1. Study suggests brain development and plasticity share similar signalling pathways

    October 17, 2017 by Ashley

    From the Goethe-Universität Frankfurt am Main press release:

    Learning and memory are two important functions of the brain that are based on the brain’s plasticity. Scientists from Goethe University Frankfurt report in the latest issue of the scientific journal Cell Reports how a trio of key molecules directs these processes. Their findings provide new leads for the therapy of Alzheimer’s disease.

    The brain is able to adapt to new situations through changing, building or reducing the contact points between nerve cells (synapses). In particular, the signal strength is regulated by constantly altering the abundance of receptors in the membrane of nerve cells. This explains why it is easier to remember information that we use frequently as opposed to information that we learned years ago and did not use anymore.

    Amparo Acker-Palmer’s research group at the Institute of Cell Biology and Neuroscience of the Goethe University focused in their study on AMPA receptors, which are the main transmitters of the stimulating signals. Nerve cells in the hippocampus, the brain region responsible for learning and memory, are able to alter the number of their “switched-on” receptors by extending or retracting them like antennae thereby regulating the strength of a signal. The Frankfurt scientists now discovered that three key molecules are involved in this regulation: GRIP1, ephrinB2 and ApoER2, the latter being a receptor for the signalling molecule Reelin.

    “These results are fascinating since it has been known for years that ephrinB2 as well as Reelin are essential for the development of the brain ” explains Amparo Acker-Palmer. “Furthermore, earlier work in my lab has shown that there is an interaction between the Reelin signalling pathway and ephrinBs when neurons migrate during brain maturation.”

    Interestingly, a single mechanism can fulfill very different functions within a cell. An earlier study by Amparo Acker-Palmer’s team already showed that macromolecular complexes consisting of ephrinB2 and ApoER2 regulate processes involved in neuronal migration. In the present study, the scientists selectively inhibited the interaction between the two proteins and could thereby demonstrate that these proteins, together with GRIP1, also influence brain plasticity in adults. When the interaction between these proteins was inhibited, neurons were unable to react to changes in the activity of their network. They also showed defects in long-term plasticity, which is the cellular basis for learning and memory.

    “Both, ApoER2 and ephrinB2 molecules have been linked to the development of Alzheimer’s, although the mechanisms of action are not clear yet,” says Amparo Acker-Palmer. “With our research we not only discovered new interactions of key molecules for the regulation of learning and memory but also shed light on potential new therapeutic targets for the treatment of Alzheimer’s disease.”


  2. Study suggests dementia risk is increased in 40-something women with high blood pressure

    October 16, 2017 by Ashley

    From the American Academy of Neurology press release:

    Women who develop high blood pressure in their 40s may be more likely to develop dementia years later, according to a study published in the October 4, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology.

    “High blood pressure in midlife is a known risk factor for dementia, but these results may help us better understand when this association starts, how changes in blood pressure affect the risk of dementia and what the differences are between men and women,” said study author Rachel A. Whitmer, PhD, of Kaiser Permanente Division of Research in Oakland, Calif.

    The study involved 7,238 people who were part of the Kaiser Permanente Northern California health care system. They all had blood pressure checks and other tests from 1964 to 1973 when they were an average age of 33, then again when they were an average age of 44. About 22 percent of the participants had high blood pressure in their 30s (31 percent of men and 14 percent of women). In their 40s, 22 percent overall had high blood pressure, but the makeup was 25 percent of men and 18 percent of women.

    Next the researchers identified the 5,646 participants who were still alive and part of the Kaiser Permanente system in 1996 and followed them for an average of 15 years to see who developed dementia. During that time, 532 people were diagnosed with dementia.

    Having high blood pressure in early adulthood, or in one’s 30s, was not associated with any increased risk of dementia. But having high blood pressure in mid-adulthood, or in one’s 40s, was associated with a 65-percent increased risk of dementia for women. Women who developed high blood pressure in their 40s were 73 percent more likely to develop dementia than women who had stable, normal blood pressure throughout their 30s and 40s.

    The results were the same when researchers adjusted for other factors that could affect risk of dementia, such as smoking, diabetes and body mass index.

    “Even though high blood pressure was more common in men, there was no evidence that having high blood pressure in one’s 30s or 40s increased the risk of dementia for men,” Whitmer said. “More research is needed to identify the possible sex-specific pathways through which the elevated blood pressure accelerates brain aging.”

    For women who made it to age 60 without dementia, the cumulative 25-year risk of dementia was 21 percent for those with high blood pressure in their 30s compared to 18 percent for those who had normal blood pressure in their 30s.

    One limitation of this study is that many developments have been made since the study started in screening for high blood pressure and the use and effectiveness of drugs for it, limiting the ability to generalize the results to today’s population.


  3. Study suggests being unaware of memory loss predicts Alzheimer’s disease

    October 14, 2017 by Ashley

    From the Centre for Addiction and Mental Health press release:

    While memory loss is an early symptom of Alzheimer’s disease, its presence doesn’t mean a person will develop dementia. A new study at the Centre for Addiction and Mental Health (CAMH) has found a clinically useful way to predict who won’t develop Alzheimer’s disease, based on patients’ awareness of their memory problems.

    People who were unaware of their memory loss, a condition called anosognosia, were more likely to progress to Alzheimer’s disease, according to the study, published today in the Journal of Clinical Psychiatry. Those who were aware of memory problems were unlikely to develop dementia.

    “If patients complain of memory problems, but their partner or caregiver isn’t overly concerned, it’s likely that the memory loss is due to other factors, possibly depression or anxiety,” says lead author Dr. Philip Gerretsen, Clinician Scientist in CAMH’s Geriatric Division and Campbell Family Mental Health Research Institute. “They can be reassured that they are unlikely to develop dementia, and the other causes of memory loss should be addressed.”

    In other cases, the partner or caregiver is more likely to be distressed while patients don’t feel they have any memory problems. In Alzheimer’s disease, lack of awareness is linked to more burden on caregivers. Both unawareness of illness (anosognosia) and memory loss (known as mild cognitive impairment) can be objectively assessed using questionnaires.

    The study, believed to be the largest of its kind on illness awareness, had data on 1,062 people aged 55 to 90 from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). This included 191 people with Alzheimer’s disease, 499 with mild cognitive impairment and 372 as part of the healthy comparison group.

    The researchers also wanted to identify which parts of the brain were affected in impaired illness awareness. They examined the brain’s uptake of glucose, a type of sugar. Brain cells need glucose to function, but glucose uptake is impaired in Alzheimer’s disease.

    Using PET brain scans, they showed that those with impaired illness awareness also had reduced glucose uptake in specific brain regions, even when accounting for other factors linked to reduced glucose uptake, such as age and degree of memory loss.

    As the next stage of this research, Dr. Gerretsen will be tracking older adults with mild cognitive impairment who are receiving an intervention to prevent Alzheimer’s dementia. This ongoing study, the PACt-MD study, combines brain training exercises and brain stimulation, using a mild electrical current to stimulate brain cells and improve learning and memory. While the main study is focused on dementia prevention, Dr. Gerretsen will be looking at whether the intervention improves illness awareness in conjunction with preventing progression to dementia.


  4. Study suggests role of inflammation in Alzheimer’s is complicated

    October 12, 2017 by Ashley

    From the Washington University School of Medicine press release:

    Scientists drilling down to the molecular roots of Alzheimer’s disease have encountered a good news/bad news scenario. A major player is a gene called TREM2, mutations of which can substantially raise a person’s risk of the disease. The bad news is that in the early stages of the disease, high-risk TREM2 variants can hobble the immune system’s ability to protect the brain from amyloid beta, a key protein associated with Alzheimer’s.

    The good news, however, according to researchers at Washington University School of Medicine in St. Louis, is that later in the disease, when the brain is dotted with toxic tangles of another Alzheimer’s protein known as tau, the absence of TREM2 protein seems to protect the brain from damage. Mice without TREM2 suffer much less brain damage than those with it.

    The findings potentially make targeting the TREM2 protein as a means of preventing or treating the devastating neurodegenerative disease a little more complicated, and suggest that doctors may want to activate TREM2 early in the disease and tamp it down later.

    “People in the Alzheimer’s field have already been trying to develop ways to target TREM2,” said senior author David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. “Now that we have this data, the question is, ‘What does one really want to do? Stimulate it or inhibit it?'”

    The study is published online the week of Oct. 9 in Proceedings of the National Academy of Sciences.

    Amyloid beta plaques start forming in the brains of Alzheimer’s patients years before the characteristic symptoms of memory loss and confusion appear. The plaques themselves appear to do minimal damage — many older people remain mentally sharp despite plentiful plaques — but their presence raises the risk of developing tau tangles, the real engine of destruction. The brain starts to die specifically in the areas where tau tangles are found.

    In the brain, the protein TREM2 is found only on immune cells known as microglia. Holtzman, along with Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology and Immunology, and others have shown that when TREM2 is absent, the immune cells can’t generate the energy they need to limit the spread of amyloid beta plaques.

    Knowing that tau also plays a key role in the development of Alzheimer’s, Holtzman, graduate student Cheryl Leyns and Jason Ulrich, PhD, an assistant professor of neurology, decided to investigate the effect of TREM2 on tau.

    The researchers turned to genetically modified mice that carry a mutant form of human tau prone to forming toxic tangles. They snipped out the TREM2 gene in some of the mice so that all the mice developed tau tangles but only some of them also had the TREM2 protein in their microglia.

    At 9 months of age, the brains of mice with tau tangles and TREM2 had visibly shrunk, particularly in areas important for memory. There was significantly less damage in the mice without TREM2.

    To their surprise, the researchers discovered there was no significant difference in the amount of tau tangles in the two groups of mice. Instead, the key difference seemed to lie in how their immune cells responded to the tau tangles. The microglia in mice with TREM2 were active, releasing compounds that in some circumstances help fight disease, but in this case primarily injured and killed nearby neurons. The microglia in mice without TREM2 were much less active, and their neurons were relatively spared.

    “Once we started seeing the difference in the microglial activation, we started to understand that this damage doesn’t have to do with tau aggregation necessarily, but with the immune system’s response to the aggregation,” said Leyns, the study’s co-first author.

    The findings suggest that the same immune cells can be involved in both protecting against and promoting neurological damage in Alzheimer’s.

    “It looks like microglial activation might have very different roles in different settings,” Holtzman said. “Amyloid seems to set off the disease. You need these amyloid-related changes to even get the disease in the first place. Maybe that’s why when you have less TREM2 function — and therefore microglial function — you’re at higher risk of developing Alzheimer’s. Less TREM2 function exacerbates amyloid-related injury. But then once the disease progresses and you start to have tau aggregation, it seems that activated microglia become harmful.”

    For years, doctors have tried to prevent or treat Alzheimer’s disease by targeting amyloid plaques or tau tangles, but no therapy has yet been proven effective. When TREM2 was identified as a major risk factor four years ago, scientists seized on it as a fresh way of thinking about — and tackling — the disease.

    These findings indicate that attempting to treat Alzheimer’s by targeting TREM2 function and microglial activation may be a thornier problem than anyone had suspected.

    “You might want to activate microglia early on, when people are just beginning to collect amyloid,” Holtzman said. “If they’re already developing symptoms, then they’re later in the disease process, so you’d probably want to suppress microglia. However, these ideas would need to be thoroughly tested in animal models before we start talking about taking it into people.”


  5. Study unveils new functions of hippocampus

    October 8, 2017 by Ashley

    From the University of Hong Kong press release:

    A research team led by Lam Woo Professor of Biomedical Engineering Ed X. Wu of the Department of Electrical and Electronic Engineering at the University of Hong Kong has made major breakthrough in unveiling the mysteries of the brain to reveal functions of an important region, hippocampus, not known to scientists before.

    The findings have recently been published in the international academic journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) in August 2017.

    The hippocampus, located underneath the cortex, plays important roles in memory and navigation. Alzheimer’s disease and other forms of dementia have been proven to have affected and damaged this area of the brain, resulting in early symptoms including short-term memory loss and disorientation. People with hippocampal damage may lose the ability to form and retain new memories. It is also closely related to other diseases such as epilepsy, schizophrenia, transient global amnesia and posttraumatic stress disorder.

    However, the role of hippocampus in complex brain networks, particularly its influence on brain-wide functional connectivity, is not well understood by scientists. Functional connectivity refers to the functional integration between spatially separated brain regions.

    Rodent experiments conducted by Dr Russell W. Chan, Dr Alex T. L. Leong and others, led by Professor Wu, revealed that low-frequency activities in the hippocampus can drive brain-wide functional connectivity in the cerebral cortex and enhance sensory responses. The cerebral cortex is the largest region of the mammalian brain and plays a key role in memory, attention, perception, cognition, awareness, thought, language, and consciousness. In other words, low-frequency activities of the hippocampus can drive the functional integration between different regions of the cerebral cortex and enhance the responsiveness of vision, hearing and touch. These results indicated that hippocampus can be considered as the heart of the brain, a breakthrough in our knowledge of how the brain works.

    Furthermore, these results also suggest that low-frequency activities in the hippocampus can enhance learning and memory since low-frequency activities usually occur during slow-wave sleep which has been associated with learning and memory. Slow-wave sleep, often referred as deep sleep, is a state that we usually enter several times each night and is necessary for survival. Alzheimer’s disease is a chronic neurodegenerative disease that usually starts slowly and worsens over time, and the most common early symptom is memory loss. These results may also have potential therapeutic implications of hippocampal neuromodulation in Alzheimer’s disease.

    These current findings are a major step in furthering our fundamental understanding of the origins and roles of brain-wide functional connectivity. These findings also signify the potentials of rsfMRI and neuromodulation for early diagnosis and enhanced treatment of brain diseases including Alzheimer’s disease, dementia, epilepsy, schizophrenia, transient global amnesia, and posttraumatic stress disorder.

    Professor Wu’s team is one of the world’s leading teams in functional magnetic resonance imaging (fMRI) research, particularly in the investigation of auditory and visual functions, and brain structural and functional connectivity. The pioneering technologies they employ include the use of optogenetics activation, pharmacological inactivation and fMRI to serve as an important tool for investigating the dynamics underlying brain activity propagation as well as the origins and roles of brain functional connectivity.

    Their earlier revelation that the thalamus, another region connecting to the cortex, is not just a relay or passive brain region as initially thought, but can initiate brain-wide neural interactions at different frequencies, had been published in the December 2016 edition of PNAS.

    The human brain is the source of our thoughts, emotions, perceptions, actions, and memories. How the brain actually works, however, remains largely unknown. One grand challenge for neuroscience in the 21st century is to achieve an integrated understanding of the large-scale brain-wide interactions, particularly the patterns of neural activities that give rise to functions and behaviour. In 2010, the National Institute of Health (NIH) in the US launched the Human Connectome Project which aims to “provide an unparalleled compilation of neural data, an interface to graphically navigate this data and the opportunity to achieve never before realised conclusions about the living human brain.” In 2013, the Obama administration in the US launched the BRAIN Initiative to “accelerate the development and application of new technologies that will enable researchers to produce dynamic pictures of the brain that show how individual brain cells and complex neural circuits interact at the speed of thought.” In November 2016, China launched its own initiative “China Brain Project,” which aims to advance basic research on the neural circuit mechanisms underlying cognition in hopes to improve brain disease diagnosis/intervention and inspire development of brain-machine intelligence technology.

    Major research findings

    Based on current knowledge, one expects the hippocampus to predominantly generate high-frequency activities and these activities are largely confined within the hippocampus. However, in this study, low-frequency optogenetic excitation of the dorsal dentate gyrus, a subregion of the hippocampus, evoked cortical and subcortical activities which are beyond the hippocampus. Furthermore, this low-frequency stimulation enhanced brain-wide functional connectivity in the bilateral hippocampus, visual cortex, auditory cortex and somatosensory cortex. Meanwhile, pharmacological inactivation of the hippocampus decreased brain-wide functional connectivity. In addition, visually evoked responses in visual regions also increased during and after such low-frequency hippocampal stimulation. Together, these experimental results highlight the role of low-frequency activity propagating along the hippocampal-cortical pathway, particularly its contribution to brain-wide functional connectivity and enhancement of sensory functions.

    The human brain only accounts for 2% of the total body weight, yet it consumes about 20% of the total body’s energy demand. Despite its importance, it is one of the least understood organs of the body. The research team’s findings have advanced our fundamental understanding of the origins and roles of brain-wide functional connectivity.

    Optogenetic and pharmacological functional magnetic resonance imaging

    The emerging integrated technique adopted by Professor Wu’s team consists of optogenetics, pharmacological neuromodulation and functional magnetic resonance imaging (fMRI). Optogenetics is a neuromodulation method that uses a combination of techniques from optics and genetics to control the activities of individual neurons in living tissues. Pharmacological neuromodulation uses drugs to manipulate the activities of neurons. fMRI is a large-view non-invasive imaging technique for detecting brain-wide activations. Researchers can make use of fMRI to visualize whole brain activity in response to different optogenetic stimulation and pharmacological manipulations. The synergistic combination of the three technologies has enormous potential to spark a new age of interdisciplinary research to advance our understanding of the brain.


  6. Study suggests smell loss predicts cognitive decline in healthy older people

    October 7, 2017 by Ashley

    From the University of Chicago Medical Center press release:

    A long-term study of nearly 3,000 adults, aged 57 to 85, found that those who could not identify at least four out of five common odors were more than twice as likely as those with a normal sense of smell to develop dementia within five years.

    Although 78 percent of those tested were normal — correctly identifying at least four out of five scents — about 14 percent could name just three out of five, five percent could identify only two scents, two percent could name just one, and one percent of the study subjects were not able to identify a single smell.

    Five years after the initial test, almost all of the study subjects who were unable to name a single scent had been diagnosed with dementia. Nearly 80 percent of those who provided only one or two correct answers also had dementia, with a dose-dependent relationship between degree of smell loss and incidence of dementia.

    “These results show that the sense of smell is closely connected with brain function and health,” said the study’s lead author, Jayant M. Pinto, MD, a professor of surgery at the University of Chicago and ENT specialist who studies the genetics and treatment of olfactory and sinus disease. “We think smell ability specifically, but also sensory function more broadly, may be an important early sign, marking people at greater risk for dementia.”

    “We need to understand the underlying mechanisms,” Pinto added, “so we can understand neurodegenerative disease and hopefully develop new treatments and preventative interventions.”

    “Loss of the sense of smell is a strong signal that something has gone wrong and significant damage has been done,” Pinto said. “This simple smell test could provide a quick and inexpensive way to identify those who are already at high risk.”

    The study, “Olfactory Dysfunction Predicts Subsequent Dementia in Older US Adults,” published September 2?, 2017, in the Journal of the American Geriatrics Society, follows a related 2014 paper, in which olfactory dysfunction was associated with increased risk of death within five years. In that study, loss of the sense of smell was a better predictor of death than a diagnosis of heart failure, cancer or lung disease.

    For both studies, the researchers used a well-validated tool, known as “Sniffin’Sticks.” These look like a felt-tip pen, but instead of ink, they are infused with distinct scents. Study subjects smell each item and are asked to identify that odor, one at a time, from a set of four choices. The five odors, in order of increasing difficulty, were peppermint, fish, orange, rose and leather.

    Test results showed that:

    • 78.1 percent of those examined had a normal sense of smell; 48.7 percent correctly identified five out of five odors and 29.4 percent identified four out of five.
    • 18.7 percent, considered “hyposmic,” got two or three out of five correct.
    • The remaining 3.2 percent, labelled “anosmic,” could identify just one of the five scents (2.2%), or none (1%).

    The olfactory nerve is the only cranial nerve directly exposed to the environment. The cells that detect smells connect directly with the olfactory bulb at the base of the brain, potentially exposing the central nervous system to environmental hazards such as pollution or pathogens. Olfactory deficits are often an early sign of Parkinson’s or Alzheimer’s disease. They get worse with disease progression.

    Losing the ability to smell can have a substantial impact on lifestyle and wellbeing, said Pinto, a specialist in sinus and nasal diseases and a member of the Section of Otolaryngology-Head and Neck Surgery at UChicago Medicine. “Smells influence nutrition and mental health,” Pinto said. People who can’t smell face everyday problems such as knowing whether food is spoiled, detecting smoke during a fire, or assessing the need a shower after a workout. Being unable to smell is closely associated with depression as people don’t get as much pleasure in life.”

    “This evolutionarily ancient special sense may signal a key mechanism that also underlies human cognition,” noted study co-author Martha K. McClintock, PhD, the David Lee Shillinglaw Distinguished Service Professor of Psychology at the University of Chicago, who has studied olfactory and pheromonal communication throughout her career.

    McClintock noted that the olfactory system also has stem cells which self-regenerate, so “a decrease in the ability to smell may signal a decrease in the brain’s ability to rebuild key components that are declining with age, leading to the pathological changes of many different dementias.”

    In an accompanying editorial, Stephen Thielke, MD, a member of the Geriatric Research, Education and Clinical Center at Puget Sound Veterans Affairs Medical Center and the psychiatry and behavioral sciences faculty at the University of Washington, wrote: “Olfactory dysfunction may be easier to quantify across time than global cognition, which could allow for more-systematic or earlier assessment of neurodegenerative changes, but none of this supports that smell testing would be a useful tool for predicting the onset of dementia.”

    “Our test simply marks someone for closer attention,” Pinto explained. “Much more work would need to be done to make it a clinical test. But it could help find people who are at risk. Then we could enroll them in early-stage prevention trials.”

    “Of all human senses,” Pinto added, “smell is the most undervalued and underappreciated — until it’s gone.”

    Both studies were part of the National Social Life, Health and Aging Project (NSHAP), the first in-home study of social relationships and health in a large, nationally representative sample of men and women ages 57 to 85.

    The study was funded by the National Institutes of Health — including the National Institute on Aging and the National Institute of Allergy and Infectious Disease — the Institute of Translational Medicine at the University of Chicago, and the McHugh Otolaryngology Research Fund.

    Additional authors were Dara Adams, David W. Kern, Kristen E. Wroblewski and William Dale, all from the University of Chicago. Linda Waite is the principal investigator of NSHAP, a transdisciplinary effort with experts in sociology, geriatrics, psychology, epidemiology, statistics, survey methodology, medicine, and surgery collaborating to advance knowledge about aging.


  7. Study suggests personality changes don’t precede clinical onset of Alzheimer’s

    October 2, 2017 by Ashley

    From the Florida State University press release:

    For years, scientists and physicians have been debating whether personality and behavior changes might appear prior to the onset of Alzheimer’s disease and related dementias.

    Now, the findings of a new and comprehensive study from FSU College of Medicine Associate Professor Antonio Terracciano and colleagues, published in the journal JAMA Psychiatry, has found no evidence to support the idea that personality changes begin before the clinical onset of mild cognitive impairment (MCI) or dementia.

    “We further found that personality remained stable even within the last few years before the onset of mild cognitive impairment,” Terracciano said.

    Terracciano, College of Medicine Associate Professor Angelina Sutin and co-authors from the National Institute on Aging examined data from the Baltimore Longitudinal Study of Aging. The study looked at personality and clinical assessments obtained between 1980 and July 2016 from more than 2,000 individuals who initially showed no cognitive impairment.

    About 18 percent of study participants later developed MCI or dementia.

    “We compared whether personality change in people who later developed dementia differed from those who remained cognitively normal,” Terracciano said. “Unlike previous research, this study examined multiple waves of self-rated personality data collected up to 36 years before participants developed any sign of dementia.”

    What the researchers found is that the trajectory of personality traits did not differ between those who would later develop dementia and those who did not.

    While personality change was not an early sign of dementia, Terracciano’s study provides further support that personality traits (including high levels of neuroticism and low levels of conscientiousness) are risk factors for dementia.

    For physicians and loved ones, personality changes remain an important consideration in the care of those who have already experienced the clinical onset of MCI or dementia. Increasing apathy, irritability, mood changes and other behavioral symptoms impact quality of life for both patients and their caregivers.

     


  8. Study suggests brain halves increase communication to compensate for aging

    September 26, 2017 by Ashley

    From the Duke Department of Neurology press release:

    Increased communication between distant brain regions helps older adults compensate for the negative aspects of aging, reports a new study published this week in Human Brain Mapping.

    The aged brain tends to show more bilateral communication than the young brain. While this finding has been observed many times, it has not been clear whether this phenomena is helpful or harmful and no study has directly manipulated this effect, until now.

    “This study provides an explicit test of some controversial ideas about how the brain reorganizes as we age,” said lead author Simon Davis, PhD. “These results suggest that the aging brain maintains healthy cognitive function by increasing bilateral communication.”

    Simon Davis and colleagues used a brain stimulation technique known as transcranial magnetic stimulation (TMS) to modulate brain activity of healthy older adults while they performed a memory task. When researchers applied TMS at a frequency that depressed activity in one memory region in the left hemisphere, communication increased with the same region in the right hemisphere, suggesting the right hemisphere was compensating to help with the task.

    In contrast, when the same prefrontal site was excited, communication was increased only in the local network of regions in the left hemisphere. This suggested that communication between the hemispheres is a deliberate process that occurs on an “as needed” basis.

    Furthermore, when the authors examined the white matter pathways between these bilateral regions, participants with stronger white matter fibers connecting left and right hemispheres demonstrated greater bilateral communication, strong evidence that structural neuroplasticity keeps the brain working efficiently in later life.

    “Good roads make for efficient travel, and the brain is no different. By taking advantage of available pathways, aging brains may find an alternate route to complete the neural computations necessary for functioning,” said Davis.

    These results suggest that greater bilaterality in the prefrontal cortex might be the result of the aging brain adapting to the damage endured over the lifespan, in an effort to maintain normal function. Future brain-stimulation techniques could target this bilateral effect in effort to promote communication between the hemispheres and, hopefully, engender healthy cognition throughout the lifespan.


  9. 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.”


  10. 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.