Diet's effect on gut bacteria could play role in reducing Alzheimer's risk

September 3, 2019

Science Daily/Wake Forest Baptist Medical Center

Could following a certain type of diet affect the gut microbiome -- the good and bad bacteria that live in the gastrointestinal tract -- in ways that decrease the risk of Alzheimer's disease?

According to researchers at Wake Forest School of Medicine, that is a fair possibility.

In a small pilot study, the researchers identified several distinct gut microbiome signatures -- the chemicals produced by bacteria -- in study participants with mild cognitive impairment (MCI) but not in their counterparts with normal cognition, and found that these bacterial signatures correlated with higher levels of markers of Alzheimer's disease in the cerebrospinal fluid of the participants with MCI.

Through cross-group dietary intervention, the study also showed that a modified Mediterranean-ketogenic diet produced changes in the gut microbiome and its metabolites that correlated with reduced levels of Alzheimer's markers in the members of both study groups.

The study appears in the current issue of EBioMedicine, a journal published by The Lancet.

"The relationship of the gut microbiome and diet to neurodegenerative diseases has recently received considerable attention, and this study suggests that Alzheimer's disease is associated with specific changes in gut bacteria and that a type of ketogenic Mediterranean diet can affect the microbiome in ways that could impact the development od dementia," said Hariom Yadav, Ph.D., assistant professor of molecular medicine at Wake Forest School of Medicine, who co-authored the study with Suzanne Craft, Ph.D., professor gerontology and geriatric medicine at the medical school and director of Wake Forest Baptist Health's Alzheimer's Disease Research Center.

The randomized, double-blind, single-site study involved 17 older adults, 11 with diagnosed MCI and six with normal cognition. These participants were randomly assigned to follow either the low-carbohydrate modified Mediterranean-ketogenic diet or a low-fat, higher carbohydrate diet for six weeks then, after a six-week "washout" period, to switch to the other diet. Gut microbiome, fecal short-chain fatty acids and markers of Alzheimer's, including amyloid and tau proteins, in cerebrospinal fluid were measured before and after each dieting period.

The study's limitations include the subject group's size, which also accounts for the lack of diversity in terms of gender, ethnicity and age.

"Our findings provide important information that future interventional and clinical studies can be based on," Yadav said. "Determining the specific role these gut microbiome signatures have in the progression of Alzheimer's disease could lead to novel nutritional and therapeutic approaches that would be effective against the disease."

https://www.sciencedaily.com/releases/2019/09/190903120514.htm

Creation of new brain cells plays an underappreciated role in Alzheimer's disease

August 30, 2019

Science Daily/University of Chicago

Researchers show how in genetic forms of Alzheimer's, a process called neurogenesis, or the creation of new brain cells, can be disrupted by the brain's own immune cells.

Much of the research on the underlying causes of Alzheimer's disease focuses on amyloid beta (Aß), a protein that accumulates in the brain as the disease progresses. Excess Aß proteins form clumps or "plaques" that disrupt communication between brain cells and trigger inflammation, eventually leading to widespread loss of neurons and brain tissue.

Aß plaques will continue to be a major focus for Alzheimer's researchers. However, new work by neuroscientists at the University of Chicago looks at another process that plays an underappreciated role in the progression of the disease.

In a new study published in the Journal of Neuroscience, Sangram Sisodia, PhD, the Thomas Reynolds Sr. Family Professor of Neurosciences at UChicago, and his colleagues show how in genetic forms of Alzheimer's, a process called neurogenesis, or the creation of new brain cells, can be disrupted by the brain's own immune cells.

Some types of early onset, hereditary Alzheimer's are caused by mutations in two genes called presenilin 1 (PS1) and presenilin 2 (PS2). Previous research has shown that when healthy mice are placed into an "enriched" environment where they can exercise, play and interact with each other, they have a huge increase in new brain cells being created in the hippocampus, part of the brain that is important for memory. But when mice carrying mutations to PS1 and PS2 are placed in an enriched environment, they don't show the same increase in new brain cells. They also start to show signs of anxiety, a symptom often reported by people with early onset Alzheimer's.

This led Sisodia to think that something besides genetics had a role to play. He suspected that the process of neurogenesis in mice both with and without Alzheimer's mutations could also be influenced by other cells that interact with the newly forming brain cells.

Focus on the microglia

The researchers focused on microglia, a kind of immune cell in the brain that usually repairs synapses, destroys dying cells and clears out excess Aß proteins. When the researchers gave the mice a drug that causes microglial cells to die, neurogenesis returned to normal. The mice with presenilin mutations were then placed into an enriched environment and they were fine; they didn't show any memory deficits or signs of anxiety, and they were creating the normal, expected number of new neurons.

"It's the most astounding result to me," Sisodia said. "Once you wipe out the microglia, all these deficits that you see in these mice with the mutations are completely restored. You get rid of one cell type, and everything is back to normal."

Sisodia thinks the microglia could be overplaying their immune system role in this case. Alzheimer's disease normally causes inflammation in the microglia, so when they encounter newly formed brain cells with presenilin mutations they may overreact and kill them off prematurely. He feels that this discovery about the microglia's role opens another important avenue toward understanding the biology of Alzheimer's disease.

"I've been studying amyloid for 30 years, but there's something else going on here, and the role of neurogenesis is really underappreciated," he said. "This is another way to understand the biology of these genes that we know significantly affect the progression of disease and loss of memory."

https://www.sciencedaily.com/releases/2019/08/190830112832.htm

A protective factor against Alzheimer's disease?

August 29, 2019

Science Daily/DZNE - German Center for Neurodegenerative Diseases

Researchers at the German Center for Neurodegenerative Diseases (DZNE) and the Institute for Stroke and Dementia Research (ISD) at the University Hospital of the Ludwig-Maximilians-Universität (LMU) in Munich have found that a protein called TREM2 could positively influence the course of Alzheimer's disease. When TREM2 is present in the cerebrospinal fluid at higher concentrations, patients at any stage of the disease have a better prognosis. This observation provides a starting point for the development of new therapeutic strategies. The study was led by Prof. Christian Haass (DZNE) and Prof. Michael Ewers (ISD, LMU) and is published in the journal Science Translational Medicine.

In the brain, TREM2 is exclusively produced by microglia, the immune cells of the brain. These cells patrol the brain and clear it from cellular waste products and debris to keep it healthy. In previous studies on mice, Haass and his colleagues demonstrated that TREM2 activates microglia to enclose and selectively destroy toxic protein aggregates typical for Alzheimer's disease. "These observations indicate that TREM2 can protect the brain from the degenerative effects of the disease -- at least in animal models," said Haass.

But what about patients with Alzheimer's disease? Does TREM2 protect the human brain as well? To answer these questions, Haass, Ewers, and their colleagues correlated the concentration of TREM2 in the cerebrospinal fluid of Alzheimer patients with their respective disease progression over several years. To this end, they used data of 385 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a large clinical dataset containing records and samples from patients and healthy seniors taken at regular checkups over many years. The study thus allows to establish associations between certain biochemical changes and disease progression.

Indeed, Haass and Ewers found that high levels of TREM2 improved the prognosis of subjects at all stages of the disease. Their memory remained more stable and the degradation of the hippocampus, a brain region responsible for learning and recollection, was less pronounced. "Our findings are clinically relevant because we found that higher levels of TREM2 were associated also with a reduced rate of the development of full blown dementia over a time period up to 11 years," explained Ewers. "Microglia activation is a double-edged sword, entailing both protective effects and neurotoxic inflammation. TREM2 signaling may play a key role in the regulation of the brain's protective immune response."

The concentration of TREM2 in the cerebrospinal fluid usually increases at early stages of the disease, when the first symptoms appear. "TREM2 production is a response to brain damage that has already occurred," said Haass. "It stimulates the microglia to protect the brain. However, this protection does not seem to be sufficient in patients with Alzheimer's disease." This is where Haass and his colleagues see an option for new therapeutic strategies. "We are currently developing a therapeutic antibody that stimulates the TREM2 function and thus improves its protective function," said Haass.

https://www.sciencedaily.com/releases/2019/08/190829150718.htm

Could marriage stave off dementia?

August 28, 2019

Science Daily/Michigan State University

Dementia and marital status could be linked, according to a new Michigan State University study that found married people are less likely to experience dementia as they age.

On the other hand, divorcees are about twice as likely as married people to develop dementia, the study indicated, with divorced men showing a greater disadvantage than divorced women.

In one of the first studies of its kind, Hui Liu, professor of sociology, and colleagues analyzed four groups of unmarried individuals: divorced or separated; widowed; never married; and cohabiters. Among them, the divorced had the highest risk of dementia.

The study, published in The Journals of Gerontology: Series B, comes at a time when 5.8 million people in the U.S. are living with Alzheimer's disease and related dementias, costing $290 billion, according to the Alzheimer's Association. It's a serious public health concern, Liu said.

"This research is important because the number of unmarried older adults in the United States continues to grow, as people live longer and their marital histories become more complex," Liu said. "Marital status is an important but overlooked social risk/protective factor for dementia."

Liu and her follow researchers analyzed nationally representative data from the Health and Retirement Study, from 2000 to 2014. The sample included more than 15,000 respondents ages 52 and older in 2000, measuring their cognitive function every two years, in person or via telephone.

The researchers also found differing economic resources only partly account for higher dementia risk among divorced, widowed and never-married respondents, but couldn't account for higher risk in cohabiters. In addition, health-related factors, such as behaviors and chronic conditions, slightly influenced risk among the divorced and married, but didn't seem to affect other marital statuses.

"These findings will be helpful for health policy makers and practitioners who seek to better identify vulnerable populations and to design effective intervention strategies to reduce dementia risk," Liu said.

https://www.sciencedaily.com/releases/2019/08/190828100542.htm

Memory loss, dementia an understudied yet widespread phenomenon among Chinese Americans

August 26, 2019

Science Daily/Rutgers University

First of their kind studies reveal the impact of immigration, gender, psychological distress, education, social engagement, and oral health on Chinese Americans' cognitive function.

The U.S. Chinese population is growing -- and graying -- rapidly. From 2000 to 2010, the Chinese American population aged 65 and over grew at a rate four times higher than the overall U.S. older adult population. As of 2016, 14% of the approximately four million Chinese Americans were aged 65 and older. As this population ages, they are increasingly susceptible to memory loss and lacking the necessary supports for healthy aging, according to four new Rutgers studies published in the Journal of the American Geriatrics Society.

The studies are the first to extensively study memory loss and dementia in the context of immigration, gender, psychological distress, education, social engagement, and oral health among older Chinese Americans. The papers explore the risk factors and offer recommendations for healthcare providers to overcome the linguistic, cultural, and socioeconomic barriers facing this vulnerable population.

"Research has found that as many as 34% of American adults aged 60 and older are cognitively impaired," said XinQi Dong, director of Rutgers University's Institute for Health, Health Care Policy and Aging Research. " Further, more than one in four people aged 65 and older will be diagnosed with dementia in their lifetime. Although these facts are known to apply to the general American population, there is little information about Alzheimer's disease and related dementias or the contributing factors among Asian Americans."

For the studies, researchers administered multiple cognitive function tests to 2,713 Chinese Americans aged 60 and older. They measured the effects of immigration and gender, psychological distress, education level and social engagement, and oral health on the three domains of cognitive function -- global cognition, episodic memory, and working memory.

Key findings:

·      Older Chinese American women experience higher rates of cognitive impairment.

·      Depression, chronic conditions, and disability are associated with cognitive decline.

·      Lower education levels increase the risk of cognitive impairment. A one-year increase in education decreases the risk by 25%.

·      Difficulties performing functional and instrumental activities of daily living are predictive of the risk of developing cognitive impairment.

·      Higher levels of perceived stress are associated with poorer episodic memory, perceptual speed, and working memory in older Chinese American adults

·      Stress negatively affects the brain and cognitive functioning throughout life.

·      Older Chinese Americans who face increased stressors from linguistic and cultural barriers have poorer cognitive functioning and faster cognitive decline.

·      41.5% of Asian Americans reported not receiving annual oral health examinations, which is linked to decreased quality of life, depression, hypertension, poor cognition, and cognitive decline.

"Chinese older adults are confronting significant life challenges and health disparities due to multiple social, structural, cultural and linguistic barriers," said Dong. "A thorough understanding of Chinese Americans' cognitive risk factors is necessary to guide the development of policy and interventions to delay the onset of memory loss," Dong continued.

"Researchers, social workers, and policymakers must collaborate to reduce health disparities and expand access to culturally-sensitive care for older Chinese American adults," he continued. "Developing programs and interventions that reduce stress, increase activity engagement, and improve quality of care, is necessary to limit memory loss among the aging U.S. Chinese population."

The studies can be found in the August 2019 Journal of the American Geriatrics Society, "Special Issue: Transforming Asian Health Equity: Findings from the PINE/PIETY Study": https://onlinelibrary.wiley.com/toc/15325415/2019/67/S3

https://www.sciencedaily.com/releases/2019/08/190826121927.htm

Heart attack patients with mild cognitive impairment get fewer treatments

August 23, 2019

Science Daily/Michigan Medicine - University of Michigan

A new study finds people who have mild cognitive impairment (MCI), which lies on the continuum of cognitive decline between normal cognition and dementia, are less likely to receive proven heart attack treatment in the hospital.

Researchers found no evidence that those with MCI would derive less benefit from evidence-based treatment that's offered to their cognitively normal peers who have heart attacks, says lead author Deborah Levine, M.D., MPH.

"Patients should get the treatments they would want if they were properly informed," says Levine, an associate professor of internal medicine and neurology at Michigan Medicine, the academic medical center of the University of Michigan.

Some people with thinking, memory and language problems have MCI. Unlike dementia, which severely interferes with daily functioning and worsens over time, MCI does not severely interfere with daily functioning and might not worsen over time. Although people with MCI have an increased risk of developing dementia, it's not an inevitable next step, Levine says.

"While some may progress to dementia, many will persist in having MCI, and a few will actually improve and revert to normal cognition," says Levine, also a member of the University of Michigan Institute for Healthcare Policy and Innovation. "Many older adults with MCI live years with good quality of life, and so face common health risks of aging like heart attack and stroke.

"Clinicians, patients and families might be overestimating the risk of dementia after a mild cognitive impairment diagnosis even without realizing it. These older adults with MCI should still receive evidence-based treatments when indicated."

The research, published in the Journal of General Internal Medicine, found pre-existing MCI was associated with significantly lower use of guideline-concordant care after a heart attack, whether catheter-based or open surgery. The study measured 609 adults ages 65 and older who were hospitalized for a heart attack between 2000 and 2011.

Levine notes both cardiac catheterization (35% less likely in patients with pre-existing MCI) and coronary revascularization (45% less likely in patients with pre-existing MCI) have been shown to be highly effective at reducing deaths and improving physical functioning after heart attack in multiple large clinical trials.

'A timely issue'

Physicians must weigh the competing risks of all health problems that increase with age, Levine says, including heart disease and cognitive decline. Many families are dealing with both concerns at once in their older loved ones.

"This is a timely issue because as the population ages, the number of seniors 85 years old and older has become the fastest-growing segment of the U.S. population," Levine says. "Seniors 85 and older are most likely to have MCI, and their incidence of heart attack has surged."

However, cardiovascular disease, including heart attack and stroke, is still the leading cause of death and serious morbidity in older adults, whether they have MCI or normal cognitive functioning.

Up to 1 in 5 adults ages 65 and older has MCI, although many may be undiagnosed, Levine says. Since the Affordable Care Act mandated coverage of cognitive impairment assessments for Medicare beneficiaries, MCI diagnoses are expected to increase, she adds.

The need to question decision-making

Although much recent medical literature addresses overtreatment, Levine says this research shows undertreatment with high-value therapies can also be a problem.

Her team's ongoing research finds physicians might not be recommending invasive treatments as often after an older patient with some memory and thinking problems has a heart attack. She encourages clinicians to reflect on the influence of MCI in their decision-making.

"It's important for providers to consider whether they are recommending against treating a patient just because they have MCI," Levine says. "Physicians can think about offering treatments to all patients when clinically indicated."

Invasive treatments may not be indicated in those with advanced dementia or a limited life expectancy, she says, but MCI does not fall in that category.

This potential disconnect in provider recommendations provides an opportunity for patients and families to empower themselves by having conversations about the care they'd want if they become ill, she says. People with MCI can still participate in these types of discussions, and families don't need to wait until an event happens to start the conversation.

"In these discussions, patients and families often think about catastrophic illnesses where life support measures may be used, but heart attacks and stroke are much more common, and they're treatable," Levine says.

"Because dementia is so feared among older adults and their families, it's understandable and appropriate that it may weigh heavily on the decisions for all types of care, including heart attack care," adds co-author Kenneth Langa, M.D., Ph.D., a professor of internal medicine at Michigan Medicine and a member of the Institute for Healthcare Policy and Innovation. "Our study emphasizes the importance of differentiating between MCI and dementia and of educating patients, families and clinicians on the relative risks of further cognitive decline versus common cardiovascular conditions for people with MCI."

An ongoing effort

Levine and colleagues used data from the Health and Retirement Study, a nationally representative longitudinal study of older Americans that's based at U-M.

Heart attack, or acute myocardial infarction, was an appealing lens to research whether patients with MCI receive guideline-based treatment, Levine says. Heart attacks are acute, emergent medical problems that are common in seniors and have robust evidence of effective treatment, she adds.

Levine's team is also studying the effect of pre-existing MCI on treatment for acute ischemic stroke, and the reasons physician recommendations and patient preferences for effective treatment after stroke or heart attack might be different if the patient already has MCI.

"Studies like this are an important first step in raising awareness on MCI so that providers, like cardiologists, can make sure they offer the best therapies available during heart attacks," says senior author Brahmajee Nallamothu, M.D., MPH, an interventional cardiologist and professor of internal medicine at Michigan Medicine.

https://www.sciencedaily.com/releases/2019/08/190823182709.htm

Carriers of Alzheimer's genetic marker have greater difficulty harnessing past knowledge

August 22, 2019

Science Daily/Baycrest Centre for Geriatric Care

Adults carrying a gene associated with a higher risk of Alzheimer's disease had a harder time accessing recently acquired knowledge, even though they didn't show any symptoms of memory problems, according to findings published in a joint Baycrest-University of Oxford study.

Researchers found that older adults carrying a specific strain of the gene, apolipoprotein E4, otherwise known as APOE4, weren't able to tap into information they had just learned to assist them on a listening test.

These findings suggest greater difficulty for these individuals to access knowledge from their memory to guide their attention in ways that would have improved their performance, according to the study published in the journal Scientific Reports. This work could lead to the development of new ways to detect individuals at risk.

The research team worked with 60 research participants (aged 40 to 61) from the Oxford Biobank who had varying combinations of APOE genes -- which includes one group of individuals with a combination of APOE3/APOE4 genes, one group of individuals with a set of APOE4 genes and one group of individuals with a set of APOE3 genes. All research participants had normal hearing, scored within the normal range of cognitive assessments and completed a questionnaire about their memory.

Each research participant listened to 92 audio clips and they were told to pay attention to where the clip was coming from, whether it was presented in the left, right or both ears. After the clip was played, they were asked which side they heard the sound from and if they responded incorrectly, the sound was replayed. Participants had a one-hour break before hearing the 92 audio clips again, but this time they were asked whether there was an additional sound at the end of the clip and to press a button when they heard it. Each clip was placed twice. During the first play-through, the clip's location was replayed and during the second play-through, the additional tone was added.

The study found that no matter the APOE genotype, all older adults were able to learn the information and remember the location of the audio clip, but individuals with the APOE4 gene had greater difficulty in identifying the additional sound at the end of the clip.

"For some reason, people with the APOE4 gene were not able to take advantage of information they learned earlier, such as the expected location of the clip, to boost their performance," says Dr. Claude Alain, a senior author on the paper and senior scientist at Baycrest's Rotman Research Institute. "This study shows we have a test that is sensitive to capture problems or challenges faced by individuals with this gene, before their deficits are observed on a standard neuropsychological assessment."

This was an exciting study looking at healthy, middle-aged people who carry a gene that increases their risk of developing Alzheimer's disease by 15-fold, says Dr. Chris Butler, a senior author on the paper and an associate professor in clinical neurosciences at the University of Oxford.

"The research could lead to more sensitive methods of detecting Alzheimer's disease in its very earliest stages, the time at which treatments are most likely to be effective," says Dr. Butler. "I was delighted to carry out this work with researchers from Baycrest."

As next steps, researchers continue to explore how the brain's ability to process what is heard changes with neurodegenerative conditions, such as mild cognitive impairment.

https://www.sciencedaily.com/releases/2019/08/190822141908.htm

Insight into cells' 'self-eating' process could pave the way for new dementia treatments

August 21, 2019

Science Daily/University of Plymouth

Cells regularly go through a process called autophagy -- literally translated as 'self-eating' -- which helps to destroy bacteria and viruses after infection.

When it works, this process counteracts neurodegenerative conditions such as dementia and Huntington's Disease, by getting rid of unwanted proteins and their resultant harm to cells.

But when autophagy fails or defects occur, it can give rise to such conditions.

Now new research by the University of Plymouth has shed light on the mechanisms behind autophagy and how it progresses -- particularly relating to a process called liquid-liquid phase separation (LLPS).

The paper was published today (Wednesday 21 August) in Nature Communications, and could provide the first steps towards new treatments for neurodegenerative diseases.

What does the science tell us?

The clearance of cell wastes by autophagy is controlled by two things involving a protein called p62 -- firstly, a chemical process that sees p62 bind a number of identical molecules together (called oligomerisation), and secondly, p62's separation of molecules within cell fluid. The demixing process is called liquid-liquid phase separation (LLPS).

It is crucial to clarify how p62 LLPS is regulated in cells, and scientists have discovered that the process is facilitated by another protein called DAXX.

The study is the first to shed light on this particular protein interaction and its subsequent roles in autophagy and cell protection.

Providing new insights into autophagy, the research helps clarify a key process that might be faltering in those who develop dementia conditions.

What the scientists say

The study was led by Dr Shouqing Luo and his research group from the University of Plymouth's Institute of Translational and Stratified Medicine (ITSMed), in collaboration with Fudan University, Shanghai and Thomas Jefferson University, Philadelphia.

Dr Luo, whose work primarily focuses on finding new autophagy pathways, as well as novel treatments for dementia diseases -- using Huntington's Disease (HD) as a model -- said: "By understanding more about autophagy and the details of the processes involved, we can identify what might be going wrong, and therefore where to target when it comes to tackling neurodegenerative diseases. This research is a major step in helping us to do that.

"The next step for us is to look at applying the science within human cells, so we can further clarify how the protein interaction and the new DAXX function are relevant to neurodegenerative conditions including HD, and whether we can target it to help prevent disease progression.

"HD is an inherited disease that causes the progressive breakdown of nerve cells in the brain. It has a broad impact on a person's functional abilities and currently there is no cure, so it's vital that we continue our work to find out how and why the disease develops."

https://www.sciencedaily.com/releases/2019/08/190821082220.htm

Link between brain immune cells and Alzheimer's disease development identified

Absence of microglia prevents plaque formation

August 21, 2019

Science Daily/University of California - Irvine

Scientists from the University of California, Irvine School of Biological Sciences have discovered how to forestall Alzheimer's disease in a laboratory setting, a finding that could one day help in devising targeted drugs that prevent it.

The researchers found that by removing brain immune cells known as microglia from rodent models of Alzheimer's disease, beta-amyloid plaques -- the hallmark pathology of AD -- never formed. Their study will appear Aug. 21 in the journal Nature Communications.

Previous research has shown most Alzheimer's risk genes are turned on in microglia, suggesting these cells play a role in the disease. "However, we hadn't understood exactly what the microglia are doing and whether they are significant in the initial Alzheimer's process," said Kim Green, associate professor of neurobiology & behavior. "We decided to examine this issue by looking at what would happen in their absence."

The researchers used a drug that blocks microglia signaling that is necessary for their survival. Green and his lab have previously shown that blocking this signaling effectively eliminates these immune cells from the brain. "What was striking about these studies is we found that in areas without microglia, plaques didn't form," Green said. "However, in places where microglia survived, plaques did develop. You don't have Alzheimer's without plaques, and we now know microglia are a necessary component in the development of Alzheimer's."

The scientists also discovered that when plaques are present, microglia perceive them as harmful and attack them. However, the attack also switches off genes in neurons needed for normal brain functioning. "This finding underlines the crucial role of these brain immune cells in the development and progression of Alzheimer's," said Green.

Professor Green and colleagues say their discovery holds promise for creating future drugs that prevent the disease. "We are not proposing to remove all microglia from the brain," Professor Green said, noting the importance of microglia in regulating other brain functions. "What could be possible is devising therapeutics that affect microglia in targeted ways."

He also believes the project's research approach offers an avenue for better understanding other brain disorders.

"These immune cells are involved in every neurological disease and even in brain injury," Professor Green said. "Removing microglia could enable researchers working in those areas to determine the cells' role and whether targeting microglia could be a potential treatment."

https://www.sciencedaily.com/releases/2019/08/190821082236.htm

Alzheimer's drug reverses brain damage from adolescent alcohol exposure in rats

Results offer clues to how adolescent binge drinking changes learning, memory in young adults

August 20, 2019

Science Daily/Duke University Medical Center

A drug used to slow cognitive decline in adults with Alzheimer's disease appears to reverse brain inflammation and neuron damage in rats exposed to alcohol during adolescence.

In a study described in the journal Scientific Reports, Duke Health researchers sought to understand how intermittent binge drinking changes the hippocampus -- a region long known to be critical for learning and memory, and also linked to anxiety -- and whether the drug, donepezil, could reverse those changes. Rats were used as a model for teens and young adults who binge drink a few times a week.

"Research has begun to show that human adolescents who drink early and consistently across the adolescent years have some deficits in brain function that can affect learning and memory, as well as anxiety and social behaviors," said senior author Scott Swartzwelder, Ph.D., professor of psychiatry at Duke.

"The changes can be subtle, but who wants even subtle deficits in their brain function or how they think and feel?" Swartzwelder said. "Studies in animal models show that adolescent alcohol exposure can change the ways nerve cells communicate with each other, and the level of plasticity in brain circuits -- compromising the ability of the brain to change and adapt. These changes can be seen in adulthood -- long after the alcohol exposure has ended"

Because they can't ethically have young people drink alcohol to study its effects, researchers use the developing brains of rats to understand the effects of "intermittent alcohol exposure," resulting in blood-alcohol levels that are consistent with those achieved by human adolescent drinkers.

The scientists observed that in addition to brain inflammation, adolescent alcohol exposure inhibited the birth of new neurons in the hippocampus, Swartzwelder said, and may even accelerate neuronal death -- making it is easier to lose existing cells and more difficult to produce new ones.

Once the rats reached adulthood, they were given donepezil, a cognition-enhancing drug that is marketed under the brand name Aricept. After four days of treatment, the researchers studied the animals' brains, looking closely at the hippocampus. The rats that received donepezil in adulthood after adolescent alcohol exposure showed less inflammation and better ability to produce new neurons compared to rats that did not receive the donepezil treatment.

"We don't know if the reversal of these alcohol effects by donepezil is permanent, but it at least transiently reverses them," Swartzwelder said.

Swartzwelder said the study helps clarify the subtle health risk of heavy drinking among young adults, which has been difficult to ascertain.

"It's obvious that not everyone who drinks during adolescence grows up and completely fails at life," Swartzwelder said. "You might not notice the deficits in obvious ways every day, but you run the risk of losing your edge. Sometimes a small impairment of brain function can have a broad ripple effect in someone's life."

Importantly, the research demonstrates the potential to repair some types of damage caused by adolescent alcohol exposure, he said. But beyond that, it could also lead to a more specific understanding of the cellular mechanisms that make the developing brain particularly vulnerable to substances such as alcohol.

The research was part of the Neurobiology of Adolescent Drinking in Adulthood (NADIA) Consortium and was supported by the National Institute on Alcohol Abuse and Alcoholism and the National Institutes of Health

https://www.sciencedaily.com/releases/2019/08/190820081840.htm

Biochemists discover new insights into what may go awry in brains of Alzheimer's patients

August 19, 2019

Science Daily/University of California - Los Angeles

More than three decades of research on Alzheimer's disease have not produced any major treatment advances for those with the disorder, according to a UCLA expert who has studied the biochemistry of the brain and Alzheimer's for nearly 30 years. "Nothing has worked," said Steven Clarke, a distinguished professor of chemistry and biochemistry. "We're ready for new ideas." Now, Clarke and UCLA colleagues have reported new insights that may lead to progress in fighting the devastating disease.

Scientists have known for years that amyloid fibrils -- harmful, elongated, water-tight rope-like structures -- form in the brains of people with Alzheimer's, and likely hold important clues to the disease. UCLA Professor David Eisenberg and an international team of chemists and molecular biologists reported in the journal Nature in 2005 that amyloid fibrils contain proteins that interlock like the teeth of a zipper. The researchers also reported their hypothesis that this dry molecular zipper is in the fibrils that form in Alzheimer's disease, as well as in Parkinson's disease and two dozen other degenerative diseases. Their hypothesis has been supported by recent studies.

Alzheimer's disease, the most common cause of dementia among older adults, is an irreversible, progressive brain disorder that kills brain cells, gradually destroys memory and eventually affects thinking, behavior and the ability to carry out the daily tasks of life. More than 5.5 million Americans, most of whom are over 65, are thought to have dementia caused by Alzheimer's.

The UCLA team reports in the journal Nature Communications that the small protein beta amyloid, also known as a peptide, that plays an important role in Alzheimer's has a normal version that may be less harmful than previously thought and an age-damaged version that is more harmful.

Rebeccah Warmack, who was a UCLA graduate student at the time of the study and is its lead author, discovered that a specific version of age-modified beta amyloid contains a second molecular zipper not previously known to exist. Proteins live in water, but all the water gets pushed out as the fibril is sealed and zipped up. Warmack worked closely with UCLA graduate students David Boyer, Chih-Te Zee and Logan Richards; as well as senior research scientists Michael Sawaya and Duilio Cascio.

What goes wrong with beta amyloid, whose most common forms have 40 or 42 amino acids that are connected like a string of beads on a necklace?

The researchers report that with age, the 23rd amino acid can spontaneously form a kink, similar to one in a garden hose. This kinked form is known as isoAsp23. The normal version does not create the stronger second molecular zipper, but the kinked form does.

"Now we know a second water-free zipper can form, and is extremely difficult to pry apart," Warmack said. "We don't know how to break the zipper."

The normal form of beta amyloid has six water molecules that prevent the formation of a tight zipper, but the kink ejects these water molecules, allowing the zipper to form.

"Rebeccah has shown this kink leads to faster growth of the fibrils that have been linked to Alzheimer's disease," said Clarke, who has conducted research on biochemistry of the brain and Alzheimer's disease since 1990. "This second molecular zipper is double trouble. Once it's zipped, it's zipped, and once the formation of fibrils starts, it looks like you can't stop it. The kinked form initiates a dangerous cascade of events that we believe can result in Alzheimer's disease."

Why does beta amyloid's 23rd amino acid sometimes form this dangerous kink?

Clarke thinks the kinks in this amino acid form throughout our lives, but we have a protein repair enzyme that fixes them.

"As we get older, maybe the repair enzyme misses the repair once or twice," he said. "The repair enzyme might be 99.9% effective, but over 60 years or more, the kinks eventually build up. If not repaired or if degraded in time, the kink can spread to virtually every neuron and can do tremendous damage."

"The good news is that knowing what the problem is, we can think about ways to solve it," he added. "This kinked amino acid is where we want to look."

The research offers clues to pharmaceutical companies, which could develop ways to prevent formation of the kink or get the repair enzyme to work better; or by designing a cap that would prevent fibrils from growing.

Clarke said beta amyloid and a much larger protein tau -- with more than 750 amino acids -- make a devastating one-two punch that forms fibrils and spreads them to many neurons throughout the brain. All humans have both beta amyloid and tau. Researchers say it appears that beta amyloid produces fibrils that can lead to tau aggregates, which can spread the toxicity to other brain cells. However, exactly how beta amyloid and tau work together to kill neurons is not yet known.

In this study, Warmack produced crystals, both the normal and kinked types, in 15 of beta amyloid's amino acids. She used a modified type of cryo-electron microscopy to analyze the crystals. Cryo-electron microscopy, whose development won its creators the 2017 Nobel Prize in chemistry, enables scientists to see large biomolecules in extraordinary detail. Professor Tamir Gonen pioneered the modified microscopy, called microcrystal electron diffraction, which enables scientists to study biomolecules of any size.

https://www.sciencedaily.com/releases/2019/08/190819164346.htm

Silent' strokes common after surgery, linked to cognitive decline

August 15, 2019

Science Daily/McMaster University

The study found that 'silent' covert strokes are actually more common than overt strokes in people aged 65 or older who have surgery.

Canadian researchers have discovered that covert -- or 'silent' -- strokes are common in seniors after they have elective, non-cardiac surgery and double their risk of cognitive decline one year later.

While an overt stroke causes obvious symptoms, such as weakness in one arm or speech problems that last more than a day, a covert stroke is not obvious except on brain scans, such as MRI. Each year, approximately 0.5 per cent of the 50 million people age 65 years or greater worldwide who have major, non-cardiac surgery will suffer an overt stroke, but until now little was known about the incidence or impacts of silent stroke after surgery.

The results of the NeuroVISION study were published today in The Lancet.

"We've found that 'silent' covert strokes are actually more common than overt strokes in people aged 65 or older who have surgery," said Dr. PJ Devereaux, co-principal investigator of the NeuroVISION study. Dr. Devereaux is a cardiologist at Hamilton Health Sciences (HHS), professor in the departments of health research methods, evidence, and impact, and medicine at McMaster University, and a senior scientist at the Population Health Research Institute of McMaster University and HHS.

Dr. Devereaux and his team found that one in 14 people over age 65 who had elective, non-cardiac surgery had a silent stroke, suggesting that as many as three million people in this age category globally suffer a covert stroke after surgery each year.

NeuroVISION involved 1,114 patients aged 65 years and older from 12 centres in North and South America, Asia, New Zealand, and Europe. All patients received an MRI within nine days of their surgery to look for imaging evidence of silent stroke. The research team followed patients for one year after their surgery to assess their cognitive capabilities. They found that people who had a silent stroke after surgery were more likely to experience cognitive decline, perioperative delirium, overt stroke or transient ischaemic attack within one year, compared to patients who did not have a silent stroke.

"Over the last century, surgery has greatly improved the health and the quality of life of patients around the world," said Dr. Marko Mrkobrada, an associate professor of medicine at University of Western Ontario and co-principal investigator for the NeuroVISION study. "Surgeons are now able to operate on older and sicker patients thanks to improvements in surgical and anesthetic techniques. Despite the benefits of surgery, we also need to understand the risks."

"Vascular brain injuries, both overt and covert, are more frequently being detected, recognized and prevented through research funded by our Institute and CIHR," says Dr. Brian Rowe, scientific director of the Institute of Circulatory and Respiratory Health, Canadian Institutes of Health Research (CIHR). "The NeuroVISION Study provides important insights into the development of vascular brain injury after surgery, and adds to the mounting evidence of the importance of vascular health on cognitive decline. The results of NeuroVISION are important and represent a meaningful discovery that will facilitate tackling the issue of cognitive decline after surgery."

https://www.sciencedaily.com/releases/2019/08/190815212759.htm

Adults with mild cognitive impairment can learn and benefit from mindfulness meditation

August 15, 2019

Science Daily/Wake Forest Baptist Medical Center

A pilot study shows promising evidence that adults with MCI can learn to practice mindfulness meditation, and by doing so may boost their cognitive reserve.

There's currently no known way to prevent older adults with mild cognitive impairment (MCI) from developing Alzheimer's disease.

But there may be a safe and feasible non-pharmacological treatment that may help patients living with MCI, according to a small pilot study in the current issue of the Journal of Alzheimer's Disease led by a neurologist and researcher with Wake Forest Baptist Health.

"Until treatment options that can prevent the progression to Alzheimer's are found, mindfulness meditation may help patients living with MCI," said Rebecca Erwin Wells, M.D., M.P.H., associate professor of neurology at Wake Forest School of Medicine, a practicing neurologist at Wake Forest Baptist Medical Center and associate director of clinical research for its Center for Integrative Medicine. "Our study showed promising evidence that adults with MCI can learn to practice mindfulness meditation, and by doing so may boost their cognitive reserve."

Mindfulness means maintaining a moment-by-moment, non-judgemental awareness of thoughts, feelings, bodily sensations, and surrounding environment.

"While the concept of mindfulness meditation is simple, the practice itself requires complex cognitive processes, discipline and commitment," Wells explained. "This study suggests that the cognitive impairment in MCI is not prohibitive of what is required to learn this new skill."

Research has demonstrated that high levels of chronic stress negatively impact the hippocampus, a part of the brain involved in memory and learning, and are associated with increased incidence of MCI and Alzheimer's. Other studies have indicated that non-drug interventions such as aerobic exercise can have positive effects on cognition, stress levels and the brain.

To test whether a mindfulness-based stress-reduction (MBSR) program could benefit adults with MCI, the study team enlisted 14 men and women between the ages of 55 and 90 with clinically diagnosed MCI and randomized them to either an eight-week course involving mindfulness meditation and yoga or a "waiting list" control group.

The researchers previously reported that the nine participants who completed the MBSR program showed trends toward improvements on measures of cognition and well-being and indications of positive impacts on the hippocampus as well as other areas of the brain associated with cognitive decline.

The newly published study adds context to those quantitative findings with a qualitative analysis of the MBSR participants' responses in interviews conducted at the end of the eight-week course.

"While the MBSR course was not developed or structured to directly address MCI, the qualitative interviews revealed new and important findings specific to MCI," Wells said. "The participants' comments and ratings showed that most of them were able to learn the key tenets of mindfulness, demonstrating that the memory impairment of MCI does not preclude learning such skills."

Those participants who practiced at least 20 minutes a day were most likely to have understood the underlying concepts of mindfulness, Wells noted.

The limitations of the study include the small sample size and that the results may not generalize to all patients with MCI, as two-thirds of the participants in this study had a college education or more. Additional research is needed to further test the preliminary hypotheses contained in this study.

The research was originally conducted at Beth Israel Deaconess Medical Center in Boston and Harvard Medical School. The study was supported by the Harvard Medical School Osher Research Center, the Division of General Medicine and Primary Care at Beth Israel Deaconess Medical Center and the National Center for Complementary and Integrative Health of the National Institutes of Health

https://www.sciencedaily.com/releases/2019/08/190815140852.htm

Dementia care program improves mental health of patients, caregivers

August 14, 2019

Science Daily/University of California - Los Angeles Health Sciences

UCLA-led research finds that a comprehensive dementia care program staffed by nurse practitioners working within a health system improves the mental and emotional health of patients and their caregivers.

While the program did not slow the progression of dementia, it did reduce patients' behavioral problems and depression, and lower the distress of caregivers, the researchers found.

The paper is published in the peer-reviewed Journal of the American Geriatrics Society.

The findings, based on data from the UCLA Alzheimer's and Dementia Care Program, suggest that such programs are a promising approach toward improving the psychological health of patients and caregivers, said Dr. David Reuben, chief of the UCLA Division of Geriatrics at the David Geffen School of Medicine at UCLA, and the study's lead author.

"Although the program was implemented at only one site, the principles of the program and model of care can be adopted and adapted to fit other health systems," he said.

The researchers examined data from people with dementia and their caregivers after a year of enrollment in UCLA's program. Participants were enrolled in the program from July 2012 to December 2014.

To determine outcomes for patients and caregivers, the researchers measured patients' cognition, ability to function and depressive symptoms. They also gauged the caregivers' emotional state and the financial, physical, psychological and social effects of the strain they experience. Caregivers typically are family members, who tend to the needs of spouses, partners or parents with dementia, a progressive condition that has no cure.

The researchers found that for 58% of 543 patients and 63% of 447 caregivers, symptoms improved or minor symptoms were maintained.

Results of the research, which was an observational study, suggest there are other effective ways to help the 6 million Americans affected by Alzheimer's or other dementias, Reuben noted.

"This study shows that providing high quality of care for persons with dementia, and providing caregiver support and education, can make a difference in health outcomes that are important to people," Reuben said.

https://www.sciencedaily.com/releases/2019/08/190814092431.htm

Migraine diagnoses positively associated with all-cause dementia

August 14, 2019

Science Daily/IOS Press

Several studies have recently focused on the association between migraine headaches and other headaches and dementia and found a positive migraine-dementia relationship. However, most of these studies have failed to simultaneously adjust for several common comorbidities, thus potentially introducing bias into their findings.

The goal of the present study, which will be published in the next issue of the Journal of Alzheimer's Disease, was to investigate the association between migraine diagnoses and dementia in patients followed in general practices in the United Kingdom.

This study was based on data from the Disease Analyzer database (IQVIA), which compiles drug prescriptions, diagnoses, and basic medical and demographic data obtained directly and in anonymous format from computer systems used in the practices of general practitioners and specialists.

The current study sample included patients who had received a migraine diagnosis in one of 67 general practices in the UK between January 1997 and December 2016 (index date). Inclusion criteria were as follows: an observation time of at least 12 months prior to the index date; a follow-up time of at least 12 months after the index date; aged between 60 and 80 years at the index date; and no diagnosis of dementia or mild cognitive impairment prior to or at the index date. After applying similar inclusion criteria, patients without migraine diagnoses were matched 1:1 to patients with migraine diagnoses based on propensity scores using a greedy algorithm and derived from the logistic regression using age, sex, index year, and co-diagnoses (i.e. diabetes mellitus, hyperlipidemia, coronary heart disease, stroke including transient ischemic attack, depression, intracranial injury, mental and behavioral disorders due to alcohol use, epilepsy, Parkinson's disease, osteoporosis). The index date for participants without migraine diagnoses was a randomly selected visit between January 1997 and December 2016. The main outcome of the study was the incidence of dementia as a function of migraine diagnosis within 10 years of the index date.

The present study included 3,727 individuals with and 3,727 individuals without a migraine diagnosis. Mean age was 67.7 years and 72.9% of patients were women. Within 10 years of the index date, 5.2% of the participants with and 3.7% of the participants without migraine diagnoses were diagnosed with dementia (p-value<0.001). The respective figures were 5.8% and 3.6% in women (p-value<0.001) and 4.5% and 3.4% in men (p-value=0.722).

However, a positive association between migraine diagnoses and all-cause dementia and Alzheimer's disease was only significant in women (Hazard Ratio (HR): 1.65; Alzheimer's disease: HR=2.27), not in men.

"Several biological and clinical hypotheses may explain the association between migraine headaches and dementia," explained Dr. Louis Jacob, PhD, from the University of Versailles Saint-Quentin-en-Yvelines. "For example, migraine headaches involve chronic pain, which has been found to substantially impact the risk of memory decline and dementia. As women usually have more severe migraine attacks, the risk of dementia in women with migraine could be higher than in men with migraine."

"We have conducted several studies focused on dementia in recent years," noted corresponding author Prof. Karel Kostev, PhD, from the Epidemiology Department of IQVIA (Germany). "We have been able to identify positive associations between osteoporosis and dementia and between epilepsy and dementia, but have also observed the negative association between some antiepileptic, antidepressant, and antihypertensive drugs and dementia incidence. Such findings demonstrate the significant role of anonymous patient data in epidemiology research for helping people recognize and avoid health risk factors in the future."

The authors of the study also noted that "further studies are warranted to gain a better understanding of the underlying mechanisms of the migraine-dementia relationship and the different sexes in the association between migraine and dementia."

The three major strengths of this study are the large number of patients available for analysis, the use of real-world data including several comorbidities, and the matched-pair design.

However, this study also has two major limitations. Although the prevalence of migraine headaches is the highest in young adults and tends to decrease with age, this study only included participants aged between 60 and 80 years, thus potentially introducing a bias into the statistical analyses. Furthermore, headaches related to an underlying ischemic cerebral lesion are frequently misdiagnosed as migraine headaches in the elderly, which may have affected the results of the present study.

https://www.sciencedaily.com/releases/2019/08/190814090605.htm

Abnormal blood pressure in middle and late life influences dementia risk

August 14, 2019

Science Daily/Johns Hopkins Medicine

In a study that spanned two and a half decades and looked at data from more than 4,700 participants, Johns Hopkins researchers have added to evidence that abnormal blood pressure in midlife persisting into late life increases the likelihood of developing dementia. Although not designed to show cause and effect, the study suggests that maintaining a healthy blood pressure throughout life may be one way to help decrease one's risk of losing brain function.

"Our results suggest that one's blood pressure during midlife may influence how blood pressure later in life relates to dementia risk," says Keenan Walker, Ph.D., assistant professor of neurology at the Johns Hopkins University School of Medicine. "We found that individuals with high blood pressure in midlife may benefit from targeting their blood pressure to normal levels in later life, as having blood pressure that is too high or too low in late life may further increase dementia risk."

In their study, they found that those people with the high blood pressure condition hypertension during middle age and during late life were 49% more likely to develop dementia than those with normal blood pressure at both times. But, putting one at even greater risk was having hypertension in middle age and then having low blood pressure in late life, which increased one's dementia risk by 62%. The findings were published Aug. 13 in JAMA.

High blood pressure was considered any measurement more than 140/90 millimeters of mercury, whereas low blood pressure was defined as less than 90/60 millimeters of mercury. A cognitive exam, caregiver reports, hospitalization discharge codes and death certificates were used to classify participant brain function and determine cognitive impairment.

High blood pressure can be genetic, but can also be the result of not enough exercise and poor diet. As people age, the top blood pressure number (systolic) oftentimes increases while the bottom number (diastolic) can decrease due to structural changes in the blood vessels. Walker says dementia itself may lead to a lowering of blood pressure, as it may disrupt the brain's autonomic nervous system. Stiffening of the arteries from disease and physical frailty can also lead to low blood pressure in late life.

According to the Centers for Disease Control and Prevention, 75 million people in the U.S. have high blood pressure, and high blood pressure can raise the risk for heart disease, as well as other health conditions.

https://www.sciencedaily.com/releases/2019/08/190814081221.htm

Genes linked to Alzheimer's risk, resilience ID'd

Genes in the brain's immune cells may point to strategy to protect against the disease

August 14, 2019

Science Daily/Washington University School of Medicine

An international team of researchers led by scientists at Washington University School of Medicine in St. Louis has identified a pair of genes that influence risk for both late-onset and early-onset Alzheimer's disease.

Most genes implicated thus far in Alzheimer's affect neurons that transmit messages, allowing different regions of the brain to communicate with one another. But the newly identified genes affect an entirely different population of cells: the brain's immune cells. The findings, published online Aug. 14 in the journal Science Translational Medicine, could provide scientists with new targets and a strategy for delaying the onset of Alzheimer's symptoms.

The genes -- known as MS4A4A and TREM2 -- operate in the microglia, the brain's immune cells. They influence Alzheimer's risk by altering levels of TREM2, a protein that is believed to help microglia cells clear excessive amounts of the Alzheimer's proteins amyloid and tau from the brain.

"The findings point to a new therapeutic strategy," said co-senior investigator Carlos Cruchaga, PhD, a professor of psychiatry and director of the NeuroGenomics and Informatics Group. "If we can do something to raise levels of the TREM2 protein in the cerebrospinal fluid, we may be able to protect against Alzheimer's disease or slow its development."

In this study, the researchers measured soluble TREM2 levels in the cerebrospinal fluid of 813 older adults, most of whom were ages 55 to 90. Of those subjects, 172 had Alzheimer's disease, 169 were cognitively normal, and another 183 had early mild cognitive impairment. They also analyzed the participants' DNA, conducting genomewide association studies to look for regions of the genome that may influence TREM2 levels in the cerebrospinal fluid.

Although variants in TREM2 are found in a very small percentage of patients with Alzheimer's disease, the gene previously had been linked to the disorder. People who carried those previously identified risk mutations were excluded from the study. Common variants in the MS4A4A gene also had been associated with risk for Alzheimer's, but this study connects those genes.

"We observed TREM2 risk variants more often in people who had Alzheimer's or were mildly cognitively impaired, compared with those who were cognitively normal," said co-senior investigator Celeste Karch, PhD, an assistant professor in the Department of Psychiatry. "It turns out that about 30 percent of the population in the study had variations in the MS4A4A gene that appear to affect their risk for developing Alzheimer's disease. Some variants protected people from Alzheimer's or made them more resilient while others increased their risk."

When the researchers dug further, they noted that variants in the MS4A4A gene cluster linked to an increase in risk for developing Alzheimer's disease are associated with lower levels of soluble TREM2 protein. The other variant, associated with higher levels of TREM2 in the cerebrospinal fluid, seemed to protect against Alzheimer's.

The research team validated its results in DNA from another 580 older adults. Once again, they found that higher soluble TREM2 levels in the cerebrospinal fluid seemed protective, while lower levels increased risk. And those protein levels -- whether high or low -- were linked to variants in the MS4A4A gene.

"For the past several years, we've been looking at TREM2 and increasing our focus on the involvement of the brain's immune cells in Alzheimer's disease" said another co-senior author, Bruno A. Benitez, MD, an assistant professor of psychiatry. "These findings give us a new therapeutic strategy to pursue, one focusing not only on neurons but on how the microglia may be involved in helping to clear damaging proteins, such as beta amyloid and tau, that are linked to Alzheimer's disease."

Those gene variants also may play a role in other diseases of the central nervous system, according to Laura Piccio, MD, PhD, an associate professor of neurology and another co-senior author.

"By combining large genetic and spinal fluid analyses with laboratory work, we have provided strong evidence of a biological link between TREM2 and proteins in the MS4A gene cluster, both of which previously had been associated with Alzheimer's disease," Piccio said. "We are beginning to elucidate a molecular pathway in microglia that could be critical not only in Alzheimer's disease but also in other neurodegenerative and inflammatory diseases in the central nervous system."

https://www.sciencedaily.com/releases/2019/08/190814140501.htm

Greater blood pressure control linked to better brain health

August 13, 2019

Science Daily/University of Texas at Austin

For adults with high blood pressure, greater blood pressure control than what's currently considered standard is associated with fewer adverse changes of the brain, which could mean lower risks of dementia and cognitive impairment, according to new research published in the Journal of the American Medical Association.

Specifically, the magnetic resonance imaging (MRI) study of 449 adults showed that those with high blood pressure who achieved systolic blood pressure of less than 120 mm Hg -- known as "intensive" blood pressure control -- had a small but significantly lower amount of white matter lesions on their brain but a slightly greater decrease in brain volume than similar patients who achieved the current standard for healthy blood pressure of 140 mm Hg.

"The great news from this research is that high blood pressure is a treatable condition, and if you treat high blood pressure aggressively, you could have a positive benefit on cognition and brain structure," said R. Nick Bryan, M.D., Ph.D., chair and professor of the Department of Diagnostic Medicine at Dell Medical School at The University of Texas at Austin. "Though the benefit may be small, it's one of the few impactful cognition-related interventions we have."

White matter brain lesions are well-documented to be associated with a greater likelihood or intensity of cognitive decline. According to the American Heart Association, high blood pressure is considered 130 mm Hg or higher.

The current study supports the findings of a related study published in January that showed intensive blood pressure control is associated with fewer incidents of cognitive adverse events. Both studies were part of a larger body of NIH-funded research known as Systolic Blood Pressure Intervention Trial (SPRINT), designed to determine the protective value of lower blood pressure for heart, kidney and brain health. Previous research within SPRINT also showed that intensive blood pressure control among people with hypertension is linked to better outcomes in terms of risks of heart attack, heart failure and death.

In the current study, researchers compared MRI scans of adults age 50 and older, average age 67 years old, with systolic blood pressure between 130 and 180 mm Hg at baseline and four years later, noting white matter lesions and brain volume.

The next step in this investigation is to understand the effects of intensive blood pressure control among younger adults, such as those in their 40s, said Bryan. "We need to understand how aggressive should we be with blood pressure control when we're earlier on in the process," he said.

https://www.sciencedaily.com/releases/2019/08/190813130435.htm

Gene linked to Alzheimer's disease is involved in neuronal communication

August 13, 2019

Science Daily/Baylor College of Medicine

A study published today in the journal Cell Reports sheds new light on how the CD2AP gene may enhance Alzheimer's disease susceptibility.

Integrating experiments in fruit flies, mice and human brains, a multi-institutional team led by researchers at Baylor College of Medicine found that the CD2AP gene is involved in synaptic transmission, the process by which neurons communicate. 

Digging deeper, the researchers discovered that CD2AP affects neuronal communication by regulating the levels of key regulatory proteins present at neuron terminals (synapses).

Dr. Joshua Shulman, associate professor of neurology at Baylor and corresponding author of the work, explains that they first worked with the laboratory fruit fly to test the effect of deleting the gene in the brain. 

The team deleted the fly equivalent of the human CD2AP gene, called cindr, and observed evidence of defective synapse structure and function. They also found that certain proteins accumulated more in the synapses of mutant flies. Among the accumulated proteins were several that regulate neural communication. 

To connect these findings with Alzheimer's disease, Shulman and his colleagues also studied a mouse in which the CD2AP gene was deleted and discovered brain changes similar to those they had found in flies. Finally, in order to establish relevance for humans, they examined a collection of more than 800 brain autopsies. 

Shulman and colleagues found that low CD2AP levels significantly correlated with abnormal turnover of synaptic proteins, and this relationship was enhanced in the setting of Alzheimer's disease.

https://www.sciencedaily.com/releases/2019/08/190813131635.htm

An alternate theory for what causes Alzheimer's disease

An alternate theory for what causes Alzheimer's disease

August 12, 2019

Science Daily/University of California - Riverside

Alzheimer's disease, the most common cause of dementia among the elderly, is characterized by plaques and tangles in the brain, with most efforts at finding a cure focused on these abnormal structures. But a University of California, Riverside, research team has identified alternate chemistry that could account for the various pathologies associated with the disease.

Plaques and tangles have so far been the focus of attention in this progressive disease that currently afflicts more than 5.5 million people in the United States. Plaques, deposits of a protein fragment called beta-amyloid, look like clumps in the spaces between neurons. Tangles, twisted fibers of tau, another protein, look like bundles of fibers that build up inside cells.

"The dominant theory based on beta-amyloid buildup has been around for decades, and dozens of clinical trials based on that theory have been attempted, but all have failed," said Ryan R. Julian, a professor of chemistry who led the research team. "In addition to plaques, lysosomal storage is observed in brains of people who have Alzheimer's disease. Neurons -- fragile cells that do not undergo cell division -- are susceptible to lysosomal problems, specifically, lysosomal storage, which we report is a likely cause of Alzheimer's disease."

Study results appear in ACS Central Science, a journal of the American Chemical Society.

An organelle within the cell, the lysosome serves as the cell's trashcan. Old proteins and lipids get sent to the lysosome to be broken down to their building blocks, which are then shipped back out to the cell to be built into new proteins and lipids. To maintain functionality, the synthesis of proteins is balanced by the degradation of proteins.

The lysosome, however, has a weakness: If what enters does not get broken down into little pieces, then those pieces also can't leave the lysosome. The cell decides the lysosome is not working and "stores" it, meaning the cell pushes the lysosome to the side and proceeds to make a new one. If the new lysosome also fails, the process is repeated, resulting in lysosome storage.

"The brains of people who have lysosomal storage disorder, another well-studied disease, and the brains of people who have Alzheimer's disease are similar in terms of lysosomal storage," Julian said. "But lysosomal storage disorder symptoms show up within a few weeks after birth and are often fatal within a couple of years. Alzheimer's disease occurs much later in life. The time frames are, therefore, very different."

Julian's collaborative team of researchers in the Department of Chemistry and the Division of Biomedical Sciences at UC Riverside posits that long-lived proteins can undergo spontaneous modifications that can make them undigestible by the lysosomes.

"Long-lived proteins become more problematic as we age and could account for the lysosomal storage seen in Alzheimer's, an age-related disease," Julian said. "If we are correct, it would open up new avenues for treatment and prevention of this disease."

He explained that the changes occur in the fundamental structure of the amino acids that make up the proteins and is the equivalent of flipping the handedness of the amino acids, with amino acids spontaneously acquiring the mirror images of their original structures.

"Enzymes that ordinarily break down the protein are then not able to do so because they are unable to latch onto the protein," Julian added. "It's like trying to fit a left-handed glove on your right hand. We show in our paper that this structural modification can happen in beta-amyloid and tau, proteins relevant to Alzheimer's disease. These proteins undergo this chemistry that is almost invisible, which may explain why researchers have not paid attention to it."

Julian explained these spontaneous changes in protein structure are a function of time, taking place if the protein hangs around for too long.

"It's been long known that these modifications happen in long-lived proteins, but no one has ever looked at whether these modifications could prevent the lysosomes from being able to break down the proteins," he said. "One way to prevent this would be to recycle the proteins so that they are not sitting around long enough to go through these chemical modifications. Currently, no drugs are available to stimulate this recycling -- a process called autophagy -- for Alzheimer's disease treatment."

The research was done in the lab on living cells provided by Byron D. Ford, a professor of biomedical sciences in the School of Medicine. The findings could have implications for other age-related diseases such as macular degeneration and cardiac diseases linked to lysosomal pathology.

Julian and Ford were joined in the research by Tyler R. Lambeth (co-first author), Dylan L. Riggs (co-first author), Lance E. Talbert, Jin Tang, Emily Coburn, Amrik S. Kang, Jessica Noll, and Catherine Augello.

Next, the team will examine the extent of the protein modifications in human brains as a function of age. The researchers will study brains of people with Alzheimer's disease as well as of people not afflicted by it.

Grants from the National Institutes of Health supported the study.

https://www.sciencedaily.com/releases/2019/08/190812144930.htm