Brain Ages Fast With Less Sleep

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.


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 PerformanceSLEEP, 2014; DOI: 10.5665/sleep.3832

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Elevated Activity in Hippocampus Linked to Alzheimer's

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.
A new approach to protecting the brain
"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.
  1. 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 SynapsesCell Reports, 2014; 7 (5): 1560 DOI:10.1016/j.celrep.2014.04.024

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This Compound May Halt Progression of Alzheimer's

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.
  1. 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 miceJournal of Experimental Medicine, 2014; 211 (6): 1049 DOI: 10.1084/jem.20131751

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Stress in Early Life No Good For Brain

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.
  1. 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 AmygdalaBiological Psychiatry, 2014; DOI:10.1016/j.biopsych.2014.04.020


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Bipolar Disorder Basic Biology

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:
  1. 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 PedigreesJAMA Psychiatry, 2014; DOI: 10.1001/jamapsychiatry.2013.4100

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MitoQ Significantly Reverses Multiple Sclerosis-like Disease in Mice

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:
  1. 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


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New Technological Tools For Autism

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.

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Mechanism Underlying Common Non-familial Parkinson's Disease

Researchers in the Taub Institute at Columbia University Medical Center (CUMC) have identified a mechanism that appears to underlie the common sporadic (non-familial) form of Parkinson's disease, the progressive movement disorder. The discovery highlights potential new therapeutic targets for Parkinson's and could lead to a blood test for the disease. The study, based mainly on analysis of human brain tissue, was published September 25 in the online edition of Nature Communications.
Studies of rare, familial (heritable) forms of Parkinson's show that a protein called alpha-synuclein plays a role in the development of the disease. People who have extra copies of the alpha-synuclein gene produce excess alpha-synuclein protein, which can damage neurons. The effect is most pronounced in dopamine neurons, a population of brain cells in the substantia nigra that plays a key role in controlling normal movement and is lost in Parkinson's. Another key feature of Parkinson's is the presence of excess alpha-synuclein aggregates in the brain.
As the vast majority of patients with Parkinson's do not carry rare familial mutations, a key question has been why these individuals with common sporadic Parkinson's nonetheless acquire excess alpha-synuclein protein and lose critical dopamine neurons, leading to the disease.
Using a variety of techniques, including gene-expression analysis and gene-network mapping, the CUMC researchers discovered how common forms of alpha-synuclein contribute to sporadic Parkinson's. "It turns out multiple different alpha-synuclein transcript forms are generated during the initial step in making the disease protein; our study implicates the longer transcript forms as the major culprits," said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and neurology at CUMC. "Some very common genetic variants in the alpha-synuclein gene, present in many people, are known to impact the likelihood that an individual will suffer from sporadic Parkinson's. In our study, we show that people with 'bad' variants of the gene make more of the elongated alpha-synuclein transcript forms. This ultimately means that more of the disease protein is made and may accumulate in the brain."
"An unusual aspect of our study is that it is based largely on detailed analysis of actual patient tissue, rather than solely on animal models," said Dr. Abeliovich. "In fact, the longer forms of alpha-synuclein are human-specific, as are the disease-associated genetic variants. Animal models don't really get Parkinson's, which underscores the importance of including the analysis of human brain tissue."
"Furthermore, we found that exposure to toxins associated with Parkinson's can increase the abundance of this longer transcript form of alpha-synuclein. Thus, this mechanism may represent a common pathway by which environmental and genetic factors impact the disease," said Dr. Abeliovich.
The findings suggest that drugs that reduce the accumulation of elongated alpha-synuclein transcripts in the brain might have therapeutic value in the treatment of Parkinson's. The CUMC team is currently searching for drug candidates and has identified several possibilities.
The study also found elevated levels of the alpha-synuclein elongated transcripts in the blood of a group of patients with sporadic Parkinson's, compared with unaffected controls. This would suggest that a test for alpha-synuclein may serve as a biomarker for the disease. "There is a tremendous need for a biomarker for Parkinson's, which now can be diagnosed only on the basis of clinical symptoms. The finding is particularly intriguing, but needs to be validated in additional patient groups," said Dr. Abeliovich. A biomarker could also speed clinical trials by giving researchers a more timely measure of a drug's effectiveness.
The study was supported by the grants from the Michael J. Fox Foundation, the National Institutes of Health, and the National Institute of Neurological Disorders and Stroke (RO1NS064433).
Journal Reference:
  1. Herve Rhinn, Liang Qiang, Toru Yamashita, David Rhee, Ari Zolin, William Vanti, Asa Abeliovich. Alternative α-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathologyNature Communications, 2012; 3: 1084 DOI: 10.1038/ncomms2032


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Cataracts and Alzheimer's Share Common Etiological Factors

In a recent study, investigators at Boston University Schools of Medicine (BUSM) and Public Health (BUSPH) identified a gene linking age-related cataracts and Alzheimer's disease. The findings, published online in PLoS ONE, contribute to the growing body of evidence showing that these two diseases, both associated with increasing age, may share common etiologic factors. 
Gyungah Jun, PhD, from the departments of medicine, ophthalmology and biostatistics at BUSM and BUSPH, served as the study's lead author. Lindsay A. Farrer, PhD, professor of medicine, neurology, ophthalmology, genetics & genomics, epidemiology and biostatistics and chief of the Biomedical Genetics Section at BUSM, was the study's senior author. 

Using the Framingham Offspring Eye Study cohort, investigators looked at brain MRI findings on or after 10 years from the original eye exam and concluded that there was a significant correlation between a quantitative measure of cortical cataract and several Alzheimer's disease-related measures of brain degeneration, in particular volume of the temporal horn which is a brain structure that is progressively enlarged in patients with Alzheimer's disease. Another strong correlation in these same individuals, between cortical cataract formation and poorer performance on several cognitive tests administered at the time of the MRI scan, further supports this link. 

With such a link not confounded by age or sex, the investigators then performed a genome-wide association study looking at nearly 190,000 single-nucleotide polymorphisms (SNPs), or DNA sequence variations. Three intronic (non-coding) SNPs in the gene encoding δ-catenin came to the fore. This protein is a key component in cell adherence and formation of cell junctional structures. Previously, δ-catenin was also implicated in brain and eye development, but not directly in either cataracts or Alzheimer's disease. To establish a more direct link of δ-catenin to Alzheimer's disease, the researchers transfected into neuronal cells δ-catenin bearing a mutation near the location of the top-associated SNPs and observed a significant and specific increase in the toxic form of amyloid β, the protein that aggregates in Alzheimer brains and thought to be central to development of the disorder. In addition, the researchers found increased deposits of δ-catenin in lens tissue obtained from autopsy-confirmed Alzheimer's cases but not from subjects lacking Alzheimer's-associated neuropathology. 

"Though much work remains to be done, a link between cataracts and Alzheimer's disease supports the idea of a systemic rather than brain-limited focus for processes leading to Alzheimer's disease," said Farrer. "This study gives hope that we are moving toward earlier diagnosis and new treatment targets for this debilitating disease." 

Juliet Moncaster, PhD, from the department of psychiatry; Sudha Seshadri, MD from department of neurology and associate professor of the Framingham Heart Study; Jacqueline Buros, BS, from the department of medicine; Ann C. McKee, MD, from the departments of neurology, pathology and laboratory medicine, the Boston University Alzheimer's Disease Center, and the Bedford Veterans Administration Hospital; and Phillip A. Wolf, MD, of the departments of neurology, epidemiology and professor of the Framingham Heart Study of BUSM and BUSPH, contributed to this paper. Researchers from the University of Toronto, the Bedford Veterans Administration Hospital, the Universití Laval and the University of Cambridge also collaborated on this study. 

This study was supported by grants from the National Institute on Aging for investigated-initiated projects (R01-AG025259, R01-AG33193, R01-AG081220, R01-AG16495, and R01-AG033040) and the Boston University Alzheimer Disease Center (P30-AG13846), National Institute of General Medical Science (R01-GM75986), Wellcome Trust, Medical Research Council, Canadian Institutes of Health Research, Alzheimer Society of Ontario, and Ontario Research Fund. 

Reference: 

Gyungah Jun, Juliet A. Moncaster, Carolina Koutras, Sudha Seshadri, Jacqueline Buros, Ann C. McKee, Georges Levesque, Philip A. Wolf, Peter St. George-Hyslop, Lee E. Goldstein, Lindsay A. Farrer. δ-Catenin Is Genetically and Biologically Associated with Cortical Cataract and Future Alzheimer-Related Structural and Functional Brain Changes. PLoS ONE, 2012; 7 (9): e43728 DOI: 10.1371/journal.pone.0043728

Boston University Medical Center.

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Dementia Associated With Low Vitamin C and Beta-carotene

Forgetfulness, lack of orientation, cognitive decline ... these are among the symptoms of Alzheimer's disease (AD). Now researchers from the University of Ulm, among them the Epidemiologist Professor Gabriele Nagel and the Neurologist Professor Christine von Arnim, have discovered that the serum-concentration of the antioxidants vitamin C and beta-carotene are significantly lower in patients with mild dementia than in control persons. It might thus be possible to influence the pathogenesis of AD by a person's diet or dietary antioxidants. 
A total of 74 AD-patients and 158 healthy controls were examined for the study that has been published in the Journal of Alzheimer's Disease (JAD). AD is a neurodegenerative disease: Alterations in the brain caused by amyloid-beta-plaques, degeneration of fibrillae and a loss of synapses are held responsible for the characteristic symptoms. Oxidative stress, which constrains the exploitation of oxygen in the human body, is suspected to promote the development of AD. Whereas so called antioxidants might protect against neurodegeneration. 

In their study, the researchers have investigated whether the serum-levels of vitamin C, vitamin E, beta-carotene as well as lycopene and coenzyme Q10 are significantly lower in the blood of AD-patients. "In order to possibly influence the onset and development of Alzheimer's disease, we need to be aware of potential risk factors," says Gabriele Nagel. Participants were recruited from the cross-sectional study IMCA ActiFE (Activity and Function in the Elderly in Ulm) for which a representative population-based sample of about 1,500 senior citizens has been examined. The 65 to 90 years old seniors from Ulm and the surrounding area underwent neuropsychological testing and answered questions regarding their lifestyle. What is more, their blood has been examined and their body mass index (BMI) was calculated. 

For the present study, scientists have compared 74 patients with mild dementia (average age 78.9 years) with a control group consisting of 158 healthy, gender-matched persons of the same age. Results are quite interesting: The concentration of vitamin C and beta-carotene in the serum of AD-patients was significantly lower than in the blood of control subjects. Whereas no such difference between the groups could be found for the other antioxidants (vitamin E, lycopene, coenzyme Q10). Potential confounding factors such as education, civil status, BMI, consumption of alcohol and tobacco have been considered in the statistical analysis. Nevertheless, additional parameters such as the storage and preparation of food as well as stressors in the life of participants might have influenced the findings. 

Therefore, results need to be confirmed in prospective surveys. "Longitudinal studies with more participants are necessary to confirm the result that vitamin C and beta-carotene might prevent the onset and development of Alzheimer's disease," says Gabriele Nagel. Vitamin C can for example be found in citrus fruits; beta-carotene in carrots, spinach or apricots. 

Source:
Christine A.F. von Arnim, Florian Herbolsheimer, Thorsten Nikolaus, Richard Peter,Hans K. Biesalski, Albert C. Ludolph, Matthias Riepe, Gabriele Nagel, and the ActiFE Ulm study group. Dietary Antioxidants and Dementia in a Population-Based Case-Control Study among Older People in South Germany. Journal of Alzheimer’s disease, 2012 DOI: 10.3233/JAD-2012-120634

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