Exercise may be the best medicine for Alzheimer's disease
College Park, Md. –New research out of the University of Maryland School of Public Health shows that exercise may improve cognitive function in those at risk for Alzheimer's by increasing the efficiency of brain activity associated with memory. Memory loss associated with Alzheimer's disease is one of the greatest fears among older Americans. While some memory loss is normal and to be expected as we age, a diagnosis of mild cognitive impairment, or MCI, signals more substantial memory loss and a greater risk for Alzheimer's, for which there currently is no cure.
The study, led by Dr. J. Carson Smith, assistant professor in the Department of Kinesiology, provides new hope for those diagnosed with MCI. It is the first to show that an exercise intervention with older adults with mild cognitive impairment (average age 78) improved not only memory recall, but also brain function, as measured by functional neuroimaging (via fMRI). The findings are published in the August issue of theJournal of Alzheimer's Disease.
“We found that after 12 weeks of being on a moderate exercise program, study participants improved their neural efficiency – basically they were using fewer neural resources to perform the same memory task,” says Dr. Smith. “No study has shown that a drug can do what we showed is possible with exercise.”
Recommended Daily Activity: Good for the Body, Good for the Brain
Two groups of physically inactive older adults (ranging from 60-88 years old) were put on a 12-week exercise program that focused on regular treadmill walking and was guided by a personal trainer. Both groups – one which included adults with MCI and the other with healthy brain function – improved their cardiovascular fitness by about ten percent at the end of the intervention. More notably, both groups also improved their memory performance and showed enhanced neural efficiency while engaged in memory retrieval tasks.
The good news is that these results were achieved with a dose of exercise consistent with the physical activity recommendations for older adults. These guidelines urge moderate intensity exercise (activity that increases your heart rate and makes you sweat, but isn't so strenuous that you can't hold a conversation while doing it) on most days for a weekly total of 150 minutes.
Measuring Exercise's Impact on Brain Health and Memory
One of the first observable symptoms of Alzheimer's disease is the inability to remember familiar names. Smith and colleagues had study participants identify famous names and measured their brain activation while engaged in correctly recognizing a name – e.g., Frank Sinatra, or other celebrities well known to adults born in the 1930s and 40s. “The task gives us the ability to see what is going on in the brain when there is a correct memory performance,” Smith explains.
Tests and imaging were performed both before and after the 12-week exercise intervention. Brain scans taken after the exercise intervention showed a significant decrease in the intensity of brain activation in eleven brain regions while participants correctly identified famous names. The brain regions with improved efficiency corresponded to those involved in the pathology of Alzheimer's disease, including the precuneus region, the temporal lobe, and the parahippocampalgyrus.
The exercise intervention was also effective in improving word recall via a “list learning task,” i.e., when people were read a list of 15 words and asked to remember and repeat as many words as possible on five consecutive attempts, and again after a distraction of being given another list of words.
“People with MCI are on a very sharp decline in their memory function, so being able to improve their recall is a very big step in the right direction,” Smith states.
The results of Smith's study suggest that exercise may reduce the need for over-activation of the brain to correctly remember something. That is encouraging news for those who are looking for something they can do to help preserve brain function.
Dr. Smith has plans for a larger study that would include more participants, including those who are healthy but have a genetic risk for Alzheimer's, and follow them for a longer time period with exercise in comparison to other types of treatments. He and his team hope to learn more about the impact of exercise on brain function and whether it could delay the onset or progression of Alzheimer's disease.(Source: EurekAlert! A service of AAAS and the University of Maryland).
Scientists ID compounds that target amyloid fibrils in Alzheimer's, other brain diseases
Study first to use ‘structural' approach in hunt for amyloid-inhibiting agents
UCLA chemists and molecular biologists have for the first time used a “structure-based” approach to drug design to identify compounds with the potential to delay or treat Alzheimer's disease, and possibly Parkinson's, Lou Gehrig's disease and other degenerative disorders.
All of these diseases are marked by harmful, elongated, rope-like structures known as amyloid fibrils, linked protein molecules that form in the brains of patients.
Structure-based drug design, in which the physical structure of a targeted protein is used to help identify compounds that will interact with it, has already been used to generate therapeutic agents for a number of infectious and metabolic diseases.
The UCLA researchers, led by David Eisenberg, director of the UCLA–Department of Energy Institute of Genomics and Proteomics and a Howard Hughes Medical Institute investigator, report the first application of this technique in the search for molecular compounds that bind to and inhibit the activity of the amyloid-beta protein responsible for forming dangerous plaques in the brain of patients with Alzheimer's and other degenerative diseases.
In addition to Eisenberg, who is also a professor of chemistry, biochemistry and biological chemistry and a member of UCLA's California NanoSystems Institute, the team included lead author Lin Jiang, a UCLA postdoctoral scholar in Eisenberg's laboratory and Howard Hughes Medical Institute researcher, and other UCLA faculty.
The research was published July 16 in eLife, a new open-access science journal backed by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust.
A number of non-structural screening attempts have been made to identify natural and synthetic compounds that might prevent the aggregation and toxicity of amyloid fibrils. Such studies have revealed that polyphenols, naturally occurring compounds found in green tea and in the spice turmeric, can inhibit the formation of amyloid fibrils. In addition, several dyes have been found to reduce amyloid's toxic effects, although significant side effects prevent them from being used as drugs.
Armed with a precise knowledge of the atomic structure of the amyloid-beta protein, Jiang, Eisenberg and colleagues conducted a computational screening of 18,000 compounds in search of those most likely to bind tightly and effectively to the protein.
Those compounds that showed the strongest potential for binding were then tested for their efficacy in blocking the aggregation of amyloid-beta and for their ability to protect mammalian cells grown in culture from the protein's toxic effects, which in the past has proved very difficult. Ultimately, the researchers identified eight compounds and three compound derivatives that had a significant effect.
While these compounds did not reduce the amount of protein aggregates, they were found to reduce the protein's toxicity and to increase the stability of amyloid fibrils — a finding that lends further evidence to the theory that smaller assemblies of amyloid-beta known as oligomers, and not the fibrils themselves, are the toxic agents responsible for Alzheimer's symptoms.
The researchers hypothesize that by binding snugly to the protein, the compounds they identified may be preventing these smaller oligomers from breaking free of the amyloid-beta fibrils, thus keeping toxicity in check.
An estimated 5 million patients in the U.S. suffer from Alzheimer's disease, the most common form of dementia. Alzheimer's health care costs in have been estimated at $178 billion per year, including the value of unpaid care for patients provided by nearly 10 million family members and friends.
In addition to uncovering compounds with therapeutic potential for Alzheimer's disease, this research presents a new approach for identifying proteins that bind to amyloid fibrils — an approach that could have broad applications for treating many diseases.(Source: EurekAlert! A service of AAAS and the University of California-Los Angeles).
Key molecular pathways leading to Alzheimer's identified
Research approach highlights potential therapeutic targets
NEW YORK—Key molecular pathways that ultimately lead to late-onset Alzheimer's disease, the most common form of the disorder, have been identified by researchers at Columbia University Medical Center (CUMC). The study, which used a combination of systems biology and cell biology tools, presents a new approach to Alzheimer's disease research and highlights several new potential drug targets. The paper was published today in the journal Nature.
Much of what is known about Alzheimer's comes from laboratory studies of rare, early-onset, familial (inherited) forms of the disease. “Such studies have provided important clues as to the underlying disease process, but it's unclear how these rare familial forms of Alzheimer's relate to the common form of the disease,” said study leader AsaAbeliovich, MD, PhD, associate professor of pathology and cell biology and of neurology in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at CUMC. “Most important, dozens of drugs that ‘work' in mouse models of familial disease have ultimately failed when tested in patients with late-onset Alzheimer's. This has driven us, and other laboratories, to pursue mechanisms of the common form of the disease.”
Non-familial Alzheimer's is complex; it is thought to be caused by a combination of genetic and environmental risk factors, each having a modest effect individually. Using so-called genome-wide association studies (GWAS), prior reports have identified a handful of common genetic variants that increase the likelihood of Alzheimer's. A key goal has been to understand how such common genetic variants function to impact the likelihood of Alzheimer's.
In the current study, the CUMC researchers identified key molecular pathways that link such genetic risk factors to Alzheimer's disease. The work combined cell biology studies with systems biology tools, which are based on computational analysis of the complex network of changes in the expression of genes in the at-risk human brain.
More specifically, the researchers first focused on the single most significant genetic factor that puts people at high risk for Alzheimer's, called APOE4 (found in about a third of all individuals). People with one copy of this genetic variant have a three-fold increased risk of developing late-onset Alzheimer's, while those with two copies have a ten-fold increased risk. “In this study,” said Dr. Abeliovich, “we initially asked: If we look at autopsy brain tissue from individuals at high risk for Alzheimer's, is there a consistent pattern?”
Surprisingly, even in the absence of Alzheimer's disease, brain tissue from individuals at high risk (who carried APOE4 in their genes) harbored certain changes reminiscent of those seen in full-blown Alzheimer's disease,” said Dr. Abeliovich. “We therefore focused on trying to understand these changes, which seem to put people at risk. The brain changes we considered were based on ‘transcriptomics'—a broad molecular survey of the expression levels of the thousands of genes expressed in brain.”
Using the network analysis tools mentioned above, the researchers then identified a dozen candidate “master regulator” factors that link APOE4 to the cascade of destructive events that culminates in Alzheimer's dementia. Subsequent cell biology studies revealed that a number of these master regulators are involved in the processing and trafficking of amyloid precursor protein (APP) within brain neurons. APP gives rise to amyloid beta, the protein that accumulates in the brain cells of patients with Alzheimer's. In sum, the work ultimately connected the dots between a common genetic factor that puts individuals at high risk for Alzheimer's, APOE4, and the disease pathology.
Among the candidate “master regulators” identified, the team further analyzed two genes, SV2A and RFN219. “We were particularly interested in SV2A, as it is the target of a commonly used anti-epileptic drug, levetiracetam. This suggested a therapeutic strategy. But more research is needed before we can develop clinical trials of levetiracetam for patients with signs of late-onset Alzheimer's disease.”
The researchers evaluated the role of SV2A, using human-induced neurons that carry the APOE4 genetic variant. (The neurons were generated by directed conversion of skin fibroblasts from individuals at high risk for Alzheimer's, using a technology developed in the Abeliovich laboratory.) Treating neurons that harbor the APOE4 at-risk genetic variant with levetiracetam (which inhibits SV2A) led to reduced production of amyloid beta. The study also showed that RFN219 appears to play a role in APP-processing in cells with the APOE4 variant.
“Our findings suggest that both SV2A and RFN219 are candidate drug targets,” said Dr. Abeliovich. “What's exciting to us is that these approaches may play a role in the development of drugs for the common non-familial form of Alzheimer's disease. This has been an enormous challenge."(Source: EurekAlert! A service of AAAS and Columbia University Medical Center).
Highest risk Alzheimer's genetic carriers take positive steps after learning risk status
No signs of increased distress, anxiety after learning Alzheimer's risk status, Penn-led study shows
BOSTON - People who found out they carried an uncommon genetic risk for Alzheimer's disease did not experience more anxiety, depression or distress than non-carriers, and were more active in efforts to reduce their risk of Alzheimer's disease - by exercising, eating a healthy diet and taking recommended vitamins and medications - report researchers from the Perelman School of Medicine at the University of Pennsylvania today at the 2013 Alzheimer's Association International Conference (AAIC). Researchers note that this study will inform how research studies and clinical practices reveal genetic and other risk factors to people interested in being tested in the future.
“This study informs our understanding of the impact of people finding out their genetic risk for Alzheimer's in the absence of any treatments to prevent dementia,” said lead study author Jason Karlawish, MD, professor of Medicine and Medical Ethics and Health Policy in Penn's Perelman School of Medicine. “We saw that, following their genetic counseling session, people took positive steps to mitigate their Alzheimer's risk, such as following a healthy diet and exercising. They might also be willing to join an Alzheimer's dementia prevention trial.”
As part of the NIH-funded REVEAL study led by Robert Green, MD, at Boston's Brigham and Women's Hospital, an analysis of 648 people tested for the Alzheimer's disease genetic risk marker APOe4 was conducted, where participants learned their risk estimate, based on genotype, gender, ethnicity and family history. Only 4 percent of participants (28 people) were in the highest risk group, carrying two copies of APOe4, while 34 percent (221) had a single copy of the gene and 62 percent (399) carried no genetic risk marker.
After a year of following the three groups, there was no inflated perceived risk of getting Alzheimer's disease, nor was there any significant difference between groups for scores on anxiety, depression and test-related distress.(Source: EurekAlert! A service of AAAS and theUniversity of Pennsylvania School of Medicine).
Path of plaque buildup in brain shows promise as early biomarker for Alzheimer's disease
Relatively early accumulation of plaques in temporal lobe was associated with cognitive decline
PHILADELPHIA—The trajectory of amyloid plaque buildup—clumps of abnormal proteins in the brain linked to Alzheimer's disease—may serve as a more powerful biomarker for early detection of cognitive decline rather than using the total amount to gauge risk, researchers from Penn Medicine's Department of Radiology suggest in a new study published online July 15 inNeurobiology of Aging.
Amyloid plaque that starts to accumulate relatively early in the temporal lobe, compared to other areas and in particular to the frontal lobe, was associated with cognitively declining participants, the study found. “Knowing that certain brain abnormality patterns are associated with cognitive performance could have pivotal importance for the early detection and management of Alzheimer's,” said senior author Christos Davatzikos, PhD,professor in the Department of Radiology, the Center for Biomedical Image Computing and Analytics, at the Perelman School of Medicine at the University of Pennsylvania.
Today, memory decline and Alzheimer's—which 5.4 million Americans live with today—is often assessed with a variety of tools, including physical and bio fluid tests and neuroimaging of total amyloid plaque in the brain. Past studies have linked higher amounts of the plaque in dementia-free people with greater risk for developing the disorder. However, it's more recently been shown that nearly a third of people with plaque on their brains never showed signs of cognitive decline, raising questions about its specific role in the disease.
Now, Dr. Davatzikos and his Penn colleagues, in collaboration with a team led by Susan M. Resnick, PhD, Chief, Laboratory of Behavioral Neuroscience at the National Institute on Aging (NIA), used Pittsburgh compound B (PiB) brain scans from the Baltimore Longitudinal Study of Aging's Imaging Studyand discovered a stronger association between memory decline and spatial patterns of amyloid plaque progression than the total amyloid burden.
“It appears to be more about the spatial pattern of this plaque progression, and not so much about the total amount found in brains. We saw a difference in the spatial distribution of plaques among cognitive declining and stable patients whose cognitive function had been measured over a 12-year period. They had similar amounts of amyloid plaque, just in different spots,” Dr. Davatzikos said. “This is important because it potentially answers questions about the variability seen in clinical research among patients presenting plaque. It accumulates in different spatial patterns for different patients, and it's that pattern growth that may determine whether your memory declines.”
The team, including first author Rachel A. Yotter, PhD, a postdoctoral researcher in the Section for Biomedical Image Analysis, retrospectively analyzed the PET PiB scans of 64 patients from the NIA's Baltimore Longitudinal Study of Aging whose average age was 76 years old. For the study, researchers created a unique picture of patients' brains by combining and analyzing PET images measuring the density and volume of amyloid plaque and their spatial distribution within the brain. The radiotracer PiB allowed investigators to see amyloid temporal changes in deposition.
Those images were then compared to California Verbal Learning Test (CLVT) scores, among other tests, from the participants to determine the longitudinal cognitive decline. The group was then broken up into two subgroups: the most stable and the most declining individuals (26 participants).
Despite lack of significant difference in the total amount of amyloid in the brain, the spatial patterns between the two groups (stable and declining) were different, with the former showing relatively early accumulation in the frontal lobes and the latter in the temporal lobes.
A particular area of the brain may be affected early or later depending on the amyloid trajectory, according to the authors, which in turn would affect cognitive impairment. Areas affected early with the plaque include the lateral temporal and parietal regions, with sparing of the occipital lobe and motor cortices until later in disease progression.
“This finding has broad implications for our understanding of the relationship between cognitive decline and resistance and amyloid plaque location, as well as the use of amyloid imaging as a biomarker in research and the clinic,” said Dr.Davatzikos. “The next step is to investigate more individuals with mild cognitive impairment, and to further investigate the follow-up scans of these individuals via the BLSA study, which might shed further light on its relevance for early detection of Alzheimer's.” (Source: EurekAlert! A service of AAAS and theUniversity of Pennsylvania School of Medicine).
Undiagnosed pre-diabetes highly prevalent in early Alzheimer's disease study
BOSTON – When Georgetown University neurologist R. Scott Turner, MD, PhD, began enrolling people with mild to moderate Alzheimer's disease into a nationwide study last year, he expected to find only a handful of participants with undiagnosed glucose intolerance, as all the patients were already under a doctor's care and those with known diabetes were excluded. But Turner says he was “shocked” by how many study participants were found to have pre-diabetes — a finding that is triggering important questions.
Turner's study examines resveratrol, a compound found in red grapes and red wine, to see if it might change glucose levels in patients with mild to moderate Alzheimer's disease (AD). Turner says resveratrol is thought to act on proteins in the brain in a way that mimics effects of a low-calorie diet.
“We know from animal studies that caloric restriction prevents diseases of aging such as diabetes and Alzheimer's,” explains Turner, director of the Georgetown University Medical Center's Memory Disorders Program. “On the flip side of the coin, having diabetes increases one's risk of developing AD. So perhaps by improving glucose tolerance, we will prevent or delay both diabetes and Alzheimer's.”
To join the resveratrol study, participants were first given a fasting glucose tolerance test to obtain a baseline level, and then retested two hours after eating. During digestion, the blood sugar level increases, but the pancreas produces insulin to lower it. A high sugar level after two hours reveals glucose intolerance (pre-diabetes) or diabetes if the level is very high.
“The number of people with glucose intolerance (pre-diabetes) was much higher than expected,” says Turner. “I was surprised by how many people didn't know they were pre-diabetic, and these are individuals who already get the best medical care.”
Five (4 percent) of 128 participants had impaired fasting glucose levels while three others (2 percent) had findings consistent with type 2 diabetes mellitus. Of the 125 subjects who completed the two-hour test, 38 (30 percent) demonstrated glucose intolerance while 16 (13 percent) had results consistent with diabetes. Thus, the overall prevalence of impaired glucose tolerance or diabetes at two hours was 43 percent – or almost half of the individuals recruited to the study.
Turner asks, “How does glucose intolerance or diabetes lead to AD? Does the inflammation associated with AD trigger glucose intolerance? Or do both events create a vicious cycle of Alzheimer's and glucose intolerance?”
Turner's study isn't designed to answer these questions, but it might provide important clues. Turner says while a glucose tolerance test is not typically ordered by neurologists, “this result suggests that perhaps we should test all our patients with early Alzheimer's. It's a simple, inexpensive study that reveals critical health information."(Source: EurekAlert! A service of AAAS and Georgetown University Medical Center).
People with Alzheimer's disease may have lower risk of cancer and vice versa
MINNEAPOLIS – Older people with Alzheimer's disease are less likely to also have cancer, and older people with cancer are less likely to also have Alzheimer's disease, according to the largest study to date on the topic, which appears in the July 10, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.
“Since the number of cases of both Alzheimer's disease and cancer increase exponentially as people age, understanding the mechanisms behind this relationship may help us better develop new treatments for both diseases,” said study author Massimo Musicco, MD, of the National Research Council of Italy in Milan.
The study involved 204,468 people age 60 and older in northern Italy during a six-year period. During that time, 21,451 people developed cancer and 2,832 people developed Alzheimer's disease.
A total of 161 people had both cancer and Alzheimer's disease, whereas that number would have been expected to be 281 for cancer and 246 for Alzheimer's disease when considering how often the diseases occur in the general population. Therefore the risk of cancer was cut in half for people with Alzheimer's disease, and the risk of Alzheimer's disease was reduced by 35 percent for people with cancer.
“While other studies have noted this relationship before, this is the largest study to date and it has several strengths over previous studies, such as looking for the presence of the second disease both before and after the first disease was diagnosed,” Musicco said. “This controls for the possibility that the presence of one disease might obscure the diagnosis of other diseases because any new symptoms might be interpreted as a consequence of the already-diagnosed disease, or in the case of cancer, people might assume that memory problems were a side effect of chemotherapy.”
The researchers found the same result in people who died during the course of the study as well as those still living, controlling for the possibility that the reduced life expectancy for the first disease would also reduce the likelihood of living to develop the second disease.(Source: EurekAlert! A service of AAAS and the American Academy of Neurology).
Penn study shows vascular link in Alzheimer's disease with cognition
Presence of vascular disease reported across different neurodegenerative diseases
PHILADELPHIA – Researchers in the Perelman School of Medicine at the University of Pennsylvania found that, across a variety of neurodegenerative diseases, cerebrovascular disease affecting circulation of blood in the brain was significantly associated with dementia. The researchers contend that people already exhibiting clinical features of Alzheimer's disease and other memory impairments may benefit from effective therapies currently available to reduce vascular problems. Thus, early management of vascular risk factors, such as high blood pressure and cholesterol, and adopting a ‘heart healthy' diet as well as exercise and other lifestyles in midlife may delay or prevent the onset of dementia due to Alzheimer's and Parkinson's disease.
The link between cerebrovascular disease was strongest with Alzheimer's disease -- as compared to other neurodegenerative diseases including frontotemporal lobar degeneration, Lou Gehrig's disease or ALS and Parkinson's disease -- and had the most pronounced effect in younger Alzheimer's patients, according to the study, published in the July 10 issue of Brain.
“While there was evidence already to suggest that vascular disease could play a role in neurodegenerative disease, this is the first study to compare the burden of vascular disease across neurodegenerative diseases with multiple, distinct or different origins,” said senior author John Q. Trojanowski, MD, PhD, director of the National Institute on Aging-funded Alzheimer's Disease Core Center at the University of Pennsylvania and professor of Pathology and Laboratory Medicine. “We were surprised to find such a strong link to vascular disease in Alzheimer's disease, especially in younger patients, in comparison to individuals with other neurodegenerative diseases.”
Penn researchers analyzed 5715 cases from the National Alzheimer's Coordinating Center (NACC) database, which have been collected from 35 past and present NIA-funded Alzheimer's centers across the US since NACC was started in 1999. This is the first study to compare the presence of cerebrovascular disease across the whole spectrum of neurogenerative diseases.
Nearly 80 percent of the more than 4600 Alzheimer's disease patients showed some degree of vascular pathology -- defined as hardened or blocked blood vessels, tissue death due to lack of blood supply, or bleeding -- in the brain, as compared to 67 percent in the control group of people with no remarkable brain disease pathology, and 66 percent in the Parkinson's pathology group.
“In the absence of any disease modifying therapies to change the course of the Alzheimer's and Parkinson's, we hope that the diligent use of existing treatments for vascular conditions and the implementation of campaigns promoting healthy lifestyles in young and middle aged people may have a positive impact on preventing or reducing dementia symptoms in Alzheimer's and Parkinson's disease “said lead study author Jon B. Toledo, MD, postdoctoral researcher at the University of Pennsylvania Perelman School of Medicine.
The study has implications from a public health perspective and for the design of clinical study cohorts that better represent the general population of people with cognitive impairment. In addition, drugs tested for Alzheimer's disease and other related dementias should consider the impact of the frequent coincident presence of cerebrovascular disease on the treatment response of new therapies for Alzheimer's, as most current trials exclude patients with vascular risk factors or cardiovascular disease. Given the prevalence of vascular problems, the researchers note that this large subset of dementia patients should be included in clinical trials to accurately represent the true population dealing with these neurodegenerative diseases, or, at least considered when predicting the clinical impact on patients in a real world population.(Source: EurekAlert! A service of AAAS and theUniversity of Pennsylvania School of Medicine).
Women suffer higher rates of decline in aging and alzheimer's disease
The rates of regional brain loss and cognitive decline caused by aging and the early stages of Alzheimer's disease (AD) are higher for women and for people with a key genetic risk factor for AD, say researchers at the University of California, San Diego School of Medicine in a study published online July 4 in the American Journal of Neuroradiology.
The linkage between APOE ∊4 – which codes for a protein involved in binding lipids or fats in the lymphatic and circulatory systems – was already documented as the strongest known genetic risk factor for sporadic AD, the most common form of the disease. But the connection between the sex of a person and AD has been less-well recognized, according to the UC San Diego scientists.
“APOE ∊4 has been known to lower the age of onset and increase the risk of getting the disease,” said the study's first author Dominic Holland, PhD, a researcher in the Department of Neurosciences at UC San Diego School of Medicine. “Previously we showed that the lower the age, the higher the rates of decline in AD. So it was important to examine the differential effects of age and APOE ∊4 on rates of decline, and to do this across the diagnostic spectrum for multiple clinical measures and brain regions, which had not been done before.”
The scientists evaluated 688 men and women over the age of 65 participating in the Alzheimer's Disease Neuroimaging Initiative, a longitudinal, multi-institution study to track the progression of AD and its effects upon the structures and functions of the brain. They found that women with mild cognitive impairment (a condition precursory to AD diagnosis) experienced higher rates of cognitive decline than men; and that all women, regardless of whether or not they showed signs of dementia, experienced greater regional brain loss over time than did men. The magnitude of the sex effect was as large as that of the APOE ∊4 allele.
“Assuming larger population-based samples reflect the higher rates of decline for women than men, the question becomes what is so different about women,” said Holland. Hormonal differences or change seems an obvious place to start, but Holland said this is largely unknown territory – at least regarding AD.
“Another important finding of this study is that men and women did not differ in the level of biomarkers of Alzheimer's disease pathology,” said co-author Linda McEvoy, PhD, an associate professor in the UCSD Department of Radiology. “This suggests that brain volume loss in women may also be caused by factors other than Alzheimer's disease, or that in women, these pathologies are more toxic. We clearly need more research on how an individual's sex affects AD pathogenesis.”
Holland acknowledged that the paper likely raises more questions than it answers. “There are many factors that may affect the sex differences we observed, such as whether the women in this study may have had higher rates of diabetes or insulin resistance than the men. We also do not know how the use of hormone replacement therapy, reproductive history or years since menopause may have affected these differences. All these issues need to be examined. There is no prevailing theory.”
But he said that just as APOE ∊4 status identifies individuals at greater risk of AD, the sex of a person might prove an important determinant in future treatment as well. Currently, there is no cure for AD or any existing therapies that slow or stop disease progression.
“The biggest impact might be down the road when disease-modifying therapies become available,” said Holland. “What works best for men might not work best for women. The same may be true for ∊4 carriers versus non-carriers.”
He added that results also feed back into clinical trial design. The sex-makeup of the sample will affect the rates of decline for both natural progression (the placebo component) and, likely, the degree of disease modification in participants receiving therapy. So a sex-based sub-analysis might be appropriate.
“Additionally, in clinical practice it may be important to expect higher rates of decline for women patients, to help anticipate when stages of decline that significantly alter quality of life would be reached."(Source: EurekAlert! A service of AAAS and theUniversity of California - San Diego).
Brain's ‘garbage truck' may hold key to treating Alzheimer's and other disorders
In a perspective piece appearing today in the journal Science, researchers at University of Rochester Medical Center (URMC) point to a newly discovered system by which the brain removes waste as a potentially powerful new tool to treat neurological disorders like Alzheimer's disease. In fact, scientists believe that some of these conditions may arise when the system is not doing its job properly.
“Essentially all neurodegenerative diseases are associated with the accumulation of cellular waste products,” said MaikenNedergaard, M.D., D.M.Sc., co-director of the URMC Center for Translational Neuromedicine and author of the article. “Understanding and ultimately discovering how to modulate the brain's system for removing toxic waste could point to new ways to treat these diseases.”
The body defends the brain like a fortress and rings it with a complex system of gateways that control which molecules can enter and exit. While this “blood-brain barrier” was first described in the late 1800s, scientists are only now just beginning to understand the dynamics of how these mechanisms function. In fact, the complex network of waste removal, which researchers have dubbed the glymphatic system, was only first disclosed by URMC scientists last August in the journal Science Translational Medicine.
The removal of waste is an essential biological function and the lymphatic system – a circulatory network of organs and vessels – performs this task in most of the body. However, the lymphatic system does not extend to the brain and, consequently, researchers have never fully understood what the brain does its own waste. Some scientists have even speculated that these byproducts of cellular function where somehow being “recycled” by the brain's cells.
One of the reasons why the glymphatic system had long eluded comprehension is that it cannot be detected in samples of brain tissue. The key to discovering and understanding the system was the advent of a new imaging technology called two-photon microscopy which enables scientists to peer deep within the living brain. Using this technology on mice, whose brains are remarkably similar to humans, Nedergaard and her colleagues were able to observe and document what amounts to an extensive, and heretofore unknown, plumbing system responsible for flushing waste from throughout the brain.
The brain is surrounded by a membrane called the arachnoid and bathed in cerebral spinal fluid (CSF). CSF flows into the interior of the brain through the same pathways as the arteries that carry blood. This parallel system is akin to a donut shaped pipe within a pipe, with the inner ring carrying blood and the outer ring carrying CSF. The CSF is draw into brain tissue via a system of conduits that are controlled by a type support cells in the brain known as glia, in this case astrocytes. The term glymphatic was coined by combining the words glia and lymphatic.
The CSF is flushed through the brain tissue at a high speed sweeping excess proteins and other waste along with it. The fluid and waste are exchanged with a similar system that parallels veins which carries the waste out of the brain and down the spine where it is eventually transferred to the lymphatic system and from there to the liver, where it is ultimately broken down.
While the discovery of the glymphatic system solved a mystery that had long baffled the scientific community, understanding how the brain removes waste – both effectively and what happens when this system breaks down – has significant implications for the treatment of neurological disorders.
One of the hallmarks of Alzheimer's disease is the accumulation in the brain of the protein beta amyloid. In fact, over time these proteins amass with such density that they can be observed as plaques on scans of the brain. Understanding what role the glymphatic system plays in the brain's inability to break down and remove beta amyloid could point the way to new treatments. Specifically, whether certainly key ‘players' in the glymphatic system, such as astrocytes, can be manipulated to ramp up the removal of waste.
“The idea that ‘dirty brain' diseases like Alzheimer may result from a slowing down of the glymphatic system as we age is a completely new way to think about neurological disorders,” said Nedergaard. “It also presents us with a new set of targets to potentially increase the efficiency of glymphatic clearance and, ultimately, change the course of these conditions.” (Source: EurekAlert! A service of AAAS and the University of Rochester Medical Center).
A second amyloid may play a role in Alzheimer's disease, UC Davis researchers find
A protein secreted with insulin travels through the bloodstream and accumulates in the brains of individuals with type 2 diabetes and dementia, in the same manner as the amyloid beta Aβ plaques that are associated with Alzheimer's disease, a study by researchers with the UC Davis Alzheimer's Disease Center has found.
The study is the first to identify deposits of the protein, called amylin, in the brains of people with Alzheimer's disease, as well as combined deposits of amylin and plaques, suggesting that amylin is a second amyloid as well as a new biomarker for age-related dementia and Alzheimer's.
“We've known for a long time that diabetes hurts the brain, and there has been a lot of speculation about why that occurs, but there has been no conclusive evidence until now,” said UC Davis Alzheimer's Disease Center Director Charles DeCarli.
“This research is the first to provide clear evidence that amylin gets into the brain itself and that it forms plaques that are just like the amyloid beta that has been thought to be the cause of Alzheimer's disease,” DeCarli said. “In fact, the amylin looks like the amyloid beta protein, and they both interact. That's why we're calling it the second amyloid of Alzheimer's disease.”
“Amylin deposition in the brain: A second amyloid in Alzheimer's disease?” is published online in the Annals of Neurology.
Type 2 diabetes is a chronic metabolic disorder that increases the risk for cerebrovascular disease and dementia, a risk that develops years before the onset of clinically apparent diabetes. Its incidence is far greater among people who are obese and insulin resistant.
Amylin, or islet amyloid polypeptide, is a hormone produced by the pancreas that circulates in the bloodstream with insulin and plays a critical role in glycemic regulation by slowing gastric emptying, promoting satiety and preventing post-prandial spikes in blood glucose levels. Its deposition in the pancreas is a hallmark of type 2 diabetes.
When over-secreted, some proteins have a higher propensity to stick to one another, forming small aggregates, called oligomers, fibrils and amyloids. These types of proteins are called amyloidogenic and include amylin and Aβ. There are about 28 amyloidogenic proteins, each of which is associated with diseases.
The study was conducted by examining brain tissue from individuals who fell into three groups: those who had both diabetes and dementia from cerebrovascular or Alzheimer's disease; those with Alzheimer's disease without diabetes; and age-matched healthy individuals who served as controls.
The research found numerous amylin deposits in the gray matter of the diabetic patients with dementia, as well as in the walls of the blood vessels in their brains, suggesting amylin influx from blood circulation. Surprisingly, the researchers also found amylin in the brain tissue of individuals with Alzheimer's who had not been diagnosed with diabetes; they postulate that these individuals may have had undiagnosed insulin resistance. They did not find amylin deposits in the brains of the healthy control subjects.
“We found that the amylin deposits in the brains of people with dementia are both independent of and co-located with the Aβ, which is the suspected cause of Alzheimer's disease,” said Florin Despa, assistant professor-in-residence in the UC Davis Department of Pharmacology. “It is both in the walls of the blood vessels of the brain and also in areas remote from the blood vessels.
“It is accumulating in the brain and we found signs that amylin is killing neurons similar to Aβ,” he continued. “And that might be the answer to the question of ‘What makes obese and type 2 diabetes patients more prone to developing dementia?'”
The researchers undertook the investigation after Despa and his colleagues found that amylin accumulates in the blood vessels and muscle of the heart. From this evidence, he hypothesized that the same thing might be happening in the brain. To test the hypothesis he received a pilot research grant through the Alzheimer's Disease Center.
The research was conducted using tissue from the brains of individuals over 65 donated to the UC Davis Alzheimer's Disease Center: 15 patients with Alzheimer's disease and type 2 diabetes; 14 Alzheimer's disease patients without diabetes; and 13 healthy controls. A series of tests, including Western blot, immunohistochemistry and ELISA (enzyme-linked immunosorbent assay) were used to test amylin accumulation in specimens from the temporal cortex.
In contrast with the healthy brains, the brain tissue infiltrated with amylin showed increased interstitial spaces, cavities within the tissue, sponginess, and blood vessels bent around amylin accumulation sites.
Despa said that the finding may offer a therapeutic target for drug development, either by increasing the rate of amylin elimination through the kidneys, or by decreasing its rate of oligomerization and deposition in diabetic patients.
“If we're smart about the treatment of pre-diabetes, a condition that promotes increased amylin secretion, we might be able to reduce the risk of complications, including Alzheimer's and dementia,” Despa said.(Source: EurekAlert! A service of AAAS and theUniversity of California - Davis Health System).
Alzheimer's disease protein controls movement in mice
HEIDELBERG, 21 June 2013 – Researchers in Berlin and Munich, Germany and Oxford, United Kingdom, have revealed that a protein well known for its role in Alzheimer's disease controls spindle development in muscle and leads to impaired movement in mice when the protein is absent or treated with inhibitors. The results, which are published in The EMBO Journal, suggest that drugs under development to target the beta-secretase-1 protein, which may be potential treatments for Alzheimer's disease, might produce unwanted side effects related to defective movement.
Alzheimer's disease is the most common form of dementia found in older adults. The World Health Organization estimates that approximately 18 million people worldwide have Alzheimer's disease. The number of people affected by the disease may increase to 34 million by 2025. Scientists know that the protein beta-secretase-1 or Bace1, a protease enzyme that breaks down proteins into smaller molecules, is involved in Alzheimer's disease. Bace1 cleaves the amyloid precursor protein and generates the damaging Abeta peptides that accumulate as plaques in the brain leading to disease. Now scientists have revealed in more detail how Bace1 works.
“Our results show that mice that lack Bace1 proteins or are treated with inhibitors of the enzyme have difficulties in coordination and walking and also show reduced muscle strength,” remarked Carmen Birchmeier, one of the authors of the paper, Professor at the Max-Delbrück-Center for Molecular Medicine in Berlin, Germany, and an EMBO Member. “In addition, we were able to show that the combined activities of Bace1 and another protein, neuregulin-1 or Nrg1, are needed to sustain the muscle spindles in mice and to maintain motor coordination.”
Muscle spindles are sensory organs that are found throughout the muscles of vertebrates. They are able to detect how muscles stretch and convey the perception of body position to the brain. The researchers used genetic analyses, biochemical studies and interference with pharmacological inhibitors to investigate how Bace1 works in mice. “If the signal strength of a specific form of neuregulin-1 known as IgNrg1 is gradually reduced, increasingly severe defects in the formation and maturation of muscle spindles are observed in mice. Furthermore, it appears that Bace1 is required for full IgNrg1 activity. The graded loss of IgNrg1 activity results in the animals having increasing difficulties with movement and coordination,” says Cyril Cheret, the first author of the work.
Drug developers are interested in stopping the Bace1 protein in its tracks because it represents a promising route to treat Alzheimer's disease. If the protein were inhibited, it would interfere with the generation of the smaller damaging proteins that accumulate in the brain as amyloid plaques and would therefore provide some level of protection from the effects of the disease. “Our data indicate that one unwanted side effect of the long-term inhibition of Bace1 might be the disruption of muscle spindle formation and impairment of movement. This finding is relevant to scientists looking for ways to develop drugs that target the Bace1 protein and should be considered,” says Birchmeier. Several Bace1 inhibitors are currently being tested in phase II and phase III clinical trials for the treatment of Alzheimer's disease.(Source: EurekAlert! A service of AAAS and the European Molecular Biology Organization).