1. Study suggests cognitive training enhanced innovative thinking and brain networks in older adults

    November 22, 2017 by Ashley

    From the Center for BrainHealth press release:

    Researchers at the Center for BrainHealth at UT Dallas have demonstrated in a pilot study that cognitive training improves innovative thinking, along with corresponding positive brain changes, in healthy adults over the age of 55.

    The study, published recently in Frontiers in Aging Neuroscience, reveals that a specific strategic cognitive training program enhanced innovation in healthy adults. Performance was measured by an individual’s ability to synthesize complex information and generate a multitude of high-level interpretations.

    “Middle-age to older adults should feel empowered that, in many circumstances, they can reverse decline and improve innovative thinking,” said Dr. Sandra Bond Chapman, Center for BrainHealth founder and chief director and lead author of the study. “Innovative cognition — the kind of thinking that reinforces and preserves complex decision-making, intellect and psychological well-being — does not need to decline with age. This study reveals that cognitive training may help enhance cognitive capacities and build resilience against decline in healthy older adults.”

    The SMART program — Strategic Memory Advanced Reasoning Training — was developed at the Center for BrainHealth. It focuses on learning strategies that foster attention, reasoning and broad-based perspective-taking.

    Center for BrainHealth researchers conducted a randomized pilot trial and compared the effect of SMART to aerobic exercise training (known to be good for brain health) and control subjects on innovative cognition. The SMART program was conducted one hour per week for 12 weeks with 2 hours of homework each week. The 58 participants were assessed at baseline-, mid- and post-training using innovative cognition measures and functional MRI, a brain scanning technology that reveals brain activity.

    “In addition to evaluating the effects of the cognitive training, this study also provided an opportunity to test a reliable assessment tool to measure innovative cognition, which has been relatively neglected due to the complexity of quantifying innovative thinking,” Chapman said.

    The 19 participants in the cognitive reasoning training group (SMART) showed significant gains pre- to post-training in high-quality innovation performance, improving their performance by an average of 27 percent from baseline to mid- and post-training periods on innovative cognition measures. The physical exercise and control groups did not show improvement. These positive gains in the reasoning training group corresponded to increased connectivity among brain cells in the central executive network of the brain, an area responsible for innovative thinking.

    “Advances in the field of MRI are allowing us to measure different aspects of brain function,” said Dr. Sina Aslan, an imaging specialist at the Center for BrainHealth. “Through this research, we are able to see that higher activity in the central executive network corresponded to improved innovation. These findings suggest that staying mentally active not only mitigates cognitive decline, but also has the potential to restore creative thinking, which is typically lost with aging.”

    While further research is needed to establish how to ensure the benefit persists, Chapman is encouraged by the results.

    “Reasoning training offers a promising cost-effective intervention to enhance innovative cognition — one of the most valued capacities and fruitful outputs of the human mind at any age.”

    The work was supported by a grant from the National Institute of Health and by grants from the T. Boone Pickens Foundation, the Lyda Hill Foundation and Dee Wyly Distinguished University Endowment.


  2. New player in Alzheimer’s disease pathogenesis identified

    by Ashley

    From the Sanford-Burnham Prebys Medical Discovery Institute press release:

    Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have shown that a protein called membralin is critical for keeping Alzheimer’s disease pathology in check. The study, published in Nature Communications, shows that membralin regulates the cell’s machinery for producing beta-amyloid (or amyloid beta, A?), the protein that causes neurons to die in Alzheimer’s disease.

    “Our results suggest a new path toward future treatments for Alzheimer’s disease,” says Huaxi Xu, Ph.D., the Jeanne and Gary Herberger Leadership Chair of SBP’s Neuroscience and Aging Research Center. “If we can find molecules that modulate membralin, or identify its role in the cellular protein disposal machinery known as the endoplasmic reticulum-associated degradation (ERAD) system, this may put the brakes on neurodegeneration.”

    ERAD is the mechanism by which cells get rid of proteins that are folded incorrectly in the ER. It also controls the levels of certain mature, functional proteins. Xu’s team found that one of the fully formed, working proteins that ERAD regulates is a component of an enzyme called gamma secretase that generates A?.

    This discovery helps fill in the picture of how Alzheimer’s disease, an incredibly complicated disorder influenced by many genetic and environmental factors. No therapies have yet been demonstrated to slow progression of the disease, which affects around 47 million people worldwide. Until such drugs are developed, patients face a steady, or sometimes rapid, decline in memory and reasoning.

    Memory loss in Alzheimer’s results from the toxic effects of A?, which causes connections between neurons to break down. A? is created when gamma secretase cuts the amyloid precursor protein into smaller pieces. While A? is made in all human brains as they age, differences in the rate at which it is produced and eliminated from the brain and in how it affects neurons, means that not everyone develops dementia.

    “We were interested in membralin because of its genetic association with Alzheimer’s, and in this study we established the connection between membralin and Alzheimer’s based on findings from the laboratory of a former colleague at SBP, Professor Dongxian Zhang,” Xu explains. “That investigation showed that eliminating the gene for membralin leads to rapid motor neuron degeneration, but its cellular function wasn’t clear.”

    Using proteomics, microscopic analysis, and functional assays, the group provided definitive evidence that membralin functions as part of the ERAD system. Later, they found that membralin-dependent ERAD breaks down a protein that’s part of the gamma secretase enzyme complex, and that reducing the amount of membralin in a mouse model of Alzheimer’s exacerbates neurodegeneration and memory problems.

    “Our findings explain why mutations that decrease membralin expression would increase the risk for Alzheimer’s,” Xu comments. “This would lead to an accumulation of gamma secretase because its degradation is disabled, and the gamma-secretase complex would then generate more A?. Those mutations are rare, but there may be other factors that cause neurons to make less membralin.”

    Xu and colleagues also observed lower levels of membralin, on average, in the brains of patients with Alzheimer’s than in unaffected individuals, demonstrating the relevance of their findings to humans.

    “Previous studies have suggested that ERAD contributes to many diseases where cells become overwhelmed by an irregular accumulation of proteins, including Alzheimer’s,” says Xu. “This study provides conclusive, mechanistic evidence that ERAD plays an important role in restraining Alzheimer’s disease pathology. We now plan to search for compounds that enhance production of membralin or the rate of ERAD to test whether they ameliorate pathology and cognitive decline in models of Alzheimer’s. That would further support the validity of this mechanism as a drug target.”


  3. Study suggests reasons why head and face pain causes more suffering

    by Ashley

    From the Duke University press release:

    Hate headaches? The distress you feel is not all in your — well, head. People consistently rate pain of the head, face, eyeballs, ears and teeth as more disruptive, and more emotionally draining, than pain elsewhere in the body.

    Duke University scientists have discovered how the brain’s wiring makes us suffer more from head and face pain. The answer may lie not just in what is reported to us by the five senses, but in how that sensation makes us feel emotionally.

    The team found that sensory neurons that serve the head and face are wired directly into one of the brain’s principal emotional signaling hubs. Sensory neurons elsewhere in the body are also connected to this hub, but only indirectly.

    The results may pave the way toward more effective treatments for pain mediated by the craniofacial nerve, such as chronic headaches and neuropathic face pain.

    “Usually doctors focus on treating the sensation of pain, but this shows the we really need to treat the emotional aspects of pain as well,” said Fan Wang, a professor of neurobiology and cell biology at Duke, and senior author of the study. The results appear online Nov. 13 in Nature Neuroscience.

    Pain signals from the head versus those from the body are carried to the brain through two different groups of sensory neurons, and it is possible that neurons from the head are simply more sensitive to pain than neurons from the body.

    But differences in sensitivity would not explain the greater fear and emotional suffering that patients experience in response to head-face pain than body pain, Wang said.

    Personal accounts of greater fear and suffering are backed up by functional Magnetic Resonance Imaging (fMRI), which shows greater activity in the amygdala — a region of the brain involved in emotional experiences — in response to head pain than in response to body pain.

    “There has been this observation in human studies that pain in the head and face seems to activate the emotional system more extensively,” Wang said. “But the underlying mechanisms remained unclear.”

    To examine the neural circuitry underlying the two types of pain, Wang and her team tracked brain activity in mice after irritating either a paw or the face. They found that irritating the face led to higher activity in the brain’s parabrachial nucleus (PBL), a region that is directly wired into the brain’s instinctive and emotional centers.

    Then they used methods based on a novel technology recently pioneered by Wang’s group, called CANE, to pinpoint the sources of neurons that caused this elevated PBL activity.

    “It was a eureka moment because the body neurons only have this indirect pathway to the PBL, whereas the head and face neurons, in addition to this indirect pathway, also have a direct input,” Wang said. “This could explain why you have stronger activation in the amygdala and the brain’s emotional centers from head and face pain.”

    Further experiments showed that activating this pathway prompted face pain, while silencing the pathway reduced it.

    “We have the first biological explanation for why this type of pain can be so much more emotionally taxing than others,” said Wolfgang Liedtke, a professor of neurology at Duke University Medical Center and a co-author on Wang’s paper, who is also treating patients with head- and face-pain. “This will open the door toward not only a more profound understanding of chronic head and face pain, but also toward translating this insight into treatments that will benefit people.”

    Chronic head-face pain such cluster headaches and trigeminal neuralgia can become so severe that patients seek surgical solutions, including severing the known neural pathways that carry pain signals from the head and face to the hindbrain. But a substantial number of patients continue to suffer, even after these invasive measures.

    “Some of the most debilitating forms of pain occur in the head regions, such as migraine,” said Qiufu Ma, a professor of neurobiology at Harvard Medical School, who was not involved in the study. “The discovery of this direct pain pathway might provide an explanation why facial pain is more severe and more unpleasant.”

    Liedtke said targeting the neural pathway identified here can be a new approach toward developing innovative treatments for this devastating head and face pain.


  4. Injury from contact sport has harmful, though temporary effect on memory

    by Ashley

    From the McMaster University press release:

    McMaster University neuroscientists studying sports-related head injuries have found that it takes less than a full concussion to cause memory loss, possibly because even mild trauma can interrupt the production of new neurons in a region of the brain responsible for memory.

    Though such losses are temporary, the findings raise questions about the long-term effects of repeated injuries and the academic performance of student athletes.

    The researchers spent months following dozens of athletes involved in high-contact sports such as rugby and football, and believe that concussions and repetitive impact can interrupt neurogenesis — or the creation of new neurons — in the hippocampus, a vulnerable region of the brain critical to memory.

    The findings were presented today (Tuesday, November 14th) at the Society for Neuroscience’s annual conference, Neuroscience 2017, in Washington D.C.

    “Not only are newborn neurons critical for memory, but they are also involved in mood and anxiety,” explains Melissa McCradden, a neuroscience postdoctoral fellow at McMaster University who conducted the work. “We believe these results may help explain why so many athletes experience difficulties with mood and anxiety in addition to memory problems.”

    For the study, researchers administered memory tests and assessed different types of athletes in two blocks over the course of two years. In the first block, they compared athletes who had suffered a concussion, uninjured athletes who played the same sport, same-sport athletes with musculoskeletal injuries, and healthy athletes who acted as a control group.

    Concussed athletes performed worse on the memory assessment called a mnemonic similarity test (MST), which evaluates a person’s ability to distinguish between images that are new, previously presented, or very similar to images previously presented.

    In the second study, rugby players were given the MST before the season started, halfway through the season, and one month after their last game. Scores for injured and uninjured athletes alike dropped midseason, compared to preseason scores, but recovered by the postseason assessment.

    Both concussed and non-concussed players showed a significant improvement in their performance on the test after a reprieve from their sport.

    For the concussed athletes, this occurred after being medically cleared to return to full practice and competition. For the rugby players, they improved after approximately a month away from the sport.

    If neurogenesis is negatively affected by concussion, researchers say, exercise could be an important tool in the recovery process, since it is known to promote the production of neurons. A growing body of new research suggests that gentle exercise which is introduced before a concussed patient is fully symptom free, is beneficial.

    “The important message here is that the brain does recover from injury after a period of reprieve,” says McCradden. “There is a tremendous potential for the brain to heal itself.”


  5. Study suggests brain activity buffers against worsening anxiety

    November 21, 2017 by Ashley

    From the Duke University press release:

    Boosting activity in brain areas related to thinking and problem-solving may also buffer against worsening anxiety, suggests a new study by Duke University researchers.

    Using non-invasive brain imaging, the researchers found that people at-risk for anxiety were less likely to develop the disorder if they had higher activity in a region of the brain responsible for complex mental operations. The results may be a step towards tailoring psychological therapies to the specific brain functioning of individual patients.

    “These findings help reinforce a strategy whereby individuals may be able to improve their emotional functioning — their mood, their anxiety, their experience of depression — not only by directly addressing those phenomena, but also by indirectly improving their general cognitive functioning,” said Ahmad Hariri, a professor of psychology and neuroscience at Duke. The results are published Nov. 17 in the journal Cerebral Cortex.

    Previous findings from Hariri’s group show that people whose brains exhibit a high response to threat and a low response to reward are more at risk of developing symptoms of anxiety and depression over time.

    In the current work, Hariri and Matthew Scult, a clinical psychology graduate student in the department of psychology and neuroscience at Duke, wanted to investigate whether higher activity in a region of the brain called the dorsolateral prefrontal cortex could help shield these at-risk individuals from future mental illness.

    “We wanted to address an area of understanding mental illness that has been neglected, and that is the flip side of risk,” Hariri said. “We are looking for variables that actually confer resiliency and protect individuals from developing problems.”

    The dorsolateral prefrontal cortex is our brain’s “executive control” center, helping us focus our attention and plan complex actions. It also plays a role in emotion regulation, and well-established types of psychotherapy, including cognitive behavioral therapy, engage this region of the brain by equipping patients with strategies to reframe or re-evaluate their emotions.

    The team drew on data from 120 undergraduate students who participated in the Duke Neurogenetics Study. Each participant completed a series of mental health questionnaires and underwent a type of non-invasive brain scan called functional Magnetic Resonance Imaging (fMRI) while engaged in tasks meant to activate specific regions of the brain.

    The researchers asked each participant to answer simple memory-based math problems to stimulate the dorsolateral prefrontal cortex. Participants also viewed angry or scared faces to activate a region of the brain called the amygdala, and played a reward-based guessing game to stimulate activity in the brain’s ventral striatum.

    Scult was particularly interested in “at-risk” individuals with the combination of high threat-related activity in the amygdala and low reward-related activity in the ventral striatum. By comparing participants’ mental health assessments at the time of the brain scans, and in a follow-up occurring on average seven months later, he found that these at-risk individuals were less likely to develop anxiety if they also had high activity in the dorsolateral prefrontal cortex.

    “We found that if you have a higher functioning dorsolateral prefrontal cortex, the imbalance in these deeper brain structures is not expressed as changes in mood or anxiety,” Hariri said.

    The dorsolateral prefrontal cortex is especially skilled at adapting to new situations, the researchers say. Individuals whose brains exhibit the at-risk signatures may be more likely to benefit from strategies that boost the brain’s dorsolateral prefrontal activity, including cognitive behavioral therapy, working memory training, or transcranial magnetic stimulation (TMS).

    But, the researchers warn, the jury is still out on whether many brain-training exercises improve the overall functioning of the dorsolateral prefrontal cortex, or only hone its ability to complete the specific task being trained. Additional studies on more diverse populations are also needed to confirm their findings.

    “We are hoping to help improve current mental health treatments by first predicting who is most at-risk so that we can intervene earlier, and second, by using these types of approaches to determine who might benefit from a given therapy,” Scult said.


  6. Study suggests declining sense of smell may help identify patients with mild cognitive impairment

    by Ashley

    From the Columbia University Medical Center press release:

    Researchers at Columbia University Medical Center (CUMC) and the New York State Psychiatric Institute (NYSPI) may have discovered a way to use a patient’s sense of smell to treat Alzheimer’s disease before it ever develops. Having an impaired sense of smell is recognized as one of the early signs of cognitive decline, before the clinical onset of Alzheimer’s disease. The researchers at CUMC and NYSPI have found a way to use that effect to determine if patients with mild cognitive impairment may respond to cholinesterase inhibitor drugs to treat Alzheimer’s disease.

    The findings were published online this week in the Journal of Alzheimer’s Disease.

    Cholinesterase inhibitors, such as donepezil, enhance cholinergic function by increasing the transmission of the neurotransmitter acetylcholine in the brain. Cholinergic function is impaired in individuals with Alzheimer’s disease. Cholinesterase inhibitors, which block an enzyme that breaks down acetylcholine, have shown some effectiveness in improving the cognitive symptoms of Alzheimer’s disease. However, they have not been proven effective as a treatment for individuals with mild cognitive impairment (MCI), a condition that markedly increases the risk of Alzheimer’s disease.

    “We know that cholinesterase inhibitors can make a difference for Alzheimer’s patients, so we wanted to find out if we could identify patients at risk for Alzheimer’s who might also benefit from this treatment,” said D.P. Devanand, MBBS, MD, professor of psychiatry, scientist in the Gertrude H. Sergievsky Center at CUMC, and co-director of the Memory Disorders Clinic and the Late Life Depression Clinic at NYSPI. “Since odor identification tests have been shown to predict progression to Alzheimer’s, we hypothesized that these tests would also allow us to discover which patients with MCI would be more likely to improve with donepezil treatment.”

    In this year-long study, 37 participants with MCI underwent odor identification testing with the University of Pennsylvania Smell Identification Test (UPSIT). The test was administered before and after using an atropine nasal spray that blocks cholinergic transmission.

    The patients were then treated with donepezil for 52 weeks, and were periodically reevaluated with the UPSIT and with memory and cognitive function tests. Those who had a greater decline in UPSIT scores, indicating greater cholinergic deficits in the brain, after using the anticholinergic nasal spray test saw greater cognitive improvement with donepezil.

    In addition, short-term improvement in odor identification from baseline to eight weeks tended to predict longer-term cognitive improvement with donepezil treatment over one year.

    “These results, particularly if replicated in larger populations, suggest that these simple inexpensive strategies have the potential to improve the selection of patients with mild cognitive impairment who are likely to benefit from treatment with cholinesterase inhibitors like donepezil,” said Dr. Devanand.


  7. Study suggests biomarker may predict early Alzheimer’s disease

    November 20, 2017 by Ashley

    From the Sanford-Burnham Prebys Medical Discovery Institute press release:

    Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a peptide that could lead to the early detection of Alzheimer’s disease (AD). The discovery, published in Nature Communications, may also provide a means of homing drugs to diseased areas of the brain to treat AD, Parkinson’s disease, as well as glioblastoma, brain injuries and stroke.

    “Our goal was to find a new biomarker for AD,” says Aman Mann, Ph.D., research assistant professor at SBP who shares the lead authorship of the study with Pablo Scodeller, Ph.D., a postdoctoral researcher at SBP. “We have identified a peptide (DAG) that recognizes a protein that is elevated in the brain blood vessels of AD mice and human patients. The DAG target, connective tissue growth factor (CTGF) appears in the AD brain before amyloid plaques, the pathological hallmark of AD.”

    “CTGF is a protein that is made in the brain in response to inflammation and tissue repair,” explains Mann. “Our finding that connects elevated levels of CTGF with AD is consistent with the growing body of evidence suggesting that inflammation plays an important role in the development of AD.”

    The research team identified the DAG peptide using in vivo phage display screening at different stages of AD development in a mouse model. In young AD mice, DAG detected the earliest stage of the disease. If the early appearance of the DAG target holds true in humans, it would mean that DAG could be used as a tool to identify patients at early, pre-symptomatic stages of the disease when treatments already available may still be effective.

    “Importantly, we showed that DAG binds to cells and brain from AD human patients in a CTGF-dependent manner” says Mann. “This is consistent with an earlier report of high CTGF expression in the brains of AD patients.”

    “Our findings show that endothelial cells, the cells that form the inner lining of blood vessels, bind our DAG peptide in the parts of the mouse brain affected by the disease,” says Erkki Ruoslahti, M.D., Ph.D., distinguished professor at SBP and senior author of the paper. “This is very significant because the endothelial cells are readily accessible for probes injected into the blood stream, whereas other types of cells in the brain are behind a protective wall called the blood-brain barrier. The change in AD blood vessels gives us an opportunity to create a diagnostic method that can detect AD at the earliest stage possible.

    “But first we need to develop an imaging platform for the technology, using MRI or PET scans to differentiate live AD mice from normal mice. Once that’s done successfully, we can focus on humans,” adds Ruoslahti.

    “As our research progresses we also foresee CTGF as a potential therapeutic target that is unrelated to amyloid beta (Aß), the toxic protein that creates brain plaques,” says Ruoslahti. “Given the number of failed clinical studies that have sought to treat AD patients by targeting Aß, it’s clear that treatments will need to be given earlier — before amyloid plaques appear — or have to target entirely different pathways.

    DAG has the potential to fill both roles — identifying at risk individuals prior to overt signs of AD and targeted delivery of drugs to diseased areas of the brain. Perhaps CTGF itself can be a drug target in AD and other brain disorders linked to inflammation. We’ll just have to learn more about its role in these diseases.”


  8. Study identifies group of brain cells responsible for keeping us awake

    November 19, 2017 by Ashley

    From the Emory Health Sciences press release:

    Scientists have identified an additional group of cells in the brain responsible for keeping us awake: the supramammillary nucleus, part of the caudal hypothalamus.

    Neurologists had suspected that a component of the “ascending arousal system” could be found in this part of the brain for more than 100 years, but the precise location had been a mystery. In mice, activating this region using targeted chemical genetic techniques resulted in prolonged wakefulness during the animals’ normal sleep periods.

    The results are scheduled for publication in Nature Communications.

    In humans, this region could be a target for bringing some brain injury patients out of a comatose state via electrical stimulation, says lead author Nigel Pedersen, MD, assistant professor of neurology at Emory University School of Medicine and an epilepsy specialist at Emory Brain Health Center.

    The supramammillary nucleus was known for its connections to the hippocampus, important for memory formation, and parts of the frontal cortex involved in focused attention, Pedersen says.

    “Given these connections, this region may be important for the voluntary maintenance of wake and attention, but more work is needed to study this,” he says.

    Pedersen conducted the research with Clifford Saper, MD, PhD, and Patrick Fuller, PhD, at Harvard Medical School and Beth Israel Deaconess Medical Center. Pedersen is continuing work at Emory on the importance of the supramammillary nucleus in memory and learning, and studying its connections to the hippocampus in relation to epilepsy control.

    For decades, neurologists had known that damage to the hypothalamus — including that seen in the mysterious post-World War I epidemic encephalitis lethargica — resulted in marked sleepiness. Now that the location and identity of the wake-promoting neurons are precisely defined, the supramammillary region joins other parts of the brain known as being involved in keeping people awake, such as the nearby lateral hypothalamus, the upper brain stem and basal forebrain.

    In the current paper, Pedersen and his colleagues used genetic engineering techniques to selectively activate particular groups of cells in the brain. They did so with a combination of a designer drug (clozapine-N-oxide) and receptors engineered to be triggered only by that drug. They injected viral vectors carrying an activation switch into the hypothalami of mice, and then gave the mice clozapine-N-oxide.

    Investigators mapped precisely where their injections went and which ones promoted wakefulness; only those involving the supramammillary nucleus did. So what does having this part of the brain stimulated “feel like” for the mice?

    “It’s hard to say, but they display a normal repertoire of behavior,” Pedersen says. “They’re not as wound up, and they don’t show stereotyped repetitive behaviors, as they would with stimulants. The main difference between these and normal mice is that there is no ‘quiet’ wakefulness or napping during the normally sleep-enriched daytime period.”

    Inhibiting the same area of the brain with similar techniques increased the amount of time mice slept, especially non-REM (rapid eye movement) sleep, although sleep was not instant upon drug administration, as has been shown for other parts of the arousal system, Pedersen says.

    “The effects of inhibition of the supramammillary region is to increase sleep, but not dramatically,” he says. “Disruption of other components of the arousal system typically has relatively mild effects. This may amount to some redundancy in the arousal network, but may also relate to the way in which different components of the arousal system have a role in particular types or components of wakefulness. We are actively exploring this idea.”

    Genetic manipulations also allowed the scientists to determine that the brain chemical glutamate was critical for wake signals. When the gene for a glutamate transporter VGLUT2 was snipped out of the supramammillary nucleus, artificial stimulation had no effect on wake and sleep.

    The presence of the enzyme nitric oxide synthase was used to identify an especially potent wake-promoting group of neurons, but their functions still depend on glutamate release. The role of the gaseous neurotransmitter nitric oxide in this brain network is not yet known, Pedersen adds.


  9. Study suggests sleep apnea may increase risk of developing Alzheimer’s disease

    by Ashley

    From the American Thoracic Society press release:

    Obstructive sleep apnea (OSA) may put elderly people at greater risk of developing Alzheimer’s disease (AD), according to new research published online in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

    In “Obstructive Sleep Apnea Severity Affects Amyloid Burden in Cognitively Normal Elderly: A Longitudinal Study,” researchers report that biomarkers for amyloid beta (Aß), the plaque-building peptides associated with Alzheimer’s disease, increase over time in elderly adults with OSA in proportion to OSA severity. Thus, individuals with more apneas per hour had greater accumulation of brain amyloid over time.

    According to the authors, AD is a neurodegenerative disorder that afflicts approximately five million older Americans. OSA is even more common, afflicting from 30 to 80 percent of the elderly, depending on how OSA is defined.

    “Several studies have suggested that sleep disturbances might contribute to amyloid deposits and accelerate cognitive decline in those at risk for AD,” said Ricardo S. Osorio, MD, senior study author and assistant professor of psychiatry at New York University School of Medicine.

    “However, so far it has been challenging to verify causality for these associations because OSA and AD share risk factors and commonly coexist.”

    He added that the purpose of this study was to investigate the associations between OSA severity and changes in AD biomarkers longitudinally, specifically whether amyloid deposits increase over time in healthy elderly participants with OSA.

    The study included 208 participants, age 55 to 90, with normal cognition as measured by standardized tests and clinical evaluations. None of the participants was referred by a sleep center, used continuous positive airway pressure (CPAP) to treat sleep apnea, was depressed, or had a medical condition that might affect their brain function. The researchers performed lumbar punctures (LPs) to obtain participants’ cerebrospinal fluid (CSF) soluble Aß levels, and then used positron emission tomography, or PET, to measure Aß deposits directly in the brain in a subset of participants.

    The study found that more than half the participants had OSA, including 36.5 percent with mild OSA and 16.8 percent with moderate to severe OSA. From the total study sample, 104 participated in a two-year longitudinal study that found a correlation between OSA severity and a decrease in CSF Aß42 levels over time. The authors said this finding is compatible with an increase in amyloid deposits in the brain; the finding was confirmed in the subset of participants who underwent amyloid PET, which showed an increase in amyloid burden in those with OSA.

    Surprisingly, the study did not find that OSA severity predicted cognitive deterioration in these healthy elderly adults. Andrew Varga, MD, PhD, study coauthor and a physician specializing in sleep medicine and neurology at the Icahn School of Medicine at Mount Sinai in New York, said this finding suggests that these changes were occurring in the preclinical stages of AD.

    “The relationship between amyloid burden and cognition is probably nonlinear and dependent on additional factors,” he added. This study finding may also be attributable to the study’s relatively short duration, highly educated participants and use of tests that fail to discern changes in cognitive abilities that are subtle or sleep-dependent, the authors wrote.

    The high prevalence of OSA the study found in these cognitively normal elderly participants and the link between OSA and amyloid burden in these very early stages of AD pathology, the researchers believe, suggest the CPAP, dental appliances, positional therapy and other treatments for sleep apnea could delay cognitive impairment and dementia in many older adults.

    “Results from this study, and the growing literature suggesting that OSA, cognitive decline and AD are related, may mean that age tips the known consequences of OSA from sleepiness, cardiovascular, and metabolic dysfunction to brain impairment,” Dr. Osorio said. “If this is the case, then the potential benefit of developing better screening tools to diagnose OSA in the elderly who are often asymptomatic is enormous.”


  10. Study investigates patterns of degeneration in Alzheimer’s disease

    November 18, 2017 by Ashley

    From the Brigham and Women’s Hospital press release:

    Alzheimer’s disease (AD) is known to cause memory loss and cognitive decline, but other functions of the brain can remain intact. The reasons cells in some brain regions degenerate while others are protected is largely unknown. In a paper to be published in Stem Cell Reports, researchers from Brigham and Women’s Hospital have found that factors encoded in the DNA of brain cells contribute to the patterns of degeneration, or vulnerability, in AD.

    AD is characterized by plaques composed of amyloid ?-protein (A?) and tangles composed of Tau protein; accumulation of A? protein leads to disruption of Tau and, eventually, neurodegeneration which affects brain regions in a variety of ways. The front, rostral, portion of the brain is generally more damaged by plaque build-up while the back, caudal, portion is generally spared.

    Though there are several mechanisms that could cause these differences, the team focused on the potential contributions of cell-autonomous factors among neuronal subtypes that could affect both the generation of and the responses to A?. In a novel application of human induced-pluripotent stem cell (iPSC) technology, the team generated powerful culture systems that represent different areas of the brain. The systems were developed by taking skin cells from patients with a familial Alzheimer’s disease mutation and turning these skin cells into stem cells. Stem cells divide to make more stem cells, providing an unlimited supply of cells. Stem cells also can be turned into any type of cell in the body, including brain cells. In this study, the authors showed that vulnerable brain cells made more toxic A? protein compared to brain cells from more protected regions of the brain.

    In addition, the researchers found that brain cells in the protected, caudal portion of the brain have a less toxic response to A? than their rostral counterparts. Though early-onset, familial Alzheimer’s disease (fAD) accounts for a small number of AD cases, the study of fAD patients, or samples in this case, can reveal important aspects of the cell and molecular mechanisms underlying all types of AD. The team is currently using this information to investigate exactly why caudal neurons are protected and what differences in cell type cause neurons to be protected from AD.

    “These findings illuminate our understanding of why some neurons are spared and why others are not spared in AD,” said Christina Muratore, PhD, of the Department of Neurology. “If we can find out more information about why these subtypes of cells are protected, we may be able to use this information to tailor therapies to protect the vulnerable cells.”