significant.

The individual components of the diet that appeared to be most strongly associated with better thinking skills were green leafy vegetables and a lower red meat intake.

Researchers say the latest findings add to the evidence that a healthier lifestyle, of which diet is one aspect, is associated with better thinking skills in later life.

Dr Janie Corley, of the University of Edinburgh's School of Philosophy, Psychology and Language Sciences, said: "Eating more green leafy vegetables and cutting down on red meat might be two key food elements that contribute to the benefits of the Mediterranean-style diet. In our sample, the positive relationship between a Mediterranean diet and thinking skills is not accounted for by having a healthier brain structure, as one might expect. Though it's possible there may be other structural or functional brain correlates with this measure of diet, or associations in specific regions of the brain, rather than the whole brain, as measured here."

https://www.sciencedaily.com/releases/2021/02/210210133340.htm

Rotten egg gas could guard against Alzheimer's disease

January 12, 2021

Science Daily/Johns Hopkins Medicine

Typically characterized as poisonous, corrosive and smelling of rotten eggs, hydrogen sulfide's reputation may soon get a face-lift thanks to Johns Hopkins Medicine researchers. In experiments in mice, researchers have shown the foul-smelling gas may help protect aging brain cells against Alzheimer's disease. The discovery of the biochemical reactions that make this possible opens doors to the development of new drugs to combat neurodegenerative disease.

The findings from the study are reported in the Jan. 11 issue of the Proceedings of the National Academies of Science.

"Our new data firmly link aging, neurodegeneration and cell signaling using hydrogen sulfide and other gaseous molecules within the cell," says Bindu Paul, M.Sc., Ph.D., faculty research instructor in neuroscience in the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine and lead corresponding author on the study.

The human body naturally creates small amounts of hydrogen sulfide to help regulate functions throughout the body, from cell metabolism to blood vessel dilation. The rapidly burgeoning field of gasotransmission shows that gases are major cellular messenger molecules, with particular importance in the brain. However, unlike conventional neurotransmitters, gases can't be stored in vesicles. Thus, gases act through very different mechanisms to rapidly facilitate cellular messaging. In the case of hydrogen sulfide, this entails the modification of target proteins by a process called chemical sulfhydration, which modulates their activity, says Solomon Snyder, D.Phil., D.Sc., M.D., professor of neuroscience at the Johns Hopkins University School of Medicine and co-corresponding author on the study.

Studies using a new method have shown that sulfhydration levels in the brain decrease with age, a trend that is amplified in patients with Alzheimer's disease. "Here, using the same method, we now confirm a decrease in sulfhydration in the AD brain," says collaborator Milos Filipovic, Ph.D., principal investigator, Leibniz-Institut für Analytische Wissenschaften -- ISAS.

For the current research, the Johns Hopkins Medicine scientists studied mice genetically engineered to mimic human Alzheimer's disease. They injected the mice with a hydrogen sulfide-carrying compound called NaGYY, developed by their collaborators at the University of Exeter in the United Kingdom, which slowly releases the passenger hydrogen sulfide molecules while traveling throughout the body. The researchers then tested the mice for changes in memory and motor function over a 12-week period.

Behavioral tests on the mice showed that hydrogen sulfide improved cognitive and motor function by 50% compared with mice that did not receive the injections of NaGYY. Treated mice were able to better remember the locations of platform exits and appeared more physically active than their untreated counterparts with simulated Alzheimer's disease.

The results showed that the behavioral outcomes of Alzheimer's disease could be reversed by introducing hydrogen sulfide, but the researchers wanted to investigate how the brain chemically reacted to the gaseous molecule.

A series of biochemical experiments revealed a change to a common enzyme called glycogen synthase β (GSK3β). In the presence of healthy levels of hydrogen sulfide, GSK3β typically acts as a signaling molecule, adding chemical markers to other proteins and altering their function. However, the researchers observed that in the absence of hydrogen sulfide, GSK3β is overattracted to another protein in the brain called Tau.

When GSK3β interacts with Tau, Tau changes into a form that tangles and clumps inside nerve cells. As Tau clumps grow, the tangled proteins block communication between nerves, eventually causing them to die. This leads to the deterioration and eventual loss of cognition, memory and motor function that is characteristic of Alzheimer's disease.

"Understanding the cascade of events is important to designing therapies that can block this interaction like hydrogen sulfide is able to do," says Daniel Giovinazzo, M.D./Ph.D. student, the first author of the study.

Until recently, researchers lacked the pharmacological tools to mimic how the body slowly makes tiny quantities of hydrogen sulfide inside cells. "The compound used in this study does just that and shows by correcting brain levels of hydrogen sulfide, we could successfully reverse some aspects of Alzheimer's disease," says collaborator on the study Matt Whiteman, Ph.D., professor of experimental therapeutics at the University of Exeter Medical School.

The Johns Hopkins Medicine team and their international collaborators plan to continue studying how sulfur groups interact with GSK3β and other proteins involved in the pathogenesis of Alzheimer's disease in other cell and organ systems. The team also plans to test novel hydrogen sulfide delivery molecules as part of their ongoing venture.

https://www.sciencedaily.com/releases/2021/01/210112110103.htm

Better heart health scores in midlife linked to lower risk of late-life dementia

Findings support views that maintaining lifelong heart health behaviors could reduce dementia risk

December 15, 2020

Science Daily/PLOS

A long-term study of 1,449 people in Finland found that those who had better scores on standard metrics of cardiovascular health in midlife, especially for behavioral factors such as smoking, had a lower risk of dementia later in life. Yajun Liang of Karolinska Institutet in Stockholm, Sweden, and colleagues present these findings in the open-access journal PLOS Medicine.

Previous research suggests that efforts to address modifiable risk factors, such as behaviors that impact heart health, could reduce the global number of people with dementia by up to one third. However, there is a lack of evidence on potential links between risk of late-life dementia and scores on standard heart health metrics in midlife and late life.

To gain further clarity on late-life risk of dementia, Liang and colleagues analyzed data on 1,449 participants in the Finnish Cardiovascular Risk Factors, Aging and Dementia study, enrolled 1972¬-1987 and assessed in 1998, and 744 dementia-free survivors were followed further into late life (2005¬-2008). Participants' heart health was evaluated from midlife to late life according to six factors classified as three behavioral (smoking status, physical activity, and body mass index) and three biological factors (fasting plasma glucose, total cholesterol, and blood pressure). Dementia was diagnosed in 61 persons in the first follow up, and additional 47 persons in the second.

The researchers found that participants with intermediate or ideal cardiovascular health scores from midlife onwards, especially for behavioral factors, had a lower risk of dementia later in life than participants with poor scores.

The researchers found no significant overall association between heart health scores measured in late life and risk of dementia. However, when looking specifically at biological factors, ideal scores in late life were actually associated with greater risk of dementia. The authors note that this could be because some biological hallmarks of dementia might overlap with "ideal" scores on these factors, such as lower blood pressure and lower cholesterol. They also note that the major limitations of this study include the lack of data on diet and midlife plasma glucose, and high rate of attrition.

These findings suggest that maintaining lifelong cardiovascular health, particularly in the areas of smoking, exercise, and body mass index, could reduce dementia risk later in life.

https://www.sciencedaily.com/releases/2020/12/201215140840.htm

Apathy could predict onset of dementia years before other symptoms

December 14, 2020

Science Daily/University of Cambridge

Apathy -- a lack of interest or motivation -- could predict the onset of some forms of dementia many years before symptoms start, offering a 'window of opportunity' to treat the disease at an early stage, according to new research from a team of scientists led by Professor James Rowe at the University of Cambridge.

Frontotemporal dementia is a significant cause of dementia among younger people. It is often diagnosed between the ages of 45 and 65. It changes behaviour, language and personality, leading to impulsivity, socially inappropriate behaviour, and repetitive or compulsive behaviours.

A common feature of frontotemporal dementia is apathy, with a loss of motivation, initiative and interest in things. It is not depression, or laziness, but it can be mistaken for them. Brain scanning studies have shown that in people with frontotemporal dementia it is caused by shrinkage in special parts at the front of the brain -- and the more severe the shrinkage, the worse the apathy. But, apathy can begin decades before other symptoms, and be a sign of problems to come.

"Apathy is one of the most common symptoms in patients with frontotemporal dementia. It is linked to functional decline, decreased quality of life, loss of independence and poorer survival," said Maura Malpetti, a cognitive scientist at the Department of Clinical Neurosciences, University of Cambridge.

"The more we discover about the earliest effects of frontotemporal dementia, when people still feel well in themselves, the better we can treat symptoms and delay or even prevent the dementia."

Frontotemporal dementia can be genetic. About a third of patients have a family history of the condition. The new discovery about the importance of early apathy comes from the Genetic Frontotemporal dementia Initiative (GENFI), a collaboration between scientists across Europe and Canada. Over 1,000 people are taking part in GENFI, from families where there is a genetic cause of Frontotemporal dementia.

Now, in a study published today in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Professor Rowe and colleagues have shown how apathy predicts cognitive decline even before the dementia symptoms emerge.

The new study involved 304 healthy people who carry a faulty gene that causes frontotemporal dementia, and 296 of their relatives who have normal genes. The participants were followed over several years. None had dementia, and most people in the study did not know whether they carry a faulty gene or not. The researchers looked for changes in apathy, memory tests and MRI scans of the brain.

"By studying people over time, rather than just taking a snapshot, we revealed how even subtle changes in apathy predicted a change in cognition, but not the other way around," explained Malpetti, the study's first author. "We also saw local brain shrinkage in areas that support motivation and initiative, many years before the expected onset of symptoms."

People with the genetic mutations had more apathy than other members of their family, which over two years increased much more than in people with normal genetics. The apathy predicted cognitive decline, and this accelerated as they approached the estimated age of onset of symptoms.

Professor Rogier Kievit from the Donders Institute, Radboud University Medical Center at Nijmegen and MRC Cognition and Brain Sciences Unit at Cambridge, said: "Apathy progresses much faster for those individuals who we know are at greater risk of developing frontotemporal dementia, and this is linked to greater atrophy in the brain. At the start, even though the participants with a genetic mutation felt well and had no symptoms, they were showing greater levels of apathy. The amount of apathy predicted cognitive problems in the years ahead."

"From other research, we know that in patients with frontotemporal dementia, apathy is a bad sign in terms of independent living and survival. Here we show its importance in the decades before symptoms begin," said Professor James Rowe from the Department of Clinical Neurosciences, joint senior author.

Professor Rowe said the study highlights the importance of investigating why someone has apathy. "There are many reasons why someone feels apathetic. It may well be an easy to treat medical condition, such as low levels of thyroid hormone, or a psychiatric illness such as depression. But doctors need to keep in mind the possibility of apathy heralding a dementia, and increasing the chance of dementia if left unaddressed, particularly if someone has a family history of dementia.

"Treating dementia is a challenge, but the sooner we can diagnose the disease, the greater our window of opportunity to try and intervene and slow or stop its progress."

https://www.sciencedaily.com/releases/2020/12/201214192356.htm

High blood pressure at any age, no matter how long you have it, may speed cognitive decline

December 14, 2020

Science Daily/American Heart Association

High blood pressure appears to accelerate a decline in cognitive performance in middle-aged and older adults, according to new research published today in Hypertension, an American Heart Association journal.

Nearly half of American adults have high blood pressure or hypertension. Having high blood pressure is a risk factor for cognitive decline, which includes such things as memory, verbal fluency, attention and concentration. Blood pressure of 120 mmHg -- 129 mmHg systolic (the top number in a reading) or higher is considered elevated. Systolic pressure above 130 mmHg, or diastolic pressure (the bottom number) of 80 mmHg or higher is considered hypertension.

"We initially anticipated that the negative effects of hypertension on cognitive function would be more critical when hypertension started at a younger age, however, our results show similar accelerated cognitive performance decline whether hypertension started in middle age or at older ages," said study author Sandhi M. Barreto, M.D., M.Sc., Ph.D., professor of medicine at the Universidade Federal de Minas Gerais in Belo Horizonte, Brazil. "We also found that effectively treating high blood pressure at any age in adulthood could reduce or prevent this acceleration. Collectively, the findings suggest hypertension needs to be prevented, diagnosed and effectively treated in adults of any age to preserve cognitive function."

Barreto and colleagues analyzed findings from an existing study that included blood pressure and cognitive health information for more than 7,000 adults in Brazil, whose average age was about 59 years old at the study's start. The study participants were followed for an average of nearly 4 years; testing included analysis of memory, verbal fluency and executive function, which includes attention, concentration and other factors associated with thinking and reasoning.

Their analysis found:

• Systolic blood pressure between 121 and 139 mmHg or diastolic blood pressure between 81 and 89 mmHg with no antihypertensive medication use was associated with accelerated cognitive performance decline among middle-aged and older individuals.

• The speed of decline in cognition happened regardless of hypertension duration, meaning high blood pressure for any length of time, even a short duration, might impact a person's speed of cognitive decline.

• Adults with uncontrolled hypertension tended to experience notably faster declines in memory and global cognitive function than adults who had controlled hypertension.

"In addition to other proven benefits of blood pressure control, our results highlight the importance of diagnosing and controlling hypertension in patients of any age to prevent or slow down cognitive decline," Barreto said. "Our results also reinforce the need to maintain lower blood pressure levels throughout life, since even prehypertension levels were associated with cognitive decline."

According to Barreto, some of the study's limitations are the relatively short follow-up period and that the participants self-reported the hypertension diagnosis at baseline.

"Although the participants of our study are adults from Brazil, we believe that our findings are applicable to other regions. Previous studies have shown that similar unhealthy behaviors and risk factors, including hypertension, are common in the development of cardiovascular diseases in different populations across the globe," Barreto said.

https://www.sciencedaily.com/releases/2020/12/201214090133.htm

Diet modifications -- including more wine and cheese -- may help reduce cognitive decline

December 10, 2020

Science Daily/Iowa State University

The foods we eat may have a direct impact on our cognitive acuity in our later years. This is the key finding of an Iowa State University research study spotlighted in an article published in the November 2020 issue of the Journal of Alzheimer's Disease.

The study was spearheaded by principal investigator, Auriel Willette, an assistant professor in Food Science and Human Nutrition, and Brandon Klinedinst, a Neuroscience PhD candidate working in the Food Science and Human Nutrition department at Iowa State. The study is a first-of-its-kind large scale analysis that connects specific foods to later-in-life cognitive acuity.

Willette, Klinedinst and their team analyzed data collected from 1,787 aging adults (from 46 to 77 years of age, at the completion of the study) in the United Kingdom through the UK Biobank, a large-scale biomedical database and research resource containing in-depth genetic and health information from half-a-million UK participants. The database is globally accessible to approved researchers undertaking vital research into the world's most common and life-threatening diseases.

Participants completed a Fluid Intelligence Test (FIT) as part of touchscreen questionnaire at baseline (compiled between 2006 and 2010) and then in two follow-up assessments (conducted from 2012 through 2013 and again between 2015 and 2016). The FIT analysis provides an in-time snapshot of an individual's ability to "think on the fly."

Participants also answered questions about their food and alcohol consumption at baseline and through two follow-up assessments. The Food Frequency Questionnaire asked participants about their intake of fresh fruit, dried fruit, raw vegetables and salad, cooked vegetables, oily fish, lean fish, processed meat, poultry, beef, lamb, pork, cheese, bread, cereal, tea and coffee, beer and cider, red wine, white wine and champaign and liquor.

Here are four of the most significant findings from the study:

1. Cheese, by far, was shown to be the most protective food against age-related cognitive problems, even late into life;

2. The daily consumption of alchohol, particularly red wine, was related to improvements in cognitive function;

3. Weekly consumption of lamb, but not other red meats, was shown to improve long-term cognitive prowess; and

4. Excessive consumption of salt is bad, but only individuals already at risk for Alzheimer's Disease may need to watch their intake to avoid cognitive problems over time.

"I was pleasantly surprised that our results suggest that responsibly eating cheese and drinking red wine daily are not just good for helping us cope with our current COVID-19 pandemic, but perhaps also dealing with an increasingly complex world that never seems to slow down," Willette said. "While we took into account whether this was just due to what well-off people eat and drink, randomized clinical trials are needed to determine if making easy changes in our diet could help our brains in significant ways."

Klinedinst added, "Depending on the genetic factors you carry, some individuals seem to be more protected from the effects of Alzheimers, while other seem to be at greater risk. That said, I believe the right food choices can prevent the disease and cognitive decline altogether. Perhaps the silver bullet we're looking for is upgrading how we eat. Knowing what that entails contributes to a better understanding of Alzheimer's and putting this disease in a reverse trajectory."

Willette and Klinedinst acknowledge the valuable contributions of the other members of the research team: Scott Le, Colleen Pappas, Nathan Hoth, Amy Pollpeter and Qian Wang in the Iowa State department of Food Science and Human Nutrition; Brittany Larsen, Neuroscience graduate program at Iowa State; Yueying Wang and Li Wang, department of Statistics at Iowa State; Shan Yu, department of Statistics, University of Virginia; Karin Allenspach, department of Veterinary Clinical Sciences at Iowa State; Jonathan Mochel, department of Biomedical Sciences at Iowa State; and David Bennett, Rush Alzheimer's Disease Center, Rush Medical Center, Rush University.

https://www.sciencedaily.com/releases/2020/12/201210145850.htm

Blood test for Alzheimer's disease predicts future cognitive decline in healthy people

December 9, 2020

Science Daily/Brigham and Women's Hospital

Today, a clinician can order a blood test to check a patient's cholesterol or hemoglobin A1c levels -- biomarkers that help predict an individual's risk of cardiovascular disease or diabetes, respectively. But despite decades of advances in the understanding of Alzheimer's disease (AD), a blood test for predicting its risk remains elusive. Imaging scans of the brain and lumbar punctures that collect cerebrospinal fluid can offer diagnoses, but such tests are expensive and cumbersome for patients. Two years ago, investigators at Brigham and Women's Hospital reported the development of a blood test for a fragment of the protein tau, a hallmark of AD. Now, that test for levels of N-terminal fragment of tau (NT1) has been evaluated in participants in the Harvard Aging Brain Study (HABS), a cohort of cognitively normal, older adults who are followed closely over time. In Nature Communications, the authors report that baseline NT1 levels in the blood were highly predictive of the risk of cognitive decline and AD dementia.

"Our findings indicate that measuring a tau fragment in plasma can help predict which elderly people are likely to decline and how quickly they are likely to decline," said corresponding author Dennis Selkoe, MD, co-director of the Ann Romney Center for Neurologic Diseases. "We're excited because there are currently no commercially available blood tests to predict risk of AD in still-healthy individuals. Having such a blood test allows us to better screen people for enrollment in AD prevention trials and represents progress toward diagnostic tests for AD in medical care."

Selkoe cautions that a commercial test for routine clinical care likely remains several years away. But for clinical trials that seek to evaluate preventive treatments for AD, such as the large-scale clinical trials led by co-author Reisa Sperling, MD, MMSc, director of the Center for Alzheimer Research and Treatment at the Brigham NT1 levels could be measured before a participant enrolls in a the trial, and potentially also as a longitudinal measure to assess treatment response. The test ultimately represents a far less costly and less invasive alternative to imaging and lumbar punctures.

The current study, led by first author Jasmeer Chhatwal, MD, PhD, now an attending physician and scientist in the Massachusetts General Hospital Department of Neurology, evaluated the predictive value of NT1 among 236 cognitively normal participants in HABS. Participants were on average 74 years old when they entered HABS and were followed for an average of five years. Blood samples were collected in the first year.

The research team found that higher levels of NT1 in blood samples taken at the beginning of the trial were strongly associated with future clinical progression. The team divided participants into those with high, medium and low NT1 levels, finding that for the group with the highest levels, the risk of advancing to mild cognitive impairment (MC I) or AD dementia was 2.4-fold. NT1 levels predicted decline across multiple areas of memory, including episodic memory -- remembering specific events or experiences such as a person's birthday or a family visit -- and also predicted how fast the participant's cognition would decline. Imaging data showed that higher baseline NT1 blood levels were associated with elevated brain levels of ?-amyloid plaques and the accumulation of tangles of tau -- both classical signs of AD.

The authors note that relatively few participants in HABS progressed to AD, an important limitation of this cohort. They found that another brain protein -- known as NfL -- which has been studied by other groups, may also be associated with cognitive decline, especially among people who already show signs of cognitive deficits. NfL was a less strong predictor than NT1 in the study.

"The NT1 tau fragment may be a reflection of damage to neurons and synapses, allowing us to use blood samples to detect what is happening in a patient's brain years before they begin experiencing symptoms," said Selkoe. "This could give us an invaluable window of time in which to evaluate interventions for preventing cognitive decline and AD dementia."

https://www.sciencedaily.com/releases/2020/12/201209115147.htm

Drug reverses age-related mental decline within days

Rapid rejuvenation of mental faculties in aged mice implicates reversible physiological 'blockage' behind age-related cognitive losses

December 1, 2020

Science Daily/University of California - San Francisco

Just a few doses of an experimental drug can reverse age-related declines in memory and mental flexibility in mice, according to a new study by UC San Francisco scientists. The drug, called ISRIB, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer, and even enhance cognition in healthy animals.

In the new study, published December 1, 2020 in the open-access journal eLife, researchers showed rapid restoration of youthful cognitive abilities in aged mice, accompanied by a rejuvenation of brain and immune cells that could help explain improvements in brain function.

"ISRIB's extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological 'blockage' rather than more permanent degradation," said Susanna Rosi, PhD, Lewis and Ruth Cozen Chair II and professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science.

"The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress," added Peter Walter, PhD, a professor in the UCSF Department of Biochemistry and Biophysics and a Howard Hughes Medical Institute investigator. "Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time."

Could Rebooting Cellular Protein Production Hold the Key to Aging and Other Diseases?

Walter has won numerous scientific awards, including the Breakthrough, Lasker and Shaw prizes, for his decades-long studies of cellular stress responses. ISRIB, discovered in 2013 in Walter's lab, works by rebooting cells' protein production machinery after it gets throttled by one of these stress responses -- a cellular quality control mechanism called the integrated stress response (ISR; ISRIB stands for ISR InhiBitor).

The ISR normally detects problems with protein production in a cell -- a potential sign of viral infection or cancer-promoting gene mutations -- and responds by putting the brakes on cell's protein-synthesis machinery. This safety mechanism is critical for weeding out misbehaving cells, but if stuck in the on position in a tissue like the brain, it can lead to serious problems, as cells lose the ability to perform their normal activities, Walter and colleagues have found.

In particular, recent animal studies by Walter and Rosi, made possible by early philanthropic support from The Rogers Family Foundation, have implicated chronic ISR activation in the persistent cognitive and behavioral deficits seen in patients after TBI, by showing that, in mice, brief ISRIB treatment can reboot the ISR and restore normal brain function almost overnight.

The cognitive deficits in TBI patients are often likened to premature aging, which led Rosi and Walter to wonder if the ISR could also underlie purely age-related cognitive decline. Aging is well known to compromise cellular protein production across the body, as life's many insults pile up and stressors like chronic inflammation wear away at cells, potentially leading to widespread activation of the ISR.

"We've seen how ISRIB restores cognition in animals with traumatic brain injury, which in many ways is like a sped-up version of age-related cognitive decline," said Rosi, who is director of neurocognitive research in the UCSF Brain and Spinal Injury Center and a member of the UCSF Weill Institute for Neurosciences. "It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step."

ISRIB Improves Cognition, Boosts Neuron and Immune Cell Function

In the new study, researchers led by Rosi lab postdoc Karen Krukowski, PhD, trained aged animals to escape from a watery maze by finding a hidden platform, a task that is typically hard for older animals to learn. But animals who received small daily doses of ISRIB during the three-day training process were able to accomplish the task as well as youthful mice, much better than animals of the same age who didn't receive the drug.

The researchers then tested how long this cognitive rejuvenation lasted and whether it could generalize to other cognitive skills. Several weeks after the initial ISRIB treatment, they trained the same mice to find their way out of a maze whose exit changed daily -- a test of mental flexibility for aged mice who, like humans, tend to get increasingly stuck in their ways. The mice who had received brief ISRIB treatment three weeks before still performed at youthful levels, while untreated mice continued to struggle.

To understand how ISRIB might be improving brain function, the researchers studied the activity and anatomy of cells in the hippocampus, a brain region with a key role in learning and memory, just one day after giving animals a single dose of ISRIB. They found that common signatures of neuronal aging disappeared literally overnight: neurons' electrical activity became more sprightly and responsive to stimulation, and cells showed more robust connectivity with cells around them while also showing an ability to form stable connections with one another usually only seen in younger mice.

The researchers are continuing to study exactly how the ISR disrupts cognition in aging and other conditions and to understand how long ISRIB's cognitive benefits may last. Among other puzzles raised by the new findings is the discovery that ISRIB also alters the function of the immune system's T cells, which also are prone to age-related dysfunction. The findings suggest another path by which the drug could be improving cognition in aged animals, and could have implications for diseases from Alzheimer's to diabetes that have been linked to heightened inflammation caused by an aging immune system.

"This was very exciting to me because we know that aging has a profound and persistent effect on T cells and that these changes can affect brain function in the hippocampus," said Rosi. "At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.

ISRIB May Have Wide-Ranging Implications for Neurological Disease

It turns out that chronic ISR activation and resulting blockage of cellular protein production may play a role in a surprisingly wide array of neurological conditions. Below is a partial list of these conditions, based on a recent review by Walter and colleague Mauro Costa-Mattioli of Baylor College of Medicine, which could potentially be treated with an ISR-resetting agent like ISRIB:

• Frontotemporal Dementia

• Alzheimer's Disease

• Amyotrophic Lateral Sclerosis (ALS)

• Age-related Cognitive Decline

• Multiple Sclerosis

• Traumatic Brain Injury

• Parkinson's Disease

• Down Syndrome

• Vanishing White Matter Disorder

• Prion Disease

ISRIB has been licensed by Calico, a South San Francisco, Calif. company exploring the biology of aging, and the idea of targeting the ISR to treat disease has been picked up by other pharmaceutical companies, Walter says.

One might think that interfering with the ISR, a critical cellular safety mechanism, would be sure to have serious side effects, but so far in all their studies, the researchers have observed none. This is likely due to two factors, Walter says. First, it takes just a few doses of ISRIB to reset unhealthy, chronic ISR activation back to a healthier state, after which it can still respond normally to problems in individual cells. Second, ISRIB has virtually no effect when applied to cells actively employing the ISR in its most powerful form -- against an aggressive viral infection, for example.

Naturally, both of these factors make the molecule much less likely to have negative side effects -- and more attractive as a potential therapeutic. According to Walter: "It almost seems too good to be true, but with ISRIB we seem to have hit a sweet spot for manipulating the ISR with an ideal therapeutic window.

https://www.sciencedaily.com/releases/2020/12/201201124144.htm

Older adults with dementia exhibit financial 'symptoms' up to six years before diagnosis

November 30, 2020

Science Daily/Johns Hopkins University Bloomberg School of Public Health

A new study led by researchers at the Johns Hopkins Bloomberg School of Public Health and the Federal Reserve Board of Governors found that Medicare beneficiaries who go on to be diagnosed with dementia are more likely to miss payments on bills as early as six years before a clinical diagnosis.

The study also found that beneficiaries diagnosed with dementia who had a lower educational status missed payments on bills beginning as early as seven years before a clinical diagnosis as compared to 2.5 years prior to a diagnosis for beneficiaries with higher educational status.

The study, which included researchers from the University of Michigan Medical School, also found that these missed payments and other adverse financial outcomes lead to increased risk of developing subprime credit scores starting 2.5 years before a dementia diagnosis. Subprime credit scores fall in the fair and lower range.

The findings, published online November 30 in JAMA Internal Medicine, suggest that financial symptoms such as missing payments on routine bills could be used as early predictors of dementia and highlight the benefits of earlier detection.

"Currently there are no effective treatments to delay or reverse symptoms of dementia," says lead author Lauren Hersch Nicholas, PhD, associate professor in the Department of Health Policy and Management at the Bloomberg School. "However, earlier screening and detection, combined with information about the risk of irreversible financial events, like foreclosure and repossession, are important to protect the financial well-being of the patient and their families."

The analysis found that the elevated risk of payment delinquency with dementia accounted for 5.2 percent of delinquencies among those six years prior to diagnosis, reaching a maximum of 17.9 percent nine months after diagnosis. Rates of elevated payment delinquency and subprime credit risk persisted for up to 3.5 years after beneficiaries received dementia diagnoses, suggesting an ongoing need for assistance managing money.

Dementia, identified as diagnostic codes for Alzheimer's Disease and related dementias in the study, is a progressive brain disorder that slowly diminishes memory and cognitive skills and limits the ability to carry out basic daily activities, including managing personal finances. About 14.7 percent of American adults over the age of 70 are diagnosed with the disease. The onset of dementia can lead to costly financial errors, irregular bill payments, and increased susceptibility to financial fraud.

For their study, the researchers linked de-identified Medicare claims and credit report data. They analyzed information on 81,364 Medicare beneficiaries living in single-person households, with 54,062 never receiving a dementia diagnosis between 1999 and 2014 and 27,302 with a dementia diagnosis during the same period. The researchers compared financial outcomes spanning 1999 to 2018 of those with and without a clinical diagnosis of dementia for up to seven years prior to a diagnosis and four years following a diagnosis. The researchers focused on missing payments for one or more credit accounts that were at least 30 days past due, and subprime credit scores, indicative of an individual's risk of defaulting on loans based on credit history.

To determine whether the financial symptoms observed were unique to dementia, the researchers also compared financial outcomes of missed payments and subprime credit scores to other health outcomes including arthritis, glaucoma, heart attacks, and hip fractures. They found no association of increased missed payments or subprime credit scores prior to a diagnosis for arthritis, glaucoma, or a hip fracture. No long-term associations were found with heart attacks.

"We don't see the same pattern with other health conditions," says Nicholas. "Dementia was the only medical condition where we saw consistent financial symptoms, especially the long period of deteriorating outcomes before clinical recognition. Our study is the first to provide large-scale quantitative evidence of the medical adage that the first place to look for dementia is in the checkbook."

https://www.sciencedaily.com/releases/2020/11/201130131416.htm

Forest fires, cars, power plants join list of risk factors for Alzheimer's disease

Airborne pollution implicated in amyloid plaques, UCSF-led study shows

November 30, 2020

Science Daily/University of California - San Francisco

A new study led by researchers at UC San Francisco has found that among older Americans with cognitive impairment, the greater the air pollution in their neighborhood, the higher the likelihood of amyloid plaques -- a hallmark of Alzheimer's disease. The study adds to a body of evidence indicating that pollution from cars, factories, power plants and forest fires joins established dementia risk factors like smoking and diabetes.

In the study, which appears in JAMA Neurology on Nov.30, 2020, the researchers looked at the PET scans of more than 18,000 seniors whose average age was 75. The participants had dementia or mild cognitive impairment and lived in zip codes dotted throughout the nation. The researchers found that those in the most polluted areas had a 10 percent increased probability of a PET scan showing amyloid plaques, compared to those in the least polluted areas.

When applied to the U.S. population, with an estimated 5.8 million people over 65 with Alzheimer's disease, high exposure to microscopic airborne particles may be implicated in tens of thousands of cases.

"This study provides additional evidence to a growing and convergent literature, ranging from animal models to epidemiological studies, that suggests air pollution is a significant risk factor for Alzheimer's disease and dementia," said senior author Gil Rabinovici, MD, of the UCSF Memory and Aging Center, Department of Neurology and the Weill Institute for Neurosciences.

Amyloid Plaques Not Indicative of All Dementias

The 18,178 participants had been recruited for the IDEAS study (Imaging Dementia -- Evidence for Amyloid Scanning), which had enrolled Medicare beneficiaries whose mild cognitive impairment or dementia had been diagnosed following comprehensive evaluation. Not all of the participants were later found to have positive PET scans -- 40 percent showed no evidence of plaques on the scan, suggesting non-Alzheimer's diagnoses like frontotemporal or vascular dementias, which are not associated with the telltale amyloid plaques.

Air pollution in the neighborhood of each participant was estimated with Environmental Protection Agency data that measured ground-level ozone and PM2.5, atmospheric particulate matter that has a diameter of less than 2.5 micrometers. The researchers also divided locations into quartiles according to the concentration of PM2.5. They found that the probability of a positive PET scan rose progressively as concentrations of pollutants increased, and predicted a difference of 10 percent probability between the least and most polluted areas.

"Exposure in our daily lives to PM2.5, even at levels that would be considered normal, could contribute to induce a chronic inflammatory response," said first author Leonardo Iaccarino, PhD, also of the UCSF Memory and Aging Center, Department of Neurology and the Weill Institute of Neurosciences. "Over time, this could impact brain health in a number of ways, including contributing to an accumulation of amyloid plaques."

Overall concentrations of PM2.5 would not be considered very high for it to have a significant association with amyloid plaques, amounting to annual averages in San Francisco during the study time, added Rabinovici.

"I think it's very appropriate that air pollution has been added to the modifiable risk factors highlighted by the Lancet Commission on dementia," he said, referring to the journal's decision this year to include air pollution, together with excessive alcohol intake and traumatic brain injury, to their list of risk factors.

The study complements previous large-scale studies that tie air pollution to dementia and Parkinson's disease, and adds novel findings by including a cohort with mild cognitive impairment -- a frequent precursor to dementia -- and using amyloid plaques as a biomarker of disease. Other studies have linked air pollution to adverse effects on cognitive, behavioral and psychomotor development in children, including a UCSF-University of Washington study that looked at its impact on the IQ of the offspring of pregnant women.

https://www.sciencedaily.com/releases/2020/11/201130113536.htm