Alzheimer’s Association: For individuals carrying a genetic mutation that causes Alzheimer’s disease, engaging in at least 2.5 hours of physical activity per week may have beneficial effects on markers of Alzheimer’s disease brain changes and may delay cognitive decline, according to a new study available online by Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association as an article in press, corrected proof.
According to the authors, these results support the benefit of physical activity on cognition and dementia progression, even in individuals with autosomal dominant Alzheimer’s disease (ADAD), a rare genetically-driven form of the disease in which the development of dementia at a relatively young age is inevitable.
The authors say their results, “show a significant relationship between physical activity, cognition, functional status and Alzheimer’s disease pathology even in individuals with genetically-driven ADAD. … The officially recommended physical activity duration of ?150 minutes per week was associated with significantly better cognition and less Alzheimer’s disease pathology in ADAD. From a public health perspective, this amount of physical activity was achieved by 70% of all ADAD individuals participating at the DIAN study. Therefore, a physically active lifestyle is achievable and may play an important role in delaying the development and progression of ADAD.”
“The results of this study are encouraging, and not only for individuals with rare genetically-caused Alzheimer’s disease,” said Maria C. Carrillo, Ph.D., Chief Science Officer for the Alzheimer’s Association. “If further research confirms this relationship between physical activity and later onset of dementia symptoms in ADAD, then we need to expand the scope of this work to see if it also is true in the millions of people with more common, late onset Alzheimer’s.”
Christoph Laske, M.D. and his research team at the University Hospital of Tübingen, Germany analyzed data generated from 275 individuals (average age 38.4) who carry a genetic mutation for ADAD and are participating in the Dominantly Inherited Alzheimer’s Network (DIAN), an international observational study of individuals and families with ADAD led by researchers at Washington University School of Medicine in St. Louis.
Researchers aimed to determine if at least 150 minutes of physical activity (walking, running, swimming, aerobics, etc.) per week—the current recommendation by the World Health Organization and the American College of Sports Medicine—would produce cognitive benefits for the study participants. One hundred fifty-six (156) were classified as high physical activity individuals (>150 minutes physical activity/week); 68 as low physical activity individuals (<150 minutes physical activity/week). Exercise intensity was not measured, but the type and frequency was corroborated by a source such as a family member or a friend.
Researchers found individuals who engaged in more physical activity scored better on the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating Sum of Boxes (CDR-SOB), which are well-accepted standard measures of cognition and function. Similarly, individuals who exercised more had lower levels of Alzheimer’s disease biomarkers in cerebrospinal fluid, including lower tau, a protein that builds up in the brains of people living with Alzheimer’s disease. However, individual trajectories of cognitive changes have not been assessed in this cross-sectional study.
“A physically active lifestyle is achievable and may play an important role in delaying the development and progression of ADAD. Individuals at genetic risk for dementia should therefore be counselled to pursue a physically active lifestyle,” the study authors conclude.
“There is a growing and increasingly strong body of scientific evidence of the beneficial impact of lifestyle factors in reducing the risk for, and perhaps even preventing, cognitive decline and dementia,” Carrillo said. “For example, at AAIC 2018 in July we heard preliminary results of SPRINT MIND, the first randomized clinical trial to demonstrate that intensive blood pressure treatment reduces new cases of mild cognitive impairment (MCI), and the combined risk of MCI plus all-cause dementia. This adds credibility to the vision of future Alzheimer’s therapy that combines drugs and modifiable risk factor interventions—as we do now in heart disease.”
To more definitively generate scientific evidence on how lifestyle choices affect brain health, the Alzheimer’s Association is currently leading a large two-year clinical trial called the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER). The study is a two-year clinical trial to evaluate whether lifestyle interventions that simultaneously target many risk factors protect cognitive function in older adults who are at increased risk for cognitive decline. U.S. POINTER is the first such study to be conducted in a large group of Americans across the United States.
“Relationship between physical activity, cognition, and Alzheimer pathology in autosomal dominant Alzheimer`s disease,” by Dr. Stephan Muller, et al, was supported by The Dominantly Inherited Alzheimer’s Network (DIAN, U19AG032438), U.S. National Institute on Aging, German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Japan Agency for Medical Research and Development, AMED, and Korea Health Industry Development Institute (KHIDI).
Provided by: Alzheimer’s Association
A biomarker in the brain’s circulation system may be Alzheimer’s earliest warning
University of Southern California: That’s important because researchers believe that the earlier Alzheimer’s is spotted, the better chance there is to stop or slow the disease.
“Cognitive impairment, and accumulation in the brain of the abnormal proteins amyloid and tau, are what we currently rely upon to diagnose Alzheimer’s disease, but blood-brain barrier breakdown and cerebral blood flow changes can be seen much earlier,” said Berislav Zlokovic, the Mary Hayley and Selim Zilkha Chair in Alzheimer’s Disease Research at the Keck School of Medicine of USC. “This shows why healthy blood vessels are so important for normal brain functioning.”
In a new review article in the Sept. 24 issue of Nature Neuroscience, Zlokovic and his colleagues recommend that the blood-brain barrier, or BBB, be considered an important biomarker—and potential drug target—for Alzheimer’s disease. Because Alzheimer’s is irreversible, and not fully understood, understanding the first step in the disease process is a critical step in fighting it.
Alzheimer’s afflicts 5.7 million Americans and is expected to impair about 14 million by 2050, according to the U.S. Centers for Disease Control and Prevention. Treatment costs total hundreds of billions of dollars annually in the United States. Alzheimer’s kills more people than breast cancer and prostate cancer combined.
The blood-brain barrier is a filtration system, letting in good things (glucose, amino acids) and keeping out bad things (viruses, bacteria, blood). It’s mostly comprised of endothelial cells lining the 400 miles of arteries, veins and capillaries that feed our brains.
Some evidence indicates that leaks in the blood-brain barrier may allow a protein called amyloid into the brain where it sticks to neurons. This triggers the accumulation of more amyloid, which eventually overwhelms and kills brain cells.
“Something is off with the system when that happens,” said Arthur Toga, director of the Laboratory of Neuro Imaging (LONI) and the USC Mark and Mary Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine. “Healthy people have amyloid in their bodies. When the system is dysregulated, amyloid can build up and cells die off.”
Blood-to-brain leaks are seen in other neurodegenerative diseases, such as Huntington’s disease, Parkinson’s and multiple sclerosis.
BBB leaks can be detected with an intravenously administered contrast substance in concert with magnetic resonance imaging. Brain microbleeds, another sign of leakage, also can be picked up with MRI. A slowdown in the brain’s uptake of glucose, visible via PET scan, can be a another result of BBB breakdown.
Zlokovic notes that these aren’t tests routinely offered at a doctor’s office.
More information: The role of brain vasculature in neurodegenerative disorders, Nature Neuroscience (2018). DOI: 10.1038/s41593-018-0234-x , https://www.nature.com/articles/s41593-018-0234-x
Provided by: University of Southern California
Scientists reveal ground-breaking plan to target cause of Alzheimer’s disease
University of Cambridge: A breakthrough has been made in the fight against Alzheimer’s disease—researchers have found a new way to target the toxic particles that destroy healthy brain cells.
Academics at the University of Cambridge and at Lund University in Sweden have devised the first strategy to ‘go after’ the cause of the devastating disease, leading to hope that new drugs could be developed to treat dementia.
Professor Michele Vendruscolo, one of the scientists who led the research hailed as a ‘world first’, said: “This is the first time that a systematic method to go after the pathogens—the cause of Alzheimer’s disease—has been proposed. Until very recently scientists couldn’t agree on what the cause was so we didn’t have a target. As the pathogens have now been identified as small clumps of proteins known as oligomers, we have been able to develop a strategy to aim drugs at these toxic particles.”
Dementia is the leading cause of death in the UK and the cost of dementia is expected to more than double in the next 25 years, from £26 billion to £55 billion. Estimates put the cost to the global economy at nearly a trillion dollars every year.
Alzheimer’s disease leads to the death of nerve cells and tissue loss throughout the brain. Over time, the brain dramatically shrinks and the cell destruction causes memory failure, personality changes, and problems carrying out daily activities.
Scientists identified abnormal deposits called protein oligomers as the most likely suspects of the cause of dementia. Although proteins are normally responsible for important cell processes, when people have Alzheimer’s disease these proteins become rogue, form clumps and kill healthy nerve cells.
Proteins need to fold into a specific structure to function properly. When this folding process fails, the cell has a serious ‘misfolding problem’, and dangerous deposits, which can cause dementia, can be formed that the brain can’t get rid of. Misfolded proteins form abnormal clusters called plaques which build up between nerve cells stopping them from signalling properly. Dying nerve cells also contain tangles which are twisted strands of protein which destroy a vital cell transport system, which means nutrients and other essential supplies can no longer move through the cells.
Professor Vendruscolo explained: “A healthy brain has a quality control system that effectively disposes of potentially dangerous masses of proteins, known as aggregates. Upon ageing, the brain becomes less able to get rid of the dangerous deposits, leading to disease. It is like a household recycling system, if you have an efficient system in place then the clutter gets disposed of in a timely manner. If not, over time, you slowly but steadily accumulate junk that you don’t need. It is the same in the brain.”
The research was carried out by an international team of scientists that also included Professor Sir Christopher Dobson, Master of St John’s College, University of Cambridge, at the Centre for Misfolding Diseases (CMD) co-founded by Sir Christopher. Their research paper has been published today in the Proceedings of the National Academy of Sciences (PNAS).
Conceptual image of neurons in the brain. Credit: Andrii Vodolazhskyi
Sir Christopher said: “This interdisciplinary study shows that it is possible not just to find compounds that target the toxic oligomers that give rise to neurodegenerative disorders but also to increase their potency in a rational manner. It now makes it possible to design molecules that have specific effects on the various stages of disorders such as Alzheimer’s disease, and hopefully to convert them into drugs that can be used in a clinical environment.”
Dementia costs the health and social care sector more than cancer and heart disease combined, and receives a disproportionately low amount of research investment—in 2012 dementia research in the UK received six times less funding than cancer research.
There have been approximately 400 clinical trials for Alzheimer’s disease but none of them have targeted specifically the pathogens that cause it. In the UK, dementia is the only condition in the top 10 causes of death without a treatment to prevent, cure or slow its progression.
Professor Vendruscolo added: “All the previous clinical trials that have focused on finding drugs to modify the disease have failed. The trials that have succeeded have given us a handful of drugs, but these drugs can only treat the symptoms of Alzheimer’s disease, not its onset and progression. Our research is based on the major conceptual step of identifying protein oligomers as the pathogens, and reports a method to systematically develop compounds to target them. This approach enables a new drug discovery strategy.”
Drug discovery involves screening of chemical libraries, identification of the active ingredient from a natural remedy or design resulting from an understanding of the target, in this case the protein oligomers. Development includes further studies, clinical trials and ultimately regulatory approval.
The team believes their first drug candidates could reach clinical trials in around two years. They have co-founded Wren Therapeutics, a biotechnology company in Cambridge, based in the newly opened Chemistry of Health building, whose mission it is to take the ideas developed at the University of Cambridge and translate them into finding new ways to diagnose and treat Alzheimer’s disease and other misfolding disorders.
The group’s new strategy is based on an innovative chemical kinetics approach developed in the last ten years by scientists led jointly by Professor Tuomas Knowles, also a Fellow at St John’s College, Sir Christopher and Professor Vendruscolo, working at the new centre in Cambridge, in collaboration with scientists at Lund University led by Professor Sara Linse.
Professor Knowles said: “We are very excited about the potential of chemical kinetics for drug discovery against protein misfolding diseases. Since the process of aggregation is highly dynamic, the framework of kinetics allows us to approach this problem in a new way and find approaches to stop the generation of toxic proteins species at their very source.”
The advance has been welcomed by leading medical experts.
Dr. David Reynolds, Chief Scientific Officer from Alzheimer’s Research UK, said: “This is a detailed academic study looking at how quickly compounds are able to stop amyloid building up into toxic clumps, which are characteristic of Alzheimer’s disease. With no treatments to slow or stop the diseases that cause dementia, it’s vital we improve approaches like this that could help refine the drug discovery progress and accelerate new treatments for people living with Alzheimer’s.”
More information: Sean Chia el al., “SAR by kinetics for drug discovery in protein misfolding diseases,” PNAS (2018). www.pnas.org/cgi/doi/10.1073/pnas.1807884115
Provided by: University of Cambridge
In landmark study, doctors say test identifies people most likely to get Alzheimer’s
Kathmandu, Research reporter: The beginning was the worst. It frustrated Janet Parkerson when her father started to forget what he had done that day or the day before.
But soon names slipped his mind, too, and then he failed to recognize people. Then he lost his ability to talk and to walk, and then he died, bedridden.
“I saw my father die of Alzheimer’s,” said Parkerson, 85. “I’ve experienced a lot of what it’s like—it’s terribly sad—and I would be very happy to help people not go through that.”
That’s why she decided to enroll in a five-year-long Alzheimer’s research study about four years ago. On Monday, she eagerly sat in the auditorium of East Ridge at Cutler Bay, her Pine Crest senior living community, alongside about 50 other fellow residents, some of whom also volunteered for the studies.
They were all there to hear from the man who recruited them for the study, David Loewenstein, a University of Miami expert in neuropsychology who has been studying Alzheimer’s for 32 years. Loewenstein spoke about one of his team’s most recent findings: For the first time, they successfully used a behavioral test to identify which patients with cognitive impairment are most likely to develop Alzheimer’s.
Loewenstein and his colleagues found patients with mild cognitive impairment, then divided them into three groups. The first was patients with underlying Alzheimer’s, as proved by their high levels of amyloid, an aggregation of a protein in the brain of Alzheimer’s patients. The second was patients who had the symptoms of Alzheimer’s, but didn’t have the high levels of amyloid, which meant they probably had another disease. And the third included patients with other neurological conditions, such as depression.
Loewenstein’s team used a cognitive stress test developed in 2013 by the University of Miami, and it involves researchers asking patients to learn a list of 15 words from three categories, five from each. Then they ask the patients to learn a new list of 15 words from the same categories.
Using the test, they found the patients with the high amyloid levels had the most trouble remembering the second list of words because the first interfered, even after the patients were given multiple attempts. This means Loewenstein’s team accurately identified patients who actually have Alzheimer’s from those who look like they do, but don’t.
“It’s a landmark finding,” Loewenstein said.
When Loewenstein finished his hourlong presentation at East Ridge on Monday, about 15 people rushed to talk to him. Most were fascinated by the fact some of them had had a part in the discovery.
Loewenstein and his team have received more than $10 million in state and federal funding for research in the last five years. In June, he was named the director of the Center for Cognitive Neuroscience and Aging at UM, which aims to tackle Alzheimer’s as it becomes a greater issue.
As more and more baby boomers get older, the number of Alzheimer’s patients is increasing. Loewenstein said if the disease isn’t stopped, in the next 10 to 15 years it will wreak havoc for patients and their families, as well as bankrupt the federal government, because the cost to care for the ill will be so high.
His team’s most recent milestone with the cognitive stress test helps researchers better understand Alzheimer’s and identify the earliest changes that take place in the brain because of it.
This test could potentially help doctors screen patients for Alzheimer’s at a much cheaper cost than through an amyloid PET scan. The test will also help scientists better select candidates with Alzheimer’s for clinical and prevention trials.
“I’m satisfied with the effort,” Loewenstein said. “We’re trying very hard, but I don’t think I’ll be completely satisfied until we have a cure or a prevention. We’re close, but we’re still not there.”
Source & ©2018 Miami Herald
Distributed by Tribune Content Agency, LLC.
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