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 declining sense of smell may help identify patients with mild cognitive impairment

    November 21, 2017 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.


  4. Study suggests ‘bursts’ of beta waves, not sustained rhythms, filter sensory processing in brain

    November 15, 2017 by Ashley

    From the Brown University press release:

    To better understand the brain and to develop potential therapies, neuroscientists have been investigating how “beta” frequency brainwaves help the brain filter distractions to process sensations. A new Brown University study stands to substantially refine what they thought was going on: What really matters is not a sustained elevation in beta wave power, but instead the rate of specific bursts of beta wave activity, ideally with perfect timing.

    The new insight, reported in the journal eLife, arose from the scientists looking beneath the covers of the typical practice of averaging beta brain wave data. With a closer examination, trial-by-trial for each subject, they saw that what really reflected attention and impacted perception were discrete, powerful bursts of beta waves at frequencies around 20 hertz.

    “When people were trying to block distraction in a brain area, the probability of seeing these beta events went up,” said senior author Stephanie R. Jones, an associate professor of neuroscience at Brown. “The brain seemed to be flexibly modulating the expression of these beta events for optimal perception.”

    The findings, made with consistency in humans and mice, can not only refine ongoing research into how beta waves arise and work in the brain, Jones said, but also provide guidance to clinicians as they develop therapies that seek to modulate beta waves.

    Testing touch

    The research team, led by graduate student Hyeyoung Shin, acquired the data through a series of experiments in which they measured beta waves in the somatosensory neocortex of humans and mice in the second leading up to inducing (or not inducing) varying amounts of a tactile sensation. Humans wore a cap of magnetoencephalography sensors, while mice had implanted electrodes. For people, the sensation was a tap on a finger tip or the foot. For mice, it was a wiggle of a whisker.

    Subjects were merely required to report the sensations they felt — people pushed a button, while mice were trained to lick a sensor in exchange for a reward. The researchers tracked the association of beta power with whether subjects accurately detected, or didn’t detect, stimuli. What they found, as expected, is that the more beta activity there was in the corresponding region of cortex, the less likely subjects were to report feeling a sensation. Elevated beta activity is known to help suppress distractions.

    A particularly good example, Shin said, was that in experiments where people were first instructed to focus on their foot, there was more beta power in the hand region of the neocortex. Correspondingly, more beta in the hand region resulted in less detection of a sensation in the hand.

    “We think that beta acts a filter mechanism,” Shin said.

    Beta bursts

    Consistently throughout various iterations of the experiments across both the human and mouse subjects, increases in beta activity did not manifest as a continuously elevated rhythm. Instead, when beta appeared, it quickly spiked in short, distinct bursts of power. Only if a subject’s beta was averaged over many trials would it look like a smooth plateau of high-power activity.

    After discovering this pattern, the researchers performed analyses to determine what features of the bursts best predicted whether subjects would report, or miss, a touch sensation. After all, it could be the number of bursts, their power, or maybe how long they lasted.

    What Shin and the team found is that number of bursts and their timing both mattered independently. If there were two or more bursts any time in the second before a sensation, it was significantly more likely to go undetected. Alternatively, if just one burst hit within 200 milliseconds of the sensation, the stimulus would also be more likely to be overlooked.

    “The ideal case was having large numbers and being close in timing to the stimulus,” Shin said.

    A better idea of beta

    While the study helps to characterize the nature of beta in the somatosensory neocortex, it doesn’t explain how it affects sensations, Jones acknowledged. But that’s why it is important that the results were in lockstep in both mice and in people. Confirming that mice model the human experience means researchers can rely on mice in experiments that delve more deeply into how beta bursts arise and what their consequence are in neurons and circuits. Shin is already doing experiments to dissect how distinct neural subpopulations contribute to beta bursts and somatosensory detection, respectively. Co-author and postdoctoral researcher Robert Law is applying computational neural models that link the human and animal recordings for further discovery.

    In the clinical realm, Jones said, an improved understanding of how beta works could translate directly into improving therapies such as transcranial magnetic stimulation or transcranial alternating current to treat neurological disorders, such as chronic pain, or depression. Rather than using those technologies to generate a consistent elevation in beta in a brain region, Jones said, it might be more effective to use them to induce (or suppress) shorter, more powerful bursts and to time those to be as close in time to a target brain activity as possible.

    “Typically with non-invasive brain stimulation you are trying to entrain a rhythm,” Jones said. “What our results suggest is that’s not what the brain is doing. The brain is doing this intermittent pattern of activity.”


  5. Higher estrogen levels linked to increased alcohol sensitivity in brain’s ‘reward center’

    November 14, 2017 by Ashley

    From the University of Illinois at Chicago press release:

    The reward center of the brain is much more attuned to the pleasurable effects of alcohol when estrogen levels are elevated, an effect that may underlie the development of addiction in women, according to a study on mice at the University of Illinois at Chicago.

    Led by Amy Lasek, assistant professor of psychiatry in the UIC College of Medicine, researchers found that neurons in a region of the brain called the ventral tegmental area, or VTA (also known as the “reward center”), fired most rapidly in response to alcohol when their estrogen levels were high. This response, according to their findings published online in the journal PLOS ONE, is mediated through receptors on dopamine-emitting neurons in the VTA.

    “When estrogen levels are higher, alcohol is much more rewarding,” said Lasek, who is the corresponding author on the paper and a researcher in the UIC Center for Alcohol Research in Epigenetics. “Women may be more vulnerable to the effects of alcohol or more likely to overindulge during certain stages of their cycle when estrogen levels are higher, or may be more likely to seek out alcohol during those stages.”

    Studies indicate that gender differences in psychiatric disorders, including addiction, are influenced by estrogen, one of the primary female sex hormones. Women are more likely to exhibit greater escalation of abuse of alcohol and other drugs, and are more prone to relapse in response to stress and anxiety.

    The VTA helps evaluate whether something is valuable or good. When neurons in this area of the brain are stimulated, they release dopamine — a powerful neurotransmitter responsible for feelings of wellness — and, in large doses, euphoria. When something good is encountered — for example, chocolate — the neurons in the VTA fire more rapidly, enforcing reward circuitry that encodes the idea that chocolate is enjoyable and something to be sought out. Over time, the VTA neurons fire more quickly at the sight, or even thought of, chocolate, explained Lasek. In addiction, VTA neurons are tuned into drugs of abuse, and fire more quickly in relation to consuming or even thinking about drugs, driving the person to seek them out — often at the expense of their own health, family, friends and jobs.

    Many animal studies have shown that alcohol increases the firing of dopamine-sensitive neurons in the VTA, but little is known about exactly why this occurs.

    Lasek and her colleagues examined the relationship between estrogen, alcohol and the VTA in female mice. They used naturally cycling mice that were allowed to go through their normal estrous cycles, akin to the menstrual cycle in women.

    Mice were evaluated to determine when they entered diestrus — the phase in the estrous cycle when estrogen levels are close to their peak.

    “In mice in diestrus, estrogen levels increase to about 10 times higher than they are in estrus, the phase in which ovulation occurs and estrogen levels drop,” Lasek said.

    VTAs were taken from mice in both estrus and diestrus and kept alive in special chambers. Electrodes recorded the activity of individual dopamine-sensitive neurons in the VTA. Next, the researchers added alcohol to the chamber. Activity increased twice as much in neurons from mice in diestrus compared to the response of neurons from mice in estrus.

    Lasek and her colleagues then blocked estrogen receptors on dopamine-sensitive neurons in VTA in mice in estrus and diestrus. With the blocker present, the response to alcohol in neurons from mice in diestrus was significantly lower compared with neurons where estrogen receptors remained functional. The estrogen receptor blocker reduced the alcohol response to levels seen in mice in estrus. The responses to alcohol in neurons from mice in estrus were unaffected by the estrogen receptor blocker.

    “The increased reward response to alcohol we see when estrogen levels are high is mediated through receptors for estrogen in the VTA,” said Mark Brodie, professor of physiology and biophysics in the UIC College of Medicine and a co-author on the paper.

    Lasek believes that the increased sensitivity to alcohol in the VTA when estrogen levels peak may play a significant role in the development of addiction in women.

    “We already know that binge drinking can lead to lasting changes in the brain, and in women, those changes may be faster and more significant due to the interaction we see between alcohol, the VTA and estrogen,” Lasek said. “Binge drinking can increase the risk of developing alcoholism, so women need to be careful about how much alcohol they drink. They should be aware that they may sometimes inadvertently over-consume alcohol because the area of the brain involved in alcohol reward is responding very strongly.”


  6. Study suggests brain activity is inherited, may inform treatment for ADHD, autism

    November 13, 2017 by Ashley

    From the Oregon Health & Science University press release:

    Every person has a distinct pattern of functional brain connectivity known as a connectotype, or brain fingerprint. A new study conducted at OHSU in Portland, Oregon, concludes that while individually unique, each connectotype demonstrates both familial and heritable relationships. The results published today in Network Neuroscience.

    “Similar to DNA, specific brain systems and connectivity patterns are passed down from adults to their children,” said the study’s principal investigator Damien Fair, Ph.D., P.A.-C., associate professor of behavioral neuroscience and psychiatry, OHSU School of Medicine. “This is significant because it may help us to better characterize aspects of altered brain activity, development or disease.”

    Using two data sets of functional MRI brain scans from more than 350 adult and child siblings during resting state, Fair and colleagues applied an innovative technique to characterize functional connectivity and machine learning to successfully identify siblings based on their connectotype.

    Through a similar process, the team also distinguished individual sibling and twin pairs from unrelated pairs in both children and adults.

    “This confirms that while unique to each individual, some aspects of the family connectome are inherited and maintained throughout development and may be useful as early biomarkers of mental or neurological conditions,” said lead author Oscar Miranda-Dominguez, Ph.D., research assistant professor of behavioral neuroscience, OHSU School of Medicine.

    Overall, the connectotype demonstrated heritability within five brain systems, the most prominent being the frontoparietal cortex, or the part of the brain that filters incoming information. The dorsal attention and default systems, important for attention or focus and internal mental thoughts or rumination, respectively, also showed significant occurrences.

    “These findings add to the way we think about normal and altered brain function,” said Fair. “Further, it creates more opportunity for personalized and targeted treatment approaches for conditions such as ADHD or autism.”


  7. Study suggests malfunctions in communication between brain cells could be at root of autism

    November 11, 2017 by Ashley

    From the Washington University School of Medicine press release:

    A defective gene linked to autism influences how neurons connect and communicate with each other in the brain, according to a study from Washington University School of Medicine in St. Louis. Rodents that lack the gene form too many connections between brain neurons and have difficulty learning.

    The findings, published Nov. 2 in Nature Communications, suggest that some of the diverse symptoms of autism may stem from a malfunction in communication among cells in the brain.

    “This study raises the possibility that there may be too many synapses in the brains of patients with autism,” said senior author Azad Bonni, MD, PhD, the Edison Professor of Neuroscience and head of the Department of Neuroscience at Washington University School of Medicine in St. Louis. “You might think that having more synapses would make the brain work better, but that doesn’t seem to be the case. An increased number of synapses creates miscommunication among neurons in the developing brain that correlates with impairments in learning, although we don’t know how.”

    Autism is a neurodevelopmental disorder affecting about one out of every 68 children. It is characterized by social and communication challenges.

    Among the many genes linked to autism in people are six genes that attach a molecular tag, called ubiquitin, to proteins. These genes, called ubiquitin ligases, function like a work order, telling the rest of the cell how to deal with the tagged proteins: This one should be discarded, that one should be rerouted to another part of the cell, a third needs to have its activity dialed up or down.

    Patients with autism may carry a mutation that prevents one of their ubiquitin genes from working properly. But how problems with tagging proteins affect how the brain is hardwired and operates, and why such problems may lead to autism, has remained poorly understood.

    To understand the role of ubiquitin genes in brain development, Bonni, first author Pamela Valnegri, PhD, and colleagues removed the ubiquitin gene RNF8 in neurons in the cerebellum of young mice. The cerebellum is one of the key brain regions affected by autism.

    The researchers found that neurons that lacked the RNF8 protein formed about 50 percent more synapses — the connections that allow neurons to send signals from one to another — than those with the gene. And the extra synapses worked. By measuring the electrical signal in the receiving cells, the researchers found that the strength of the signal was doubled in the mice that lacked the protein.

    The cerebellum is indispensable for movement and learning motor skills such as how to ride a bicycle. Some of the recognizable symptoms of autism — such as motor incoordination and a tendency to walk tippy-toed — involve control of movement.

    The animals missing the RNF8 gene in the neurons of their cerebellum did not have any obvious problems with movement: They walked normally and appeared coordinated. When the researchers tested their ability to learn motor skills, however, the mice without RNF8 failed miserably.

    The researchers trained the mice to associate a quick puff of air to the eye with the blinking of a light. Most mice learn to shut their eyes when they see the light blink, to avoid the irritation of the coming air puff. After a week of training, mice with a functioning copy of the gene closed their eyes in anticipation more than three quarters of the time, while mice without the gene shut their eyes just a third of the time.

    While it is best known for its role in movement, the cerebellum is also important in higher cognitive functions such as language and attention, both of which are affected in autism. People with autism often have language delays and pay unusually intense attention to objects or topics that interest them. The cerebellum may be involved not only in motor learning but in other features of autism as well, the researchers said.

    Of course, there is a world of difference between a mouse that can’t learn to shut its eyes and a person with autism who struggles to communicate. But the researchers said the findings suggest that changing how many connections neurons make with each other can have important implications for behavior.

    Since this paper was written, Bonni and colleagues have tested the other autism-associated ubiquitin genes. Inhibition of all genes tested cause an increase in the number of synapses in the cerebellum.

    “It’s possible that excessive connections between neurons contribute to autism,” Bonni said. “More work needs to be done to verify this hypothesis in people, but if that turns out to be true, then you can start looking at ways of controlling the number of synapses. It could potentially benefit not just people who have these rare mutations in ubiquitin genes but other patients with autism.”


  8. Locus coeruleus activity linked with hyperarousal in PTSD

    November 9, 2017 by Ashley

    From the Elsevier press release:

    A new study in Biological Psychiatry has linked signs of heightened arousal and reactivity — a core symptom of posttraumatic stress disorder (PTSD) — to overactivity of the locus coeruleus (LC), a brain region that mediates arousal and reactivity. By combining bodily responses and brain imaging data, the new paper by Dr. Christoph Mueller-Pfeiffer at the University of Zurich, Switzerland and colleagues is the first to provide direct human evidence for a theory over 30 years old. Pinpointing the origin of symptoms in the brain is a major step in efforts to improve treatment options for patients with the disorder.

    “The authors are to be congratulated on imaging this part of the brain,” said Dr. John Krystal, Editor of Biological Psychiatry. “Demonstrating the presence of LC hyperactivity in PTSD sets the stage for clarifying the relationship of LC activity to stress response, resilience, PTSD symptoms, and the treatment of PTSD,” he added.

    In the study, first author Christoph Naegeli, also of University of Zurich, and colleagues analyzed 54 participants who had been exposed to trauma, about half of whom developed PTSD. When the participants listened to random bursts of white noise, those who were diagnosed with PTSD had more frequent eye blinks, and increased heart rate, skin conductance and pupil area responses — indicators of the body’s autonomic response — than participants without PTSD.

    Using functional magnetic resonance imaging to measure brain activity, Naegeli and colleagues found that patients with PTSD had larger brain responses in the LC and other regions wired to the LC that control alertness and motor preparation. According to Mueller-Pfeiffer, the increased brain activity and autonomic responses measured in the participants provide a biologically plausible explanation for hypervigilance and exaggerated startle responses in PTSD. However, LC activation was not directly associated with arousal symptoms. Thus, direct links between LC hyperactivity and PTSD symptom severity still need to be demonstrated.

    The study may also reveal new avenues for treating these common and disabling symptoms of PTSD. “Our results suggest that targeting locus coeruleus system hyperactivity with new pharmacological or psychotherapeutic interventions are approaches worthy of further investigation,” said Dr. Mueller-Pfeiffer.


  9. Study suggests gene therapy protecting against age-related cognitive, memory deficits

    November 4, 2017 by Ashley

    From the Universitat Autònoma de Barcelona press release:

    Researchers from the Institute of Neurosciences at the Universitat Autònoma de Barcelona (INc-UAB) and the Vall d’Hebron Research Institute (VHIR) are the first to demonstrate that regulation of the brain’s Klotho gene using gene therapy protects against age-related learning and memory problems in mice.

    The study, published in Molecular Psychiatry (Nature group), opens the door to advancing in the research and development of therapies based on this neuroprotective gene.

    Researchers from the UAB demonstrated in a previous study that Klotho regulates age-associated processes, increasing life expectancy when over-expressed and accelerating the development of learning and memory deficiencies when inhibited.

    Now they have demonstrated in vivo for the first time that one dose of this gene injected into the central nervous system prevents the cognitive decline associated with aging in old animals which were treated at a younger age.

    The results, which form part of the PhD thesis of Anna Massó, first author of the article, are part of a study led by INc-UAB researchers Dr Miguel Chillón, ICREA researcher at the Department of Biochemistry and Molecular Biology of the UAB and the VHIR; Dr Lydia Giménez-Llort from the Department of Psychiatry and Legal Medicine of the UAB; and with the collaboration of Dr Assumpció Bosch, also from the Department of Biochemistry and Molecular Biology.

    “The therapy is based on an increase in the levels of this protein in the brain using an adeno-associated viral vector (AAV). Taking into account that the study was conducted with animals which aged naturally, we believe this could have the therapeutic ability to treat dementia and neurodegenerative disorders such as Alzheimer’s or multiple sclerosis, among others,” Miguel Chillón points out.

    The researchers patented their therapy and have licensed it to Kogenix Therapeutics. The company includes UAB participation and is based in the United States. It was launched by Dr Miguel Chillón and Dr Assumpció Bosch, together with the entrepreneur Menachem Abraham and Dr Carmela Abraham, professor of Biochemistry and Pharmacology at the Boston University School of Medicine, a pioneering centre in the study of Klotho in the central nervous system for more than a decade.

    The objective of Kogenix is to achieve the initial capital needed to advance in the pre-clinical trials already being conducted with animal models of Alzheimer’s disease. This will give way to the development of a drug to be used in gene therapy against neurodegenerative diseases based on small molecules which enhance the expression of the gene and/or the use of fragments of the Klotho protein itself.

    “In basic research studies and clinical trials the AAVs have shown to be safe and effective in the implementation of a central nervous system gene therapy. In fact, the Food and Drug Administration made the first gene therapy available in the United States in August and additional approvals are expected,” Dr Assumpció Bosch states.


  10. Study finds mapping brain connectivity with MRI may predict outcomes for cardiac arrest survivors

    November 3, 2017 by Ashley

    From the Johns Hopkins Medicine press release:

    A new study led by Johns Hopkins researchers found that measures of connectivity within specific cerebral networks were strongly linked to long-term functional outcomes in patients who had suffered severe brain injury following a cardiac arrest.

    A description of the findings, published in October in the journal Radiology, suggests that mapping and measuring such connectivity may result in highly accurate and reliable markers of long-term recovery trajectories in people with neurological damage caused by heart attacks, strokes, brain hemorrhage or trauma.

    “By analyzing functional MRI data we are able to see where brain network disruption is occurring, and determine how these changes relate to the likelihood of recovery from brain damage,” says Robert Stevens, M.D., associate professor of anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine, and the paper’s senior author.

    Cardiac arrest, or the sudden loss of heart function, affects an estimated 535,000 people in the United States each year, according to the American Heart Association. The loss of blood flow, and its restoration through resuscitation, is associated with rapid and widespread damage to the brain, leading to disabling neurological and cognitive problems in survivors.

    Several modifiable factors, such as timeliness and quality of cardiac resuscitation and the strict control of body temperature to avoid fever, strongly influence the magnitude of brain damage and the prospects for recovery, says Stevens.

    He adds that current methods to predict how an individual will recover over time are limited, but advanced imaging techniques such as quantitative brain mapping using MRI data could transform practice by allowing clinicians to make better-informed decisions about care. MRI can specifically and accurately identify changes in tissue structure, blood flow and functional activation. Functional connectivity is determined by analyzing the temporal correlation of functional activation in different parts of the brain, thereby establishing the strength of connections between anatomically distinct regions. Clusters of brain regions that are highly correlated are called networks, and the degree of correlation can be measured within and between networks.

    For their study, the Hopkins researchers and their colleagues assessed the brain’s functional activation in 46 patients who were in a coma after cardiac arrest between July 2007 and October 2013. MRI was performed on all patients on average 12.6 days after cardiac arrest, and the analysis focused on four networks in the brain: dorsal attention network (DAN, which is active when a person uses energy to focus attention); default mode network (DMN, which is active when an individual is at rest); executive control network (ECN, which is active while initiating tasks and is associated with reward and inhibition); and salience network (SN, a network that determines the importance of stimuli and may direct activation of other cognitive networks). Of the participants, 32 were men, and the average age was 49.

    One year after the patients’ cardiac arrests, the researchers assessed survivors with the Cerebral Performance Category (CPC) Scale, a commonly used measure of neurological function following cardiac arrest. The test uses a scale from 1 to 5, with 1 indicating minimal to no disability and 5 indicating brain death. Eleven of the 46 patients who had favorable outcomes (a score of 1 or 2) showed higher connectivity within the DMN network, as well as greater anti-correlation (when one is active the other is not) between the SN and ECN and the SN and DMN, when compared with patients who had an unfavorable outcome (CPC greater than 2). Remarkably, the functional connectivity markers predicted outcomes more accurately when compared with structural measures of, for example, tissue damage, used in conventional MRI scans.

    “These findings highlight a potential realm of precision medicine using brain network biomarkers that are discriminative and predictive of outcomes,” says Haris Sair, M.D., interim director of neuroradiology at the Johns Hopkins University School of Medicine and the study’s lead author. “In the future, connectivity biomarkers may help guide new therapies for targeted treatment to improve brain function.”