Posts Tagged ‘aging’

The discovery sheds new light on the origins of this most common cause of dementia, a hallmark of which is the buildup of tangled tau protein filaments in the brain.

The finding could also lead to new treatments for Alzheimer’s and other diseases that progressively destroy brain tissue, conclude the researchers in a paper about their work that now features in the journal Neuron.

Scientists from Massachusetts General Hospital (MGH) in Charlestown and the Johns Hopkins School of Medicine in Baltimore, MD, led the study, which set out to investigate how tau protein might contribute to brain cell damage.

Alzheimer’s disease does not go away and gets worse over time. It is the sixth most common cause of death in adults in the United States, where an estimated 5.7 million people have the disease.

Exact causes of Alzheimer’s still unknown

Exactly what causes Alzheimer’s and other forms of dementia is still a mystery to science. Evidence suggests that a combination of environment, genes, and lifestyle is involved, with different factors having different amounts of influence in different people.

Most cases of Alzheimer’s do not show symptoms until people are in their 60s and older. The risk of getting the disease rises rapidly with age after this.

Brain studies of people with the disease — together with postmortem analyses of brain tissue — have revealed much about how Alzheimer’s changes and harms the brain.

“Age-related changes” include: inflammation; shrinkage in some brain regions; creation of unstable, short-lived molecules known as free radicals; and disruption of cellular energy production.

The brain of a person with Alzheimer’s disease also has two distinguishing features: plaques of amyloid protein that form between cells, and tangles of tau protein that form inside cells. The recent study concerns the latter.

Changes to tau behavior

Brain cells, or neurons, have internal structures known as microtubules that support the cell and its function. They are highly active cell components that help carry substances from the body of the cell out to the parts that connect it to other cells.

In healthy brain cells, tau protein normally “binds to and stabilizes” the microtubules. Tau behaves differently, however, in Alzheimer’s disease.

Changes in brain chemistry make tau protein molecules come away from the microtubules and stick to each other instead.

Eventually, the detached tau molecules form long filaments, or neurofibrillary tangles, that disrupt the brain cell’s ability to communicate with other cells.

The new study introduces the possibility that, in Alzheimer’s disease, tau disrupts yet another mechanism that involves communication between the nucleus of the brain cell and its body.

Communication with cell nucleus

The cell nucleus communicates with the rest of the cell using structures called nuclear pores, which comprise more than 400 different proteins and control the movement of molecules.

Studies on the causes of amyotrophic lateral sclerosis, frontotemporal, and other types of dementia have suggested that flaws in these nuclear pores are involved somehow.

The recent study reveals that animal and human cells with Alzheimer’s disease have faulty nuclear pores, and that the fault is linked to tau accumulation in the brain cell.

“Under disease conditions,” explains co-senior study author Bradley T. Hyman, the director of the Alzheimer’s Unit at MGH, “it appears that tau interacts with the nuclear pore and changes its properties.”

He and his colleagues discovered that the presence of tau disrupts the orderly structure of nuclear pores containing the major structural protein Nup98. In Alzheimer’s disease cells, there were fewer of these pores and those that were there tended to be stuck to each other.

‘Mislocalized’ Nup98
They also observed another curious change involving Nup98 inside Alzheimer’s disease brain cells. In cells with aggregated tau, the Nup98 was “mislocalized” instead of staying in the nuclear pore.

They revealed that this feature was more exaggerated in brain tissue of people who had died with more extreme forms of Alzheimer’s disease.

Finally, when they added human tau to living cultures of rodent brain cells, the researchers found that it caused mislocalization of Nup98 in the cell body and disrupted the transport of molecules into the nucleus.

This was evidence of a “functional link” between the presence of tau protein and damage to the nuclear transport mechanism.

The authors note, however, that it is not clear whether the Nup98-tau interaction uncovered in the study just occurs because of disease or whether it is a normal mechanism that behaves in an extreme fashion under disease conditions.

They conclude:

“Taken together, our data provide an unconventional mechanism for tau-induced neurodegeneration.”

https://www.medicalnewstoday.com/articles/322991.php

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machine-learning-model-provides-early-dementia-diagnosis-306451

A machine learning-based model using data routinely gathered in primary care identified patients with dementia in such settings, according to research recently published in BJGP Open.

“Improving dementia care through increased and timely diagnosis is a priority, yet almost half of those living with dementia do not receive a timely diagnosis,” Emmanuel A. Jammeh, PhD, of the science and engineering department at Plymouth University in the United Kingdom, and colleagues wrote.

“A cost-effective tool that can be used by [primary care providers] to identify patients likely to be living with dementia, based only on routine data would be extremely useful. Such a tool could be used to select high-risk patients who could be invited for targeted screening,” they added.

The researchers used Read codes, a set of clinical terms used in the U.K. to summarize data for general practice, to develop a machine learning-based model to identify patients with dementia. The Read codes were selected based on their significant association with patients with dementia, and included codes for risk factors, symptoms and behaviors that are collected in primary care. To test the model, researchers collected Read-encoded data from 26,483 patients living in England aged 65 years and older.

Jammeh and colleagues found that their machine-based model achieved a sensitivity of 84.47% and a specificity of 86.67% for identifying dementia.

“This is the first demonstration of a machine-learning approach to identifying dementia using routinely collected [National Health Service] data, researchers wrote.

“With the expected growth in dementia prevalence, the number of specialist memory clinics may be insufficient to meet the expected demand for diagnosis. Furthermore, although current ‘gold standards’ in dementia diagnosis may be effective, they involve the use of expensive neuroimaging (for example, positron emission tomography scans) and time-consuming neuropsychological assessments which is not ideal for routine screening of dementia,” they continued.

The model will be evaluated with other datasets, and have its validation tested “more extensively” at general practitioner practices in the future, Jammeh and colleagues added. – by Janel Miller

https://www.healio.com/family-medicine/geriatric-medicine/news/online/%7B62392171-6ad7-481a-9289-bd69df49d4a4%7D/machine-learning-based-model-may-identify-dementia-in-primary-care

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For what is thought to be the largest study of its kind, the researchers analyzed brain scans of 31,227 people aged 9 months–105 years.

In a paper that now features in the Journal of Alzheimer’s Disease, they describe how they identified “patterns of aging” from the brain scans.

These were done using single photon emission computed tomography (SPECT) and came from people with psychiatric conditions such as attention deficit hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder. They were all attending a psychiatric clinic that was based at several locations.

Each participant underwent two SPECT brain scans — one during a resting state, and another during completion of “a concentration task” — giving a total of 62,454 scans.

The scientists found that they could predict a person’s age from the pattern of blood flow in their brain.

Brain circulation varied over lifespan
They observed that blood flow varied from childhood into older age throughout the lifespan. They also saw that brain aging was more visible in scans of men and those with schizophrenia, anxiety, bipolar disorder, and ADHD.

Brain aging was also more strongly associated with use of cannabis and alcohol.

“Based on one of the largest brain imaging studies ever done,” says lead study author Dr. Daniel G. Amen, a psychiatrist and founder of Amen Clinics in Costa Mesa, CA, “we can now track common disorders and behaviors that prematurely age the brain.”

He suggests that improving the treatment of these disorders could “slow or even halt the process of brain aging.”

https://www.medicalnewstoday.com/articles/322852.php

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Even the occasional drink is harmful to health, according to the largest and most detailed research carried out on the effects of alcohol, which suggests governments should think of advising people to abstain completely.

The uncompromising message comes from the authors of the Global Burden of Diseases study, a rolling project based at the University of Washington, in Seattle, which produces the most comprehensive data on the causes of illness and death in the world.

Alcohol, says their report published in the Lancet medical journal, led to 2.8 million deaths in 2016. It was the leading risk factor for premature mortality and disability in the 15 to 49 age group, accounting for 20% of deaths.

Current alcohol drinking habits pose “dire ramifications for future population health in the absence of policy action today”, says the paper. “Alcohol use contributes to health loss from many causes and exacts its toll across the lifespan, particularly among men.”

Most national guidelines suggest there are health benefits to one or two glasses of wine or beer a day, they say. “Our results show that the safest level of drinking is none.”

The study was carried out by researchers at the Institute of Health Metrics and Evaluation (IHME), who investigated levels of alcohol consumption and health effects in 195 countries between 1990 to 2016. They used data from 694 studies to work out how common drinking was and from 592 studies including 28 million people worldwide to work out the health risks.

Moderate drinking has been condoned for years on the assumption that there are some health benefits. A glass of red wine a day has long been said to be good for the heart. But although the researchers did find low levels of drinking offered some protection from heart disease, and possibly from diabetes and stroke, the benefits were far outweighed by alcohol’s harmful effects, they said.

Drinking alcohol was a big cause of cancer in the over-50s, particularly in women. Previous research has shown that one in 13 breast cancers in the UK were alcohol-related. The study found that globally, 27.1% of cancer deaths in women and 18.9% in men over 50 were linked to their drinking habits.

In younger people globally the biggest causes of death linked to alcohol were tuberculosis (1.4% of deaths), road injuries (1.2%), and self-harm (1.1%).

In the UK, the chief medical officer Sally Davies has said there is no safe level of drinking, but the guidance suggests that drinkers consume no more than 14 units a week to keep the risks low. Half a pint of average-strength lager contains one unit and a 125ml glass of wine contains around 1.5 units.

While the study shows that the increased risk of alcohol-related harm in younger people who have one drink a day is small (0.5%), it goes up incrementally with heavier drinking: to 7% among those who have two drinks a day (in line with UK guidance) and 37% for those who have five.

One in three, or 2.4 billion people around the world, drink alcohol, the study shows. A quarter of women and 39% of men drink. Denmark has the most drinkers (95.3% of women, and 97.1% of men). Pakistan has the fewest male drinkers (0.8%) and Bangladesh the fewest women (0.3%). Men in Romania and women in Ukraine drink the most (8.2 and 4.2 drinks a day respectively), while women in the UK take the eighth highest place in the female drinking league, with an average of three drinks a day.

“Alcohol poses dire ramifications for future population health in the absence of policy action today. Our results indicate that alcohol use and its harmful effects on health could become a growing challenge as countries become more developed, and enacting or maintaining strong alcohol control policies will be vital,” said the report’s senior author, Prof Emmanuela Gakidou.

“Worldwide we need to revisit alcohol control policies and health programmes, and to consider recommendations for abstaining from alcohol. These include excise taxes on alcohol, controlling the physical availability of alcohol and the hours of sale, and controlling alcohol advertising. Any of these policy actions would contribute to reductions in population-level consumption, a vital step toward decreasing the health loss associated with alcohol use.”

Dr Robyn Burton, of King’s College London, said in a commentary in the Lancet that the conclusions of the study were clear and unambiguous. “Alcohol is a colossal global health issue and small reductions in health-related harms at low levels of alcohol intake are outweighed by the increased risk of other health-related harms, including cancer,” she wrote.

“There is strong support here for the guideline published by the Chief Medical Officer of the UK who found that there is ‘no safe level of alcohol consumption’.”

Public health policy should be to prioritise measures to reduce the numbers who drink through price increases, taxation, or setting the price according to the strength of the drink (minimum unit pricing), followed by curbs on marketing and restricting the places where people can buy alcohol.

“These approaches should come as no surprise because these are also the most effective measures for curbing tobacco-related harms, another commercially mediated disease, with an increasing body of evidence showing that controlling obesity will require the same measures,” she wrote.

Ben Butler, a Drinkaware spokesperson, said: “This new study supports existing evidence about the harms associated with alcohol. Our research shows that over a quarter of UK adults typically exceed the low risk drinking guidelines and are running the risk of serious long term illnesses.”

But David Spiegelhalter, Winton professor for the public understanding of risk at the University of Cambridge, said the data showed only a very low level of harm in moderate drinkers and suggested UK guidelines were very low risk.

“Given the pleasure presumably associated with moderate drinking, claiming there is no ‘safe’ level does not seem an argument for abstention,” he said. “There is no safe level of driving, but government do not recommend that people avoid driving. Come to think of it, there is no safe level of living, but nobody would recommend abstention.”

https://www.theguardian.com/society/2018/aug/23/no-healthy-level-of-alcohol-consumption-says-major-study


Illustration of how pH imbalance inside endosomes may contribute to Alzheimer’s disease

Johns Hopkins Medicine scientists say they have found new evidence in lab-grown mouse brain cells, called astrocytes, that one root of Alzheimer’s disease may be a simple imbalance in acid-alkaline—or pH—chemistry inside endosomes, the nutrient and chemical cargo shuttles in cells.

Astrocytes work to clear so-called amyloid beta proteins from the spaces between neurons, but decades of evidence has shown that if the clearing process goes awry, amyloid proteins pile up around neurons, leading to the characteristic amyloid plaques and nerve cell degeneration that are the hallmarks of memory-destroying Alzheimer’s disease.

The new study, described online June 26 in Proceedings of the National Academy of Sciences, also reports that the scientists gave drugs called histone deacetylase (HDAC) inhibitors to pH-imbalanced mice cells engineered with a common Alzheimer’s gene variant. The experiment successfully reversed the pH problem and improved the capacity for amyloid beta clearance.

HDAC inhibitors are approved by the U.S. Food and Drug Administration for use in people with certain types of blood cancers, but not in people with Alzheimer’s. They cautioned that most HDAC inhibitors cannot cross the blood-brain barrier, a significant challenge to the direct use of the drugs for brain disorders. The scientists say they are planning additional experiments to see if HDAC inhibitors have a similar effect in lab-grown astrocytes from Alzheimer’s patients, and that there is the potential to design HDAC inhibitors that can cross the barrier.

However, the scientists caution that even before those experiments can happen, far more research is needed to verify and explain the precise relationship between amyloid proteins and Alzheimer’s disease, which affects an estimated 50 million people worldwide. To date, there is no cure and no drugs that can predictably or demonstrably prevent or reverse Alzheimer’s disease symptoms.

“By the time Alzheimer’s disease is diagnosed, most of the neurological damage is done, and it’s likely too late to reverse the disease’s progression,” says Rajini Rao, Ph.D., professor of physiology at the Johns Hopkins University School of Medicine. “That’s why we need to focus on the earliest pathological symptoms or markers of Alzheimer’s disease, and we know that the biology and chemistry of endosomes is an important factor long before cognitive decline sets in.”

Nearly 20 years ago, scientists at Johns Hopkins and New York University discovered that endosomes, circular compartments that ferry cargo within cells, are larger and far more abundant in brain cells of people destined to develop Alzheimer’s disease. This hinted at an underlying problem with endosomes that could lead to an accumulation of amyloid protein in spaces around neurons, says Rao.

To shuttle their cargo from place to place, endosomes use chaperones—proteins that bind to specific cargo and bring them back and forth from the cell’s surface. Whether and how well this binding occurs depends on the proper pH level inside the endosome, a delicate balance of acidity and alkalinity, or acid and base, that makes endosomes float to the surface and slip back down into the cell.

Embedded in the endosome membrane are proteins that shuttle charged hydrogen atoms, known as protons, in and out of endosomes. The amount of protons inside the endosome determines its pH.

When fluids in the endosome become too acidic, the cargo is trapped within the endosome deep inside the cell. When the endosome contents are more alkaline, the cargo lingers at the cell’s surface for too long.

To help determine whether such pH imbalances occur in Alzheimer’s disease, Johns Hopkins graduate student Hari Prasad scoured scientific studies of Alzheimer’s disease looking for genes that were dialed down in diseased brains compared with normal ones. Comparing a dataset of 15 brains of Alzheimer’s disease patients with 12 normal ones, he found that 10 of the 100 most frequently down-regulated genes were related to the proton flow in the cell.

In another set of brain tissue samples from 96 people with Alzheimer’s disease and 82 without it, gene expression of the proton shuttle in endosomes, known as NHE6, was approximately 50 percent lower in people with Alzheimer’s disease compared with those with normal brains. In cells grown from people with Alzheimer’s disease and in mouse astrocytes engineered to carry a human Alzheimer’s disease gene variant, the amount of NHE6 was about half the amount found in normal cells.

To measure the pH balance within endosomes without breaking open the astrocyte, Prasad and Rao used pH sensitive probes that are absorbed by endosomes and emit light based on pH levels. They found that mouse cell lines containing the Alzheimer’s disease gene variant had more acidic endosomes (average of 5.37 pH) than cell lines without the gene variant (average of 6.21 pH).

“Without properly functioning NHE6, endosomes become too acidic and linger inside astrocytes, avoiding their duties to clear amyloid beta proteins,” says Rao.

While it’s likely that changes in NHE6 happen over time in people who develop sporadic Alzheimer’s disease, people who have inherited mutations in NHE6 develop what’s known as Christianson syndrome in infancy and have rapid brain degeneration.

Prasad and Rao also found that a protein called LRP1, which picks up amyloid beta proteins outside the astrocyte and delivers them to endosomes, was half as abundant on the surface of lab grown mouse astrocytes engineered with a human gene variant called APOE4, commonly linked to Alzheimer’s disease.

Looking for ways to restore the function of NHE6, Prasad searched databases of yeast studies to find that HDAC inhibitors tend to increase expression of the NHE6 gene in yeast. This gene is very similar across species, including flies, mice and humans.

Prasad and Rao tested nine types of HDAC inhibitors on cell cultures of mouse astrocytes engineered with the APOE4 gene variant. Broad-spectrum HDAC inhibitors increased NHE6 expression to levels associated with mouse astrocytes that did not have the Alzheimer’s gene variant. They also found that HDAC inhibitors corrected the pH imbalance inside endosomes and restored LRP1 to the astrocyte surface, resulting in efficient clearance of amyloid beta protein.

More information: Hari Prasad et al. Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1801612115

https://medicalxpress.com/news/2018-08-ph-imbalance-brain-cells-contribute.html

by SUKANYA CHARUCHANDRA

Even when Parkinson’s patients don’t have mutations in a gene called LRRK2, more of the active enzyme the gene generates is present in their brains than in healthy brains, researchers reported last week (July 25) in Science Translational Medicine. The finding suggests that LRRK2 inhibitors could help to reduce harmful effects of the enzyme in the vast majority of Parkinson’s patients.

“This is the really interesting bit of data … the demonstration that when you look in the brains of individuals with idiopathic Parkinson’s [where the cause is unknown], that there’s evidence that LRRK2 is activated,” says Patrick Lewis, who studies Parkinson’s disease at University College London and the University of Reading in the UK. He has collaborated with one of the paper’s coauthors but was not involved in this study.

Ten percent of Parkinson’s cases have known genetic causes. Three percent of cases are due to a mutation in LRRK2, the gene encoding the LRRK2 enzyme. The enzyme is highly active in Parkinson’s patients with a mutated LRRK2 gene, and the increased enzyme activity has been linked to the development of the disease.

In the new study, Timothy Greenamyre, a professor of neurology at the University of Pittsburgh, and his team wanted to look at the level of active LRRK2 in patients without an LRRK2 mutation. “Because [LRRK2] is a low-abundance protein, people have had difficulty detecting it,” Greenamyre says. To spot active LRRK2, the researchers first developed two versions of an assay: the first detects the active enzyme and the second, the inactive enzyme. In the first detection method, researchers used two different antibodies, one that binds to a specific subunit that acts as a known indicator of the active enzyme and another that binds to a different proximal portion of it. When both antibodies bind successfully, their close contact generates a fluorescent signal—a sign of active LRRK2. The second method detects a protein known to regulate LRRK2 activity. Higher levels of this protein indicate lower levels of available active LRRK2.

The team used the assay on postmortem brain tissue from Parkinson’s disease patients and from healthy individuals. The researchers observed higher levels of the active LRRK2 enzyme in substantia nigra dopamine-producing neurons—the death of which indicate neurodegenerative disease—in the brain tissue of Parkinson’s patients’ with no mutation in the LRRK2 gene than in healthy brain tissue.

“We have been wondering for a very long time whether LRRK2 plays a role in sporadic Parkinson’s disease,” says Mark Cookson, who studies the neurodegenerative disorder in the National Institutes of Health’s Laboratory of Neurogenetics. He has collaborated with Greenamyre before but was not involved in this work. According to Cookson, this study provides “defensive evidence” of LRRK2’s role in the disease, even in patients without a mutation in the gene.

In the next set of experiments, Greenamyre and his colleagues wanted to see if active LRRK2 turned up in two rat models of Parkinson’s disease. In the first rodent model, the animals were given the toxin rotenone to induce symptoms of the disease. Even without a mutation in the LRRK2 gene, the rats had higher levels of active LRRK2 protein. In the rats’ brains, the active LRRK2 enzymes were linked with clumps of another protein, α-synuclein. The clumps eventually help form Lewy bodies, a characteristic feature of Parkinson’s brains. In the second rodent model, the researchers overexpressed wildtype α-synuclein in the rats’ substantia nigra, which caused levels of active LRRK2 to rise. When the group treated the rotenone-rodent model with a drug that inhibited the LRRK2 protein, the number of clumps and Lewy bodies dropped.

The team also observed higher levels of reactive oxygen species (ROS)—chemically responsive molecules such as peroxides—in the brains of both rat models of Parkinson’s disease. As a result, Greenamyre and his colleagues wanted to see if directly increasing ROS led to more active LRRK2. In a third set of experiments, the team dosed healthy human cell lines with hydrogen peroxide and found the addition of the ROS increased the levels of LRRK2. A spike in ROS levels, the researchers suggest, activates LRRK2, which in turn aids in the development of some classic Parkinson’s features. Blocking the production of ROS resulted in a drop in active LRRK2. The result gives clues to an environmental cause for Parkinson’s disease.

Pharmaceutical companies are already developing LRRK2 inhibitors that can help the small percentage of Parkinson’s patients that have a mutation in the LRRK2 gene. “The inhibitors may benefit patients not only with the mutation but also patients who have idiopathic diseases—they’re much more common,” says coauthor Dario Alessi, a professor who studies signaling pathways in neurodegenerative disorders at the University of Dundee in the UK.

LRRK2 inhibitors, the researchers note, cause mild, yet reversible side effects, in the lungs and kidneys.

R.D. Maio et al., “LRRK2 activation in idiopathic Parkinson’s disease,” Science Translational Medicine, doi:10.1126/scitranslmed.aar5429, 2018.

https://www.the-scientist.com/news-opinion/key-enzyme-active-in-brains-of-patients-without-parkinsons-mutation-64599

by Bob Yirka

A team of researchers from several institutions in Iceland and the U.S. has conducted a unique blood serum investigation and discovered multiple protein networks that are involved in the aging process. In their paper published in the journal Science, the group describes their study and what they found.

Prior research has shown that when older mice have their blood systems connected to younger mice, the older mice experience improvements in age-related organ deterioration. This finding has led scientists to suspect that aging might be caused by something in the blood. In this new effort, the researchers sought to test this idea by studying proteins in the circulatory system.

The study consisted of analyzing blood samples from 5,457 people living in Iceland, all of whom were over the age of 65 and who were participants in an ongoing study called Age, Gene/Environment Susceptibility. The volunteers had also been chosen specifically to represent a cross section of the people living in Iceland. The major part of the blood analysis involved creating a panel of DNA aptamers (short sequences that bind to proteins) that could be used to recognize proteins, both known and unknown. Blood serum from the volunteers was then compared against the panels and the results were analyzed by a computer looking for patterns.

The researchers report that they discovered 27 networks that showed evidence of coordinated pattern expression. These networks, or modules, as the researchers call them, were different from one another in size and form and were made of proteins from both tissue and organs. They also report that many of the modules had expression patterns that have in the past been associated with age-related diseases such as heart disease and metabolic syndrome—and there were some that were also associated with mortality in the years after the samples were taken from the volunteers. The group suggests their findings offer more evidence of the role blood serum plays in the aging process.

The researchers report that they also looked for the means by which the networks they discovered are regulated and found that approximately 60 percent of mechanisms involved are unknown.

More information: Valur Emilsson et al. Co-regulatory networks of human serum proteins link genetics to disease, Science (2018). DOI: 10.1126/science.aaq1327

https://m.medicalxpress.com/news/2018-08-blood-serum-reveals-networks-proteins.html