Autism and Eye Contact: Genes very much are involved

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


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Early Signs of Alzheimer's: Sleeping Issues

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.

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Traumatic brain injury and dementia: A Missing link

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

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Brain Training Games Reduce Dementia

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

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

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.

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After receiving the injection, patients underwent another EEG, then magnetic resonance imaging (MRI) -- which measures blood flow in the brain, another way to quantify brain activity and determine where in the brain it is taking place. Finally, patients took a standardized cognitive test, designed to measure memory, executive functioning, naming, visuospatial ability and semantic function - capabilities all affected by Alzheimer's disease.

In the seven patients able to complete the study protocol successfully, Press and colleagues analyzed changes in their EEGs. (Blood flow analysis from the MRI data is still underway.) Overall, higher doses of the anti-seizure drug appeared to normalize abnormalities seen in the patients' EEG profiles. That is, researchers saw overall increases in brain wave frequencies that had been abnormally low in Alzheimer's disease patients prior to receiving the higher dose of levetiracetam, and, likewise, saw decreases in those that had been abnormally high.

"It's worth noting, we did not demonstrate any improvementafter a single dose of medication in this study," said Press. "It's too early to use the drug widely, but we're preparing for a larger, longer study."

The risk of developing Alzheimer's disease increases sharply with age. Today, it affects more than 5 million Americans, a figure that is projected to reach 16 million by 2050 as the population ages. In recent years, researchers have focused on developing techniques to clear the brain of amyloid and tau protein plaques that build up and wreak havoc in the brains of patients with Alzheimer's disease.

"These strategies have not led to new therapies to date," said Press. "There have been a lot of disappointments. So our findings represent an interesting new avenue."

Press' co-investigators included co-lead author Christian S. Musaeus and Emiliano Santarnecchi of the Berenson-Allen Center for Non-invasive Brain Stimulation at BIDMC; Mouhsin M. Shafi and Susan T. Herman of the Department of Neurology at BIDMC. This research was supported by a grant from the Fidelity Biosciences Research Initiative and private donations.

Source: BETH ISRAEL DEACONESS MEDICAL CENTER

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Why Autistic Kids Avoid Eye Contact: Image Studies

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.

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Diet effect on Alzheimer's gene carriers

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.

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The study was co-written by Alexandra Moser, a Ph.D. student in the USC Neuroscience Graduate Program.

Ninety percent of the study was supported by National Institutes of Health grant AG034103. The five-year $1.6 million grant awarded in 2011. Ten percent of the study was covered by another NIH grant, AG051521. The five-year $3 million grant was awarded in 2015. Both grants cover several research studies.

Source: NIH

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Genome-wide DNA damage from Cigarette Smoking

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.
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The researchers are also performing more studies to uncover factors influencing where and whether nucleotide excision DNA repair occurs. To do that, they need to map sites of actual damage on the genome itself, not just the damaged snippets that are excised during repairs.
In one such project, they have developed a sensitive, high-resolution method for mapping actual DNA damage caused by ultraviolet light. By combining that method with repair mapping, they have found that the UV damage to DNA appears to be essentially uniform, although the repair process is not. Repair seems to be affected by a host of factors, including how actively a given stretch of DNA is being copied out to encode the making of proteins. They are currently applying this method to BaP to complement the repair map they have generated.
That again points to the likelihood of hotspots where repair is less likely to occur and mutations are more likely to arise.
"I'm certain," said Sancar, "that all this information will lead to a better understanding of why certain people are predisposed to cancer, and which smoking-related mutations lead to lung cancer specifically."

And that, in turn, could have implications for the development of more targeting therapies down the line.
Source: UNIVERSITY OF NORTH CAROLINA HEALTH CARE

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Brain Benefits From Simple Physical Activity

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."
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.

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Dementia with Lewy bodies, new international guidelines

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.
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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/.

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