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

Mapping the structure of protein aggregate that leads to Alzheimer's

August 12, 2019

Science Daily/Binghamton University

A research team including faculty at Binghamton University and University of Colorado Denver are the first to map the molecular structure of an aggressive protein aggregate that causes acceleration of Alzheimer's disease.

"Approximately 10 percent of Alzheimer's cases result from familial mutations," said Wei Qiang, assistant professor of biophysical chemistry at Binghamton University. "The other 90 percent cases are caused by misfolded wild-type amyloid proteins. We need to understand the molecular basis of the disease pathology. In doing so, we might one day create drugs that prevent the degenerative effects of the disease."

Alzheimer's disease starts developing when toxic protein fragments called beta amyloids form into chains known as fibrils, which build upon and kill brain cells. Qiang, along with researchers at the University of Colorado Denver, used high-resolution solid-state nuclear magnetic resonance spectroscopy to study these fibrils. Their work revealed that these fibrils may possess major variations in the molecular structure of amyloid depositions in the human brain. More importantly, the fibrils could serve as "seeds" for further fibril deposition, which is a potential risk factor in Alzheimer's pathology.

"This work describes a molecular structural model for a pathologically relevant beta-amyloid fibril variant," said Qiang. "We showed that this variant could lead to rapid seeding of new amyloid fibrils, which potentially contributes to the spreading and amplification of amyloid deposition in human brains."

Qiang and his team are looking at several other types of fibril variants and specifically, the correlation between the structural variations, their seeding abilities and the resulted cellular toxicity levels.

"We have already obtained exciting results and a new manuscript describing these further finding is in preparation," said Qiang.

https://www.sciencedaily.com/releases/2019/08/190812144924.htm

Tissue model reveals role of blood-brain barrier in Alzheimer's

Tissue model reveals role of blood-brain barrier in Alzheimer's

August 12, 2019

Science Daily/Massachusetts Institute of Technology

A new study shows how the Alzheimer's disease allows toxins to pass through the blood-brain barrier, further harming neurons.

Beta-amyloid plaques, the protein aggregates that form in the brains of Alzheimer's patients, disrupt many brain functions and can kill neurons. They can also damage the blood-brain barrier -- the normally tight border that prevents harmful molecules in the bloodstream from entering the brain.

MIT engineers have now developed a tissue model that mimics beta-amyloid's effects on the blood-brain barrier, and used it to show that this damage can lead molecules such as thrombin, a clotting factor normally found in the bloodstream, to enter the brain and cause additional damage to Alzheimer's neurons.

"We were able to show clearly in this model that the amyloid-beta secreted by Alzheimer's disease cells can actually impair barrier function, and once that is impaired, factors are secreted into the brain tissue that can have adverse effects on neuron health," says Roger Kamm, the Cecil and Ida Green Distinguished Professor of Mechanical and Biological Engineering at MIT.

The researchers also used the tissue model to show that a drug that restores the blood-brain barrier can slow down the cell death seen in Alzheimer's neurons.

Kamm and Rudolph Tanzi, a professor of neurology at Harvard Medical School and Massachusetts General Hospital, are the senior authors of the study, which appears in the journal Advanced Science. MIT postdoc Yoojin Shin is the paper's lead author.

Barrier breakdown

The blood vessel cells that make up the blood-brain barrier have many specialized proteins that help them to form tight junctions -- cellular structures that act as a strong seal between cells.

Alzheimer's patients often experience damage to brain blood vessels caused by beta-amyloid proteins, an effect known as cerebral amyloid angiopathy (CAA). It is believed that this damage allows harmful molecules to get into the brain more easily. Kamm decided to study this phenomenon, and its role in Alzheimer's, by modeling brain and blood vessel tissue on a microfluidic chip.

"What we were trying to do from the start was generate a model that we could use to understand the interactions between Alzheimer's disease neurons and the brain vasculature," Kamm says. "Given the fact that there's been so little success in developing therapeutics that are effective against Alzheimer's, there has been increased attention paid to CAA over the last couple of years."

His lab began working on this project several years ago, along with researchers at MGH who had engineered neurons to produce large amounts of beta-amyloid proteins, just like the brain cells of Alzheimer's patients.

Led by Shin, the researchers devised a way to grow these cells in a microfluidic channel, where they produce and secrete beta-amyloid protein. On the same chip, in a parallel channel, the researchers grew brain endothelial cells, which are the cells that form the blood-brain barrier. An empty channel separated the two channels while each tissue type developed.

After 10 days of cell growth, the researchers added collagen to the central channel separating the two tissue types, which allowed molecules to diffuse from one channel to the other. They found that within three to six days, beta-amyloid proteins secreted by the neurons began to accumulate in the endothelial tissue, which led the cells to become leakier. These cells also showed a decline in proteins that form tight junctions, and an increase in enzymes that break down the extracellular matrix that normally surrounds and supports blood vessels.

As a result of this breakdown in the blood-brain barrier, thrombin was able to pass from blood flowing through the leaky vessels into the Alzheimer's neurons. Excessive levels of thrombin can harm neurons and lead to cell death.

"We were able to demonstrate this bidirectional signaling between cell types and really solidify things that had been seen previously in animal experiments, but reproduce them in a model system that we can control with much more detail and better fidelity," Kamm says.

Plugging the leaks

The researchers then decided to test two drugs that have previously been shown to solidify the blood-brain barrier in simpler models of endothelial tissue. Both of these drugs are FDA-approved to treat other conditions. The researchers found that one of these drugs, etodolac, worked very well, while the other, beclomethasone, had little effect on leakiness in their tissue model.

In tissue treated with etodolac, the blood-brain barrier became tighter, and neurons' survival rates improved. The MIT and MGH team is now working with a drug discovery consortium to look for other drugs that might be able to restore the blood-brain barrier in Alzheimer's patients.

"We're starting to use this platform to screen for drugs that have come out of very simple single cell screens that we now need to validate in a more complex system," Kamm says. "This approach could offer a new potential form of Alzheimer's treatment, especially given the fact that so few treatments have been demonstrated to be effective."

https://www.sciencedaily.com/releases/2019/08/190812130834.htm

Alzheimer's disease destroys neurons that keep us awake

Study suggests Tau tangles, not amyloid plaques, drive daytime napping that precedes dementia

August 12, 2019

Science Daily/University of California - San Francisco

Researchers and caregivers have noted that excessive daytime napping can develop long before the memory problems associated with Alzheimer's disease begin to unfold. Prior studies have considered this excessive daytime napping to be compensation for poor nighttime sleep caused by Alzheimer's-related disruptions in sleep-promoting brain regions, while others have argued that the sleep problems themselves contribute to the progression of the disease. But now UC San Francisco scientists have provided a striking new biological explanation for this phenomenon, showing instead that Alzheimer's disease directly attacks brain regions responsible for wakefulness during the day.

The new research demonstrates that these brain regions (including the part of the brain impacted by narcolepsy) are among the first casualties of neurodegeneration in Alzheimer's disease, and therefore that excessive daytime napping -- particularly when it occurs in the absence of significant nighttime sleep problems -- could serve as an early warning sign of the disease. In addition, by associating this damage with a protein known as tau, the study adds to evidence that tau contributes more directly to the brain degeneration that drives Alzheimer's symptoms than the more extensively studied amyloid protein.

"Our work shows definitive evidence that the brain areas promoting wakefulness degenerate due to accumulation of tau -- not amyloid protein -- from the very earliest stages of the disease," said study senior author Lea T. Grinberg, MD, PhD, an associate professor of neurology and pathology at the UCSF Memory and Aging Center and a member of the Global Brain Health Institute and UCSF Weill Institute for Neurosciences.

Wakefulness Centers Degenerate in Alzheimer's Brains

In the new study, published August 12, 2019 in Alzheimer's and Dementia, lead author Jun Oh, a Grinberg lab research associate, and colleagues precisely measured Alzheimer's pathology, tau protein levels and neuron numbers in three brain regions involved in promoting wakefuless from 13 deceased Alzheimer's patients and seven healthy control subjects, which were obtained from the UCSF Neurodegenerative Disease Brain Bank.

Compared to healthy brains, Oh and colleagues found that the brains of Alzheimer's patients had significant tau buildup in all three wakefulness-promoting brain centers they studied -- the locus coeruleus (LC), lateral hypothalamic area (LHA), and tuberomammillary nucleus (TMN) -- and that these regions had lost as many as 75 percent of their neurons.

"It's remarkable because it's not just a single brain nucleus that's degenerating, but the whole wakefulness-promoting network," Oh said. "Crucially this means that the brain has no way to compensate because all of these functionally related cell types are being destroyed at the same time."

Oh and colleagues also studied brain samples from seven patients with progressive supranuclear palsy (PSP) and corticobasal disease (CBD), two distinct forms of neurodegenerative dementia caused by tau accumulation. In contrast to the Alzheimer's disease brains, wakefulness-promoting neurons appeared to be spared in the PSP and CBD brains, despite comparable levels of tau buildup in these tissue samples.

"It seems that the wakefulness-promoting network is particularly vulnerable in Alzheimer's disease," Oh said. "Understanding why this is the case is something we need to follow up in future research."

Studies point to role of tau protein in Alzheimer's symptoms

The new results are in line with an earlier study by Grinberg's group which showed that people who died with elevated levels of tau protein in their brainstem -- corresponding to the earliest stages of Alzheimer's disease -- had already begun to experience changes in mood, such as anxiety and depression, as well as increased sleep disturbances.

"Our new evidence for tau-linked degeneration of the brain's wakefulness centers provides a compelling neurobiological explanation for those findings," Grinberg said. "It suggests we need to be much more focused on understanding the early stages of tau accumulation in these brain areas in our ongoing search for Alzheimer's treatments."

These studies add to a growing recognition among some researchers that tau buildup is more closely linked to the actual symptoms of Alzheimer's than the more widely studied amyloid protein, which has so far failed to yield effective Alzheimer's therapies.

For instance, another recent study by the Grinberg lab measured tau buildup in the brains of patients who died with different clinical manifestations of Alzheimer's disease, including variants that involved language impairment or visual problems instead of more typical memory loss. They found that differences in local tau burden in these patients' brains closely matched their symptoms: patients with language impairments had more tau accumulation in language related brain areas than in memory regions, while patients with visual problems had higher tau levels in visual brain areas.

"This research adds to a growing body of work showing that tau burden is likely a direct driver of cognitive decline," Grinberg said.

Increased focus on the role of tau in Alzheimer's suggests that treatments currently in development at UCSF's Memory and Aging Center and elsewhere that directly tackle tau pathology have the potential to improve sleep and other early symptoms of Alzheimer's disease, in addition to holding a key to slowing the progress of the disease overall, the authors say.

https://www.sciencedaily.com/releases/2019/08/190812075523.htm

Depression symptoms in Alzheimer's could be signs for cognitive decline

August 9, 2019

Science Daily/Massachusetts General Hospital

Depression symptoms in cognitively healthy older individuals together with brain amyloid, a biological marker of Alzheimer's could trigger changes in memory and thinking over time.

Increasingly, Alzheimer's disease (AD) research has focused on the preclinical stage, when people have biological evidence of AD but no or minimal symptoms, and when interventions might have the potential to prevent future decline of older adults. Researchers from Massachusetts General Hospital (MGH) have shed important new light on this area, reporting in a study published in JAMA Network Open that depression symptoms in cognitively healthy older individuals together with brain amyloid, a biological marker of AD, could trigger changes in memory and thinking over time.

"Our research found that even modest levels of brain amyloid deposition can impact the relationship between depression symptoms and cognitive abilities," says Jennifer Gatchel, MD, PhD, of the MGH Division of Geriatric Psychiatry, and lead author of the study. "This raises the possibility that depression symptoms could be targets in clinical trials aimed at delaying the progression of Alzheimer's disease. Further research is needed in this area"

Past research has shown an association between depression and cognitive deficits in older individuals. The MGH study, however, is among the first to reveal that this association is influenced by the presence of cortical amyloid in unimpaired older adults, even when depression symptoms are mild to moderate. Data were collected by researchers over a seven-year period from 276 community-dwelling older adults, all participants in the landmark Harvard Aging Brain Study (HABS). What they discovered was a significant link between worsening depression symptoms and declining cognition over two to seven years that was influenced by AD pathology, as measured by PET imaging of brain amyloid.

"Our findings offer evidence that in healthy older adults, depression symptoms together with brain amyloid may be associated with early changes in memory and in thinking," explains Gatchel. "Depression symptoms themselves may be among the early changes in the preclinical stages of dementia syndromes. Just as importantly, these stages represent a clinical window of opportunity for closely monitoring at-risk individuals, and for potentially introducing interventions to prevent or slow cognitive decline."

MGH researchers also learned from their extensive work that not all older adults with depression symptoms and cortical amyloid will experience failing cognition. Other risk factors investigated by the authors that could modify the relationship between depression and cognition include brain metabolism and volume of the hippocampus, the part of the brain associated with learning and forming of new memories. The authors also note that other mechanisms, including tau-mediated neurodegeneration, hypertension, hypercortisolemia and inflammation, may be involved and need to be investigated.

"These findings underscore the fact that depression symptoms are multi-factorial and may actually work synergistically with amyloid and related processes to affect cognition over time in older adults," notes Gatchel. "This is an area we will continue to actively study."

https://www.sciencedaily.com/releases/2019/08/190809113023.htm

Positive effect of music and dance on dementia proven by New Zealand study

August 8, 2019

Science Daily/University of Otago

A pilot study has shown the powerful influence music and dance can have on older adults with dementia.

Stereotypically viewed as passive and immobile, older adults with dementia seem to have experienced an improved quality of life after exposure to music and dance through a University of Otago, New Zealand, pilot study.

Researchers from the Department of Dance and Department of Psychological Medicine used familiar, reminiscent music and the natural gestures of a group of 22 participants to create an original series of dance exercises.

Lead author Ting Choo, Dance Studies Masters graduate, says the aim was to promote a better quality of life for people with dementia by providing memory stimulation, mood moderation and social interaction.

Performed over 10 weekly sessions, the intuitive movement re-embodiment (IMR) programme provided humour, imagination, and intuition which motivated the participants to dance and interact with joy.

The study results, published in the American Journal of Alzheimer's Disease & Other Dementias, show participants reported significant improvements in their quality of life after session six.

"They responded to the music greatly and showed enthusiasm in moving to the music regardless of their physical limitation. Positive responses such as memory recalling, spontaneous dancing and joking with each other were observed in every session.

"These observations have certainly reversed the stereotypical understanding of this group of people being passive and immobile. The music stimulates their responses much better than verbal instructions," Ms Choo says.

The researchers now intend to expand the pilot study, refining and enlarging the IMR programme to better cater to the needs and conditions of the participants.

Ms Choo hopes further research will gain the programme support and recognition from the medical community.

"There is scope for future exploration of creativity and dementia."

She believes the use of arts, including painting, music, drama and dance, has been undervalued in the clinical field, due to a lack of standardized conduct and consistent study results.

"As a former dancer and current dance educator, I understand the 'less important role' of arts in the society, as well as the insignificant therapeutic effects of music and dance for dementia, when compared to clinical research of much larger scale," she says.

https://www.sciencedaily.com/releases/2019/08/190808091401.htm

###

Good heart health at age 50 linked to lower dementia risk later in life

Findings support policies to improve midlife cardiovascular health to promote later brain health

August 7, 2019

Science Daily/BMJ

Good cardiovascular health at age 50 is associated with a lower risk of dementia later in life, finds a study of British adults published by The BMJ today.

The researchers say their findings support public health policies to improve cardiovascular health in middle age to promote later brain health.

Dementia is a progressive disease that can start to develop 15-20 years before any symptoms appear, so identifying factors that might prevent its onset is important.

The American Heart Association's "Life Simple 7" cardiovascular health score, initially designed for cardiovascular disease, has been put forward as a potential tool for preventing dementia.

Designed for "primordial" prevention, where the aim is to prevent the development of risk factors themselves in order to affect risk of disease, it is the sum of four behavioural (smoking, diet, physical activity, body mass index) and three biological (fasting glucose, blood cholesterol, blood pressure) metrics, categorised into poor (scores 0-6), intermediate (7-11), and optimal (12-14) cardiovascular health.

But the evidence remains inconsistent. So to address this uncertainty, an international research project led by Séverine Sabia from the French National Institute of Health and Medical Research and University College London, examined the association between the Life Simple 7 cardiovascular health score at age 50 and risk of dementia over the next 25 years.

Their findings are based on cardiovascular data collected from 7,899 British men and women at age 50 in the Whitehall II Study, which is looking at the impact of social, behavioural, and biological factors on long term health.

Participants were free of cardiovascular disease and dementia at age 50. Dementia cases were identified using hospital, mental health services, and death registers until 2017.

Of the 7,899 participants, 347 cases of dementia were recorded over an average follow-up period of 25 years. Average age at dementia diagnosis was 75 years.

After taking account of potentially influential factors, the researchers found that adherence to the Life Simple 7 cardiovascular health recommendations in midlife was associated with a lower risk of dementia later in life.

Compared with an incidence rate of dementia of 3.2 per 1000 person years among the group with a poor cardiovascular score, those with an intermediate score had an incidence of 1.8 per 1000 person years, while those with an optimal score had an incidence of 1.3 per 1000 person years.

This is an observational study, so can't establish cause, and the researchers point to some limitations, for example relying on self-reported measures and potentially missing cases of dementia in patient records.

However, higher cardiovascular health score at age 50 was also associated with higher whole brain and grey matter volumes in MRI scans 20 years later. And reductions in dementia risk were also evident across the continuum of the cardiovascular score, suggesting that even small improvements in cardiovascular risk factors at age 50 may reduce dementia risk in old age, say the researchers.

"Our findings suggest that the Life's Simple 7, which comprises the cardiovascular health score, at age 50 may shape the risk of dementia in a synergistic manner," they write. "Cardiovascular risk factors are modifiable, making them strategically important prevention targets. This study supports public health policies to improve cardiovascular health as early as age 50 to promote cognitive health," they conclude.

Researchers in a linked editorial agree that the study provides further support for the UK Government's recent policy focus on vascular health in midlife. "However, other evidence makes clear that vascular health at 50 is determined by factors earlier in the life course, including inequality and social and economic determinants," they say.

"Reducing the risk of dementia is a leading concern in aging societies. We know that risk can change across generations, and in the UK the prevalence of dementia has decreased by nearly 25% when standardised for age," they add.

They conclude: "Although the Whitehall study cannot reflect the UK's population, estimates obtained from this cohort reinforce the need for action to shift population risk profiles for cognitive decline and dementia across the life course."

https://www.sciencedaily.com/releases/2019/08/190807190812.htm

Dietary choline associates with reduced risk of dementia

August 6, 2019

Science Daily/University of Eastern Finland

A new study by researchers at the University of Eastern Finland is the first to observe that dietary intake of phosphatidylcholine is associated with a reduced risk of dementia. Phosphatidylcholine was also linked to enhanced cognitive performance. The main dietary sources of phosphatidylcholine were eggs and meat. The findings were published in the American Journal of Clinical Nutrition.

Choline is an essential nutrient, usually occurring in food in various compounds. Choline is also necessary for the formation of acetylcholine, which is a neurotransmitter. Earlier studies have linked choline intake with cognitive processing, and adequate choline intake may play a role in the prevention of cognitive decline and Alzheimer's disease. In fact, choline is nowadays used in a multinutrient medical drink intended for the treatment of early Alzheimer's.

The new study now shows that the risk of dementia was 28% lower in men with the highest intake of dietary phosphatidylcholine, when compared to men with the lowest intake. Men with the highest intake of dietary phosphatidylcholine also excelled in tests measuring their memory and linguistic abilities. These findings are significant, considering that more than 50 million people worldwide are suffering from a memory disorder that has led to dementia, and the number is expected to grow as the population ages. Alzheimer's disease is the most common cause of dementia, for which no cure currently exists. The new findings may, therefore, play a vital role in the prevention of dementia. Successful dementia prevention is a sum of many things and in this equation, even small individual factors can have a positive effect on the overall risk, possibly by preventing or delaying the disease onset.

"However, this is just one observational study, and we need further research before any definitive conclusions can be drawn," Maija Ylilauri, a PhD Student at the University of Eastern Finland points out.

The data for the study were derived from the Kuopio Ischaemic Heart Disease Risk Factor Study, KIHD. At the onset of the study in 1984-1989, researchers analysed approximately 2,500 Finnish men aged between 42 and 60 for their dietary and lifestyle habits, and health in general. These data were combined with their hospital records, cause of death records and medication reimbursement records after an average follow-up period of 22 years. In addition, four years after the study onset, approximately 500 men completed tests measuring their memory and cognitive processing. During the follow-up, 337 men developed dementia.

The analyses extensively accounted for other lifestyle and nutrition related factors that could have explained the observed associations. In addition, the APOE4 gene, which predisposes to Alzheimer's disease and is common in the Finnish population, was accounted for, showing no significant impact on the findings. The key sources of phosphatidylcholine in the study population's diet were eggs (39%) and meat (37%).

https://www.sciencedaily.com/releases/2019/08/190806101530.htm

Characteristics of older adults with moderately severe dementia

August 7, 2019

Science Daily/Wiley

A study published in the Journal of the American Geriatrics Society has found that many characteristics among older adults with moderately severe dementia differ depending on whether they live at home or in residential care or nursing facilities.

The study used a nationally-representative dataset of U.S. older adults and included 728 people newly identified as having moderately severe dementia between 2012 and 2016. Sixty four percent received care at home, 19% in residential care, and 17% in a nursing facility.

Individuals living at home were two to five times more likely to be members of disadvantaged populations (such as being a racial/ethnic minority, not being born in the United States, and having less than a high school education). Those living at home also had worse health and more symptoms than those living in residential care or nursing facilities.

When researchers extrapolated their results, they estimated that 3.3 million older U.S. adults developed moderately severe dementia between 2012 and 2016.

"In our experience, many people live at home with dementia even when things get hard, yet we know virtually nothing about this population. Prior research focused on people with advanced dementia in nursing homes," said lead author Krista L. Harrison, PhD, of the University of California San Francisco. "Our study is one of the first to describe people living at home at a stage of dementia plus moderate functional impairment and to compare this population to people with dementia in other settings in the United States. This is a key step towards better understanding and addressing the geriatric palliative care needs of people with dementia wherever they live."

https://www.sciencedaily.com/releases/2019/08/190807092344.htm

Amyloid is a less accurate marker for measuring severity, progression of Alzheimer's

August 6, 2019

Science Daily/University of Pennsylvania School of Medicine

Researchers find fluorodeoxyglucose (FDG) PET is a better indicator of cognitive performance when compared to PET scans that detect amyloid protein.

While the presence of beta-amyloid plaques in the brain may be a hallmark of Alzheimer's disease, giving patients an amyloid PET scan is not an effective method for measuring their cognitive function, according to a new study from researchers in the Perelman School of Medicine at the University of Pennsylvania and Thomas Jefferson University. The researchers concluded that fluorodeoxyglucose (FDG) PET, which measures the brain's glucose consumption as a marker of neural activity, is a stronger approach for assessing the progression and severity of Alzheimer's and mild cognitive impairment (MCI) as compared to florbetapir-PET scans, which reveal amyloid protein deposits in the brain. This suggests that FDG-PET is also a better means for determining the effectiveness of Alzheimer's therapies, as well as tracking patients' disease advancement, in both clinical and research settings. Results of this study are detailed in the August issue of the Journal of Alzheimer's Disease.

"Both florbetapir-PET and FDG-PET are approved diagnostic methods for Alzheimer's disease, and both appear to be effective in indicating some sort of cognitive impairment. However, we have now shown that FDG-PET is significantly more precise in clinical studies, and it is also available for routine use with modest costs," said the study's co-principal investigator Abass Alavi, MD, PhD, a professor of Radiology at Penn. "Our results support the notion that amyloid imaging does not reflect levels of brain function, and therefore it may be of limited value for assessing patients with cognitive decline."

Alzheimer's disease, the most common cause of dementia, is the sixth leading cause of death in the United States, affecting up to 5.8 million Americans currently. As clinicians aim to spot and treat the symptoms of dementia in its earliest stages, PET plays an increasingly pivotal role in diagnosing and monitoring Alzheimer's disease, as well as MCI, a condition that often precedes dementia.

Two of the most significant biomarkers found in Alzheimer's are decreased glucose uptake and the accumulation of amyloid plaques in the brain. PET scans use different radioactive drugs, called radiotracers, to measure these biomarkers within the brain tissue of patients with cognitive impairment. FDG-PET is one of the most commonly used imaging techniques to diagnose Alzheimer's. However, in recent years, several other radiotracers, such as florbetapir, have been developed to detect the deposition of amyloid plaques.

Recently, the effectiveness of amyloid imaging as a strategy for monitoring dementia symptoms has been called into question. While the presence of amyloid plaques in the brain is considered as being characteristic of Alzheimer's, some studies have shown that large amounts of amyloid plaques were present in healthy, non-demented individuals. Conversely, recent clinical trials have shown that the intended removal of amyloid from the brains of patients with Alzheimer's disease led to no change in, or even worsened, cognitive performance.

In this study, the researchers evaluated 63 individuals, including 19 with clinically diagnosed Alzheimer's disease, 23 with MCI, and 21 healthy individuals. The study participants underwent both FDG- and florbetapir-PET imaging. They were then assessed with a Mini Mental Status Examination (MMSE), a widely used diagnostic test for detecting and assessing the severity of cognitive impairment. The researchers used a novel "global quantification approach" to generate data from five different regions of the brain, which were correlated with the results from the MMSE scores.

The study revealed that both FDG- and florbetapir-PET scans are able to effectively discriminate the individuals with dementia from the healthy control group. However, when compared with the MMSE scores, the correlation between low cognitive performance and high levels of amyloid was significantly weaker than the correlation between FDG and low cognitive performance for all groups included in the study. This suggests that FDG-PET is a more sensitive indicator of cognitive decline.

"Amyloid imaging has a value in diagnosing or ruling out Alzheimer's disease, but it's a bit like all or nothing. Our study shows that it can reveal disease, but you wouldn't be able to differentiate between someone who had very mild or very severe symptoms," said co-principal investigator Andrew Newberg, MD, a professor of Radiology at Thomas Jefferson University, who added that these findings have important implications for clinical research.

"In a clinical drug trial, for example, it may be more relevant to do an FDG-PET scan, rather than using amyloid as a marker, to find out whether the therapy is working," Newberg said.

While FDG-PET may not be a perfect diagnostic tool, the study confirms that currently it is the best available method for monitoring symptoms of dementia, according to Alavi.

"Right now, FDG is king when it comes to looking at brain function, not only in Alzheimer's disease, but also diseases like vascular dementia and cancer," Alavi said.

https://www.sciencedaily.com/releases/2019/08/190806121133.htm

How some older brains decline before people realize it

August 5, 2019

Science Daily/Johns Hopkins University

Some older adults without noticeable cognitive problems have a harder time than younger people in separating irrelevant information from what they need to know at a given time, and a new Johns Hopkins University study could explain why.

The findings offer an initial snapshot of what happens in the brain as young and old people try to access long-term memories, and could shed light on why some people's cognitive abilities decline with age while others remain sharp.

"Your task performance can be impaired not just because you can't remember, but because you can't suppress other memories that are irrelevant," said senior author Susan Courtney, a cognitive neuroscientist at Johns Hopkins. "Some 'memory problems' aren't a matter of memory specifically, but a matter of retrieving the correct information at the right time to solve the problem at hand."

The findings were just posted in Neurobiology of Aging.

The researchers had 34 young adults (18 to 30) and 34 older adults (65-85) perform a mental arithmetic task while their brain activity was measured through functional magnetic resonance imaging, or fMRI. Other images were also collected to measure the integrity of the connections between brain areas called white matter tracts.

The task compared the participants' ability to inhibit irrelevant information automatically retrieved from long term memory. They were asked to indicate whether a proposed solution to an addition or multiplication problem was correct or not -- for instance 8x4=12 or 8+4=32. These examples would create interference as participants considered the right answer because although they should answer "incorrect," the proposed solution seems correct at first glance, based on long-term memories of basic math. This interference did not exist when participants were asked to answer clearly false equations like 8x4=22. Making the task even more complicated, the subjects were sometimes asked to switch to multiplication after they saw the addition symbol and vice versa.

Older people were a fraction of a second slower at answering the questions than younger participants, particularly when there was interference, but the more dramatic difference showed up in the brain scans. Older individuals who had more difficulty with interference also had more frontal brain activation than young adults.

The brain imaging demonstrated that in some aging participants, fibers connecting the front and back of the brain appear to have been damaged over the years. However other older individuals had fibers similar to much younger subjects. The greater the integrity of these fibers, the better the participant's task performance, said lead author Thomas Hinault, a postdoctoral fellow at Johns Hopkins.

"Everyone we studied had good functioning memory, but still we saw differences," Hinault said. "There are so many disruptions in the world and being able to suppress them is crucial for daily life."

The researchers were surprised to find that during parts of the task that were the trickiest, where participants had to switch between multiplication and addition and were asked to add after they saw a multiplication command or vice versa, the people with the strongest brain fiber connections counterintuitively performed even better. Something about deliberately exercising the mind in this fashion made the most agile minds even more so.

"If you have good connections between brain networks, that will help," Courtney said. "If not, you have interference."

https://www.sciencedaily.com/releases/2019/08/190805134032.htm