Alzheimer risk genes converge on microglia

March 18, 2020

Science Daily/VIB (the Flanders Institute for Biotechnology)

Our DNA determines a large part of our risk for Alzheimer's disease, but it remained unclear how many genetic risk factors contribute to disease. A team led by Prof. Bart De Strooper (VIB-KU Leuven) and Dr. Mark Fiers now show that many of risk factors affect brain maintenance cells called microglia, and more particularly their response to amyloid-beta, one of the proteins aggregating in the brains of Alzheimer patients. The individual effects of small genetic variations are likely small, but the combination of hundreds of such subtle alterations might tip the balance and cause disease.

Why do some people get Alzheimer's disease while others do not, even when growing very old? Despite decades of research, we still don't know the full answer to this question. Epidemiological studies show that about two-thirds of a person's risk for Alzheimer's disease is genetically determined. A few dozen risk genes have been identified, however, recent evidence shows that there could be hundreds of additional genetic variants that each contribute in a small but significant way to disease risk.

From risk gene to disease mechanism

Bart De Strooper (VIB-KU Leuven) has been studying the mechanisms of Alzheimer's disease for decades. His team tries to find out what this combined genetic risk can teach us about how the disease develops in our brain: "Two crucial questions arise from the myriad of genetic studies. First, what is the link between these Alzheimer risk genes and the amyloid-beta plaques or tau tangles we find in Alzheimer brains; and second, are they all involved in one central cellular or molecular pathway, or do they define many parallel pathways that all lead to Alzheimer's?"

The researchers set out to understand when these genes are expressed and in particular, whether they respond to tau or amyloid?beta pathology. "When it comes to risk, you always need to take the context into account," explain Mark Fiers, co-lead author of the study. "If you don't wear your seatbelt in the car, there is no problem as long as you don't have an accident."

With this in mind, the researchers aimed to understand under which circumstances genetic risk for Alzheimer's comes into play. Fiers: "Almost every person develops some degree of Alzheimer pathology in the brain, i.e. amyloid-beta plaques and tau tangles. However, some people remain cognitively healthy despite a high pathology load, while others develop Alzheimer symptoms quite rapidly."

"To gain more insight we checked gene expression in two different mouse models of Alzheimer's, one displaying amyloid-beta and the other tau pathology, at different ages," says Annerieke Sierksma, a postdoctoral researcher in De Strooper's lab. "We identified that many of the genes linked to Alzheimer's risk are particularly responsive to amyloid-beta but not to tau pathology."

Microglia activation

The team identified 11 new risk genes that are significantly upregulated when facing increased amyloid-beta levels. All these genes are expressed in microglia, cells that play a key role in brain maintenance.

Ashley Lu, a PhD student closely involved in the analysis: "We could confirm that microglia exposed to amyloid-beta drastically switch to an activated status, something that occurs to a much lesser extent in the tau mice. These new insights indicate that a large part of the genetic risk of Alzheimer's disease involves the microglial response to amyloid-beta."

Understanding genetic risk 

Should we rethink the classical gene?based view, where certain mutations or genetic variants lead to disease? De Strooper thinks so: "One single genetic variant within a functional network will not lead to disease. However, multiple variants within the same network may tip the balance to a disease?causing disturbance. Such a hypothesis could also explain the conundrum that some /individuals with a lot of amyloid-beta in their brain do not develop clinical symptoms."

"While amyloid-beta might be the trigger of the disease, it is the genetic make?up of the microglia, and possibly other cell types, which determines whether a pathological response is induced," adds Fiers. "Identifying which genetic variants are crucial to such network disturbances and how they lead to altered gene expression will be the next big challenge."

Why mice?

"Profiling of postmortem brain tissue only provides insights into the advanced stages of the disease and does not allow to delineate cause-consequence relationships," explains De Strooper. "Genetically modified mouse models on the other hand only partially recapitulate the disease, but they allow for detailed insights into the initial steps of disease, which is of high relevance for preventative therapeutic interventions."

https://www.sciencedaily.com/releases/2020/03/200318104501.htm

Diet may help preserve cognitive function

April 14, 2020

Science Daily/NIH/National Eye Institute

According to a recent analysis of data from two major eye disease studies, adherence to the Mediterranean diet -- high in vegetables, whole grains, fish, and olive oil -- correlates with higher cognitive function. Dietary factors also seem to play a role in slowing cognitive decline. Researchers at the National Eye Institute (NEI), part of the National Institutes of Health, led the analysis of data from the Age-Related Eye Disease Study (AREDS) and AREDS2. They published their results today in the journal Alzheimer's and Dementia.

"We do not always pay attention to our diets. We need to explore how nutrition affects the brain and the eye" said Emily Chew, M.D., director of the NEI Division of Epidemiology and Clinical Applications and lead author of the studies.

The researchers examined the effects of nine components of the Mediterranean diet on cognition. The diet emphasizes consumption of whole fruits, vegetables, whole grains, nuts, legumes, fish, and olive oil, as well as reduced consumption of red meat and alcohol.

AREDS and AREDS2 assessed over years the effect of vitamins on age-related macular degeneration (AMD), which damages the light-sensitive retina. AREDS included about 4,000 participants with and without AMD, and AREDS2 included about 4,000 participants with AMD. The researchers assessed AREDS and AREDS2 participants for diet at the start of the studies. The AREDS study tested participants' cognitive function at five years, while AREDS2 tested cognitive function in participants at baseline and again two, four, and 10 years later. The researchers used standardized tests based on the Modified Mini-Mental State Examination to evaluate cognitive function as well as other tests. They assessed diet with a questionnaire that asked participants their average consumption of each Mediterranean diet component over the previous year.

Participants with the greatest adherence to the Mediterranean diet had the lowest risk of cognitive impairment. High fish and vegetable consumption appeared to have the greatest protective effect. At 10 years, AREDS2 participants with the highest fish consumption had the slowest rate of cognitive decline.

The numerical differences in cognitive function scores between participants with the highest versus lowest adherence to a Mediterranean diet were relatively small, meaning that individuals likely won't see a difference in daily function. But at a population level, the effects clearly show that cognition and neural health depend on diet.

The researchers also found that participants with the ApoE gene, which puts them at high risk for Alzheimer's disease, on average had lower cognitive function scores and greater decline than those without the gene. The benefits of close adherence to a Mediterranean diet were similar for people with and without the ApoE gene, meaning that the effects of diet on cognition are independent of genetic risk for Alzheimer's disease.

https://www.sciencedaily.com/releases/2020/04/200414084316.htm

Not finding new goals post-retirement associated with greater cognitive decline

Risk appears to be more prominent in women than men, study says

March 16, 2020

Science Daily/American Psychological Association

Certain middle-aged and older adults, especially women Certain middle-aged and older adults, especially women who tend to disengage from difficult tasks and goals after they retire, may be at greater risk of cognitive decline as they age, according to research published by the American Psychological Association.

"This study raises questions about how individual differences in motivation and gender may play a role in cognitive declines and points to the potential importance of continuing to engage in mentally stimulating activities in retirement," said lead author Jeremy Hamm, PhD, of North Dakota State University. "This may be a significant challenge for people who have a tendency to let go of goals when they encounter initial obstacles and setbacks."

The study, published in the journal Psychology and Aging, analyzed data from Midlife in the United States, a national longitudinal survey of 7,108 participants aimed at identifying the factors that influence health as people age. Hamm and his team used a subset of 732 participants from the survey to examine the differences in cognitive function between retired adults and similar others who chose to continue working past retirement age. Half of the participants were female and 94% of participants were white.

Previous research has shown that retiring is associated with an increased risk of cognitive decline, but little is known about the motivation factors that could make someone more susceptible to such a decrease, according to Hamm.

"Our premise was that not all those who retire are likely to be at higher risk of decline. We thought that individuals who retire may be more or less at risk, depending on their tendency to disengage from challenging tasks and goals that could otherwise provide a source of mental stimulation," he said.

Researchers measured participants' level of goal disengagement, or people's tendency to lower their ambitions and decrease commitment to personal goals. Participants were asked to rate their level of agreement with statements such as "To avoid disappointments, I don't set my goals too high" and "I feel relieved when I let go of some of my responsibilities" on a scale of one to four.

Participants also took a test by telephone to measure basic cognitive functions, such as memory, reasoning and processing speed.

The study found that retired women who were prone to disengagement had steeper declines in cognitive functioning than their peers who remained employed. However, no differences emerged between retired and working men who were prone to disengagement, whose higher socioeconomic status may have protected them from early declines, according to Hamm.

"Our findings suggest not everyone who retires is at greater risk of cognitive declines. There are many opportunities to engage in mentally stimulating activities in retirement, such as reading or playing word games," he said. "However, personal agency and motivation may come to the fore at this stage of the lifespan since these activities often need to be self-initiated and autonomously maintained."

https://www.sciencedaily.com/releases/2020/03/200316090346.htm

Music therapy helps stroke patients

Research examines benefits of sessions on a stroke and rehabilitation unit

March 5, 2020

Science Daily/Anglia Ruskin University

New research has found that music therapy sessions have a positive effect on the neurorehabilitation of acute stroke patients, as well as their mood.

The study -- the first large-scale investigation into the feasibility of delivering these exercises -- was led by Dr Alex Street, of Anglia Ruskin University (ARU), and was carried out on a 26-bed stroke and rehabilitation unit at Addenbrooke's hospital in Cambridge.

In total, 177 patients took part in 675 Neurologic Music Therapy (NMT) sessions over a two-year period. The researchers investigated its success among patients, their relatives, and health professionals, and the results are published in the journal Topics in Stroke Rehabilitation.

Music therapy is understood to help stroke patients through mood regulation, improved concentration, and promoting changes in the brain to improve function, known as neural reorganisation. Physical benefits include better arm function and gait.

Lots of repetition, or 'massed practice', is central to neurorehabilitation. In addition to playing physical instruments (keyboard, drums and hand-held percussion), iPads featuring touchscreen instruments were used in the trial to help patients with hand rehabilitation, through improving finger dexterity, and cognitive training.

NMT sessions were run alongside existing stroke rehabilitation treatment, including physiotherapy, occupational therapy, speech therapy, and clinical psychology.

Of the 139 patients, relatives and hospital staff who completed questionnaires, the average response was that NMT was "helpful" or "very helpful." And of the 52 patients who completed mood scale questionnaires, there was a reduction in "sad" and an increase in "happy" responses immediately following a session.

Speech and language therapists observed a positive impact on patient arousal and engagement, and reported that it may help patients overcome low mood and fatigue -- both common following stroke -- and therefore be beneficial for their rehabilitation.

Following the success of the trial, the Cambridge Institute for Music Therapy Research at Anglia Ruskin University (ARU) and Addenbrooke's hospital are developing a proposal to establish a permanent NMT post on the stroke ward, funded by the NHS.

Dr Alex Street, Senior Research Fellow within the Cambridge Institute for Music Therapy Research at Anglia Ruskin University (ARU), said: "Our study found that Neurologic Music Therapy was received enthusiastically by patients, their relatives, and staff.

"The fact 675 sessions were carried out in two years is in itself an indication of the success of the treatment. It shows that staff are referring patients because they understand the mechanisms of the exercises and can see how it can benefit their patients. It also shows that patients are willing to do the exercises, with each one participating in an average of five sessions.

"Staff felt that using music and instruments allowed patients to achieve a high amount of repetition to help achieve their goals. They felt that the exercises appear less clinical, because the patients are playing music with the music therapist, and they are receiving immediate feedback from the exercises, through the sounds they create. Further research is necessary to establish potential effects of music therapy on recovery rate and length of hospital stay."

https://www.sciencedaily.com/releases/2020/03/200305203539.htm

Caffeine boosts problem-solving ability but not creativity

While the drug is known to increase focus, alertness and motor skills, its effect on creative thinking had not been studied previously

March 5, 2020

Science Daily/University of Arkansas

Want to boost creativity? Caffeine may not be the way to go according to a news study.

Caffeine increases the ability to focus and problem solve, but a new study by a University of Arkansas researcher indicates it doesn't stimulate creativity.

"In Western cultures, caffeine is stereotypically associated with creative occupations and lifestyles, from writers and their coffee to programmers and their energy drinks, and there's more than a kernel of truth to these stereotypes," wrote Darya Zabelina, assistant professor of psychology and first author of the study recently published in the journal Consciousness and Cognition.

While the cognitive benefits of caffeine -- increased alertness, improved vigilance, enhanced focus and improved motor performance -- are well established, she said, the stimulant's affect on creativity is less known.

In the paper, Zabelina differentiates "convergent" from "divergent" thinking. The former is defined as seeking a specific solution to a problem, for example, the "correct" answer. The latter is characterized by idea generation where a large set of apt, novel or interesting responses would be suitable. Caffeine was shown to improve convergent thinking in the study, while consuming it had no significant impact on divergent thinking.

For the study, 80 volunteers were randomly given either a 200mg caffeine pill, equivalent to one strong cup of coffee, or a placebo. They were then tested on standard measures of convergent and divergent thinking, working memory and mood. In addition to the results on creativity, caffeine did not significantly affect working memory, but test subjects who took it did report feeling less sad.

"The 200mg enhanced problem solving significantly, but had no effect on creative thinking," said Zabelina. "It also didn't make it worse, so keep drinking your coffee; it won't interfere with these abilities."

https://www.sciencedaily.com/releases/2020/03/200305135050.htm

Alzheimer's: Can an amino acid help restore memories?

March 3, 2020

Science Daily/CNRS

Scientists at the Laboratoire des Maladies Neurodégénératives (CNRS/CEA/Université Paris-Saclay) and the Neurocentre Magendie (INSERM/Université de Bordeaux) have just shown that a metabolic pathway plays a determining role in Alzheimer's disease's memory problems. This work, published on 3 March 2020 in Cell Metabolism, also shows that supplying a specific amino acid as a nutritional supplement in a mouse model of Alzheimer's restores spatial memory affected early. This is a promising path for reducing memory loss related to that disease.

The brain uses a large part of the energy available to our body. To work properly, neurons and the surrounding cells, particularly astrocytes, must cooperate. The early phase of Alzheimer's disease is characterized by a reduction in this energy metabolism, but until now we did not know whether this deficit contributed directly to the cognitive symptoms of Alzheimer's disease.

A collaborative study has shown in a mouse model of Alzheimer's disease that a decrease in the use of glucose by astrocytes reduces L-serine production. This amino acid is mainly produced by these brain cells and its biosynthesis path is altered in patients. L-serine is the precursor of D-serine, known to stimulate NMDA receptors, essential for brain function and to the establishment of memory. So by producing less L-serine, astrocytes cause reduced activity in these receptors, which alters neuronal plasticity and the associated memorization capacities. Scientists have also demonstrated that memorization functions in mice were restored by supplying nutritional L-serine.

With the identification of the role of L-serine in memory disorders and the experimental efficacy of nutritional supplementation, new strategies appear that may complement medical treatment, to combat early symptoms of Alzheimer's disease and other diseases that display metabolic deficits, like Parkinson's and Huntington's. Since L-serine is available as a nutritional supplement, this compound should be rigorously tested in humans, through controlled clinical trials.

https://www.sciencedaily.com/releases/2020/03/200303113357.htm

Study of 418,000 Europeans finds different foods linked to different types of stroke

February 24, 2020

Science Daily/European Society of Cardiology

Different types of food are linked to risks of different types of stroke, according to the largest study to investigate this, published in the European Heart Journal today (Monday).

Until now, most studies have looked at the association between food and total stroke (all types of stroke combined), or focused on ischaemic stroke only. However, the current study of more than 418,000 people in nine European countries investigated ischaemic stroke and haemorrhagic stroke separately.

The study found that while higher intakes of fruit, vegetables, fibre, milk, cheese or yoghurt were each linked to a lower risk of ischaemic stroke, there was no significant association with a lower risk of haemorrhagic stroke. However, greater consumption of eggs was associated with a higher risk of haemorrhagic stroke, but not with ischaemic stroke.

Ischaemic stroke occurs when a blood clot blocks an artery supplying blood to the brain or forms somewhere else in the body and travels to the brain where it blocks blood flow. Haemorrhagic stroke occurs when there is bleeding in the brain that damages nearby cells. About 85% of strokes are ischaemic and 15% are haemorrhagic. Stroke is the second leading cause of deaths worldwide.

Dr Tammy Tong, the first author of the paper and a nutritional epidemiologist at the Nuffield Department of Population Health, University of Oxford (UK), said: "The most important finding is that higher consumption of both dietary fibre and fruit and vegetables was strongly associated with lower risks of ischaemic stroke, which supports current European guidelines. The general public should be recommended to increase their fibre and fruit and vegetable consumption, if they are not already meeting these guidelines.

"Our study also highlights the importance of examining stroke subtypes separately, as the dietary associations differ for ischaemic and haemorrhagic stroke, and is consistent with other evidence, which shows that other risk factors, such as cholesterol levels or obesity, also influence the two stroke subtypes differently."

The total amount of fibre (including fibre from fruit, vegetables, cereal, legumes, nuts and seeds) that people ate was associated with the greatest potential reduction in the risk of ischaemic stroke. Every 10g more intake of fibre a day was associated with a 23% lower risk, which is equivalent to around two fewer cases per 1000 of the population over ten years.

Fruit and vegetables alone were associated with a 13% lower risk for every 200g eaten a day, which is equivalent to one less case per 1000 of the population over ten years. No foods were linked to a statistically significant higher risk of ischaemic stroke.

Based on UK estimates, two thick slices of wholemeal toast provide 6.6g of fibre, a portion of broccoli (around eight florets) provides about 3g, and a medium raw, unpeeled apple provides about 1.2g of fibre. The European Society of Cardiology (ESC) and the World Health Organization Regional Office for Europe recommend consuming at least 400g of fruit and vegetables a day; the ESC also suggests people should consume 30-45g of fibre a day.

The researchers found that for every extra 20g of eggs consumed a day there was a 25% higher risk of haemorrhagic stroke, equivalent to 0.66 extra cases per 1000 (or around two cases per 3000) of the population over ten years. An average large-sized egg weighs approximately 60g. Egg consumption in the EPIC study was low overall, with an average of less than 20g eaten a day.

The researchers say the associations they found between different foods and ischaemic and haemorrhagic stroke might be explained partly by the effects on blood pressure and cholesterol.

Dr Tong and her colleagues analysed data from 418,329 men and women in nine countries (Denmark, Germany, Greece, Italy, The Netherlands, Norway, Spain, Sweden and the United Kingdom) who were recruited to the European Prospective Investigation into Cancer and Nutrition (EPIC) study between 1992 and 2000. The participants completed questionnaires asking about diet, lifestyle, medical history and socio-demographic factors, and were followed up for an average of 12.7 years. During this time, there were 4281 cases of ischaemic stroke and 1430 cases of haemorrhagic stroke.

Food groups studied included meat and meat products (red meat, processed meat and poultry), fish and fish products (white fish and fatty fish), dairy products (including milk, yogurt, cheese), eggs, cereals and cereal products, fruit and vegetables (combined and separately), legumes, nuts and seeds, and dietary fibre (total fibre and cereal, fruit and vegetable fibre).

Major strengths of the study include the large numbers of people studied in several different countries and long follow-up period. Most types of food were included in the study, although information on diet was collected at only one point in time, when the participants joined the study. As the study is observational it cannot show that the foods studied cause an increase or decrease in risk of ischaemic or haemorrhagic stroke, only that they are associated with different risks. Information on medication use (including statins) was not available.

https://www.sciencedaily.com/releases/2020/02/200224102024.htm

Time of day affects global brain fluctuations

February 18, 2020

Science Daily/PLOS

As the day progresses, the strength of the brain's global signal fluctuation shows an unexpected decrease, according to a study published on February 18 in the open-access journal PLOS Biology by Csaba Orban and a multi-disciplinary team of scientists from the Faculty of Engineering, Yong Loo Lin School of Medicine and N.1 Institute of Health at the National University of Singapore.

Circadian rhythms govern diverse aspects of physiology including sleep/wake cycles, cognition, gene expression, temperature regulation, and endocrine signaling. But despite the clear influence of circadian rhythms on physiology, most studies of brain function do not report or consider the impact of time of day on their findings.

To address this gap in knowledge, the team analysed functional magnetic resonance imaging (fMRI) data of approximately 900 subjects who were scanned between 8 am and 10 pm on two different days as part of the Human Connectome Project. Multiple studies have shown that the brain's global signal fluctuates more strongly when one is drowsy (e.g. after insufficient sleep), and fluctuates less when one is more alert (e.g. after coffee). Based on known circadian variation in sleepiness, the authors hypothesized that global signal fluctuation would be lowest in the morning, increase in the mid-afternoon and dip in the early evening.

Instead, they observed a cumulative decrease in global signal fluctuation as the day progressed. This global decrease was most prominent in visual and somatosensory brain regions, which are known for expressing dynamic fluctuations within individuals over time. Across the whole brain, time of day was also associated with marked decreases in resting-state functional connectivity -- the correlated activity between different brain regions when no explicit task is being performed.

"We were surprised by the size of the overall time-of-day effects, since the global fMRI signal is affected by many factors and there is substantial variation across individuals. At the present moment we don't have a good explanation of the directionality of our findings. However, the fact that we also observed slight time-of-day-associated variation in the breathing patterns of participants suggests that we may also need to consider clues outside of the brain to fully understand these effects," said Csaba Orban, first author of the study.

Based on the findings, the authors recommend that researchers explicitly report the time of day of fMRI scans and other experimental protocols and measurements, as this could help account for between-study variation in results and potentially even failure to replicate findings.

"We hope these findings will motivate fellow neuroscientists to give more consideration to potential effects of time of day on measures of brain activity, especially in other large-scale studies where subjects are often scanned throughout the day for logistical reasons," said Thomas Yeo, the study's senior author.

https://www.sciencedaily.com/releases/2020/02/200218143717.htm

Memory games: Eating well to remember

February 18, 2020

Science Daily/University of Technology Sydney

A healthy diet is essential to living well, but should we change what we eat as we age? Researchers have found strong evidence of the link between food groups and memory loss and its comorbidities. Her findings point to a need for age-specific dietary guidelines as the links may vary with age -- people aged 80+ with a low consumption of cereals are at highest risk of memory loss and comorbid heart disease.

UTS research fellow Dr Luna Xu has studied data from 139,000 older Australians and found strong links between certain food groups, memory loss and comorbid heart disease or diabetes.

Dr Xu found high consumption of fruit and vegetables was linked to lowered odds of memory loss and its comorbid heart disease. High consumption of protein-rich foods was associated with a better memory.

Dr Xu also found the link between food group and memory status may vary among different older age groups. People aged 80 years and over with a low consumption of cereals are at the highest risk of memory loss and its comorbid heart disease, her research showed.

"Our present study implies that the healthy eating suggestions of cereals consumption in the prevention of memory loss and comorbid heart disease for older people may differ compared to other age groups," said Dr Xu, who holds a Heart Foundation postdoctoral research fellowship.

She said the study pointed to a need for age-specific healthy dietary guidelines.

Memory loss is one of the main early symptoms for people with dementia, which is the second leading cause of death of Australians. People living with dementia have on average between two and eight comorbid conditions, which may accelerate cognitive and functional impairment. The most common comorbidities in dementia include cardiovascular diseases, diabetes and hypertension.

"The dietary intervention in chronic disease prevention and management, by taking into consideration the fact that older populations often simultaneously deal with multiple chronic conditions, is a real challenge," Dr Xu said.

"To achieve the best outcome for our ageing population, strong scientific evidence that supports effective dietary intervention in preventing and managing co-occurring chronic conditions, is essential."

https://www.sciencedaily.com/releases/2020/02/200218124351.htm

A good blood supply is good for memory

February 14, 2020

Science Daily/DZNE - German Center for Neurodegenerative Diseases

Memory performance and other cognitive abilities benefit from a good blood supply to the brain. This applies in particular to people affected by a condition known as "sporadic cerebral small vessel disease." Researchers of the German Center for Neurodegenerative Diseases (DZNE) and the University Medicine Magdeburg report on this in the journal "BRAIN." Their study suggests that blood perfusion of the so-called hippocampus could play a key role in age- and disease-related memory problems.

Inside the human brain there is a small structure, just a few cubic centimeters in size, which is called the "hippocampus" because its shape resembles a seahorse. Strictly speaking, the hippocampus exists twice: once in each brain hemisphere. It is considered the control center of memory. Damage to the hippocampus, such as it occurs in Alzheimer's and other brain diseases, is known to impair memory. But what role does blood supply in particular play? A team of scientists headed by Prof. Stefanie Schreiber and Prof. Emrah Duezel, both affiliated to the DZNE and the University Medicine Magdeburg, investigated this question. The researchers used high-resolution magnetic resonance imaging (MRI) to examine the blood supply to the hippocampus of 47 women and men aged 45 to 89 years. The study participants also underwent a neuropsychological test battery, which assessed, in particular, memory performance, speech comprehension and the abilty to concentrate.

A double supply line

"It has been known for some time that the hippocampus is supplied by either one or two arteries. It also happens that only one of the two hippocampi, which occur in every brain, is supplied by two vessels. This varies between individuals. The reasons are unknown," explained Schreiber. "Maybe there is a genetic predisposition. However, it is also possible that the individual structure of the blood supply develops due to life circumstances. Then the personal lifestyle would influence the blood supply to the hippocampus." In the cognition tests, those study participants in whom at least one hippocampus was doubly supplied generally scored better. "The fact that the blood supply is fundamentally important for the brain is certainly trivial and has been extensively documented. We were therefore particularly focused on the hippocampus and the situation of a disease of the brain vessels. Little is actually known about this."

Patients benefited in particular

Of the study subjects, 27 did not manifest signs of brain diseases. The remaining twenty participants showed pathological alterations in brain blood vessels, which were associated with microbleeding. "In these individuals, sporadic cerebral small vessel disease had been diagnosed prior to our investigations," said Dr. Valentina Perosa, lead author of the current study, who is currently doing postdoctoral research in Boston, USA. These individuals exhibited a broad spectrum of neurological anomalies, including mild cognitive impairment. "The healthy subjects generally scored better on cognitive tests than the study participants with small vessel disease. Among the participants with disease, those with at least one hippocampus supplied by two arteries reached better scores in cognition. They particularly benefited from the double supply. This may be due to a better supply not only of blood but also of oxygen. However, this is just a guess," said Perosa.

Starting point for therapies?

"Our study shows a clear link between blood supply to the hippocampus and cognitive performance," Schreiber summarised the results. "This suggests that brain blood flow might play a key role in the declining of memory performance, whether caused by age or disease." Such findings help to understand disease mechanisms and can also be useful for the development of novel treatment options, she indicates: "At present we can only speculate, because we don't know, but it is possible that lifestyle has an influence on the formation of the blood vessels that supply the hippocampus. This would then be a factor that can be influenced and thus a potential approach for therapies and also for prevention. This is a topic we intend to investigate."

https://www.sciencedaily.com/releases/2020/02/200214134725.htm

Subtle decline in cognition predicts progression to Alzheimer's pathology

February 14, 2020

Science Daily/University of California - San Diego

Researchers report that abnormal levels of beta-amyloid plaques in brain predict cognitive decline and higher risk of developing Alzheimer's disease, but also that cognitive performance predicts progression from normal to abnormal levels of beta-amyloid.

Alzheimer's disease (AD) is progressive, but slow to develop -- or at least to reveal itself. In a new study, published online February 14, 2020 in the journal Biological Psychiatry, researchers at University of California San Diego School of Medicine, with colleagues elsewhere, report that early, subtle differences in cognitive performance, such as fewer words recalled on a memory test, are a sign that harmful proteins are accumulating in the brain, even if levels of those proteins do not yet qualify as dangerous.

Pathologically, AD is primarily characterized by the accumulation of protein plaques called β-amyloid (Aβ), which gradually accumulate in the brain, disrupting cell function and eventually killing affected neurons. A second type of protein, called tau, also accumulates abnormally inside neurons, damaging functions.

In the progression of AD, Aβ levels build in the brain, but the process leading to abnormally high levels is typically long. It is often years or decades before consequential symptoms of severe cognitive impairment appear. A new framework from the National Institute on Aging and Alzheimer's Association defines the first stage of AD to be individuals with abnormal levels of Aβ who are still cognitively normal.

"Although AD pathology, and Aβ in particular, appear long before severe cognitive deficits appear," said first author Jeremy A. Elman, PhD, assistant professor in the Department of Psychiatry at UC San Diego School of Medicine, "recent evidence suggests more subtle cognitive changes may appear earlier in the disease than commonly appreciated."

Elman and colleagues, including senior author William S. Kremen, PhD, professor of psychiatry at UC San Diego School of Medicine, sought to determine whether poor cognitive performance, however subtle, might be a predictor that current Aβ-negative levels (accumulations below the threshold for AD diagnosis) were likely to become Aβ-positive.

"Once a person reaches the point of being Aβ-positive, it means that there is already substantial underlying pathology," said Kremen. "It would be advantageous to identify at-risk individuals before they develop substantial amyloid burden to improve treatment efficacy and slow progression to AD dementia."

The researchers conducted a pair of non-invasive cognitive tests on 292 participants in the Alzheimer's Disease Neuroimaging Initiative, an ongoing study to assess whether the use of medical imaging, biological markers and clinical assessments can be combined to measure the progression of cognitive decline and early AD.

All of the participants were Aβ-negative at baseline testing and displayed no dementia; 40 participants would progress to Aβ-positivity during the study and follow-up period.

The scientists found that participants who tested with lower baseline cognition were at significantly higher risk of progressing to Aβ-positivity. That is, low test scores indicating poorer cognitive function suggested amyloid plaque levels that, while not yet considered to be problematic, were likely rising and would ultimately reach the threshold definition of AD.

"We found that subthreshold levels of baseline Aβ were predictive of future accumulation, adding to evidence that even low levels of Aβ are clinically relevant, but that cognitive performance was still significantly predictive even after controlling for this pathology," said Elman.

The findings, wrote the researchers, suggest that low-cost, non-invasive cognitive testing is useful for identifying persons who may be at risk for developing AD, making them ideal candidates for therapeutic intervention and clinical trials.

https://www.sciencedaily.com/releases/2020/02/200214134653.htm

Can bilingualism protect the brain even with early stages of dementia?

Researchers find bilingualism provides the brain with greater cognitive reserve, delaying onset of symptoms

February 13, 2020

Science Daily/York University

Psychology researchers provide new evidence that bilingualism can delay symptoms of dementia. Researchers found bilingualism provides the brain with greater cognitive reserve, delaying onset of symptoms.

Alzheimer's disease is the most common form of dementia, making up 60 to 70 per cent of dementia cases. Of all activities with neuroplastic benefits, language use is the most sustained, consuming the largest proportion of time within a day. It also activates regions across the entire brain. Ellen Bialystok, Distinguished Research Professor in York's Department of Psychology, Faculty of Health, and her team tested the theory that bilingualism can increase cognitive reserve and thus delay the age of onset of Alzheimer's disease symptoms in elderly patients.

Their study is believed to be the first to investigate conversion times from mild cognitive impairment to Alzheimer's disease in monolingual and bilingual patients. Although bilingualism delays the onset of symptoms, Bialystok says, once diagnosed, the decline to full-blown Alzheimer's disease is much faster in bilingual people than in monolingual people because the disease is actually more severe.

"Imagine sandbags holding back the floodgates of a river. At some point the river is going to win," says Bialystok. "The cognitive reserve is holding back the flood and at the point that they were when they were diagnosed with mild cognitive impairment they already had substantial pathology but there was no evidence of it because they were able to function because of the cognitive reserve. When they can no longer do this, the floodgates get completely washed out, so they crash faster."

In the five-year study, researchers followed 158 patients who had been diagnosed with mild cognitive impairment. For the study, they classified bilingual people as having high cognitive reserve and monolingual people as having low cognitive reserve.

Patients were matched on age, education, and cognitive level at the time of diagnosis of mild cognitive impairment. The researchers followed their six-month interval appointments at a hospital memory clinic to see the point at which diagnoses changed from mild cognitive impairment to Alzheimer's disease. The conversion time for bilinguals, 1.8 years after initial diagnosis, was significantly faster than it was for monolinguals, who took 2.6 years to convert to Alzheimer's disease. This difference suggests that bilingual patients had more neuropathology at the time they were diagnosed with mild cognitive impairment than the monolinguals, even though they presented with the same level of cognitive function.

These results contribute to the growing body of evidence showing that bilinguals are more resilient in dealing with neurodegeneration than monolinguals. They operate at a higher level of functioning because of the cognitive reserve, which means that many of these individuals will be independent longer, Bialystok says. This study adds new evidence by showing that the decline is more rapid once a clinical threshold has been crossed, presumably because there is more disease already in the brain.

"Given that there is no effective treatment for Alzheimer's or dementia, the very best you can hope for is keeping these people functioning so that they live independently so that they don't lose connection with family and friends. That's huge."

https://www.sciencedaily.com/releases/2020/02/200213132619.htm

Stimulation of nerve cluster during stroke may have beneficial effects

February 12, 2020

Science Daily/American Heart Association

Promising new stimulation treatment increases blood flow to the brain, improves hand strength in patients with minor stroke and may decrease disability in many patients with stroke. Nerve cluster stimulation could provide a new treatment option to stroke patients who aren't eligible for clot-dissolving drugs or clot removal.

In patients unable to have the clots that caused their stroke dissolved or removed, a promising new stimulation treatment that increases blood flow to the brain may become an option, according to two preliminary studies to be presented at the American Stroke Association's International Stroke Conference 2020 -- Feb. 19-21 in Los Angeles. Researchers also found the treatment improved hand strength in those with minor strokes and may decrease disability in patients with severe stroke.

Two prior trials of the stimulation of the sphenopalatine ganglion (SPG), at the back of the nose, showed beneficial effects in patients with stroke. Leveraging prior pivotal randomized controlled trial results, one of the new studies analyzes the same patient group to quantify the full range of benefit at 3 months. Building on a prior investigation assessing the stimulation therapy's immediate physiologic effects, the other new study determined the range of patients who show improved brain blood flow and motor function during stimulation.

"The stimulation treatment involves inserting a toothpick-sized electrode through a tiny opening in the upper palate of the mouth, positioning it very close to the SPG that sends nerves to blood vessels going to the brain. Stimulating that cluster of nerve cells causes blood vessels to dilate and enhance collateral blood flow to the brain in stroke patients without removing the clot that caused the stroke," said Jeffrey L. Saver, M.D., an author of both studies and professor of neurology at The David Geffen School of Medicine at the University of California, Los Angeles.

Assessing the True Impact-24b: Magnitude of benefit of Sphenopalatine Ganglion Stimulation for acute ischemic stroke with confirmed cortical involvement (Oral Presentation 11/Ordonez)

Researchers performed a new analysis of data from a randomized trial in order to estimate the extent of benefit of SPG stimulation among patients with stroke involving the brain's cortex, the outer part of the brain that plays an important role in consciousness and is thought to benefit when collateral blood flow around a clot-caused stroke is enhanced.

The study analyzed the full range of disability outcomes for 520 patients with confirmed low blood flow in the cortex who were ineligible for treatments to dissolve or remove a clot, usually because they had arrived at the hospital too late or the therapies were not available at that location. As part of the trial, 244 received SPG stimulation, and 276 received a control procedure involving vibrations with no actual electrical stimulation of the area. SPG stimulation was initiated 8-24 hours after stroke symptoms began.

After three months, researchers estimate that out of every 1,000 patients treated with SPG stimulation:

• 146 more will be less disabled; and

• 76 more will be functionally independent (able to walk and take care of their own basic needs).

"Even for patients who are not candidates to receive clot-dissolving drugs or to have the clot removed, we may now have other options in the future. This is good news, because while stroke treatment has really come forward in the last 20 years with regards to reopening and restoring blood flow, we've lagged behind in figuring out what to do for patients who are ineligible to receive the standard treatments," said Fausto Ordonez, M.D., lead author of the study and a vascular neurology fellow at the University of California, Los Angeles.

Diverse patients show physiologic benefit from refined Sphenopalatine Ganglion electrode placement and stimulation level selection to augment blood flow and neurologic function in acute ischemic stroke (The Impact-24m Trial) (Oral Presentation 114/Saver)

In this study, researchers assessed improvements in SPG stimulation techniques and early physiologic effects in 50 patients with anterior circulation ischemic strokes presenting 8-24 hours after last known well time and with mild deficits who were not eligible for clot-dissolving drugs or clot removal, either because their symptoms were too mild or they arrived at the hospital too long after the onset of stroke symptoms.

Using electrodes and CT scans to guide placement, it takes minutes to correctly implant the stimulation electrodes. Because the SPG also sends nerves to the face and the tear ducts, the proper amount of stimulation for each person could be comfortably determined by monitoring facial tingling or tear production.

Researchers found:

• During SPG stimulation (tested on the second day of five days of treatment), blood flow to the brain and head increased by an average of 44%;

• During stimulation, grip strength in the weaker arm increased 26%, and pinch strength increased 42%;

• After seven days after treatment, recovery in the patients who received SPG stimulation was significantly better (improved total neurologic deficit scores) than matched controls from previous studies of other treatments; and

• Benefits were evident no matter the age, sex, severity of stroke, time before treatment or which side of the body had weakness due to the stroke.

"SPG stimulation substantially increases brain blood flow and improves neurologic function across a broad range of patients when treatment begins up to 24 hours after stroke onset. This helps to explain why it is emerging as a potentially important new therapy for severe ischemic stroke," said Saver, who is also a member of the American Heart Association Stroke Systems of Care Advisory Group.

Since none of the patients in both studies received clot-busting medications or had their clots mechanically removed, it is unclear whether SPG stimulation could also benefit patients who received those treatments.

"Currently, the guidelines-based stroke treatments aim to remove the clot to restore blood flow. In these studies of SPG stimulation, the clot that's blocking blood flow is left untreated, and the SPG treatment is used to enhance collateral blood flow around the blockage. Potentially, SPG treatment could also preserve blood flow and brain tissue while a patient is being transferred to a hospital that can complete the clot removal treatment," Saver said.

https://www.sciencedaily.com/releases/2020/02/200212084407.htm

Optimism linked to lower stroke severity, inflammation

February 12, 2020

Science Daily/American Heart Association

Stroke survivors with high levels of optimism had lower inflammation levels, reduced stroke severity and less physical disability after three months, compared to those who are less optimistic, according to preliminary research presented at the Nursing Symposium of the American Stroke Association's International Stroke Conference 2020 -- Feb. 18-21 in Los Angeles.

In a small study of 49 stroke survivors, researchers examined the relationship among optimism, inflammation, stroke severity and physical disability for three months after a stroke. Researchers said that understanding how these elements relate to or impact one another may provide a scientific framework to develop new strategies for stroke recovery.

"Our results suggest that optimistic people have a better disease outcome, thus boosting morale may be an ideal way to improve mental health and recovery after a stroke," said Yun-Ju Lai, Ph.D., M.S., R.N., the study's first author and a postdoctoral fellow in the neurology department at The University of Texas Health Science Center at Houston.

Post-stroke inflammation is detrimental to the brain and impairs recovery. Optimism has been associated with lower inflammation levels and improved health outcomes among people with medical conditions, however, no prior studies assessed if this association exists among stroke patients.

This pilot study is a secondary analysis of data collected from a repository of neurological diseases. Outcomes included optimism levels from the revised Life Orientation Test, a standard psychological tool for measuring optimism; stroke severity evaluation through the National Institutes of Health Stroke Scale, and levels of inflammatory markers -- interleukin-6 (IL-6), tumor necrosis factor alpha (TNF?) and C-reactive protein (CRP).

As optimism levels increased, stroke severity and the inflammatory markers IL-6 and CRP decreased even after considering other possible variables. However, this was not true of TNF?.

"Patients and their families should know the importance of a positive environment that could benefit the patient," Lai said. "Mental health does affect recovery after a stroke."

https://www.sciencedaily.com/releases/2020/02/200212084408.htm

Taller young men may have lower dementia risk

February 11, 2020

Science Daily/eLife

Men who are taller in young adulthood, as an indicator of early-life circumstances, may have a lower risk of dementia in old age, suggests a study published today in eLife.

Finding ways to identify individuals at risk of dementia is essential. It can help people take preventive measures or plan for their future care. The study, originally posted on bioRxiv, indicates that young adult height might be one potential risk factor to consider.

Previous studies have suggested that height may be a risk factor for dementia, but much of this research was not able to take into account genetic, environmental, or other early-life factors that may be linked to both height and dementia.

"We wanted to see if body height in young men is associated with diagnosis of dementia, while exploring whether intelligence test scores, educational level, and underlying environmental and genetic factors shared by brothers explain the relationship," says lead author Terese Sara Høj Jørgensen, Assistant Professor at the Section of Social Medicine, Department of Public Health, University of Copenhagen, in Denmark.

To do this, Jørgensen and her colleagues analysed data on 666,333 Danish men born between 1939 and 1959, including 70,608 brothers and 7,388 twins, from Danish national registries. They found a total of 10,599 men who developed dementia later in life.

Their adjusted analysis of this group showed that there was about a 10% reduction in the risk of developing dementia for about every 6cm of height in individuals above the average height. When the team took into account the potential role of intelligence or education, the unadjusted relationship between height and dementia risk was only slightly reduced.

They found that the relationship between height and dementia also existed when they looked at brothers with different heights, suggesting that genetics and family characteristics alone do not explain why shorter men had a greater dementia risk. This was also true when they studied data concerning twins, although the results for this group were less certain.

"A key strength of our study is that it adjusted for the potential role of education and intelligence in young men's dementia risk, both of which may build up cognitive reserve and make this group less vulnerable to developing dementia," explains senior author Merete Osler, Professor at the Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, and at the University of Copenhagen.

'Cognitive reserve' refers to the brain's ability to improvise and solve problems that come up in everyday life. Osler says that adjusting for education and intelligence reduces the likelihood that the relationship between height and dementia is really explained by cognitive reserve.

"Together, our results point to an association between taller body height in young men and a lower risk of dementia diagnosis later in life, which persists even when adjusted for educational level and intelligence test scores," Osler says. "Our analysis of the data concerning brothers confirms these findings, and suggests the association may have common roots in early-life environmental exposures that are not related to family factors shared by brothers."

She adds that an important limitation of the study is the uncertainty as to whether these findings are generalisable to women, as previous studies on potential gender differences in the relationship between height and dementia are mostly inconclusive.

https://www.sciencedaily.com/releases/2020/02/200211103826.htm

How the brain's immune system could be harnessed to improve memory

February 11, 2020

Science Daily/RMIT University

Inflammation can send the brain's immune cells into damaging hyperdrive, an effect that has been linked to neurodegenerative diseases that affect memory, like dementia. A new study finds these same immune cells can also be activated to have the reverse effect, powering memory and learning.

When it comes to memory, immune cells are known as the "bad cops" of the brain. But new research shows they could also be turned into "good cops" to power memory and learning.

Inflammation can send the brain's immune cells into damaging hyperdrive, and this has been linked to neurodegenerative diseases that affect memory, like dementia.

In the new study, researchers at RMIT University found that these same immune cells -- known as microglia -- can also be activated to have the reverse effect.

When the microglia were altered in rats, their performance in simple memory tasks improved by up to 50%, rather than deteriorating.

While the effect was temporary, the discovery suggests these cells could be targeted in the development of new therapies designed to enhance memory formation, with the hope of preventing cognitive decline as people grow older.

Worldwide, around 50 million people have dementia, with nearly 10 million new cases each year. In Australia, dementia and ageing-related cognitive decline affect 9% of people aged over 65.

Chief Investigator and senior author, Associate Professor Sarah Spencer, said the unexpected results of the study expanded our understanding of memory formation and the role of neuroinflammation in memory loss.

"Cognitive decline is a big problem for our ageing population, and we currently have very few treatments to treat or prevent it," Spencer said.

"Even in healthy adults, optimising how well we learn and remember can give us a substantial performance edge at work and socially.

"Our study has for the first time shown a link between changes in the immune cells of healthy brains and improved cognitive function.

"While it's early days and a lot more research is needed, we hope our findings may lead to new therapies that can stimulate these immune cells to boost memory and keep our brains powering as we age."

Activating memory with activated microglia

In the study, published in Journal of Neuroinflammation, the researchers worked with a unique type of rat to test the effect of microglia on cognitive function.

The study looked how the rats performed memory tasks when the immune cells were present and compared this with their performance when almost all the microglia were knocked out.

They found that removing almost all the microglia made no difference in memory tasks.

But when the microglia regenerated, this led to astounding results: researchers ran the same memory tests on the rats and they performed 25-50% better than normal rats.

Importantly, the regenerated microglia were a different shape -- similar to the "activated" shape that these cells have when dealing with inflammation.

"We are still exploring what makes these cells different when they repopulate the brain, but their shape tells us they may be more active than usual, potentially making the neurons more effective to encourage better memory," Spencer, an NHMRC Career Development Fellow at RMIT, said.

"The effect doesn't last. As the microglia go back to their usual shape, memory performance also goes back to normal.

"The next stage in the research is closely investigating these regenerated microglia to better understand the mechanisms at work, with the aim of finding ways to turn the temporary memory boost into a long-lasting effect."

Microglia-suppressing therapies are currently being tested in clinical trials in the US, as potential treatments for Multiple Sclerosis.

"With our new understanding of the role of microglia in memory, it may be possible in future to test the therapies originally designed for MS and assess their potential in improving cognitive function as well," Spencer said.

Spencer is a leading researcher in the Neurodevelopment in Health and Disease program at RMIT, a multi-disciplinary research group in the School of Health and Biomedical Sciences established to identify the determinants of healthy brain development, and early origins of neurological disease.

https://www.sciencedaily.com/releases/2020/02/200211103731.htm

Scientists develop non-invasive method to predict onset of dementia

Screening using EMR data could help with early identification of Alzheimer's disease risk

February 11, 2020

Science Daily/Regenstrief Institute

Information gathered from routine visits to the doctor is enough to accurately predict a person's risk of developing Alzheimer's disease and related dementias, according to new research led by scientists from Regenstrief Institute, Indiana University and Merck. The researchers developed and tested machine learning algorithms using data from electronic medical records to identify patients who may be at risk for developing the dementia.

At least 50 percent of older primary care patients living with Alzheimer's disease and related dementias never receive a diagnosis. And many more live with symptoms for two to five years before being diagnosed. Currently, tests to screen for dementia risk are invasive, time-consuming and expensive.

"The great thing about this method is that it's passive, and it provides similar accuracy to the more intrusive tests that are currently used," said lead researcher Malaz Boustani, M.D., MPH, a research scientist at Regenstrief Institute and a professor at Indiana University School of Medicine. "This is a low cost, scalable solution that can provide substantial benefit to patients and their families by helping them prepare for the possibility of life with dementia and enabling them to take action."

Developing machine learning algorithms for predicting dementia

The research team, which also included scientists from Georgia State, Albert Einstein College of Medicine and Solid Research Group, recently published its findings on two different machine learning approaches. The paper published in the Journal of the American Geriatrics Society analyzed the results of a natural language processing algorithm, which learns rules by analyzing examples, and the Artificial Intelligence in Medicine article shared the results from a random forest model, which is built using an ensemble of decision trees. Both methods showed similar accuracy at predicting the onset of dementia within one and three years of diagnosis.

In order to train the algorithms, researchers gathered data on patients from the Indiana Network for Patient Care. The models used information on prescriptions and diagnoses, which are structured fields, as well as medical notes, which are free text, to predict the onset of dementia. Researchers found that the free text notes were the most valuable to helping identify people at risk of developing the disease.

"This research is exciting because it potentially provides significant benefit to patients and their families," said Patrick Monahan, PhD, study author from IU School of Medicine and a Regenstrief affiliate scientist. "Clinicians can provide education on behavior and habits to help patients cope with their symptoms and live a better quality of life."

Zina Ben Miled, PhD, M.S., a study author from the Purdue School of Engineering and Technology at IUPUI and a Regenstrief affiliate scientist, said, "The early risk identification allows an opportunity for doctors and families to put a care plan in place. I know from experience what a burden it can be to deal with a dementia diagnosis. The window provided by this test is so important to help improve the quality of life for both patients and their families."

In addition to the benefit to families, these methods can also provide significant cost savings for patients and health systems. They replace the need for expensive tests and allow clinicians to screen entire populations to identify those most at risk. Delaying the onset of symptoms also saves a significant amount of money on treatment.

The next step is to deploy these machine learning algorithms in real-life clinics to test if they help identify more true cases of dementia as well as to learn how they impact a patient's willingness to follow up on the results.

https://www.sciencedaily.com/releases/2020/02/200211103723.htm

Toxic protein, linked to Alzheimer's and neurodegenerative diseases, exposed in new detail

Columbia-led team harnesses two powerful technologies to identify promising targets for diagnosing and treating neurodegenerative diseases

February 6, 2020

Science Daily/The Zuckerman Institute at Columbia University

The protein tau has long been implicated in Alzheimer's and a host of other debilitating brain diseases. But scientists have struggled to understand exactly how tau converts from its normal, functional form into a misfolded, harmful one. Now, researchers at Columbia University's Zuckerman Institute and Mayo Clinic in Florida have used cutting-edge technologies to see tau in unprecedented detail. By analyzing brain tissue from patients, this research team has revealed that modifications to the tau protein may influence the different ways it can misfold in a person's brain cells. These differences are closely linked to the type of neurodegenerative disease that will develop -- and how quickly that disease will spread throughout the brain.

The study, published today in Cell, employed two complementary techniques to map the structure of tau and decipher the effects of additional molecules, called post-translational modifications (PTMs), on its surface. These new structural insights could accelerate the fight against neurodegenerative diseases, by helping researchers identify new biomarkers that detect these disorders before symptoms arise and design new drugs that target specific PTMs, preventing the onset of disease before it wreaks havoc on the brain.

"Tau has long been a protein of significant interest due to its prevalence in disease," said Anthony Fitzpatrick, PhD, a Principal Investigator at Columbia's Mortimer B. Zuckerman Mind Brain Behavior Institute who led the study. "In today's publication, we lay out compelling evidence that PTMs play an important structural role in tauopathies, the collection of neurodegenerative diseases characterized by toxic buildup of misfolded tau."

No two tauopathies are exactly alike. Each affects different parts of the brain -- even different cell types -- which can lead to different symptoms. Alzheimer's, for example, arises in the hippocampus, and so affects memory. Chronic traumatic encephalopathy, a disorder most often seen in survivors of traumatic brain injury, can lead to problems with movement, memory or emotion, depending on which areas of the brain are affected.

Scientists have used traditional imaging techniques to find clues to how tangles of tau, comprised of individual fibers, or filaments, are implicated in these diseases. But painting a complete picture has proven difficult.

"The brains of patients with neurodegenerative diseases are easy to identify: entire sections have been eaten away, replaced by large clumps and tangles of misfolded proteins like tau," said Tamta Arakhamia, an undergraduate at Columbia's School of General Studies, a research assistant in the Fitzpatrick lab and the paper's co-first author. "However, tau filaments are 10,000 times thinner than the width of a human hair, making them extraordinarily difficult to study in detail."

To address this challenge, Dr. Fitzpatrick recently pioneered the use of cryo-electron microscopy, or cryo-EM, to visualize individual tau filaments from diseased human brain tissue. Cryo-EM is a Nobel Prize-winning technology developed, in part, by researchers at Columbia University. Cryo-EM images samples using a beam of electrons and has proven indispensable for investigations into extremely small biological structures. Using cryo-EM, Dr. Fitzpatrick's team has reconstructed the structures of tau filaments, providing new insights into how they form, grow, and spread throughout the brain.

For all its ability to provide highly detailed snapshots of proteins, cryo-EM has limits. To overcome these limits, Dr. Fitzpatrick and his team to paired it with a second technology: mass spectrometry.

"Cryo-EM does not provide a complete picture because it cannot fully recognize the microscopic PTMs on tau's surface," said Christina Lee, an undergraduate student at Columbia College, a research assistant in the Fitzpatrick lab and the paper's co-first author. "But mass spectrometry can pinpoint the chemical composition of PTMs on the surface of tau."

Working with co-corresponding author Leonard Petrucelli, PhD, Ralph B. and Ruth K. Abrams Professor of Neuroscience at Mayo Clinic in Florida, and Nicholas Seyfried, PhD, professor of biochemistry at Emory University School of Medicine, the researchers used cryo-EM and mass spectrometry to analyze the brain tissue from patients diagnosed with two tauopathies: Alzheimer's disease and corticobasal degeneration, or CBD. CBD is a rare but extremely aggressive tauopathy, affecting only one in every 10,000 people. Unlike Alzheimer's, which is thought to arise due to a number of factors including tau, CBD is primarily associated with misbehaving tau proteins.

"Studying a primary tauopathy like CBD helps us to figure out how tau becomes toxic to brain cells," said Dr. Petrucelli. "We hope to extrapolate that knowledge to secondary tauopathies, such as Alzheimer's disease."

The scientists' analysis of brain tissue samples revealed several key insights. Most notably, the researchers found that cross-talk between PTMs on the surface of tau influences the structure of the tau filaments, contributing to differences in tau filaments observed across the various tauopathies -- and even variations from patient to patient.

"Collectively, these results suggest that PTMs may not only be serving as markers on the proteins' surface, but are actually influencing the behavior of tau," said Dr. Fitzpatrick, who is also an assistant professor of biochemistry and molecular biophysics at Columbia's Vagelos College of Physicians and Surgeons.

Moving forward, Dr. Fitzpatrick and his team plan to expand this work to other tauopathies. Today's findings on Alzheimer's and CBD hold immense promise for the field, particularly in the development of new disease models -- such as lab-grown organoids, or mini-brains -- that may serve to accurately recapitulate what is actually happening in the brains of patients.

"Our findings will inspire new approaches for developing diagnostic tools and designing drugs, such as targeting PTM vulnerabilities to slow disease progression," said Dr. Fitzpatrick, who is also a member of Columbia's Taub Institute for Research on Alzheimer's Disease and the Aging Brain. "Neurodegenerative diseases are among the most complex and distressing class of illnesses, but through our work and that of our colleagues and collaborators, we are building a roadmap toward successful diagnostics and therapeutics."

https://www.sciencedaily.com/releases/2020/02/200206144841.htm

Aerobic exercise training linked to enhanced brain function

Regular aerobic exercise may decrease the likelihood of developing Alzheimer's disease

February 3, 2020

Science Daily/IOS Press

Individuals at risk for Alzheimer's disease (AD) because of family history or genetic predisposition who engaged in six months of aerobic exercise training improved their brain glucose metabolism and higher-order thinking abilities (e.g., planning and mental flexibility) called executive function; these improvements occurred in conjunction with increased cardiorespiratory fitness. The results of this study are published in a special issue of Brain Plasticity devoted to Exercise and Cognition.

Drugs currently available to treat AD have limited therapeutic capacity. At a time when both the human and monetary costs of the disease are projected to rise dramatically in the coming decades, there is a critical need to provide individuals with readily-deployable strategies that can decrease the likelihood of acquiring the disease or slow its progression. Researchers therefore investigated whether exercise training in asymptomatic individuals harboring risk for AD improves markers associated with AD.

"This study is a significant step toward developing an exercise prescription that protects the brain against AD, even among people who were previously sedentary," explained lead investigator Ozioma C. Okonkwo, PhD, of the Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health.

The study investigated 23 cognitively normal, relatively young older adults with a family history or genetic risk for AD. All patients had a sedentary lifestyle. They underwent a battery of assessments, including cardiorespiratory fitness testing, measurement of daily physical activity, brain glucose metabolism imaging (a measure of neuronal health), and cognitive function tests.

Half of the participants were randomly assigned to receive information about maintaining an active lifestyle but no further intervention. The other half participated in a moderate intensity treadmill training program with a personal trainer, three times per week for 26 weeks.

Compared to the participants maintaining their usual level of physical activity, individuals assigned to the active training program improved their cardiorespiratory fitness, spent less time sedentary after the training program ended, and performed better on cognitive tests of executive functioning (but not episodic memory). Executive function, an aspect of cognition that is known to decline with the progression of AD, comprises the mental processes enabling individuals to plan, focus attention, remember instructions, and juggle multiple tasks successfully. The participants' improved cardiorespiratory fitness was associated with increased brain glucose metabolism in the posterior cingulate cortex, an area of the brain linked to AD.

"This research shows that a lifestyle behavior -- regular aerobic exercise -- can potentially enhance brain and cognitive functions that are particularly sensitive to the disease. The findings are especially relevant to individuals who are at a higher risk due to family history or genetic predisposition," noted Dr. Okonkwo. The lead author on the study, Max Gaitán, MEd, of the Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, remarked that "an important next step would be to conduct a larger, more definitive, study. If these findings are replicated, they would have a tremendous impact on quality of later life, providing individuals with more years of independent living, active engagement with loved ones, and building memories."

https://www.sciencedaily.com/releases/2020/02/200203104450.htm

Patterns in the brain shed new light on how we function

January 30, 2020

Science Daily/Newcastle University

The patterns created by neurons in the brain can be used to shine a light on how the brain functions, and take us a step closer to creating intelligent robots, scientists claim.

Publishing their research today in PLoS Computational Biology, the international team from the universities of Newcastle and Zurich, ETH Zurich and the California Institute of Technology, show that the way the neurons are structured and the patterns they make can be used to explain how they behave and function.

Modelling the neurons in the visual cortex -- those responsible for sight -- the researchers showed the seemingly random patterns could be explained by simple developmental rules.

In turn, these recurring patterns can be used to better understand how neurons organise their connections to communicate with one another.

Co-author of the study Dr Roman Bauer, a Research Fellow in the School of Computing, explains:

"At first glance, the network of neurons in the human brain appears so tangled and complex you would think it impossible to start to understand how they all connect together.

"But what we have shown is that certain neurons make particular patterns which follow some quite simple rules.

"If we can spot these patterns in the brain then we can use them to predict how those particular neurons are behaving."

Focussing their work on the connections between the thalamus and cortical regions of the brain, Dr Bauer says that if we can understand how animals sense visual stimuli and recognise objects it could revolutionise current technology.

"When we change the orientation of an object, the brain still recognises it as the same object and easily adjusts to the changing situation. But current AI has a real problem with that.

"If we can simplify the brain to a few key patterns that can be translated by technology then it might be possible to create artificial intelligence that truly mimics the human brain.

"More importantly, by understanding what healthy network looks like, it will allow us to spot changes or abnormalities and inform new treatments."

https://www.sciencedaily.com/releases/2020/01/200130144337.htm