1. Study suggests another gene that may significantly influence development of dementia and Alzheimer’s

    September 21, 2017 by Ashley

    From the University of Southern California press release:

    The notorious genetic marker of Alzheimer’s disease and other forms of dementia, ApoE4, may not be a lone wolf.

    Researchers from USC and the University of Manchester have found that another gene, TOMM40, complicates the picture. Although ApoE4 plays a greater role in some types of aging-related memory ability, TOMM40 may pose an even greater risk for other types.

    TOMM40 and APOE genes are neighbors, adjacent to each other on chromosome 19, and they are sometimes used as proxies for one another in genetic studies. At times, scientific research has focused chiefly on one APOE variant, ApoE4, as the No. 1 suspect behind Alzheimer’s and dementia-related memory decline. The literature also considers the more common variant of APOE, ApoE3, neutral in risk for Alzheimer’s disease.

    USC researchers believe their new findings raise a significant research question: Has TOMM40 been misunderstood as a sidekick to ApoE4 when it is really a mastermind, particularly when ApoE3 is present?

    “Typically, ApoE4 has been considered the strongest known genetic risk factor for cognitive decline, memory decline, Alzheimer’s disease or dementia-related onset,” said T. Em Arpawong, the study’s lead author and a post-doctoral fellow in the USC Dornsife College of Letters, Arts and Sciences Department of Psychology. “Although prior studies have found some variants of this other gene TOMM40 may heighten the risk for Alzheimer’s disease, our study found that a TOMM40 variant was actually more influential than ApoE4 on the decline in immediate memory – the ability to hold onto new information.”

    Studies have shown that the influence of genes associated with memory and cognitive decline intensifies with age. That is why the scientists chose to examine immediate and delayed verbal test results over time in conjunction with genetic markers.

    “An example of immediate recall is someone tells you a series of directions to get somewhere and you’re able to repeat them back,” explained Carol A. Prescott, the paper’s senior author who is a professor of psychology at USC Dornsife College and professor of gerontology at the USC Davis School of Gerontology. “Delayed recall is being able to remember those directions a few minutes later, as you’re on your way.”

    The study was published in the journal PLOS ONE on Aug. 11.

    Prescott and Arpawong are among the more than 70 researchers at USC who are dedicated to the prevention, treatment and potential cure of Alzheimer’s disease. The memory-erasing illness is one of the greatest health challenges of the century, affecting 1 in 3 seniors and costing $236 billion a year in health care services. USC researchers across a range of disciplines are examining the health, societal and political effects and implications of the disease.

    In the past decade, the National Institute on Aging has nearly doubled its investment in USC research. The investments include an Alzheimer Disease Research Center.

    Tracking memory loss

    For the study, the team of researchers from USC and The University of Manchester utilized data from two surveys: the U.S. Health and Retirement Study and the English Longitudinal Study of Ageing. Both data sets are nationally representative samples and include results of verbal memory testing and genetic testing.

    The research team used verbal test results from the U.S. Health and Retirement Survey, collected from 1996 to 2012, which interviewed participants via phone every two years. The researchers utilized the verbal memory test scores of 20,650 participants, aged 50 and older who were tested repeatedly to study how their memory changed over time.

    To test immediate recall, an interviewer read a list of 10 nouns and then asked the participant to repeat the words back immediately. For delayed recall, the interviewer waited five minutes and then asked the participant to recall the list. Test scores ranged from 0 to 10.

    The average score for immediate recall was 5.7 words out of 10, and the delayed recall scoring average was 4.5 words out of 10. A large gap between the two sets of scores can signal the development of Alzheimer’s or some other form of dementia.

    “There is usually a drop-off in scores between the immediate and the delayed recall tests,” Prescott said. “In evaluating memory decline, it is important to look at both types of memory and the difference between them. You would be more worried about a person who has scores of 10 and 5 than a person with scores of 6 and 4.”

    The first person is worrisome because five minutes after reciting the 10 words perfectly, he or she can recall only half of them, Prescott said. The other person wasn’t perfect on the immediate recall test, but five minutes later, was able to remember a greater proportion of words.

    To prevent bias in the study’s results, the researchers excluded participants who reported that they had received a likely diagnosis of dementia or a dementia-like condition, such as Alzheimer’s. They also focused on participants identified as primarily European in heritage to minimize population bias. Results were adjusted for age and sex.

    The researchers compared the U.S. data to the results of an independent replication sample of participants, age 50 and up, in the English Longitudinal Study of Aging from 2002 to 2012. Interviews and tests were conducted every two years.

    Genetic markers of dementia

    To investigate whether genes associated with immediate and delayed recall abilities, researchers utilized genetic data from 7,486 participants in the U.S. Health and Retirement Study and 6,898 participants in the English Longitudinal Study of Ageing.

    The researchers examined the association between the immediate and delayed recall results with 1.2 million gene variations across the human genome. Only one, TOMM40, had a strong link to declines in immediate recall and level of delayed recall. ApoE4 also was linked but not as strongly.

    “Our findings indicate that TOMM40 plays a larger role, specifically, in the decline of verbal learning after age 60,” the scientists wrote. “Further, our analyses showed that there are unique effects of TOMM40 beyond ApoE4 effects on both the level of delayed recall prior to age 60 and decline in immediate recall after 60.”

    Unlike ApoE4, the ApoE3 variant is generally thought to have no influence on Alzheimer’s disease or memory decline. However, the team of scientists found that adults who had ApoE3 and a risk variant of TOMM40, were more likely to have lower memory scores. The finding suggests that TOMM40 affects memory – even when ApoE4 is not a factor.

    The team suggested that scientists should further examine the association between ApoE3 and TOMM40 variants and their combined influence on decline in different types of learning and memory.

    “Other studies may not have detected the effects of TOMM40,” Prescott said. “The results from this study provide more evidence that the causes of memory decline are even more complicated than we thought before, and they raise the question of how many findings in other studies have been attributed to ApoE4 that may be due to TOMM40 or a combination of TOMM40 and ApoE4.”


  2. Intermittent electrical brain stimulation may improve memory

    September 20, 2017 by Ashley

    From the Medical College of Georgia at Augusta University press release:

    Intermittent electrical stimulation of an area deep inside the brain that degenerates in Alzheimer’s appears to improve working memory, scientists report.

    Conversely, continuous deep brain stimulation, like the type used for Parkinson’s and currently under study in humans with Alzheimer’s, impairs memory, according to study results in adult non-human primates reported in the journal Current Biology.

    With intermittent stimulation — currently not used in any application in the brain in patients — the monkeys were able to remember things up to five times longer in a standard test of working memory.

    “That takes a monkey from being sort of a middle-of-the-pack performer to the top of the class,” says Dr. David T. Blake, neuroscientist in the Department of Neurology at the Medical College of Georgia at Augusta University. “A monkey who is a poor performer becomes a middle-of-the-pack performer after two to three months of this stimulation.”

    In the new studies, scientists used the technique of placing hair-thin electrodes into the brain to deliver electricity and increase the activity of the nucleus basalis of Meynert, a small area in the forebrain that is inexplicably degenerated in both Parkinson’s and Alzheimer’s.

    “The natural response of many brain systems to continuous input is to start to ignore the input,” says Blake. In fact, constant stimulation in other areas like the globus pallidus garners desired clinical benefit like tremor reduction in Parkinson’s disease.

    “In the case of Parkinson’s, deep brain stimulation is effectively downregulating that part of the brain,” says Blake, the study’s corresponding author. “What we wanted to do instead was to upregulate an area.”

    Their goals included making more of the chemical messenger acetylcholine available in the region. The nucleus basalis has a large concentration of neurons that are connected to brain areas critical for memory and cognition, and under healthy conditions have a ready supply of acetylcholine that enables the important communication between them.

    As we age, acetylcholine levels in the brain naturally decrease, but Alzheimer’s causes a dramatic multiplier effect that takes us from being forgetful to a different level, says Dr. Alvin V. Terry, chair of the MCG Department of Pharmacology and Toxicology and a study coauthor.

    They started with continuous stimulation, like the clinical approaches, and saw an unexpected decline in performance. Equally surprising, they found intermittent stimulation resulted in more available acetylcholine in the region and better performance.

    In fact, use of the cholinesterase inhibitor donepezil restored memory performance in animals that received constant stimulation but had no impact on those whose memory was already enhanced by intermittent stimulation.

    “Normally neurons don’t fire nonstop,” Terry notes. “They are pulsing if you will.”

    Sixty pulses per second for 20 seconds followed by a 40-second interval without stimulation provided optimal benefit in the study.

    The scientists suspect the benefit resulted from the impact of increased levels of acetylcholine directly on neurons and their supportive cells in that region. However it may also result from a slight increase in blood flow to the brain region, they write. Cholinesterase inhibitors, drugs used to treat Alzheimer’s, are known to increase blood flow to the brain about 10-15 percent in humans. Blood flow is typically reduced in Alzheimer’s.

    The MCG team has submitted a grant proposal to start a clinical trial in early Alzheimer’s using their new evidence of the benefits of intermittent pulsing. They note that a variety of brain regions and stimulation patterns are currently under study in clinical trials in the United States and Europe.

    The adult but not aged monkeys in the current study were already part of an investigation to determine whether stimulation could improve the sense of touch, which also decreases with age. The scientists realized that with stimulation the monkeys were able to detect finger taps essentially 100 percent of the time versus about 60 percent of the time without it.

    So they also used a classic working memory task in which a colored square cue shows up, then disappears, followed by a delay and then a choice between a cue-colored square and a distractor square. The monkeys get a food reward for making the cue match.

    “There was every reason to think that we would find what we found if we could actually boost acetylcholine, and switching from continuous to intermittent stimulation was the step that was necessary to do that,” Blake says.

    In fact, after months of intermittent stimulation, the monkeys got more adept at the memory test even without the stimulation.

    While that seems like more good news, the reason for the enduring effect is not 100 percent clear: it could be the brain cells make more connections, it could be more acetylcholine keeps getting released, it could be both, the scientists note.

    “There are two main classes of effects that acetylcholine has in the central nervous system,” Blake says. “It changes the way neurons talk to each other. It causes some neurons to become more active, some to become less active. The second class of effects is that it improves blood flow,” he says. More blood means more of the energy source glucose and vital oxygen get to the brain, so it’s not surprising that the brain becomes healthier over time with these increased assets, Blake says. “The idea is that it’s going to have a longer-term effect,” Terry adds.

    Deep brain stimulation, which is comparable to a pacemaker for the heart, also is more selective than drugs, appearing to only stimulate acetylcholine in the targeted brain site. We have acetylcholine receptors all over our body and cholinesterase inhibitors make more of the chemical available bodywide, increasing the risk of side effects like nausea, loss of appetite, joint pain and muscle cramping.

    In fact, responses to intermittent stimulation in the study were as strong as those experienced by patients taking high doses of cholinesterase inhibitors, the scientists report.

    “The primary drugs that are used to treat Alzheimer’s enhance this cholinergic function but they are nonspecific so they are causing all these peripheral side effects,” Terry says. “This is a much more selective way of enhancing that region.”

    Deep brain stimulation basically supplements the normal brain processes that enable the release of acetylcholine, Blake says. The brain operates on a combined biochemical and electrical system that has electrical spikes running the length of an axon — long arms that reach from one neuron to another neuron or other cell type. Where two cells connect is called a synapse and the electrical spike results in the release of acetylcholine at the synapse, which impacts the cell it touches possibly activating it electrically or changing how it functions some other way. Electrical activation of a single neuron actually also activates other neurons in close proximity.

    The success of implanted defibrillators/pacemakers and deep brain stimulation for Parkinson’s has led to the exploration of its potential for problems like Alzheimer’s. The Food and Drug Administration approved deep brain stimulation for Parkinson’s and essential tremor in 1997.

    Aging baby boomers, who began turning 65 in 2011, are drivers behind dramatic increases in those at risk for Alzheimer’s and other age-related dementia. By 2050, the population age 65 and over is projected to reach 83.7 million, almost double the estimated population of 43.1 million in 2012, according to the U.S. Census Bureau.


  3. ‘Waves’ of neural activity give new clues about Alzheimer’s

    September 18, 2017 by Ashley

    From the SINC press release:

    While unconscious during deep sleep, millions of neurons’ activity travels across the cerebral cortex. This phenomenon, known as slow waves, is related to the consolidation of memory. The European project called SloW Dyn, led by Spanish scientists, has now revealed anomalies in this activity in mice displaying a decline similar to Alzheimer’s.

    During deep sleep, large populations of neurons in the cerebral cortex and subcortical brain structures simultaneously discharge electrical pulses. They are slow oscillations, that travel as ‘waves’ of neural activity from one point to another in the cortex once every one to four seconds.

    “This global rhythmic activity, controlled by the cerebral cortex, is associated with a lack of consciousness,” says Mavi Sanchez-Vives, director of the Neuroscience Systems group at the August Pi i Sunyer Biomedical Research Institute (IDIBAPS, Barcelona), whose research team has suggested that it is the default activity of the cortical circuits.

    These oscillations consolidate memory and synaptic plasticity and maintain metabolic and cellular function, among others. Within the framework of the European SloW Dyn (Slow Wave Dynamics) project which the neuroscientist leads, researchers have now discovered differences in this brain activity between healthy mice and mice with cognitive decline similar to Alzheimer’s due to premature aging.

    “We detected a decrease in the frequency of the oscillations which were also more irregular and had a lower high-frequency content of 15 to 100 hertz,” points out Sanchez-Vives, also from the Catalan Institution for Research and Advanced Studies (ICREA).

    The study, published in the journal Frontiers in Aging Neuroscience, highlights how some of these changes have also been registered in patients with Alzheimer’s disease for which reason, according to the authors, the animal model could help in studying the disease.

    Cause or effect of diseases

    The relationship between slow oscillations and neurodegenerative diseases is twofold. When there are pathologies that disturb cortical circuits, they are often reflected in the disruption of slow waves. “We are studying what those changes tell us about the altered underlying mechanisms,” says the researcher.

    Furthermore, the wave alterations will likely be associated with sleep problems, which may influence the development of a disease. “For example, if slow wave sleep periods are disrupted, cognitive functions such as attention and memory can be negatively affected,” Sanchez-Vives notes.

    In order to measure these oscillations, scientists use EEGs which record a person’s brain activity while sleeping. Throughout the SloW Dyn project, experts will measure the waves of thousands of people and will ascertain how they change with age. The tools which they have developed for this purpose are an instrument that registers brain activity and an app.

    “This will provide massive information about the composition of sleep, the synchronization of brain activity and the anomalies that can occur as a result of aging or specific pathologies,” highlights the scientist. Researchers hope that these records will also give them clues about the therapeutic potential of restoring slow waves when they are impaired.

    Disconnecting consciousness

    SloW Dyn has been given over 660,000 euros in funding and will last 36 months. At present, the international consortium is midway through this period. One of the ultimate objectives is to develop a model that mathematically describes these oscillations and thus be able to make predictions.

    “We are trying to understand a phenomenon which, although seemingly very simple, has the power to disconnect consciousness,” summarises Sanchez-Vives.

    The Pompeu Fabra University (Barcelona), the Italian Institute of Technology, the University of Chicago (USA), the National Centre for Scientific Research (France) and the company Rythm (France) are also participating in the project led by IDIBAPS.

    Within Horizon 2020-the framework programme for funding research in the European Union-, SloW Dyn is part of the Human Brain Project, one of the Flagship Future and Emerging Technology Research Initiatives (FET Flagships).


  4. New possibility of studying how Alzheimer’s disease affects the brain at different ages

    September 16, 2017 by Ashley

    From the Lund University press release:

    Alzheimer’s disease can lead to several widely divergent symptoms and, so far, its various expressions have mainly been observed through the behaviour and actions of patients. Researchers at Lund University in Sweden have now produced images showing the changes in the brain associated with these symptoms — a development which increases knowledge and could facilitate future diagnostics and treatment.

    Symptoms vary in cases of Alzheimer’s disease and often relate to the phase of life in which the disease first occurs. People who become ill before the age of 65 often suffer early on from diminished spatial perception and impaired orientation. Elderly patients more often suffer the symptoms traditionally associated with the disease: above all, memory impairment.

    “Now we have a tool which helps us to identify and detect various sub-groups of Alzheimer’s disease. This facilitates the development of drugs and treatments adapted to various forms of Alzheimer’s,” explains Michael Schöll, researcher at Lund University and the University of Gothenburg.

    Diagnostics could also be facilitated, mainly among younger patients in whom it is particularly difficult to arrive at a correct diagnosis.

    Confident in approval for clinical use

    The findings, published in the journal Brain, are based on studies of around 60 Alzheimer’s patients at Skåne University Hospital and a control group consisting of 30 people with no cognitive impairment.

    Once Alzheimer’s disease has taken hold, it gradually results in the tau protein, present in the brain, forming lumps and destroying the transport routes of the neurons. This can be clearly detected with the new imaging method.

    The method includes a device known as a PET camera and a trace substance, a particular molecule, which binds to tau. The imaging method is currently only used in research, where the current study is one of several contributing to increased knowledge about the disease:

    “The changes in the various parts of the brain that we can see in the images correspond logically to the symptoms in early onset and late onset Alzheimer’s patients respectively,” explains Oskar Hansson, professor of neurology at Lund University and consultant at Skåne University Hospital.

    Oskar Hansson believes that the imaging method will be in clinical use within a few years.


  5. A decline in navigational skills could predict neurodegenerative disease

    September 14, 2017 by Ashley

    From the Cell Press press release:

    Changes in how humans map their surroundings and construct and follow directions as they age have been understudied compared to effects on memory and learning. However, age-related declines in navigational ability are independent of those more well-known cognitive downturns, and could form the basis for tools for the early diagnosis of Alzheimer’s disease. Researchers discuss this possibility in a review published August 30 in the journal Neuron.

    “In humans, navigation is much more cumbersome to research than learning or memory,” says Thomas Wolbers, a neuroscientist specializing in aging and cognition at the German Center for Neurodegenerative Diseases. “But it has such a dramatic impact on everyday life, and the key structures of the ‘navigational network’ in the brain are very sensitive to both ordinary healthy aging and pathological factors.”

    Currently, Alzheimer’s disease is diagnosed based on an individual’s medical history, genetic risk factors, and performance on tests that measure memory, language, and reasoning impairments. Wolbers and his colleagues from the United States and the United Kingdom suggest that navigational impairments are among the earliest signs of the Alzheimer’s progression. Healthy older individuals, for instance, strongly prefer to map objects and landmarks relative to their body position (an egocentric strategy) rather than in relation to external objects such as global landmarks or boundaries (an allocentric strategy). This strategic bias makes it much more difficult for them to learn the spatial layout of an environment and can thus reduce their mobility, a worrisome sign in younger people.

    “It can take up to 10 years after the onset of Alzheimer’s for someone to show abnormal results on the standard cognitive tests that are available today, and that’s 10 years that you’ve lost for treating it, should an effective therapy come along down the road,” says Wolbers. “This is where navigation-based diagnostics could contribute, by reducing that window.”

    Navigational testing is held back by a pair of obstacles, though both are receding. The first is the lack of standard tests for navigational tasks and population norms with which to evaluate results. More-affordable and portable virtual reality technology is making standardized test conditions possible, however, while co-author Jan Wiener (@Jan_Wiener) of the United Kingdom’s Bournemouth University is one of the scientists behind the mobile app Sea Hero Quest, a game designed to collect population data on navigation decisions for dementia research.

    The second holdup is that navigational abilities vary wildly from person to person, more so than for memory or other cognitive functions, Wolbers says. An effective diagnostic tool might need to be longitudinal, tracking an individual’s navigation behaviors at different points in time throughout their life and looking for signs of early or accelerated decline. “We need longitudinal human data to be able to definitively say whether a change in navigational function can be used to predict whether Alzheimer’s or any other neurodegenerative disease will develop later on,” Wolbers says.

    With such data and the improved virtual reality setups, the researchers conclude that a navigational test battery analogous to those used for memory and learning will be feasible. For now, Wolbers suggests that people train and use the navigational skills hardwired into their brains, especially in an age of commonplace in-car and handheld GPS technology.

    “There is growing evidence that if you rely too much on that technology it can have a detrimental effect on your navigational ability and in the long term may even be a risk to develop pathological conditions,” he says.


  6. Noninvasive eye scan could detect key signs of Alzheimer’s disease years before patients show symptoms

    September 12, 2017 by Ashley

    From the Cedars-Sinai press release:

    Cedars-Sinai neuroscience investigators have found that Alzheimer’s disease affects the retina — the back of the eye — similarly to the way it affects the brain. The study also revealed that an investigational, noninvasive eye scan could detect the key signs of Alzheimer’s disease years before patients experience symptoms.

    Using a high-definition eye scan developed especially for the study, researchers detected the crucial warning signs of Alzheimer’s disease: amyloid-beta deposits, a buildup of toxic proteins. The findings represent a major advancement toward identifying people at high risk for the debilitating condition years sooner.

    The study, published in JCI Insight, comes amid a sharp rise in the number of people affected by the disease. Today, more than 5 million Americans have Alzheimer’s disease. That number is expected to triple by 2050, according to the Alzheimer’s Association.

    “The findings suggest that the retina may serve as a reliable source for Alzheimer’s disease diagnosis,” said the study’s senior lead author, Maya Koronyo-Hamaoui, PhD, a principal investigator and associate professor in the departments of Neurosurgery and Biomedical Sciences at Cedars-Sinai.

    “One of the major advantages of analyzing the retina is the repeatability, which allows us to monitor patients and potentially the progression of their disease.”

    Yosef Koronyo, MSc, a research associate in the Department of Neurosurgery and first author on the study, said another key finding from the new study was the discovery of amyloid plaques in previously overlooked peripheral regions of the retina. He noted that the plaque amount in the retina correlated with plaque amount in specific areas of the brain.

    “Now we know exactly where to look to find the signs of Alzheimer’s disease as early as possible,” said Koronyo.

    Keith L. Black, MD, chair of Cedars-Sinai’s Department of Neurosurgery and director of the Maxine Dunitz Neurosurgical Institute, who co-led the study, said the findings offer hope for early detection when intervention could be most effective.

    “Our hope is that eventually the investigational eye scan will be used as a screening device to detect the disease early enough to intervene and change the course of the disorder with medications and lifestyle changes,” said Black.

    For decades, the only way to officially diagnose the debilitating condition was to survey and analyze a patient’s brain after the patient died. In recent years, physicians have relied on positron emission tomography (PET) scans of the brains of living people to provide evidence of the disease but the technology is expensive and invasive, requiring the patient to be injected with radioactive tracers.

    In an effort to find a more cost-effective and less invasive technique, the Cedars-Sinai research team collaborated with investigators at NeuroVision Imaging, Commonwealth Scientific and Industrial Research Organisation, University of Southern California, and UCLA to translate their noninvasive eye screening approach to humans.

    The published results are based on a clinical trial conducted on 16 Alzheimer’s disease patients who drank a solution that includes curcumin, a natural component of the spice turmeric. The curcumin causes amyloid plaque in the retina to “light up” and be detected by the scan. The patients were then compared to a group of younger, cognitively normal individuals.

    Koronyo-Hamaoui and Koronyo also were key authors of the original results, published in the journal Neuroimage in 2011 and first presented at the Alzheimer’s Association’s International Conference in 2010.


  7. Less REM sleep tied to greater risk of dementia

    September 9, 2017 by Ashley

    From the American Academy of Neurology (AAN) press release:

    People who get less rapid eye movement (REM) sleep may have a greater risk of developing dementia, according to a new study published in the August 23, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology. REM sleep is the sleep stage when dreaming occurs.

    There are five stages of sleep. Stage one is light sleep. Stage two is when the body begins to prepare for deeper sleep, including stages three and four. Stage five is REM sleep. During this dream stage, the eyes move rapidly and there is increased brain activity as well as higher body temperature, quicker pulse and faster breathing. The first REM stage occurs about an hour to an hour-and-a-half into sleep and then recurs multiple times throughout the night as the cycles repeat.

    “Sleep disturbances are common in dementia but little is known about the various stages of sleep and whether they play a role in dementia risk,” said study author Matthew P. Pase, PhD, of Swinburne University of Technology in Australia. “We set out to discover which stages of sleep may be linked to dementia and while we did not find a link with deep sleep, we did with REM sleep.”

    For the study, researchers looked at 321 people with an average age of 67 from Massachusetts who participated in The Framingham Heart Study. During that study, sleep cycles were measured for each participant. Researchers collected the sleep data and then followed participants for an average of 12 years. During that time, 32 people were diagnosed with some form of dementia and of those, 24 were determined to have Alzheimer’s disease.

    The people who developed dementia spent an average of 17 percent of their sleep time in REM sleep, compared to 20 percent for those who did not develop dementia. After adjusting for age and sex, researchers found links between both a lower percentage of REM sleep and a longer time to get to the REM sleep stage and a greater risk of dementia. In fact, for every percent reduction in REM sleep there was a 9 percent increase in the risk of dementia. The results were similar after researchers adjusted for other factors that could affect dementia risk or sleep, such as heart disease factors, depression symptoms and medication use.

    Other stages of sleep were not associated with an increased dementia risk.

    “Our findings point to REM sleep as a predictor of dementia,” said Pase. “The next step will be to determine why lower REM sleep predicts a greater risk of dementia. By clarifying the role of sleep in the onset of dementia, the hope is to eventually identify possible ways to intervene so that dementia can be delayed or even prevented.”

    Limitations of the study include a small sample size. Studies on larger groups of people need to be done to confirm findings. There was also no data available on shift work among study participants, which can cause unusual sleep patterns and possibly lead to sleep disorders.


  8. Toward an early Alzheimer’s test

    by Ashley

    From the Arizona State University press release:

    According to Paul Coleman, an Alzheimer’s researcher at the ASU-Banner Neurodegenerative Disease Research Center (NDRC), one of the greatest difficulties plaguing efforts to find effective treatments for Alzheimer’s is the enormous lag between the disease’s inception and the appearance of clinical symptoms.

    In a new study, Coleman and his colleagues demonstrate the promise of an early blood test for Alzheimer’s disease. The results suggest that Alzheimer’s can be detected even before the onset of symptoms in persons at genetic risk for Alzheimer’s disease.

    In addition to the NDRC, study collaborators include ASU, the Mayo Clinic, University of Rochester, Banner Alzheimer Institute and Barrow Neurological Institute.

    The new method successfully distinguished between Alzheimer’s, Parkinson’s and healthy controls, indicating that the test does not simply identify general phenomena of neurodegeneration but is able to pick out AD from other degenerative brain conditions.

    “What we’ve done in our paper is to replicate our own work multiple times with different populations and even using different technologies,” Coleman says. “We also presented data showing the ability to detect people at risk of a future diagnosis for Alzheimer’s disease.”

    The method accomplishes this feat by examining white blood cells or leucocytes. Here, segments of RNA known as transcripts — derived from specific DNA genes — hold vital clues regarding health.

    The study was recently published in the journal Neurobiology of Aging.

    Hidden menace

    Alzheimer’s disease continues its pitiless ascent. The illness afflicts 11 percent of those 65 or older, with the figure soaring to 45 percent for people over 85. Current trends predict some 14 million Americans will be afflicted with the disease by mid-century at a towering cost of a trillion dollars.

    Along its path of destruction, Alzheimer’s tears out its victim’s memory, reasoning capacity and personal identity, necessitating around-the-clock care, before death eventually ensues. The crippling toll of the disease on patients, family and society at large makes it a global health crisis of frightening proportions.

    Researchers now know that by the time the first outward manifestations of Alzheimer’s appear, in the form of confusion, memory loss and other classic hallmarks, Alzheimer’s has been ravaging the brain for decades. If the disease could be identified much earlier — close to its origin — there is hope that perhaps it could be slowed or even halted in its tracks.

    Given the vital need for a safe and reliable early diagnostic for Alzheimer’s, many previous efforts have taken aim at the problem. Ideally, such a method should be appropriate for primary care settings, allowing a broad swath of the public to be accurately and regularly tested.

    Until now, however, efforts to develop a reliable early diagnostic for Alzheimer’s have run aground. Further, the accuracy of diagnosis even after the disease has entered its clinical phase, remains poor.

    Signposts of disorder

    It has long been known that Alzheimer’s produces changes in the brain, which can stimulate genes relating to conditions like stress and inflammation. Expression of these genes appears in the blood in the form of specific RNA transcripts.

    The research results clearly demonstrate that these RNA transcripts can be combined into a potent early diagnostic or biomarker, able to distinguish normal patients from those with Alzheimer’s or Parkinson’s disease and — most importantly — make accurate predictions about patients at risk for future development of Alzheimer’s disease.

    The diagnostic precision of the new test is significant. Existing diagnostic screening results for known AD cases (identified through clinical and neuropathological factors), showed diagnostic sensitivity was between 71 percent and 87 percent while specificity ranged from 44 percent to 70 percent. (In medical diagnosis, sensitivity is the ability of a test to correctly identify those with the disease, known as the true positive rate, whereas specificity refers to the ability of the test to correctly identify those without the disease or the true negative rate.)

    Such diagnoses are typically conducted in specialized facilities devoted to the study of Alzheimer’s. As the authors note, the accuracy of standard diagnosis falls significantly in primary care settings. The result is that Alzheimer’s is generally detected very late in the disease process, if it is correctly identified at all — a blueprint for treatment failure, because the illness has already irreparably damaged the brain. The high rate of misdiagnosis leads to frequently unnecessary and ineffective treatment.

    Disease in the cross-hairs

    In a fresh approach, the authors identify RNA transcripts in blood using two different RNA-analysis techniques, known as cDNA array and reverse transcriptase polymerase chain reaction (RT-PCR). Results of the two methods were in close agreement and were further shown to be replicable across multiple sample populations. This allowed the researchers to design a consistent suite of transcripts that could be used to diagnose the disease. This multivariate analysis demonstrated impressive accuracy in a number of critical experiments described in the new paper.

    The study divides 177 blood and 27 post-mortem brain samples into several groups, establishing that careful analysis of RNA transcripts in blood samples has the ability to distinguish early clinical AD, Parkinson’s disease (PD), and cognitively healthy patients. It can accurately identify those carrying two copies of the APOE4 gene — known to be a severe risk factor for developing Alzheimer’s. Transcript screening was also used to identify those at risk for future cognitive impairment due to having at least one direct relative with AD.

    The study reveals that both cDNA and RT-PCR methods managed to distinguish probable AD from normal controls with an accuracy of 93.8 percent, using just 5 RNA transcripts for the test. As the authors note, the blood test’s’ accuracy may be even higher as some of the “false positives” — healthy cases mischaracterized as AD — may be from subjects who are actually positive for pre-symptomatic manifestations of Alzheimer’s.

    Assessing future risk

    The results demonstrate that multivariate analysis of transcripts in blood samples provide an accurate and minimally invasive strategy for diagnosis of AD and early detection of AD risk. Further, the results were consistent with examination of the same transcripts identified in the post-mortem brains of subjects with Alzheimer’s compared with those diagnosed with Parkinson’s disease and with normal controls. (The brain samples, obtained through the Banner Sun Health Research Institute, were taken from a region known to be vulnerable to the most devastating effects of Alzheimer’s.)

    In addition to RNA transcripts linked with inflammation and stress, the study examines a series of epigenetic transcripts — RNA sequences that have undergone post-transcriptional modification. Results again found a strong correlation between the presence of these epigenetic markers and AD, implying they may also provide a compelling diagnostic tool.

    Future refinements should sharpen the method’s ability to accurately identify Alzheimer’s disease at an early stage — prior to the onset of clinical symptoms — in a primary care setting, with just a simple blood extraction. Efforts to conduct long term longitudinal studies and hunt for additional diagnostic transcripts should eventually be combined with testing of new therapeutics aimed at early intervention.

    Intriguingly, one or more of the many existing drugs for Alzheimer’s which have failed in clinical trials, may actually succeed in slowing or arresting Alzheimer’s if they can be delivered early enough in the disease process. Further, trials for new drugs targeting at-risk patients can be ramped up significantly if a simple, non-invasive blood test can replace costly imaging like PET scan.

    The new early diagnostic therefore represents a promising milestone in the war on Alzheimer’s disease.


  9. Physical activity in midlife not linked to cognitive fitness in later years

    September 8, 2017 by Ashley

    From the Johns Hopkins University Bloomberg School of Public Health press release:

    A study led by Johns Hopkins Bloomberg School of Public Health researchers that tracked activity levels of 646 adults over 30 years found that, contrary to previous research, exercise in mid-life was not linked to cognitive fitness in later years.

    The finding suggests that physical activity may not help maintain cognitive function, or help avoid or delay the onset of the debilitating conditions like dementia and Alzheimer’s. Alzheimer’s affects as many as 30 million, mostly older people throughout the world. With no known treatment or cure, researchers are trying to identify measures that might help delay Alzheimer’s onset or limit its reach.

    The study, which appears online in the Journal of Alzheimer’s Disease, did find that activity levels among study participants in the later years were associated with high cognitive function two years later. This supports earlier research findings that exercise may help to maintain cognitive fitness in the short term.

    “This study reminds us that physical activity has all sorts of benefits for people, including promoting cardiovascular health, managing optimal weight levels and maintaining bone and muscle mass,” says Alden L. Gross, assistant professor in the Bloomberg School’s Department of Epidemiology. “Unfortunately it is too early for us to say the same about exercise and Alzheimer’s, especially as a possible long-term preventive measure.”

    There is no known treatment or cure for Alzheimer’s or dementia, syndromes that involves declining memory, confusion and eventually limited ability to perform daily tasks. To date, there are no preventive measures, such as physical exercise, brain games or a diet regimen, that have been proven to help delay or altogether prevent its onset. In the US, an estimated five million adults are currently living with Alzheimer’s, according to the Centers for Disease Control and Prevention (CDC), and the CDC predicts that this number will rise to 14 million by 2050.

    The researchers undertook the study because of a growing consensus that physical activity levels helps prevent Alzheimer’s, however much of the evidence for this thinking is based on cross-sectional studies that compare responses from one group of participants with another at a given point in time or within a very short duration, typically several years. Such studies can be valuable for confirming associations, or links, but not at establishing actual causation because of what is known as reverse causation: it is possible that people who eventually develop dementia may reduce their physical activity and exercise as dementia advances. That’s where longitudinal studies, which look at the same group of participants over a long time, are more helpful.

    The researchers used data from the Johns Hopkins Precursors study, which registered students studying at Johns Hopkins School of Medicine between 1948 and 1964 and tracked them with annual questionnaires about their overall health. The researchers note that the cohort’s homogeneity — students at a selective medical school — meant that any differences in physical activity and later cognitive function could not be explained by other differences among participants.

    The median age for study participants was 46 years in 1978 and 77 years in 2008. Every several years, the questionnaire asked about exercise, physical activity and physical limitations. The researchers used responses from 1978 through 2008 from 646 participants (598 men, 48 women) to calculate so-called metabolic equivalents, which quantify physical activity levels. Participants were also asked whether they regularly exercise to a sweat.

    The team administered cognitive tests in 2008, and, using participants’ medical records, scored for dementia through 2011. The researchers identified 28, or 4.5 percent of the cohort, to have Alzheimer’s.

    No physical activity measure in mid-life was associated with late-life cognitive fitness or onset of dementia. The study confirmed findings of other cross-sectional studies, that higher levels of physical activity and exercise measured close in time to the cognitive testing were associated with better cognitive functioning. The authors also looked at whether patterns of change in physical activity levels over the life span were associated with cognitive health and found no relationships.

    The idea that exercise might play a role in preventing or limiting Alzheimer’s makes sense, the researchers say, because physical activity, at least in mouse models, has shown less accumulation of B-amyloid plaques, which are thought to play a role in dementia, including Alzheimer’s. In addition, physical activity improves blood flow to the brain, which is linked to better cognitive performance. This may explain why studies find that exercise may contribute to cognitive fitness in the short term.

    “These findings have implications for intervention work moving forward,” says Gross. “We still need to focus on causes and mechanisms of Alzheimer’s and dementia, since we don’t yet know which preventive measures may or may not work. For now, when I speak in the community about Alzheimer’s, I find that people take some relief in understanding that there wasn’t anything that anyone might have done to avoid a loved one developing Alzheimer’s. Of course, the goal for researchers is to identify factors that may help older people maintain their cognitive function into their later years. More long-term studies like the Precursors study are needed.”


  10. Visual impairment among older adults associated with poor cognitive function

    September 7, 2017 by Ashley

    From the JAMA Network Journals press release:

    In a nationally representative sample of older U.S. adults, visual impairment was associated with worse cognitive function, according to a study published by JAMA Ophthalmology.

    The number of individuals in the U.S. with vision problems is anticipated to double by 2050. Visual dysfunction and poor cognition are highly prevalent among older adults; however, the relationship is not well defined. Suzann Pershing, M.D., M.S., of the Stanford University School of Medicine, Palo Alto, Calif., and colleagues conducted an analysis of two national data sets, the National Health and Nutrition Examination Survey (NHANES), 1999-2002, and the National Health and Aging Trends Study (NHATS), 2011-2015, to examine the association of measured and self-reported visual impairment (VI) with cognition in older US adults.

    The NHANES included 2,975 respondents, ages 60 years and older, who completed a test measuring cognitive performance. The NHATS included 30, 202 respondents ages 65 years and older with dementia status assessment. The researchers found that VI was significantly associated with worse cognitive function after adjusting for demographics, health, and other factors. These findings were most pronounced for visual acuity measured at distance and by self-report.

    The study notes some limitations, including that the results presented in this analysis are observational, and a causative relationship between VI and cognitive dysfunction cannot be established without longitudinal studies.

    “Further research is warranted to better understand longitudinal and causal relationships between visual and cognitive decline. However, from a policy perspective, should causality be established, this may contribute to the value of vision screening, not only to identify patients who may benefit from treatment of correctable eye diseases but also to suspect broader limitations in function from cognitive and directly visual tasks,” the authors write.