NeuroGenetics

May be not Alzheimer's but hearing loss related memory problems

noreply@blogger.com (Unknown) — Mon, 21 Jan 2019 05:18:00 +0000

Older adults concerned about displaying early symptoms of Alzheimer's disease should also consider a hearing check-up, suggest recent findings.

What might appear to be signs of memory loss could actually point to hearing issues, says Dr. Susan Vandermorris, one of the study's authors and a clinical neuropsychologist at Baycrest.

A recent Baycrest study, published in the Canadian Journal on Aging, found that the majority (56 per cent) of participants being evaluated for memory and thinking concerns and potential brain disorders had some form of mild to severe hearing loss, but only about 20 per cent of individuals used hearing aids. Among the participants, a quarter of them did not show any signs of memory loss due to a brain disorder.

"We commonly see clients who are worried about Alzheimer's disease because their partner complains that they don't seem to pay attention, they don't seem to listen or they don't remember what is said to them," says Dr. Vandermorris. "Sometimes addressing hearing loss may mitigate or fix what looks like a memory issue. An individual isn't going to remember something said to them if they didn't hear it properly."

Hearing loss is the third most common chronic health condition in older adults, which is experienced by 50 per cent of individuals over the age of 65 and 90 per cent of people over the age of 80. It takes an average of 10 years before people seek treatment and less than 25 per cent of individuals who need hearing aids will buy them.

Hearing status is not always addressed in neuropsychology clinics, but can impact performance on memory assessments done verbally, adds Dr. Vandermorris.

"Some people may be reluctant to address hearing loss, but they need to be aware that hearing health is brain health and help is available," she adds.

The study analyzed results from 20 individuals who were receiving a neuropsychological assessment at Baycrest. Participants completed a hearing screening test after their cognitive evaluation.

Neuropsychologists were privy to hearing test results after their initial assessment, which altered some of their recommendations. For example, some clients were referred to a hearing clinic for a full audiology assessment or to consider using a hearing aid, as well as provided education on hearing loss and communication.

"Since hearing loss has been identified as a leading, potentially modifiable risk factor for dementia, treating it may be one way people can reduce the risk," says Marilyn Reed, another author on the study and practice advisor with Baycrest's audiology department. "People who can't hear well have difficulty communicating and tend to withdraw from social activities as a way of coping. This can lead to isolation and loneliness, which can impact cognitive, physical and mental health."

This study builds on earlier research that analyzed how addressing memory problems could benefit older adults seeking hearing loss treatment.

"We are starting to learn more about the important role hearing plays in the brain health of our aging population," says Dr. Kate Dupuis, lead author on the study, a former postdoctoral fellow at Baycrest, clinical neuropsychologist and Schlegel Innovation Leader at the Sheridan Centre for Elder Research. "In order to provide the best care to our older clients, it is imperative that neuropsychologists and hearing care professionals work together to address the common occurrence of both cognitive and hearing loss in individuals."

Since the studies, Baycrest's Neuropsychology and Cognitive Health Program and Hearing Services have incorporated general screening for hearing and memory issues into their assessments, as well as provided educational materials to clients.

Next steps for the study will involve optimizing screening strategies for hearing loss in memory assessments and ongoing interprofessional collaborations to create educational tools that counsel clients about the relationship between hearing, memory and brain health.

###

The study was made possible with support from the neuropsychology and cognitive health and audiology programs at Baycrest. The research team included Iris Yusupov, Dr. Kelly Murphy, Dr. Dmytro Rewilak and Dr. Kathryn Stokes.

SOURCE: BAYCREST CENTRE FOR GERIATRIC CARE

Long Sleeping hours during pregnancy and late stillbirth may be linked

noreply@blogger.com (Unknown) — Mon, 21 Jan 2019 05:16:00 +0000

Sleeping more than nine hours per night during pregnancy may be associated with late stillbirth, a new Michigan Medicine-led international study suggests.

Researchers analyzed online surveys involving 153 women who had experienced a late stillbirth (on or after 28 weeks of pregnancy) within the previous month and 480 women with an ongoing third-trimester pregnancy or who had recently delivered a live born baby during the same period.

The findings, which appear in journal Birth, suggest an association between lengthy periods of undisturbed maternal sleep and stillbirths that were independent of other risk factors. But researchers caution that further research is needed to better understand the relationship and what it means for pregnant women.

"Pregnant women often report waking up and getting up in the middle of the night," says lead author Louise O'Brien, Ph.D., M.S., a University of Michigan researcher in the Division of Sleep Medicine, Department of Neurology and the Department of Obstetrics and Gynecology at Michigan Medicine.

"While multiple awakenings during the night may concern some women, in the context of stillbirth it appears to be protective."

O'Brien says further studies need to delve deeper into what may drive the relationship between maternal sleep and stillbirths, with particular focus on how the autonomic nervous system - the control system that regulates bodily function - and the hormonal system are regulated during sleep in late pregnancy.

She notes that blood pressure reaches its lowest point during sleep but when someone is awakened, there is a surge in the nervous system activity that causes transient increases in blood pressure. It's possible that these brief increases in blood pressure are able to prevent long periods of relatively low pressure. This is important, O'Brien says, because low blood pressure has been linked with fetal growth problems, preterm birth, and stillbirth.

O'Brien also cautions that "pregnant women should not be waking themselves up at night." Very disruptive sleep has also been associated with poor pregnancy outcomes, including growth restriction and preterm growth.

She notes that while there is already evidence that very disrupted sleep and clinical sleep disorders are associated with poor pregnancy outcomes, few studies have looked at the opposite end of the spectrum, such as long periods of undisturbed sleep

"Our findings add to research indicating that maternal sleep plays a role in fetal wellbeing," she says. "Studies aiming to reduce stillbirths should consider maternal sleep as this is a potentially modifiable risk factor. Understanding the role of maternal sleep may help us identify interventions that would put us in a better position to advise women."

Stillbirth effects about 1 in 160 pregnancies in the U.S., with about 24,000 babies stillborn in the country every year - 10 times as many deaths that occur from Sudden Infant Death Syndrome (SIDS). About half of all stillbirths happen after 28 weeks of pregnancy and many remain unexplained.

Rates are even worse in low income countries but the stillbirth rate in the U.S. is still higher than in many other Western countries

Smoking, advanced maternal age, diabetes, obesity and drug abuse are among well-established risk factors for stillbirths. Maternal sleep practices, however, cover a relatively new area of investigation.

The new study follows other research looking at possible ties between maternal sleep and fetal wellbeing in recent years, including studies suggesting that women who report that they sleep on their backs have an increased risk of stillbirths. While the current study asked about maternal sleep position, not enough women reported sleeping on their backs for any meaningful analysis.

"Maternal sleep has been overlooked as a potential area for maternal and newborn health interventions even though it is related to many of the major, well-established risk factors for poor pregnancy outcomes. Until recently, it hasn't been on the radar for stillbirth research," O'Brien says.

"Many risk factors for stillbirths are not able to be modified once pregnancy has begun. But we should be looking at every possible intervention that may prevent poor outcomes. Progress in reducing stillbirth deaths has been slow but stillbirth is an urgent global health issue that should be at the center of more research programs."

SOURCE: MICHIGAN MEDICINE - UNIVERSITY OF MICHIGAN

Natural Solution to Skin Wrinkles Comes From Maple Leaf Extract

noreply@blogger.com (Unknown) — Tue, 21 Aug 2018 12:18:00 +0000

Maple trees are best known for their maple syrup and lovely fall foliage. But it turns out that the beauty of those leaves could be skin-deep -- and that's a good thing. Today, scientists report that an extract from the leaves may prevent wrinkles.

The researchers are presenting their results at the 256th National Meeting & Exposition of the American Chemical Society (ACS). ACS, the world's largest scientific society, is holding the meeting here through Thursday. It features more than 10,000 presentations on a wide range of science topics.

The scientists had previously studied the chemistry and health benefits of sap and syrup obtained from sugar maple and red maple trees. Historical records suggested that other parts of the trees could also be useful, according to Navindra P. Seeram, Ph.D., the project's principal investigator. "Native Americans used leaves from red maple trees in their traditional system of medicine," he notes, "so why should we ignore the leaves?"

Skin elasticity is maintained by proteins such as elastin. Wrinkles form when the enzyme elastase breaks down elastin in the skin as part of the aging process. "We wanted to see whether leaf extracts from red maple trees could block the activity of elastase," says Hang Ma, Ph.D., who is presenting the work at the meeting and is a research associate in Seeram's lab.

The researchers, who are at the University of Rhode Island, zeroed in on phenolic compounds in the leaves known as glucitol-core-containing gallotannins (GCGs) and examined each compound's ability to inhibit elastase activity in a test tube. The scientists also conducted computational studies to examine how the GCGs interact with elastase to block its activity, and how the molecules' structures affect that blocking ability. GCGs containing multiple galloyl groups (a type of phenolic group) were more effective than those with a single galloyl group. But these compounds can do more than interfere with elastase. In prior work, Seeram's group showed that these same GCGs might be able to protect skin from inflammation and lighten dark spots, such as unwanted freckles or age spots.

Seeram and Ma plan to do further testing. "You could imagine that these extracts might tighten up human skin like a plant-based Botox®, though they would be a topical application, not an injected toxin," Seeram says. And the fact that the extracts are derived from trees would be appreciated by consumers who are looking for natural, plant-based ingredients in their skincare products.

The researchers have taken steps to get the extracts into products, having developed a proprietary patent-pending formulation containing GCGs from summer and fall maple leaves and maple sap, which they named MaplifaTM (pronounced "mape-LEAF-uh" to reflect its origin). They have licensed it to botanical extracts supplier Verdure Sciences based in Indiana and are hoping to eventually find a market for the formulation in the cosmetics sector or even in dietary supplements.

If these products come to fruition, the team's findings could benefit the local economy. "Many botanical ingredients traditionally come from China, India and the Mediterranean, but the sugar maple and the red maple only grow in eastern North America," Seeram says. Farmers in the region, who currently only harvest sap from the maple trees, could tap the leaves as a value-added product for an additional source of income. Even better, the process would be sustainable because leaves could be collected during normal pruning or when they fall from the trees in autumn.

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Original Abstract:

Skin wrinkling is a declining process of skin cell function associated with aging caused by the loss of skin elasticity over time. Skin elasticity is maintained by skin extracellular matrix proteins such as elastin. Elastase, a member of the chymotrypsin family of proteases, is responsible for the breakdown of skin elastin. Therefore, inhibition of elastase enzyme is a plausible management for skin elastin degradation and thus, elastase inhibitors, including natural products, are being investigated as anti-wrinkle cosmetic agents. We previously reported on the skin protective effects, including anti-glycation and anti-melanogenic properties, of a series of glucitol-core containing gallotannins (GCGs) from a proprietary phenolic-enriched red maple (Acer rubrum) leaves extract (MaplifaTM). However, the effect of these GCGs on elastase enzyme is unknown. Herein, we investigated the inhibitory effects of MaplifaTM GCGs including ginnalin B (GB), ginnalin C (GC), ginnalin A (GA), maplexin F (MF) and maplexin J (MJ) on elastase enzyme. The GCGs (at 500 μM) showed inhibitory activities ranging from 21.3 - 62.5% and the GCGs with multiple galloyl group including GA (2 galloyls), MF (3 galloyls), and MJ (4 galloyls) showed superior activity to those GCGs with a mono-galloyl group (namely, GB and GC). The mechanisms of the GCGs' inhibitory effects on elastase enzyme were further studied by using an enzyme kinetic assay and computational docking method. Our data suggest that MaplifaTM GCGs may have anti-wrinkle activity through the inhibition of elastase enzyme warranting further studies on its cosmetic applications.

Source: American Chemical Society

Autism and Eye Contact: Genes very much are involved

noreply@blogger.com (Unknown) — Thu, 13 Jul 2017 12:35:00 +0000

We have now a lot of evidence on genetic components in many disorders including neurological in both adults and kids. Autism is one such problem that has many genes involved. Research is still in full swing to find more genes and related pathways. However, one can find autistic features more phenotypically before genotyping. Eye contact is one of them. Studies have shown that autistic kids make less eye contact. This has been shown to have genetic component now. New research has uncovered compelling evidence that genetics plays a major role in how children look at the world and whether they have a preference for gazing at people's eyes and faces or at objects. The discovery by researchers at Washington University School of Medicine in St. Louis and Emory University School of Medicine in Atlanta adds new detail to understanding the causes of autism spectrum disorder. The results show that the moment-to-moment movements of children's eyes as they seek visual information about their environment are abnormal in autism and under stringent genetic control in all children.

The study is published online July 12 in the journal Nature.

"Now that we know that social visual orientation is heavily influenced by genetic factors, we have a new way to trace the direct effects of genetic factors on early social development, and to design interventions to ensure that children at risk for autism acquire the social environmental inputs they need to grow and develop normally," said lead author John N. Constantino, MD, the Blanche F. Ittleson Professor of Psychiatry and Pediatrics at Washington University. "These new findings demonstrate a specific mechanism by which genes can modify a child's life experience. Two children in the same room, for example, can have completely different social experiences if one carries an inherited tendency to focus on objects while the other looks at faces, and these differences can play out repeatedly as the brain develops early in childhood."

The researchers studied 338 toddlers ages 18 to 24 months using eye-tracking technology, developed at Emory, allowing them to trace young children's visual orientation to faces, eyes or objects as the children watched videos featuring people talking and interacting.

The children, who were part of the Missouri Family Registry, a database of twins that is maintained at Washington University School of Medicine, included 41 pairs of identical twins -- such twins share 100 percent of their DNA -- and 42 sets of fraternal twins -- who share only about 50 percent of their DNA. In addition, the researchers studied 84 unrelated children and 88 children diagnosed with autism spectrum disorder.

Constantino, with fellow investigators Warren R. Jones, PhD, and Ami Klin, PhD, of Emory University School of Medicine, evaluated the eye-tracking data. Each twin was tested independently, at different times, without the other twin present.

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How much one identical twin looked at another person's eyes or face was almost perfectly matched by his or her co-twin. But in fraternal twins, eye movements in one twin accounted for less than 10 percent of the variation in the eye movements of his or her co-twin. Identical twins also were more likely to move their eyes at the same moments in time, in the same directions, toward the same locations and the same content, mirroring one another's behavior to within as little as 17 milliseconds. Taken together, the data indicate a strong influence of genetics on visual behavior.

"The moment-to-moment match in the timing and direction of gaze shifts for identical twins was stunning and inferred a very precise level of genetic control," said Constantino, who directs the William Greenleaf Eliot Division of Child and Adolescent Psychiatry at Washington University. "We have spent years studying the transmission of inherited susceptibility to autism in families, and it now appears that by tracking eye movements in infancy, we can identify a key factor linked to genetic risk for the disorder that is present long before we can make a clinical diagnosis of autism."

The effects persisted as the children grew. When the twins were tested again about a year later, the same effects were found: Identical twins remained almost perfectly matched in where they looked, but fraternal twins became even more different than they were when initially evaluated.

Autism spectrum disorder is a lifelong condition that affects about 1 in 68 children in the United States. It is known to be caused by genetic factors, and earlier work by the Emory University team had shown that babies who look progressively less at people's eyes, beginning as early as 2-6 months of age, have an elevated risk for autism. Meanwhile, Constantino and others in the group have studied how subtle behaviors and symptoms that characterize autism aggregate in the close relatives of individuals with autism, as a way to identity inherited susceptibilities that run in families and contribute to autism risk.

"Studies like this one break new ground in our understanding of autism spectrum disorder: Establishing a direct connection between the behavioral symptoms of autism and underlying genetic factors is a critical step on the path to new treatments," said Lisa Gilotty, PhD, chief of the Research Program on Autism Spectrum Disorders at the National Institute of Mental Health, which provided support for the study in tandem with the Eunice Kennedy Shriver Institute of Child Health and Human Development.

Those new treatments could include interventions that motivate very young children to focus their gazes more on faces and less on objects.

"Testing infants to see how they are allocating visual attention represents a new opportunity to evaluate the effects of early interventions to specifically target social disengagement, as a way to prevent the most challenging disabilities associated with autism," said senior author Warren R. Jones, PhD, director of autism research at the Marcus Autism Center at Emory. "Such interventions might be appropriate for infants showing early signs of risk or those who have been born into families in which autism has affected close relatives. In addition, learning why some infants who tend to not look at eyes and faces develop without social disability is another priority."

The small percentage of healthy children who tended to avoid looking at eyes and faces may provide researchers with insight on how to successfully compensate for those tendencies and therefore inform the development of higher-impact interventions that will produce the best possible outcomes for infants with inherited susceptibility to autism.

Constantino JN, Kennon-McGill S, Weichselbaum C, Marrus N, Haider A, Glowinski AL, Gillespie S, Klaiman C, Klin A, Jones W. Infant viewing of social scenes is under genetic control and is atypical in autism. Nature. Published online July 12, 2017.

Source: WASHINGTON UNIVERSITY SCHOOL OF MEDICINE

Early Signs of Alzheimer's: Sleeping Issues

noreply@blogger.com (Unknown) — Fri, 07 Jul 2017 02:51:00 +0000

Are you suffering from sleep disturbances? Do you have trouble getting sound sleep every day? Do you toss around too much during the night without much sleep? Do you get up every day tired because you didn't get enough sleep? Well, all these seem to be linked to early signs of Alzheimer's. Poor sleep may be a sign that people who are otherwise healthy may be more at risk of developing Alzheimer's disease later in life than people who do not have sleep problems, according to a study published in the July 5, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology. Researchers have found a link between sleep disturbances and biological markers for Alzheimer's disease found in the spinal fluid.

"Previous evidence has shown that sleep may influence the development or progression of Alzheimer's disease in various ways," said study author Barbara B. Bendlin, PhD, of the University of Wisconsin-Madison. "For example, disrupted sleep or lack of sleep may lead to amyloid plaque buildup because the brain's clearance system kicks into action during sleep. Our study looked not only for amyloid but for other biological markers in the spinal fluid as well."

Amyloid is a protein that can fold and form into plaques. Tau is a protein that forms into tangles. These plaques and tangles are found in the brains of people with Alzheimer's disease.

For the study, researchers recruited 101 people with an average age of 63 who had normal thinking and memory skills but who were considered at risk of developing Alzheimer's, either having a parent with the disease or being a carrier of a gene that increases the risk for Alzheimer's disease called apolipoprotein E or APOE. Participants were surveyed about sleep quality. They also provided spinal fluid samples that were tested for biological markers of Alzheimer's disease.

Researchers found that people who reported worse sleep quality, more sleep problems and daytime sleepiness had more biological markers for Alzheimer's disease in their spinal fluid than people who did not have sleep problems. Those biological markers included signs of amyloid, tau and brain cell damage and inflammation.

"It's important to identify modifiable risk factors for Alzheimer's given that estimates suggest that delaying the onset of Alzheimer's disease in people by a mere five years could reduce the number of cases we see in the next 30 years by 5.7 million and save $367 billion in health care spending," said Bendlin.

While some of these relationships were strong when looking at everyone as a group, not everyone with sleep problems has abnormalities in their spinal fluid. For example, there was no link between biological markers in the spinal fluid and obstructive sleep apnea.

The results remained the same when researchers adjusted for other factors such as use of medications for sleep problems, amount of education, depression symptoms or body mass index.

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"It's still unclear if sleep may affect the development of the disease or if the disease affects the quality of sleep," said Bendlin. "More research is needed to further define the relationship between sleep and these biomarkers."

Bendlin added, "There are already many effective ways to improve sleep. It may be possible that early intervention for people at risk of Alzheimer's disease may prevent or delay the onset of the disease."

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One limitation of the study was that sleep problems were self-reported. Monitoring of sleep patterns by health professionals may be beneficial in future studies.

The study was supported by the National Institute on Aging and the National Institutes of Health National Center for Advancing Translational Sciences.

To learn more about Alzheimer's disease, visit http://www.aan.com/patients.

The American Academy of Neurology is the world's largest association of neurologists and neuroscience professionals, with 32,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer's disease, stroke, migraine, multiple sclerosis, concussion, Parkinson's disease and epilepsy.

Source: AAN, America.

Traumatic brain injury and dementia: A Missing link

noreply@blogger.com (Unknown) — Fri, 07 Jul 2017 01:45:00 +0000

Although much research has examined traumatic brain injury (TBI) as a possible risk factor for later life dementia from neurodegenerative diseases such as Alzheimer's disease (AD), little is known regarding how TBI influences the rate of age-related cognitive change. A new study now shows that history of TBI (with loss of consciousness) does not appear to affect the rate of cognitive change over time for participants with normal cognition or even those with AD dementia.

More than 10 million individuals worldwide are affected annually by TBI, however the true prevalence is likely even greater given that a majority of TBIs are mild in severity and may not be recognized or reported. TBI is a major public health and socioeconomic concern resulting in $11.5 billion in direct medical costs and $64.8 billion in indirect costs to the U.S. health system in 2010 alone.

According to the researchers the relationship between TBI and long-term cognitive trajectories remains poorly understood due to limitations of previous studies, including small sample sizes, short follow-up periods, biased samples, high attrition rates, limited or no reports of exposure to repetitive head impacts (such as those received through contact sports), and very brief cognitive test batteries.

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In an effort to examine this possible connection, researchers compared performance on cognitive tests over time for 706 participants (432 with normal cognition; 274 AD dementia) from the National Alzheimer's Coordinating Center database. Normal and AD dementia participants with a history of TBI with loss of consciousness were matched to an equal number of demographically and clinically similar participants without a TBI history. The researchers also examined the possible role of genetics in the relationship between TBI and cognitive decline by studying a gene known to increase risk for AD dementia, the APOE ε4 gene.

"Although we expected the rates of cognitive change to differ significantly between those with a history of TBI compared to those with no history of TBI, we found no significant difference between the groups, regardless of their APOE genotype," explained corresponding author Robert Stern, PhD, Director of the Clinical Core of the Boston University Alzheimer's Disease Center (BU ADC) and professor of neurology, neurosurgery and anatomy and neurobiology at Boston University School of Medicine.

These findings appear in the Journal of Alzheimer's Disease. The study's first author Yorghos Tripodis, PhD, Associate Director of the Data Management and Biostatistics Core of the BU ADC and associate professor of Biostatistics at Boston University School of Public Health, cautioned, "Our findings should still be interpreted cautiously due to the crude and limited assessment of TBI history available through the NACC database." The researchers recommended that future studies should collect information on the number of past TBIs (including mild TBIs, as well as exposure to sub-concussive trauma through contact sports and other activities) along with time since TBI, which may play a significant role in cognitive change.
Source: BOSTON UNIVERSITY MEDICAL CENTER

Brain Training Games Reduce Dementia

noreply@blogger.com (Unknown) — Tue, 04 Jul 2017 03:41:00 +0000

Training your brain for reducing dementia development chances is the new mantra these days. There are so many games and websites now-a-days that boast their abilities in reducing individuals chances of developing memory loss or dementia. Its proven fact that regular reading, gaming and brain teasers help reduce the progress or atleast the speed of development of dementia. Now, researchers at the University of Cambridge have developed a game to train the brain that could help improve the memory of patients in the very earliest stages of dementia. This study has been published in "The International Journal of Neuropsychopharmacology".

Amnestic mild cognitive impairment (aMCI) has been described as the transitional stage between 'healthy ageing' and dementia. It is characterised by day-to-day memory difficulties and problems of motivation. At present, there are no approved drug treatments for the cognitive impairments of patients affected by the condition.

Cognitive training has shown some benefits, such as speed of attentional processing, for patients with aMCI, but training packages are typically repetitive and boring, affecting patients' motivation. To overcome this problem, researchers from the Departments of Psychiatry and Clinical Neurosciences and the Behavioural and Clinical Neuroscience Institute at the University of Cambridge developed 'Game Show', a memory game app, in collaboration with patients with aMCI, and tested its effects on cognition and motivation.

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The researchers randomly assigned forty-two patients with amnestic MCI to either the cognitive training or control group. Participants in the cognitive training group played the memory game for a total of eight one-hour sessions over a four-week period; participants in the control group continued their clinic visits as usual.

In the game, which participants played on an iPad, the player takes part in a game show to win gold coins. In each round, they are challenged to associate different geometric patterns with different locations. Each correct answer allows the player to earn more coins. Rounds continue until completion or after six incorrect attempts are made. The better the player gets, the higher the number of geometric patterns presented - this helps tailor the difficulty of the game to the individual's performance to keep them motivated and engaged. A game show host encourages the player to maintain and progress beyond their last played level.

The results showed that patients who played the game made around a third fewer errors, needed fewer trials and improved their memory score by around 40%, showing that they had correctly remembered the locations of more information at the first attempt on a test of episodic memory. Episodic memory is important for day-to-day activities and is used, for example, when remembering where we left our keys in the house or where we parked our car in a multi-story car park. Compared to the control group, the cognitive training group also retained more complex visual information after training.

In addition, participants in the cognitive training group indicated that they enjoyed playing the game and were motivated to continue playing across the eight hours of cognitive training. Their confidence and subjective memory also increased with gameplay. The researchers say that this demonstrates that games can help maximise engagement with cognitive training.

"Good brain health is as important as good physical health. There's increasing evidence that training the brain can be beneficial for boosting cognition and brain health, but it needs to be based on sound research and developed with patients," says Professor Barbara Sahakian, co-inventor of the game: "It also need to be enjoyable enough to motivate users to keep to their programmes. Our game allowed us to individualise a patient's cognitive training programme and make it fun and enjoyable for them to use."

Dr George Savulich, the lead scientist on the study, adds: "Patients found the game interesting and engaging and felt motivated to keep training throughout the eight hours. We hope to extend these findings in future studies of healthy ageing and mild Alzheimer's disease."

The researchers hope to follow this published study up with a future large-scale study and to determine how long the cognitive improvements persist.

The design of 'Game Show' was based on published research from the Sahakian Laboratory at the University of Cambridge. The study was funded by Janssen Pharmaceuticals and Wellcome.

In 2015, Professor Sahakian and colleagues showed that another iPad game developed by her team was effective at improving the memory of patients with schizophrenia, helping them in their daily lives at work and living independently. The University of Cambridge Wizard memory game is available through PEAK via the App Store and Google Play.

Reference

George Savulich, Thomas Piercy, Chris Fox, John Suckling, James Rowe, John O'Brien, Barbara Sahakian. Cognitive training using a novel memory game on an iPad in patients with amnestic mild cognitive impairment (aMCI). The International Journal of Neuropsychopharmacology; 3 July 2017; DOI: 10.1093/ijnp/pyx040

Source: UNIVERSITY OF CAMBRIDGE

Alzheimer's subjects brain activity restored to normal with anti-epilepsy drug

noreply@blogger.com (Unknown) — Thu, 29 Jun 2017 03:44:00 +0000

In the last decade, mounting evidence has linked seizure-like activity in the brain to some of the cognitive decline seen in patients with Alzheimer's disease. Patients with Alzheimer's disease have an increased risk of epilepsy and a nearly half may experience subclinical epileptic activity -- disrupted electrical activity in the brain that doesn't result in a seizure but which can be measured by electroencephalogram (EEG) or other brain scan technology.

In a recent feasibility study, clinician-scientists at Beth Israel Deaconess Medical Center (BIDMC) tested an anti-epileptic drug for its potential impact on the brain activity of patients with mild Alzheimer's disease. The team, led by Daniel Z. Press, MD, of the Berenson-Allen Center for Non-invasive Brain Stimulation at BIDMC, documented changes in patients' EEGs that suggest the drug could have a beneficial effect. The research was published in the Journal of Alzheimer's Disease.

"In the field of Alzheimer's disease research, there has been a major search for drugs to slow its progression," said Press, an Instructor of Neurology in the Cognitive Neurology Unit at BIDMC and an Associate Professor of Neurology at Harvard Medical School. "If this abnormal electrical activity is leading to more damage, then suppressing it could potentially slow the progression of the disease."

In this double-blind within-subject study, a small group of patients with mild Alzheimer's disease visited BIDMC three times. At each visit, patients were given a baseline (EEG) to measure the electrical activity in the brain. Next, patients were given injections containing either inactive placebo or the anti-seizure drug levetiracetam, at either a low dose (2.5 mg/kg) or a higher dose (7.5 mg/kg). Neither patients nor medical professionals knew which injections patients were receiving, but each patient eventually got one of each type, in a random order.

Why Autistic Kids Avoid Eye Contact: Image Studies

noreply@blogger.com (Unknown) — Mon, 19 Jun 2017 12:23:00 +0000

Individuals with autism spectrum disorder (ASD) often find it difficult to look others in the eyes. This avoidance has typically been interpreted as a sign of social and personal indifference, but reports from people with autism suggests otherwise. Many say that looking others in the eye is uncomfortable or stressful for them - some will even say that "it burns" - all of which points to a neurological cause. Now, a team of investigators based at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital has shed light on the brain mechanisms involved in this behavior. They reported their findings in a Scientific Reports paper published online this month.

"The findings demonstrate that, contrary to what has been thought, the apparent lack of interpersonal interest among people with autism is not due to a lack of concern," says Nouchine Hadjikhani, MD, PhD, director of neurolimbic research in the Martinos Center and corresponding author of the new study. "Rather, our results show that this behavior is a way to decrease an unpleasant excessive arousal stemming from overactivation in a particular part of the brain."

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The key to this research lies in the brain's subcortical system, which is responsible for the natural orientation toward faces seen in newborns and is important later for emotion perception. The subcortical system can be specifically activated by eye contact, and previous work by Hadjikhani and colleagues revealed that, among those with autism, it was oversensitive to effects elicited by direct gaze and emotional expression. In the present study, she took that observation further, asking what happens when those with autism are compelled to look in the eyes of faces conveying different emotions.

Using functional magnetic resonance imaging (fMRI), Hadjikhani and colleagues measured differences in activation within the face-processing components of the subcortical system in people with autism and in control participants as they viewed faces either freely or when constrained to viewing the eye-region. While activation of these structures was similar for both groups exhibited during free viewing, overactivation was observed in participants with autism when concentrating on the eye-region. This was especially true with fearful faces, though similar effects were observed when viewing happy, angry and neutral faces.

The findings of the study support the hypothesis of an imbalance between the brain's excitatory and inhibitory signaling networks in autism - excitatory refers to neurotransmitters that stimulate the brain, while inhibitory refers to those that calm it and provide equilibrium. Such an imbalance, likely the result of diverse genetic and environmental causes, can strengthen excitatory signaling in the subcortical circuitry involved in face perception. This in turn can result in an abnormal reaction to eye contact, an aversion to direct gaze and consequently abnormal development of the social brain.

In revealing the underlying reasons for eye-avoidance, the study also suggests more effective ways of engaging individuals with autism. "The findings indicate that forcing children with autism to look into someone's eyes in behavioral therapy may create a lot of anxiety for them," says Hadjikhani, an associate professor of Radiology at Harvard Medical School. "An approach involving slow habituation to eye contact may help them overcome this overreaction and be able to handle eye contact in the long run, thereby avoiding the cascading effects that this eye-avoidance has on the development of the social brain."

The researchers are already planning to follow up the research. Hadjikhani is now seeking funding for a study that will use magnetoencephalography (MEG) together with eye-tracking and other behavioral tests to probe more deeply the relationship between the subcortical system and eye contact avoidance in autism.

The co-authors of the Scientific Reports study are Nicole R. Zürcher, Amandine Lassalle and Noreen Ward of the MGH Martinos Center; Jakob Åsberg Johnels, Eva Billstedt and Christopher Gillberg of Gothenburg University, Gothenburg, Sweden; Quentin Guillon of the Lyon Neuroscience Research Center, Lyon, France; Loyse Hippolyte of the University of Lausanne, Lausanne, France; and Eric Lemonnier of CRA, of Limoges, France. The study was supported by the Swiss National Science Foundation (grant PP00P3-130191), the Centre d'Imagerie BioMédicale of the University of Lausanne, as well as the Foundation Rossi Di Montalera, the LifeWatch Foundation, the AnnMarie and Per Ahlqvist Foundation, the Torsten Soderberg Foundation and the Swedish Science Council.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News.

Source:MASSACHUSETTS GENERAL HOSPITAL

The co-authors of the Scientific Reports study are Nicole R. Zürcher, Amandine Lassalle and Noreen Ward of the MGH Martinos Center; Jakob Åsberg Johnels, Eva Billstedt and Christopher Gillberg of Gothenburg University, Gothenburg, Sweden; Quentin Guillon of the Lyon Neuroscience Research Center, Lyon, France; Loyse Hippolyte of the University of Lausanne, Lausanne, France; and Eric Lemonnier of CRA, of Limoges, France. The study was supported by the Swiss National Science Foundation (grant PP00P3-130191), the Centre d'Imagerie BioMédicale of the University of Lausanne, as well as the Foundation Rossi Di Montalera, the LifeWatch Foundation, the AnnMarie and Per Ahlqvist Foundation, the Torsten Soderberg Foundation and the Swedish Science Council.

The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology.

Diet effect on Alzheimer's gene carriers

noreply@blogger.com (Unknown) — Wed, 14 Jun 2017 12:35:00 +0000

Is there a real link between what we eat and onset of a disease such as Alzheimer's? Does obesity click some of the genes associated with neurodegenerative disorders? A diet high in cholesterol, fat and sugar may influence the development of Alzheimer's disease in people who carry the ApoE4 gene, a leading risk factor for the memory-erasing disease, indicates a new USC study. The study on mice, published June 12 in the journal eNeuro, is the latest to explore the association between obesity and Alzheimer's disease, both of which are associated with inflammation and both of which affect millions of people.

For the study, researchers at the USC Davis School of Gerontology compared the effects of a poor diet on groups of mice that either had the Alzheimer's-associated ApoE4 gene or the relatively benign variant of the gene, ApoE3. After eating an unhealthy diet, the mice with the ApoE4 gene showed more Alzheimer's plaques - a marker for inflammation - in their brains, but those with ApoE3 did not.

"Part of what the results are saying is that risk doesn't affect everybody the same, and that's true for most risk factors," said Christian Pike, the lead author of the study and a professor for the USC Davis School of Gerontology. "Your genes have a big role in what happens to you, but so does your environment and your modifiable lifestyle factors. How much you exercise becomes important and what you eat becomes important."

Alzheimer's and obesity are among the intractable problems that USC researchers in multiple disciplines are seeking to unravel.

Both are widespread and costly. An estimated 5.4 million Americans have Alzheimer's, which costs an estimated $286 billion a year. The USC Schaeffer Center for Health Policy and Economics predicts the number of U.S. patients diagnosed with Alzheimer's will more than double to 9.1 million in the next 35 years. By then, total care costs will top $1.5 trillion.

An estimated 72 million American adults are obese - representing about 30 percent of the nation's adult population, according to the Centers for Disease Control and Prevention. Annual health care costs for obesity in the United States range between $147 billion to $210 billion.

As a research institution devoted to promoting lifelong health, USC has more than 70 researchers across a range of disciplines who 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.

ApoE4 and ApoE3 are two variants of a gene that codes for a protein, apolipoprotein E, which binds fats and cholesterol to transport them to the body's lymphatic and circulatory systems and to the brain. The ApoE4 variant is linked to increased inflammation, Alzheimer's and cardiovascular disease.

ApoE3, which does not increase risk for the disease, is much more common variant, appearing in an estimated 70 to 75 percent of the population. ApoE4 appears in around 10 to 15 percent of the population.

Science has shown that Alzheimer's affects more women than men. Having one copy of ApoE4 quadruples women's risk for developing the disease. But having two copies of ApoE4 is an issue for men and women, raising their risk for the disease by a factor of 10.

Still, some people with ApoE3 and ApoE4 never develop Alzheimer's. Knowing this, Pike wanted to explore whether obesity and diet, in the presence of either gene, would affect the disease's development.

For 12 weeks, a group of mice with ApoE4 were placed on a control diet that was 10 percent fat and 7 percent sucrose, while another group of mice with ApoE4 ate a Western diet that was of 45 percent fat and 17 percent sucrose. A similar test was run on mice with ApoE3.

On the unhealthy diet, both the mice with ApoE4 and those with ApoE3 gained weight and became pre-diabetic. But most significantly, those with ApoE4 on the unhealthy diet quickly developed the signature plaques that obstruct cognition and memory.

However, Alzheimer's symptoms did not worsen for the ApoE3 mice that ate a Western diet.

"What happens to you in life is a combination of the genes that you have, the environment and behaviors, such as diet," Pike said. "Our thinking is that the risk of Alzheimer's associated with obesity is going to be regulated to some degree by the genes that we have."

The results in the mice indicate a relationship between diet and the growth of plaques and other signs of brain inflammation for mice with ApoE4.

Pike said further study is needed to understand the relationship between the two. Research already has shown that even a brief spate of poor diet can inflame glia, the brain cells responsible for immunity response.

"That means there are probably components directly in the diet, and one of those are fatty acids, like palmitic acid, that trigger inflammation because they can go in and directly affect glia," Pike said. "But that may be just one inflammation-related component of Alzheimer's disease."

"There's probably a variety of different signals that affect the brain," he added. "People even suggest that signals coming from the gut - the microbiome - are influential."

Pike noted that women and men with risk factors for Alzheimer's may also respond differently to the effects of diet - an issue worth further exploration, he said.

Genome-wide DNA damage from Cigarette Smoking

noreply@blogger.com (Unknown) — Tue, 13 Jun 2017 12:18:00 +0000

Innovation comes from the laboratory of Nobel laureate Aziz Sancar, MD, PhD, the Sarah Graham Kenan Professor of Biochemistry and Biophysics at UNC's School of Medicine. In a study published in the Proceedings of the National Academy of Sciences, Sancar and his team developed a useful technique for mapping sites on the genome that are undergoing repair following a common type of DNA damage. They then used that technique to map all damage caused by the major chemical carcinogen - benzo[α]pyrene. Scientists have known for decades that smoking cigarettes causes DNA damage, which leads to lung cancer. Now, for the first time, this technique effectively map the DNA damage at high resolution across the genome.

"This is a carcinogen that accounts for about 30 percent of the cancer deaths in the United States, and we now have a genome-wide map of the damage it causes," Sancar said.

Maps like these will help scientists better understand how smoking-induced cancers originate, why some people are more vulnerable or resistant to cancers, and how these cancers might be prevented. Sancar also hopes that providing such stark and specific evidence of smoking's harm at the cellular level might induce some smokers to kick the habit. There are about 40 million smokers in the United States and a billion worldwide.

"It would be good if this helps raise awareness of how harmful smoking can be," he said. "It also would be helpful to drug developers if we knew exactly how DNA damage is repaired throughout the entire genome."

BaP: Earth's Top Chemical Carcinogen?

Benzo[α]pyrene (BaP) is a member of a family of simple, hardy, carbon-rich hydrocarbons - polycyclic aromatic hydrocarbons - that can form even in outer space. Scientists think these molecules might have seeded simple carbon-based life on Earth and other planets. But for more evolved and complex DNA-based life forms - humans for example - BaP poses a serious environmental hazard. It's a byproduct of burning organic compounds, such as tobacco plants. Everyday forms of combustion, from forest fires to diesel engines and barbecue grills, put a lot of BaP into our air, soil, and food. But nothing in ordinary life delivers it into human tissue more efficiently than puffing on a lit cigarette.

Typically, when a toxic hydrocarbon gets into a person through breathing or eating, enzymes in our blood break it down into smaller, safer molecules. That happens for BaP, too, but the protective reactions also yield a compound called benzo[α]pyrene diol epoxide (BPDE), which turns out to be worse than BaP itself.

BPDE reacts chemically with DNA, forming a very tight bond at the nucleobase guanine. This bond, or adduct, means that the genes can no longer make proper proteins and DNA can't be duplicated properly during cell division. And if that happens, disease can be the result.

"If a BPDE adduct occurs in a tumor suppressor gene and isn't repaired in a timely manner, it can lead to a permanent mutation that turns a cell cancerous," said Wentao Li, PhD, a postdoctoral researcher and lead author of the study.

There is no doubt about the basic carcinogenicity of chemical reaction. Paint a moderate dose of BaP on the skin of a lab mouse, and tumors are almost certain to erupt. BaP, via BPDE, has long been recognized as a promoter of multiple types of cancer and is considered the single most important cause of lung cancer.

Repairs underway

Sancar's new method for mapping BaP-induced DNA damage enables scientists to identify the sites on the genome where cells are trying to repair the damage. Sancar won a share of the 2015 Nobel Prize for Chemistry for teasing apart the detailed workings of this biochemical repair process.

Known as nucleotide excision repair, it involves the recruitment of special proteins that perform DNA surgery. They snip out the affected strand of DNA. If all goes well, DNA-synthesizing enzymes then reconstruct the missing section of DNA from another unaffected strand. This is possible because all cell-based life forms on Earth have two complementary strands of DNA. Meanwhile, the snipped-out damaged section of DNA floats free until garbage-disposal molecules eventually degrade it.

Those free-floating bits of damaged DNA may be garbage to the cell, but they are solid gold for a scientist who wants to map all damage in a genome. With the new method, scientists can tag and collect these cast-off snippets, sequence them, and then fit together their sequences - like tiny pieces of a giant puzzle - to create a map of the genome. In the end, scientists have a complete map of the sites where repairs to damaged DNA have begun.

Given the effort and expense required for DNA sequencing, the initial, proof-of-principle map published by Sancar, Li and colleagues doesn't have the highest resolution possible. But it points the way towards the routine scientific use of such maps, especially as costs drop, to better understand how DNA-damaging events lead to disease and death.

This mapping technique should help answer several questions, such as:

What dose of a toxin is needed to overwhelm the average person's nucleotide excision repair capacity?
Which variations - and in which genes - give people more or less capacity to repair such DNA damage?
Are there certain spots on the genome where successful repairs are inherently less likely?

Even with their initial, medium-resolution map, Sancar and colleagues were able to show that repairs of BPDE damage tend to occur more often when the BPDE-burdened guanine (G) is next to a cytosine (C) rather than a thymine (T) or adenine (A). This suggests there are "hotspots" of higher risk for BPDE-induced mutation.

"Understanding this bias in repair should help us better understand why exposures to toxins such as BaP tend to cause certain gene mutations," Li said.

Looking forward

In studies published in 2015 and 2016, Sancar and colleagues used earlier versions of their technique to map two other types of DNA-adduct damage: one wrought by ultraviolet light and the other by the common chemo drug cisplatin. Those mapping studies required an extra chemical step - removing the damage from an excised snippet before sequencing it - because the DNA-reading enzyme needed for the sequencing process would otherwise get stuck at the adduct. In contrast, the new technique employs "translesional" enzymes with dimensions that allow it to keep reading a strand of DNA even when a bulky BPDE adduct is present.

"This new method can be applied to any type of DNA damage that involves nucleotide excision repair," Sancar said.

Sancar, Li, and their colleagues are now using the new technique to map DNA damage repair associated with other environmental toxins. Their next project focuses on aflatoxins, a family of mold-produced molecules often found in poorly stored nuts and grains. These toxins damage DNA and are major causes of liver cancer in developing countries.

Brain Benefits From Simple Physical Activity

noreply@blogger.com (Unknown) — Tue, 13 Jun 2017 12:07:00 +0000

There is currently enormous interest in the beneficial effects of aerobic exercise on a wide range of brain functions including mood, memory, attention, motor/reaction times, and even creativity. Understanding the immediate effects of a single bout of exercise is the first step to understanding how the positive effects of exercise may accrue over time to cause long-lasting changes in select brain circuits. Researchers not only summarize the behavioral and cognitive effects of a single bout of exercise, but also summarize data from a large number of neurophysiological and neurochemical studies in both humans and animals showing the wide range of brain changes that result from a single session of physical exercise (i.e., acute exercise).

According to principal investigator Wendy A. Suzuki, PhD, Professor of Neural Science and Psychology in the Center for Neural Science, New York University, "Exercise interventions are currently being used to help address everything from cognitive impairments in normal aging, minimal cognitive impairment (MCI), and Alzheimer's disease to motor deficits in Parkinson's disease and mood states in depression. Our review highlights the neural mechanisms and pathways by which exercise might produce these clinically relevant effects."

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The investigators summarized a large and growing body of research examining the changes that occur at the cognitive/behavioral, neurophysiological, and neurochemical levels after a single bout of physical exercise in both humans and animals. They reviewed brain imaging and electrophysiological studies, including electroencephalography (EEG), functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRS), and transcranial magnetic stimulation (TMS). They then turned to neurochemical studies, including lactate, glutamate and glutamine metabolism, effects on the hypothalamic-pituitary-adrenal (HPA) axis through cortisol secretion, and neurotrophins such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). Neurotransmitter studies of monoamines (dopamine, serotonin, epinephrine and norepinephrine), acetylcholine, glutamate and gamma-aminobutyric acid (GABA) were reviewed, as well as neuromodulators such as endogenous opioids and endocannabinoids.

This extensive review resulted in three main observations. First, the most consistent behavioral effects of acute exercise are improved executive function, enhanced mood, and decreased stress levels. Second, neurophysiological and neurochemical changes that have been reported after acute exercise show that widespread brain areas and brain systems are activated. Third, one of the biggest open questions in this area is the relationship between the central neurochemical changes following acute exercise, that have mainly been described in rodents, and the behavioral changes seen after acute exercise reported in humans. Bridging this gap will be an important area of future study.

Co-author Julia C. Basso, PhD, post-doctoral research fellow, Center for Neural Science at New York University, commented, "The studies presented in this review clearly demonstrate that acute exercise has profound effects on brain chemistry and physiology, which has important implications for cognitive enhancements in healthy populations and symptom remediation in clinical populations."

Source: Brain Plasticity.

Dementia with Lewy bodies, new international guidelines

noreply@blogger.com (Unknown) — Fri, 09 Jun 2017 12:03:00 +0000

ROCHESTER, Minn. -- Susan Williams, wife of the late actor and comedian Robin Williams, called Lewy body disease "the terrorist inside my husband's brain. An estimated 1.4 million Americans have dementia with Lewy bodies, making it the second-leading cause of dementia after Alzheimer's disease. A degenerative and ultimately fatal brain disease, dementia with Lewy bodies frequently is misdiagnosed as Alzheimer's or Parkinson's disease.

According to research reported online Wednesday, June 7, in Neurology, the international Dementia with Lewy Bodies Consortium issued new guidelines about diagnosing and treating the disease and called for more clinical trials into the illness.

"The updated clinical criteria and associated biomarkers hopefully will lead to earlier and more accurate diagnosis, and that is key to helping patients confront this challenging illness and maximize their quality of life," says Bradley Boeve, M.D., a co-author of the paper and a neurologist at Mayo Clinic, which sponsored an international dementia with Lewy bodies conference with roughly 400 clinicians, scientists, patients and care partners in Fort Lauderdale, Florida, in December 2015.

Yesterday's report is the first publication to come out of the conference. The previous consensus guidelines were published in 2005. By weighting clinical signs and biomarkers, the new recommendations give detailed guidance to help diagnose dementia with Lewy bodies. Its' symptoms include:

Cognitive problems: Confusion, reduced attention span and memory loss
Fluctuating attention: Drowsiness, staring into space, daytime naps and disorganized speech
Visual hallucinations: Seeing animals or people that aren't there.
Sleep difficulties: Physically acting out dreams while asleep and excessive daytime sleepiness
Movement disorders: Slowed movement, rigid muscles, tremors or shuffling walk
Poor regulations of body function: Dizziness, falls and bowel issues.
Depression: Persistent sadness and loss of interest

"Despite dementia with Lewy bodies being relatively common, some physicians and many in the public still have never heard of this disorder," Dr. Boeve says.

Protein deposits -- named after Frederick Lewy who discovered them -- develop in brain cells and are believed to cause some to die and others to malfunction. The new guidelines give treatment recommendations, such as using medications called cholinesterase inhibitors to try to improve cognition by triggering nerve impulses from one brain cell to the next.

"Previously, there has been little agreement on the optimal medication and non-medication approaches for patients and their families," Dr. Boeve notes.

###

The report has more than 60 contributors, worldwide experts in their field, including first author Ian McKeith, M.D., of Newcastle University in England and senior author Kenji Kosaka, M.D., of Yokohama City University Medical Center in Japan.

In addition to Dr. Boeve, Mayo Clinic co-authors are Dennis Dickson, M.D.; Tanis Ferman, Ph.D.; Neill Graff-Radford, M.D.; Kejal Kantarci, M.D.; Angela Lunde; Pamela McLean, Ph.D.; Melissa Murray, Ph.D.; and Owen Ross, Ph.D.

The National Institute on Aging and National Institute of Neurological Disorders and Stroke of the National Institutes of Health supported this work, among others. The authors noted conflict of interest disclosures.

About Mayo Clinic

Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit mayoclinic.org/about-mayo-clinic or newsnetwork.mayoclinic.org/.

Blood biomarker for Huntington's disease

noreply@blogger.com (Unknown) — Thu, 08 Jun 2017 11:58:00 +0000

The first blood test that can predict the onset and progression of Huntington's disease has been identified by a UCL-led study. The researchers say their findings, published in Lancet Neurology, should help test new treatments for the genetic brain disorder, which is fatal and currently incurable. "This is the first time a potential blood biomarker has been identified to track Huntington's disease so strongly," said the study's senior author, Dr Edward Wild (UCL Institute of Neurology).

The test measures the neurofilament light chain (neurofilament), a protein released from damaged brain cells, which has been linked to other neurodegenerative diseases but hasn't been studied in the blood of Huntington's disease (HD) patients before.

The team, led by scientists at UCL Huntington's Disease Centre working with colleagues in Sweden, the USA, Canada, France and the Netherlands, measured neurofilament levels in blood samples from the TRACK-HD study, an international project that followed 366 volunteers for three years. They found that levels of the brain protein were increased throughout the course of HD -- even in carriers of the HD genetic mutation who were many years from showing symptoms of the disease. HD mutation carriers had neurofilament concentrations that were 2.6 times that of the control participants, and the level rose throughout the disease course from premanifest to stage 2 disease.

In the group who had no symptoms at the start of the study, the level of neurofilament predicted subsequent disease onset, as volunteers with high neurofilament levels in the blood at the start were more likely to develop symptoms in the following three years. After taking into account factors already known to predict progression -- age and a genetic marker -- the blood level of neurofilament was still able to independently predict onset, progression and the rate of brain shrinkage as measured by MRI scans.

Currently, the best biomarkers available are measured with neuroimaging or cerebrospinal fluid, which are more difficult and expensive to obtain than a blood test. The researchers say that predicting progression in mutation carriers who do not yet show symptoms has been particularly challenging.

"We have been trying to identify blood biomarkers to help track the progression of HD for well over a decade, and this is the best candidate that we have seen so far," said Dr Wild. "Neurofilament has the potential to serve as a speedometer in Huntington's disease, since a single blood test reflects how quickly the brain is changing. That could be very helpful right now as we are testing a new generation of so-called 'gene silencing' drugs that we hope will put the brakes on the condition. Measuring neurofilament levels could help us figure out whether those brakes are working."

The researchers caution that the test is not expected to be immediately helpful for individual patients. "This is the first time neurofilament has been measured in blood, so much more work is needed to understand the potential and limitations of this test," said Lauren Byrne (UCL Institute of Neurology), the study's first author. "In the future, if drugs to slow HD become available, it may well be used to guide treatment decisions. For now, this test is most promising as a much-needed tool to help us design and run clinical trials of new drugs."

Dr Robert Pacifici, chief scientific officer of CHDI Foundation, a US non-profit Huntington's disease research foundation, welcomed the development. "I can see neurofilament becoming a valuable tool to assess neuroprotection in clinical trials so that we can more quickly figure out whether new drugs are doing what we need them to. As a drug hunter, this is great news."

The study's funders included the CHDI foundation, GlaxoSmithKline, Swedish Research Council, European Research Council, Wallenberg Foundation and Wolfson Foundation.

About Huntington's disease:

Huntington's disease is a fatal genetic neurological disease. It usually develops in adulthood and causes abnormal involuntary movements, psychiatric symptoms and dementia. Approximately 10,000 people in the UK have HD with around 25,000 at risk. It is incurable, and no effective treatments exist to slow it down. Patients usually die within 20 years of the start of symptoms. HD is caused by a single known genetic mutation, and each child of a carrier of the mutation has a 50% chance of inheriting the disease.

Source: UNIVERSITY COLLEGE LONDON

Child obesity linked to drinking diet beverages during pregnancy

noreply@blogger.com (Unknown) — Wed, 07 Jun 2017 03:17:00 +0000

Children born to women who had gestational diabetes and drank at least one artificially sweetened beverage per day during pregnancy were more likely to be overweight or obese at age 7, compared to children born to women who had gestational diabetes and drank water instead of artificially sweetened beverages, according to a study led by researchers at the National Institutes of Health. Childhood obesity is known to increase the risk for certain health problems later in life, such as diabetes, heart disease, stroke and some cancers. The study appears online in the International Journal of Epidemiology.

According to the study authors, as the volume of amniotic fluid increases, pregnant women tend to increase their consumption of fluids. To avoid extra calories, many pregnant women replace sugar-sweetened soft drinks and juices with beverages containing artificial sweeteners. Citing prior research implicating artificially sweetened beverages in weight gain, the study authors sought to determine if diet beverage consumption during pregnancy could influence the weight of children.

"Our findings suggest that artificially sweetened beverages during pregnancy are not likely to be any better at reducing the risk for later childhood obesity than sugar-sweetened beverages," said the study's senior author, Cuilin Zhang, Ph.D., in the Epidemiology Branch at NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). "Not surprisingly, we also observed that children born to women who drank water instead of sweetened beverages were less likely to be obese by age 7."

The researchers analyzed data collected from 1996 to 2002 by the Danish National Birth Cohort, a long-term study of pregnancies among more than 91,000 women in Denmark. At the 25th week of pregnancy, the women completed a detailed questionnaire on the foods they ate. The study also collected data on the children's weight at birth and at 7 years old.

In the current study, the NICHD team limited their analysis to data from more than 900 pregnancies that were complicated by gestational diabetes, a type of diabetes that occurs only during pregnancy. Approximately 9 percent of these women reported consuming at least one artificially sweetened beverage each day. Their children were 60 percent more likely to have a high birth weight, compared to children born to women who never drank sweetened beverages. At age 7, children born to mothers who drank an artificially sweetened beverage daily were nearly twice as likely to be overweight or obese. Consuming a daily artificially sweetened beverage appeared to offer no advantages over consuming a daily sugar-sweetened beverage. At age 7, children born to both groups were equally likely to be overweight or obese. However, women who substituted water for sweetened beverages reduced their children's obesity risk at age 7 by 17 percent. It is not well understood why drinking artificially sweetened beverages compared to drinking water may increase obesity risk.

The authors cited an animal study that associated weight gain with changes in the types of bacteria and other microbes in the digestive tract. Another animal study suggested that artificial sweeteners may increase the ability of the intestines to absorb the blood sugar glucose. Other researchers found evidence in rodents that, by stimulating taste receptors, artificial sweeteners desensitized the animals' digestive tracts, so that they felt less full after they ate and were more likely to overeat. The authors caution that more research is necessary to confirm and expand on their current findings.

Although they could account for many other factors that might influence children's weight gain, such as breastfeeding, diet and physical activity levels, their study couldn't definitively prove that maternal artificially sweetened beverage consumption caused the children to gain weight. The authors mention specifically the need for studies that use more contemporary data, given recent upward trends in the consumption of artificially sweetened beverages. They also call for additional investigation on the effects of drinking artificially sweetened beverages among high-risk racial/ethnic groups.

Zhu, Y., et al. Maternal consumption of artificially sweetened beverages during pregnancy, and offspring growth through 7 years of age: a prospective cohort study. Int J Epidemiol. DOI: https://doi.org/10.1093/ije/dyx095

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): NICHD conducts and supports research in the United States and throughout the world on fetal, infant and child development; maternal, child and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit NICHD's website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

How neurons use crowd-sourcing to make decisions

noreply@blogger.com (Unknown) — Wed, 07 Jun 2017 02:55:00 +0000

SANTA FE INSTITUTE: How do we make decisions? Or rather, how do our neurons make decisions for us? Do individual neurons have a strong say or is the voice in the neural collective? One way to think about this question is to ask how many of my neurons you would have to observe to read my mind. If you can predict I am about to say the word "grandma" by watching one of my neurons then we could say our decisions can be attributed to single, perhaps "very vocal," neurons. In neuroscience such neurons are called "grandmother" neurons after it was proposed in the 1960's that there may be single neurons that uniquely respond to complex and important percepts like a grandmother's face.

On the other hand, if you can only read my mind by polling many of my neurons then it would appear the decision a collective one, distributed across hundreds, thousands, or even millions of neurons. A big debate in neuroscience is whether single-neuron encoding or distributed encoding is most relevant for understanding how the brain functions.

In fact, both may be right. In research recently published in Frontiers in Neuroscience, Bryan Daniels, Jessica Flack, and David Krakauer of the Santa Fe Institute's collective computation group (C4) tackle this problem using data recorded from the neurons of a macaque monkey tasked by the experimenter with making a simple decision.

In an area of the brain involved in the decision-making process, Daniels and colleagues find that as the monkey initially processes the data, polling many neurons is required to get a good prediction of the monkey's decision. Then, as the time for committing to a decision approaches, this pattern shifts. The neurons start to agree and eventually each one on its own is maximally predictive. Hence at first the "neural voice" is heterogeneous and collective, but as the neurons get close to the decision point, the "neural voice" becomes homogenous and, in a sense, individualistic, as any neuron on its own is sufficient to read the monkey's mind.

Daniels says a possible explanation for this odd behavior is that the system has two tasks to solve. It must gather good information from noisy data and it must use this information to produce a coherent decision. To find regularities in the input it polls many individual neurons, as the crowd's answer is more reliable than any single neuron's when the data are noisy. But, as Krakauer says, ultimately a decision has to be made. The neurons agree on an answer by sharing their information to come to a consensus. This explanation echoes results in other collective systems, from animal societies to systems studied in statistical physics. Flack says this commonality suggests a general principle of collective computation: It has two phases -- an information accumulation phase that uses crowdsourcing to collect reliable information and a consensus phase that allows the system to act.

Microglia May Be Involved in Alzheimer's, Parkinson's, Huntington's, Schizophrenia, Autism and Depression

noreply@blogger.com (Unknown) — Mon, 05 Jun 2017 01:16:00 +0000

Scientists have, for the first time, characterized the molecular markers that make the brain's front lines of immune defense--cells called microglia--unique. In the process, they discovered further evidence that microglia may play roles in a variety of neurodegenerative and psychiatric illnesses, including Alzheimer's, Parkinson's and Huntington's diseases as well as schizophrenia, autism and depression.

"Microglia are the immune cells of the brain, but how they function in the human brain is not well understood," says Rusty Gage, professor in Salk's Laboratory of Genetics, the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease, and a senior author of the new work. "Our work not only provides links to diseases but offers a jumping off point to better understand the basic biology of these cells."

Genes that have previously been linked to neurological diseases are turned on at higher levels in microglia compared to other brain cells, the team reported in Science on May 25, 2017. While the link between microglia and a number of disorders has been explored in the past, the new study offers a molecular basis for this connection.

"These studies represent the first systematic effort to molecularly decode microglia," says Christopher Glass, a Professor of Cellular and Molecular Medicine and Professor of Medicine at University of California San Diego, also senior author of the paper. "Our findings provide the foundations for understanding the underlying mechanisms that determine beneficial or pathological functions of these cells."

Microglia are a type of macrophage, white blood cells found throughout the body that can destroy pathogens or other foreign materials. They're known to be highly responsive to their surroundings and respond to changes in the brain by releasing pro-inflammatory or anti-inflammatory signals. They also prune back the connections between neurons when cells are damaged or diseased. But microglia are notoriously hard to study. They can't be easily grown in a culture dish and quickly die outside of a living brain.

Nicole Coufal, a pediatric critical care doctor at UC San Diego, who also works in the Gage lab at Salk, wanted to make microglia from stem cells. But she realized there wasn't any way to identify whether the resulting cells were truly microglia.

"There was not a unique marker that differentiated microglia from circulating macrophages in the rest of the body," she says.

David Gosselin and Dylan Skola in the Glass lab, together with Coufal and their collaborators, set out to characterize the molecular characteristics of microglia. They worked with neurosurgeons at UC San Diego to collect brain tissue from 19 patients, all of who were having brain surgery for epilepsy, a brain tumor or a stroke. They isolated microglia from areas of tissue that were unaffected by disease, as well as from mouse brains, and then set out to study the cells. The work was made possible by a multidisciplinary collaboration between bench scientists, bioinformaticians and clinicians.

The team used a variety of molecular and biochemical tests--performed within hours of the cells being collected--to characterize which genes are turned on and off in microglia, how the DNA is marked up by regulatory molecules, and how these patterns change when the cells are cultured.

Microglia, they found, have hundreds of genes that are more highly expressed than other types of macrophages, as well as distinct patterns of gene expression compared to other types of brain cells. After the cells were cultured, however, the gene patterns of the microglia began to change. Within just six hours, more than 2,000 genes had their expression turned down by at least fourfold. The results underscore how dependent microglia are on their surroundings in the brain, and why researchers have struggled to culture them.

Next, the researchers analyzed whether any of the genes that were upregulated in microglia compared to other cells had been previously implicated in disease. Genes linked to a variety of neurodegenerative and psychiatric diseases, they found, were highly expressed in microglia.

"A really high proportion of genes linked to multiple sclerosis, Parkinson's and schizophrenia are much more highly expressed in microglia than the rest of the brain," says Coufal. "That suggests there's some kind of link between microglia and the diseases."

For Alzheimer's, more than half of the genes known to affect a person's risk of developing the disease were expressed more highly in microglia than other brain cells.

In mice, however, many of the disease genes weren't as highly expressed in microglia. "That tells us that maybe mice aren't the best model organisms for some of these diseases," Coufal says.

More work is needed to understand exactly how microglia may be altered in people with diseases, but the new molecular profile of microglia offers a way for researchers to begin trying to better culture the cells, or coax stem cells to develop into microglia for future studies.

Other researchers on the study were Baptiste Jaeger, Carolyn O'Connor, Conor Fitzpatrick, Monique Pena, and Amy Adair of the Salk Institute; Inge Holtman, Johannes Schlachetzki, Eniko Sajti, Martina Pasillas, David Gona, and Michael Levy of the University of California San Diego; and Richard Ransohoff of Biogen.

The work and the researchers involved were supported by grants from the Larry L. Hillblom Foundation, National Institutes of Health, Canadian Institute of Health Research, Multiple Sclerosis Society of Canada, University of California San Diego, Dutch MS Research Foundation, the Gemmy and Mibeth Tichelaar Foundation, the DFG, the JPB Foundation, Dolby Family Ventures, The Paul G. Allen Family Foundation, the Engman Foundation, the Ben and Wanda Hildyard Chair in Hereditary Diseases.

About the Salk Institute for Biological Studies:

Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.

Get Amazon fire HD10 and echo dot for 149

noreply@blogger.com (Unknown) — Fri, 31 Mar 2017 02:55:00 +0000

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Brain Ages Fast With Less Sleep

noreply@blogger.com (Unknown) — Thu, 03 Jul 2014 01:37:00 +0000

Researchers at Duke-NUS Graduate Medical School Singapore (Duke-NUS) have found evidence that the less older adults sleep, the faster their brains age. These findings, relevant in the context of Singapore's rapidly ageing society, pave the way for future work on sleep loss and its contribution to cognitive decline, including dementia.

Past research has examined the impact of sleep duration on cognitive functions in older adults. Though faster brain ventricle enlargement is a marker for cognitive decline and the development of neurodegenerative diseases such as Alzheimer's, the effects of sleep on this marker have never been measured.

The Duke-NUS study examined the data of 66 older Chinese adults, from the Singapore-Longitudinal Aging Brain Study(1). Participants underwent structural MRI brain scans measuring brain volume and neuropsychological assessments testing cognitive function every two years. Additionally, their sleep duration was recorded through a questionnaire. Those who slept fewer hours showed evidence of faster ventricle enlargement and decline in cognitive performance.

"Our findings relate short sleep to a marker of brain aging," said Dr June Lo, the lead author and a Duke-NUS Research Fellow. "Work done elsewhere suggests that seven hours a day(2) for adults seems to be the sweet spot for optimal performance on computer based cognitive tests. In coming years we hope to determine what's good for cardio-metabolic and long term brain health too," added Professor Michael Chee, senior author and Director of the Centre for Cognitive Neuroscience at Duke-NUS.

1) The Singapore-Longitudinal Aging Brain Study (started in 2005) follows a cohort of healthy adults of Chinese ethnicity aged 55 years and above. This study is one of the few in Asia that tracks the brain structures and cognitive functions of older adults so closely.

2) Data collected by Lumosity, an online brain-training program, suggests that self-reported sleep duration of seven hours is associated with the best cognitive test scores in over 150,000 adults. As of now it is unknown if this amount of sleep is optimum for cardio metabolic and long-term brain health.

Source: Duke-NUS Graduate Medical School Singapore

June C. Lo, Kep Kee Loh, Hui Zheng, Sam K.Y. Sim, Michael W.L. Chee. Sleep Duration and Age-Related Changes in Brain Structure and Cognitive Performance. SLEEP, 2014; DOI: 10.5665/sleep.3832

Elevated Activity in Hippocampus Linked to Alzheimer's

noreply@blogger.com (Unknown) — Tue, 01 Jul 2014 15:52:00 +0000

Patients with Alzheimer's disease run a high risk of seizures. While the amyloid-beta protein involved in the development and progression of Alzheimer's seems the most likely cause for this neuronal hyperactivity, how and why this elevated activity takes place hasn't yet been explained -- until now.

A new study by Tel Aviv University researchers, published in Cell Reports, pinpoints the precise molecular mechanism that may trigger an enhancement of neuronal activity in Alzheimer's patients, which subsequently damages memory and learning functions. The research team, led by Dr. Inna Slutsky of TAU's Sackler Faculty of Medicine and Sagol School of Neuroscience, discovered that the amyloid precursor protein (APP), in addition to its well-known role in producing amyloid-beta, also constitutes the receptor for amyloid-beta. According to the study, the binding of amyloid-beta to pairs of APP molecules triggers a signalling cascade, which causes elevated neuronal activity. Elevated activity in the hippocampus -- the area of the brain that controls learning and memory -- has been observed in patients with mild cognitive impairment and early stages of Alzheimer's disease. Hyperactive hippocampal neurons, which precede amyloid plaque formation, have also been observed in mouse models with early onset Alzheimer's disease. "These are truly exciting results," said Dr. Slutsky. "Our work suggests that APP molecules, like many other known cell surface receptors, may modulate the transfer of information between neurons."

With the understanding of this mechanism, the potential for restoring memory and protecting the brain is greatly increased.

Building on earlier research

The research project was launched five years ago, following the researchers' discovery of the physiological role played by amyloid-beta, previously known as an exclusively toxic molecule. The team found that amyloid-beta is essential for the normal day-to-day transfer of information through the nerve cell networks. If the level of amyloid-beta is even slightly increased, it causes neuronal hyperactivity and greatly impairs the effective transfer of information between neurons.

In the search for the underlying cause of neuronal hyperactivity, TAU doctoral student Hilla Fogel and postdoctoral fellow Samuel Frere found that while unaffected "normal" neurons became hyperactive following a rise in amyloid-beta concentration, neurons lacking APP did not respond to amyloid-beta. "This finding was the starting point of a long journey toward decoding the mechanism of APP-mediated hyperactivity," said Dr. Slutsky.

The researchers, collaborating with Prof. Joel Hirsch of TAU's Faculty of Life Sciences, Prof. Dominic Walsh of Harvard University, and Prof. Ehud Isacoff of University of California Berkeley, harnessed a combination of cutting-edge high-resolution optical imaging, biophysical methods and molecular biology to examine APP-dependent signalling in neural cultures, brain slices, and mouse models. Using highly sensitive biophysical techniques based on fluorescence resonance energy transfer (FRET) between fluorescent proteins in close proximity, they discovered that APP exists as a dimer at presynaptic contacts, and that the binding of amyloid-beta triggers a change in the APP-APP interactions, leading to an increase in calcium flux and higher glutamate release -- in other words, brain hyperactivity.

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"We have now identified the molecular players in hyperactivity," said Dr. Slutsky. "TAU postdoctoral fellow Oshik Segev is now working to identify the exact spot where the amyloid-beta binds to APP and how it modifies the structure of the APP molecule. If we can change the APP structure and engineer molecules that interfere with the binding of amyloid-beta to APP, then we can break up the process leading to hippocampal hyperactivity. This may help to restore memory and protect the brain."
Previous studies by Prof. Lennart Mucke's laboratory strongly suggest that a reduction in the expression level of "tau" (microtubule-associated protein), another key player in Alzheimer's pathogenesis, rescues synaptic deficits and decreases abnormal brain activity in animal models. "It will be crucial to understand the missing link between APP and 'tau'-mediated signalling pathways leading to hyperactivity of hippocampal circuits. If we can find a way to disrupt the positive signalling loop between amyloid-beta and neuronal activity, it may rescue cognitive decline and the conversion to Alzheimer's disease," said Dr. Slutsky.

Source: American Friends of Tel Aviv University.

Hilla Fogel, Samuel Frere, Oshik Segev, Shashank Bharill, Ilana Shapira, Neta Gazit, Tiernan O’Malley, Edden Slomowitz, Yevgeny Berdichevsky, Dominic M. Walsh, Ehud Y. Isacoff, Joel A. Hirsch, Inna Slutsky. APP Homodimers Transduce an Amyloid-β-Mediated Increase in Release Probability at Excitatory Synapses. Cell Reports, 2014; 7 (5): 1560 DOI:10.1016/j.celrep.2014.04.024

This Compound May Halt Progression of Alzheimer's

noreply@blogger.com (Unknown) — Sat, 28 Jun 2014 22:05:00 +0000

Without a steady supply of blood, neurons can't work. That's why one of the culprits behind Alzheimer's disease is believed to be the persistent blood clots that often form in the brains of Alzheimer's patients, contributing to the condition's hallmark memory loss, confusion and cognitive decline.

New experiments in Sidney Strickland's Laboratory of Neurobiology and Genetics at Rockefeller University have identified a compound that might halt the progression of Alzheimer's by interfering with the role amyloid-β, a small protein that forms plaques in Alzheimer's brains, plays in the formation of blood clots. This work is highlighted in the July issue of Nature Reviews Drug Discovery.

For more than a decade, potential Alzheimer's drugs have targeted amyloid-β, but, in clinical trials, they have either failed to slow the progression of the disease or caused serious side effects. However, by targeting the protein's ability to bind to a clotting agent in blood, the work in the Strickland lab offers a promising new strategy, according to the highlight, which will be published in print on July 1.

This latest study builds on previous work in Strickland's lab showing amyloid-β can interact with fibrinogen, the clotting agent, to form difficult-to-break-down clots that alter blood flow, cause inflammation and choke neurons.

"Our experiments in test tubes and in mouse models of Alzheimer's showed the compound, known as RU-505, helped restore normal clotting and cerebral blood flow. But the big pay-off came with behavioral tests in which the Alzheimer's mice treated with RU-505 exhibited better memories than their untreated counterparts," Strickland says. "These results suggest we have found a new strategy with which to treat Alzheimer's disease."

Treatment with the compound RU-505 improved the chronic and damaging inflammation (red) in the brains of mice exhibiting Alzheimer's (top), as compared to Alzheimer's mice that went untreated (bottom)

RU-505 emerged from a pack of 93,716 candidates selected from libraries of compounds, the researchers write in the June issue of the Journal of Experimental Medicine. Hyung Jin Ahn, a research associate in the lab, examined these candidates with a specific goal in mind: Find one that interferes with the interaction between fibrinogen and amyloid-β. In a series of tests that began with a massive, automated screening effort at Rockefeller's High Throughput Resource Center, Ahn and colleagues winnowed the 93,000 contenders to five. Then, test tube experiments whittled the list down to one contender: RU-505, a small, synthetic compound. Because RU-505 binds to amyloid-β and only prevents abnormal blood clot formation, it does not interfere with normal clotting. It is also capable of passing through the blood-brain barrier.

"We tested RU-505 in mouse models of Alzheimer's disease that over-express amyloid- β and have a relatively early onset of disease. Because Alzheimer's disease is a long-term, progressive disease, these treatments lasted for three months," Ahn says. "Afterward, we found evidence of improvement both at the cellular and the behavioral levels."

The brains of the treated mice had less of the chronic and harmful inflammation associated with the disease, and blood flow in their brains was closer to normal than that of untreated Alzheimer's mice. The RU-505-treated mice also did better when placed in a maze. Mice naturally want to escape the maze, and are trained to recognize visual cues to find the exit quickly. Even after training, Alzheimer's mice have difficulty in exiting the maze. After these mice were treated with RU-505, they performed much better.

"While the behavior and the brains of the Alzheimer's mice did not fully recover, the three-month treatment with RU-505 prevents much of the decline associated with the disease," Strickland says.

The researchers have begun the next steps toward developing a human treatment. Refinements to the compound are being supported by the Robertson Therapeutic Development Fund and the Tri-Institutional Therapeutic Discovery Institute. As part of a goal to help bridge critical gaps in drug discovery, these initiatives support the early stages of drug development, as is being done with RU-505.

"At very high doses, RU-505 is toxic to mice and even at lower doses it caused some inflammation at the injection site, so we are hoping to find ways to reduce this toxicity, while also increasing RU-505's efficacy so smaller doses can accomplish similar results," Ahn says.

Source: Rockefeller University

H. J. Ahn, J. F. Glickman, K. L. Poon, D. Zamolodchikov, O. C. Jno-Charles, E. H. Norris, S. Strickland. A novel A -fibrinogen interaction inhibitor rescues altered thrombosis and cognitive decline in Alzheimer's disease mice. Journal of Experimental Medicine, 2014; 211 (6): 1049 DOI: 10.1084/jem.20131751

Stress in Early Life No Good For Brain

noreply@blogger.com (Unknown) — Sat, 28 Jun 2014 21:44:00 +0000

Forr children, stress can go a long way. A little bit provides a platform for learning, adapting and coping. But a lot of it — chronic, toxic stress like poverty, neglect and physical abuse — can have lasting negative impacts.

A team of University of Wisconsin-Madison researchers recently showed these kinds of stressors, experienced in early life, might be changing the parts of developing children’s brains responsible for learning, memory and the processing of stress and emotion. These changes may be tied to negative impacts on behavior, health, employment and even the choice of romantic partners later in life.

The study, published in the journal Biological Psychiatry, could be important for public policy leaders, economists and epidemiologists, among others, says study lead author and recent UW Ph.D. graduate Jamie Hanson.

“We haven’t really understood why things that happen when you’re 2, 3, 4 years old stay with you and have a lasting impact,” says Seth Pollak, co-leader of the study and UW-Madison professor of psychology.

Yet, early life stress has been tied before to depression, anxiety, heart disease, cancer, and a lack of educational and employment success, says Pollak, who is also director of the UW Waisman Center’s Child Emotion Research Laboratory.

“Given how costly these early stressful experiences are for society … unless we understand what part of the brain is affected, we won’t be able to tailor something to do about it,” he says.

For the study, the team recruited 128 children around age 12 who had experienced either physical abuse, neglect early in life or came from low socioeconomic status households.

Researchers conducted extensive interviews with the children and their caregivers, documenting behavioral problems and their cumulative life stress. They also took images of the children’s brains, focusing on the hippocampus and amygdala, which are involved in emotion and stress processing. They were compared to similar children from middle-class households who had not been maltreated.

Hanson and the team outlined by hand each child’s hippocampus and amygdala and calculated their volumes. Both structures are very small, especially in children (the word amygdala is Greek for almond, reflecting its size and shape in adults), and Hanson and Pollak say the automated software measurements from other studies may be prone to error.

Indeed, their hand measurements found that children who experienced any of the three types of early life stress had smaller amygdalas than children who had not. Children from low socioeconomic status households and children who had been physically abused also had smaller hippocampal volumes. Putting the same images through automated software showed no effects.

Behavioral problems and increased cumulative life stress were also linked to smaller hippocampus and amygdala volumes.

Why early life stress may lead to smaller brain structures is unknown, says Hanson, now a postdoctoral researcher at Duke University’s Laboratory for NeuroGenetics, but a smaller hippocampus is a demonstrated risk factor for negative outcomes. The amygdala is much less understood and future work will focus on the significance of these volume changes.

“For me, it’s an important reminder that as a society we need to attend to the types of experiences children are having,” Pollak says. “We are shaping the people these individuals will become.”

But the findings, Hanson and Pollak say, are just markers for neurobiological change; a display of the robustness of the human brain, the flexibility of human biology. They aren’t a crystal ball to be used to see the future.

Source: University of Wisconsin-Madison.

Jamie L. Hanson, Brendon M. Nacewicz, Matthew J. Sutterer, Amelia A. Cayo, Stacey M. Schaefer, Karen D. Rudolph, Elizabeth A. Shirtcliff, Seth D. Pollak, Richard J. Davidson. Behavior Problems After Early Life Stress: Contributions of the Hippocampus and Amygdala. Biological Psychiatry, 2014; DOI:10.1016/j.biopsych.2014.04.020

Bipolar Disorder Basic Biology

noreply@blogger.com (Unknown) — Fri, 14 Feb 2014 00:04:00 +0000

Scientists know there is a strong genetic component to bipolar disorder, but they have had an extremely difficult time identifying the genes that cause it. So, in an effort to better understand the illness's genetic causes, researchers at UCLA tried a new approach.

Instead of only using a standard clinical interview to determine whether individuals met the criteria for a clinical diagnosis of bipolar disorder, the researchers combined the results from brain imaging, cognitive testing, and an array of temperament and behavior measures. Using the new method, UCLA investigators -- working with collaborators from UC San Francisco, Colombia's University of Antioquia and the University of Costa Rica -- identified about 50 brain and behavioral measures that are both under strong genetic control and associated with bipolar disorder. Their discoveries could be a major step toward identifying the specific genes that contribute to the illness.

The results are published in the Feb. 12 edition of the Journal JAMA Psychiatry.

A severe mental illness that affects about 1 to 2 percent of the population, bipolar disorder causes unusual shifts in mood and energy, and it interferes with the ability to carry out everyday tasks. Those with the disorder can experience tremendous highs and extreme lows -- to the point of not wanting to get out of bed when they're feeling down. The genetic causes of bipolar disorder are highly complex and likely involve many different genes, said Carrie Bearden, a senior author of the study and an associate professor of psychiatry and psychology at the UCLA Semel Institute for Neuroscience and Human Behavior.

"The field of psychiatric genetics has long struggled to find an effective approach to begin dissecting the genetic basis of bipolar disorder," Bearden said. "This is an innovative approach to identifying genetically influenced brain and behavioral measures that are more closely tied to the underlying biology of bipolar disorder than the clinical symptoms alone are."

The researchers assessed 738 adults, 181 of whom have severe bipolar disorder. They used high-resolution 3-D images of the brain, questionnaires evaluating temperament and personality traits of individuals diagnosed with bipolar disorder and their non-bipolar relatives, and an extensive battery of cognitive tests assessing long-term memory, attention, inhibitory control and other neurocognitive abilities.

Approximately 50 of these measures showed strong evidence of being influenced by genetics. Particularly interesting was the discovery that the thickness of the gray matter in the brain's temporal and prefrontal regions -- the structures that are critical for language and for higher-order cognitive functions like self-control and problem-solving -- were the most promising candidate traits for genetic mapping, based on both their strong genetic basis and association with the disease.

"These findings are really just the first step in getting us a little closer to the roots of bipolar disorder," Bearden said. "What was really exciting about this project was that we were able to collect the most extensive set of traits associated with bipolar disorder ever assessed within any study sample. These data will be a really valuable resource for the field."

The individuals assessed in this study are members of large families living in Costa Rica's central valley and Antioquia, Colombia. The families were founded by European and native Amerindian populations about 400 years ago and have a very high incidence of bipolar disorder. The groups were chosen because they have remained fairly isolated since their founding and their genetics are therefore simpler for scientists to study than those of general populations.

The fact that the findings aligned so closely with those of previous, smaller studies in other populations was surprising even to the scientists, given the subjects' unique genetic background and living environments.

"This suggests that even if the specific genetic variants we identify may be unique to this population, the biological pathways they disrupt are likely to also influence disease risk in other populations," Bearden said.

The researchers' next step is to use the genomic data they collected from the families -- including full genome sequences and gene expression data -- to begin identifying the specific genes that contribute to risk for bipolar disorder. The researchers also plan to extend their investigation into the children and teens in these families. They hypothesize that many of the bipolar-related brain and behavioral differences found in adults with bipolar disorder had their origins in adolescent neurodevelopment.

Journal Reference:

Scott C. Fears, Susan K. Service, Barbara Kremeyer, Carmen Araya, Xinia Araya, Julio Bejarano, Margarita Ramirez, Gabriel Castrillón, Juliana Gomez-Franco, Maria C. Lopez, Gabriel Montoya, Patricia Montoya, Ileana Aldana, Terri M. Teshiba, Zvart Abaryan, Noor B. Al-Sharif, Marissa Ericson, Maria Jalbrzikowski, Jurjen J. Luykx, Linda Navarro, Todd A. Tishler, Lori Altshuler, George Bartzokis, Javier Escobar, David C. Glahn, Jorge Ospina-Duque, Neil Risch, Andrés Ruiz-Linares, Paul M. Thompson, Rita M. Cantor, Carlos Lopez-Jaramillo, Gabriel Macaya, Julio Molina, Victor I. Reus, Chiara Sabatti, Nelson B. Freimer, Carrie E. Bearden. Multisystem Component Phenotypes of Bipolar Disorder for Genetic Investigations of Extended Pedigrees. JAMA Psychiatry, 2014; DOI: 10.1001/jamapsychiatry.2013.4100

MitoQ Significantly Reverses Multiple Sclerosis-like Disease in Mice

noreply@blogger.com (Unknown) — Thu, 02 Jan 2014 21:47:00 +0000

Researchers at Oregon Health & Science University have discovered that an antioxidant designed by scientists more than a dozen years ago to fight damage within human cells significantly helps symptoms in mice that have a multiple sclerosis-like disease.

The antioxidant -- called MitoQ -- has shown some promise in fighting neurodegenerative diseases. But this is the first time it has been shown to significantly reverse an MS-like disease in an animal. The discovery could lead to an entirely new way to treat multiple sclerosis, which affects more than 2.3 million people worldwide. Multiple sclerosis occurs when the body's immune system attacks the myelin, or the protective sheath, surrounding nerve fibers of the central nervous system. Some underlying nerve fibers are destroyed. Resulting symptoms can include blurred vision and blindness, loss of balance, slurred speech, tremors, numbness and problems with memory and concentration.

The antioxidant research was published in the December edition of Biochimica et Biophysica Acta Molecular Basis of Disease. The research team was led by P. Hemachandra Reddy, Ph.D., an associate scientist in the Division of Neuroscience at OHSU's Oregon National Primate Research Center. To conduct their study, the researchers induced mice to contract a disease called experimental autoimmune encephalomyelitis, or EAE, which is very similar to MS in humans. They separated mice into four groups: a group with EAE only; a group that was given the EAE, then treated with the MitoQ; a third group that was given the MitoQ first, then given the EAE; and a fourth "control" group of mice without EAE and without any other treatment. After 14 days, the EAE mice that had been treated with the MitoQ exhibited reduced inflammatory markers and increased neuronal activity in the spinal cord -- an affected brain region in MS -- that showed their EAE symptoms were being improved by the treatment. The mice also showed reduced loss of axons, or nerve fibers and reduced neurological disabilities associated with the EAE. The mice that had been pre-treated with the MitoQ showed the least problems. The mice that had been treated with MitoQ after EAE also showed many fewer problems than mice who were just induced to get the EAE and then given no treatment.

"The MitoQ also significantly reduced inflammation of the neurons and reduced demyelination," Reddy said. "These results are really exciting. This could be a new front in the fight against MS."

Even if the treatment continues to show promise, testing in humans would be years away. The next steps for Reddy's team will be to understand the mechanisms of MitoQ neuroprotection in different regions of the brain, and how MitoQ protects mitochondria within the brain cells of the EAE mice. Mitochondria, components within all human cells, convert energy into forms that are usable by the cell. There is a built-in advantage with MitoQ. Unlike many new drugs, MitoQ has been tested for safety in numerous clinical trails with humans. Since its development in the late 1990s, researchers have tested MitoQ's ability to decrease oxidative damage in mitochondria.

"It appears that MitoQ enters neuronal mitochondria quickly, scavenges free radicals, reduces oxidative insults produced by elevated inflammation, and maintains or even boosts neuronal energy in affected cells," said Reddy. The hope has been that MitoQ might help treat neurodegenerative diseases like Alzheimer's and Parkinson's. Studies evaluating its helpfulness in treating those diseases are ongoing.

Journal Reference:

Peizhong Mao, Maria Manczak, Ulziibat P. Shirendeb, P. Hemachandra Reddy. MitoQ, a mitochondria-targeted antioxidant, delays disease progression and alleviates pathogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis.Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2013; 1832 (12): 2322 DOI:10.1016/j.bbadis.2013.09.005

New Technological Tools For Autism

noreply@blogger.com (Unknown) — Wed, 26 Sep 2012 12:04:00 +0000

Researchers in Georgia Tech's Center for Behavior Imaging have developed two new technological tools that automatically measure relevant behaviors of children, and promise to have significant impact on the understanding of behavioral disorders such as autism.

One of the tools -- a system that uses special gaze-tracking glasses and facial-analysis software to identify when a child makes eye contact with the glasses-wearer -- was created by combining two existing technologies to develop a novel capability of automatic detection of eye contact. The other is a wearable system that uses accelerometers to monitor and categorize problem behaviors in children with behavioral disorders.

Both technologies already are being deployed in the Center for Behavior Imaging's (CBI) ongoing work to apply computational methods to screening, measurement and understanding of autism and other behavioral disorders.

Children at risk for autism often display distinct behavioral markers from a very young age. One such marker is a reluctance to make frequent or prolonged eye contact with other people. Discovering an automated way to detect this and other telltale behavioral markers would be a significant step toward scaling autism screening up to much larger populations than are currently reached. This is one goal of the five-year, $10 million "Expeditions" project, funded in fall 2010 by the National Science Foundation under principal investigator and CBI Director Jim Rehg, also a professor in Georgia Tech's School of Interactive Computing.

The eye-contact tracking system begins with a commercially available pair of glasses that can record the focal point of their wearer's gaze. Researchers took video of a child captured by a front-facing camera on the glasses, worn by an adult who was interacting with the child. The video was then processed using facial recognition software available from a second manufacturer. Combine the glasses' hard-wired ability to detect wearer gaze with the facial-recognition software's ability to detect the child's gaze direction, and the result is a system able to detect eye contact in a test interaction with a 22-month-old with 80 percent accuracy. The study was conducted in Georgia Tech's Child Study Lab (CSL), a child-friendly experimental facility richly equipped with cameras, microphones and other sensors.

"Eye gaze has been a tricky thing to measure in laboratory settings, and typically it's very labor-intensive, involving hours and hours of looking at frames of video to pinpoint moments of eye contact," Rehg said. "The exciting thing about our method is that it can produce these measures automatically and could be used in the future to measure eye contact outside the laboratory setting. We call these results preliminary because they were obtained from a single subject, but all humans' eyes work pretty much the same way, so we're confident the successful results will be replicated with future subjects."

The other new system, developed in collaboration with the Marcus Autism Center in Atlanta and Dr. Thomas Ploetz of Newcastle University in the United Kingdom, is a package of sensors, worn via straps on the wrists and ankles, that uses accelerometers to detect movement by the wearer. Algorithms developed by the team analyze the sensor data to automatically detect episodes of problem behavior and classify them as aggressive, self-injurious or disruptive (e.g., throwing objects).

Researchers first developed the algorithms by putting the sensors on four Marcus clinic staff members who together performed some 1,200 different behavior instances, and the system detected "problem" behaviors with 95 percent accuracy and classified all behaviors with 80 percent accuracy. They then used the sensors with a child diagnosed along the autism spectrum, and the system detected the child's problem-behavior episodes with 81 percent accuracy and classified them with 70 percent accuracy.

"These results are very promising in leading the way toward more accurate and reliable measurement of problem behavior, which is important in determining whether treatments targeting these behaviors are working," said CSL Director Agata Rozga, a research scientist in the School of Interactive Computing and co-investigator on the Expeditions award. "Our ultimate goal with this wearable sensing system is to be able to gather data on the child's behavior beyond the clinic, in settings where the child spends most of their time, such as their home or school. In this way, parents, teachers and others who care for the child can be potentially alerted to times and situations when problem behaviors occur so that they can address them immediately."

"What these tools show is that computational methods and technologies have great promise and potential impact on the lives of many children and their parents and caregivers," said Gregory Abowd, Regents' Professor in the School of Interactive Computing and a prominent researcher in technology and autism. "These technologies we are developing, and others developed and explored elsewhere, aim to bring more effective early-childhood screening to millions of children nationwide, as well as enhance care for those children already diagnosed on the autism spectrum."

Both technologies were presented in early September at the 14th ACM International Conference on Ubiquitous Computing (Ubicomp 2012). Among the other devices under study at CSL are a camera/software system that can track children's facial expressions and customized speech analysis software to detect vocalization patterns.

Georgia Institute of Technology.