ScienceDaily (June 6, 2012) — One of the top suspects behind killer vascular diseases is the victim of mistaken identity, according to researchers from the University of California, Berkeley, who used genetic tracing to help hunt down the real culprit.

Within the walls of blood vessels are smooth muscle cells and newly discovered vascular stem cells. The stem cells are multipotent and are not only able to differentiate into smooth muscle cells, but also into fat, cartilage and bone cells. UC Berkeley researchers provide evidence that the stem cells are contributing to clogged and hardened arteries. (Credit: Song Li illustration)

The guilty party is not the smooth muscle cells within blood vessel walls, which for decades was thought to combine with cholesterol and fat that can clog arteries. Blocked vessels can eventually lead to heart attacks and strokes, which account for one in three deaths in the United States.

Instead, a previously unknown type of stem cell — a multipotent vascular stem cell — is to blame, and it should now be the focus in the search for new treatments, the scientists report in a new study appearing June 6 in the journal Nature Communications.

"For the first time, we are showing evidence that vascular diseases are actually a kind of stem cell disease," said principal investigator Song Li, professor of bioengineering and a researcher at the Berkeley Stem Cell Center. "This work should revolutionize therapies for vascular diseases because we now know that stem cells rather than smooth muscle cells are the correct therapeutic target."

The finding that a stem cell population contributes to artery-hardening diseases, such as atherosclerosis, provides a promising new direction for future research, the study authors said.

"This is groundbreaking and provocative work, as it challenges existing dogma," said Dr. Deepak Srivastava, who directs cardiovascular and stem cell research at the Gladstone Institutes in San Francisco, and who provided some of the mouse vascular tissues used by the researchers. "Targeting the vascular stem cells rather than the existing smooth muscle in the vessel wall might be much more effective in treating vascular disease."

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ScienceDaily (June 6, 2012) — Swiss researchers have succeeded in generating detailed three-dimensional images of the spatial distribution of amyloid plaques in the brains of mice afflicted with Alzheimer’s disease. These plaques are accumulations of small pieces of protein in the brain and are a typical characteristic of Alzheimer’s. The new technique used in the investigations provides an extremely precise research tool for a better understanding of the disease. In the future, scientists hope that it will also provide the basis for a new and reliable diagnosis method.

Virtual cut. (Credit: Image courtesy of Paul Scherrer Institut (PSI))

The results were achieved within a joint project of two teams of researchers — one from the Paul Scherrer Institute (PSI) and ETH Zurich, the other from the École Polytechnique Fédérale de Lausanne (EPFL). They have been published in the journal Neuroimage.

Alzheimer’s disease is responsible for about 60% to 80% of all cases of dementia. This disease affects people differently, but the most common initial symptom is the difficulty in remembering new information, because the disease first affects brain regions involved in the formation of new memories. Alzheimer’s dementia is characterized by typical brain lesions that spread to other brain regions as the disease progresses. One of these lesions, the so-called amyloid plaque, is composed of the accumulation of extracellular protein aggregates. These lesions appear early in the course of the disease and there is a high interest in detecting them in patients to diagnose or evaluate the progression of the disease. Recently, medical imaging methods have been developed and validated for this purpose. These allow regional amount of amyloid deposits to be measured, but individual plaques cannot be quantified.

The latest results obtained by researchers from the Paul Scherrer Institute (PSI), ETH Zurich and the École Polytechnique Fédérale de Lausanne (EPFL) show that imaging single plaques is feasible under certain conditions. “This achievement could help to advance the development and evaluation of new imaging diagnostic markers for ultimately improving the diagnosis of Alzheimer’s disease,” explains Matthias Cacquevel, one of the authors at EPFL.

Precise plaque distribution in 3D

Using a method known as Phase Contrast Imaging, the researchers were able, within a short time, to make visible the exact three-dimensional distribution of amyloid plaques in the brains of mice with Alzheimer’s. Before this achievement, the only possibility of studying the distribution of amyloid plaques at the single-plaque level was to perform time-consuming studies. “Until now, for such an investigation, the brain had to be cut into slices and the slices coloured so that the plaques became visible,” explains Bernd Pinzer, from the Paul Scherrer Institute, who carried out the investigations. “This process is the gold standard amongst such investigations. It is, however, very time-consuming, as everything has to be done by hand. At the same time, it provides much less information than our new method. Naturally, we compared the results from our new method with those obtained using this traditional method, and they showed excellent agreement.”

As a first concrete result, the researchers determined the distribution of plaques in the brains of a number of mice with different stages of the disease. For each brain, the scientists obtained a three-dimensional image of the overall plaque distribution so that the development of the disease could be followed in detail. With conventional processes, it would hardly have been possible to gather such comprehensive information.

Developments for reliable diagnostic techniques

"One goal is to use the phase contrast technique to help improve imaging methods which make visible the plaques in the brain of a living patient, and thereby allow a reliable diagnosis of Alzheimer’s disease to be made," explains Pinzer. "These methods are under constant development and it is important to compare their results with those achieved using a known and reliable method. Now it will be possible to directly compare the two sets of 3D images of a mouse brain produced both by a diagnostic method and by our phase contrast technique. One of the diagnostic methods available is Positron Emission Tomography (PET), in which special molecules are attached to the plaques and, after some time, emit gamma radiation, which can be ascertained externally."

Although the deposited radiation dose required — which is high, in order to generate the necessary high resolution — prevents measurements being made on living animals at the moment, the method is already an outstanding research tool, which will lead to a better understanding of Alzheimer’s disease. “This tool will allow much more precise studies on how amyloid plaques are distributed,” explains Matthias Cacquevel, one of the authors at EPFL. “The relationship between plaques and the symptoms of the disease are still unclear, and information on how these plaques spread throughout the brain is also missing.”

Comprehensive information from changes in the light

These investigations were carried out at the Swiss Light Source (SLS) at PSI. The SLS generates synchrotron light — X-rays that are very intensive and well focused. The investigation is similar to a conventional X-ray examination — the scientists pass the X-rays through the object under investigation and determine how they have changed on their way. A normal X-ray picture, however, only shows how strongly the light is attenuated by the object; in a sense, it shows the shadow of the object. The problem is that various kinds of soft tissue attenuate X-rays in approximately the same way, which makes it difficult to distinguish between them.

"With the phase contrast method that we are using here, we also take into consideration the fact that different tissues deviate the light slightly from its original direction by a different amount. In physics, this effect is known to generate a so-called X-ray phase shift," explains Marco Stampanoni, Professor of X-Ray Microscopy at the Institute of Biomedical Technology at the ETH Zürich and Project Manager at PSI. The team he is leading built up the measuring station and designed the experiment. "Our instrument is able to measure such subtle shifts very precisely and transform this information into understandable images."

Phase Contrast Imaging for various medical applications

"While we cannot carry out an investigation on patients using the phase contrast method to detect Alzheimer’s disease, we are close to developing diagnostic tools for other diseases," emphasises Stampanoni. "We have already shown, in a pilot study on the imaging of tumours in the female breast, how useful the additional information can be. A first step in the direction of the hospital is the development of a mammography facility, the first prototype of which can be used in a doctor’s practice."

Source: Science Daily

June 6, 2012

A 25-year follow-up study reveals that 68% of patients with juvenile myoclonic epilepsy (JME) became seizure-free, with nearly 30% no longer needing antiepileptic drug (AED) treatment. Findings published today in Epilepsia, a journal of the International League Against Epilepsy (ILAE), report that the occurrence of generalized tonic-clonic seizures preceded by bilateral myoclonic seizures, and AED polytherapy significantly predicted poor long-term seizure outcome.

Patients with JME experience “jerking” of the arms, shoulders, and sometimes the legs. Previous evidence suggests that JME is a common type of epilepsy (in up to 11% of people with epilepsy), occurring more frequently in females than in males, and with onset typically in adolescence.. There is still much debate among experts over the long-term outcome of JME, and about which factors predict seizure outcome.

To further investigate JME outcomes and predictive factors, Dr. Felix Schneider and colleagues from the Epilepsy Center at the University of Greifswald in Germany studied data from 12 male and 19 female patients with JME. All participants had a minimum of 25 years follow-up which included review of medical records, and telephone or in-person interviews.

Sixty-eight percent of the 31 JME patients became free of seizures, and 28% discontinued AED treatment due to seizure-freedom. Significant predictors of poor long-term seizure outcome included: occurrence of generalized tonic-clonic seizures (GTCS - formerly known as grand mal seizures) that affect the entire brain and which are preceded by bilateral myoclonic seizures (abnormal movements on both sides of the body and a regimen of AED polytherapy.

Researchers also determined that remission of GTCS using AED therapy significantly increased the possibility of complete seizure-freedom. However, once AED therapy is discontinued, the occurrence of photoparoxysmal responses (brain discharges in response to brief flashes of light) significantly predicted an increased risk of seizure recurrence.

"Our findings confirm the feasibility of personalized treatment of the individual JME patient," concludes Dr. Schneider. "Life-long AED therapy is not necessarily required in many patients to maintain seizure freedom. Understanding the predictors for successful long-term seizure outcome will aid clinicians in their treatment options for those with JME.”

Provided by Wiley

Source: medicalxpress.com

ScienceDaily (June 5, 2012) — In a discovery that could help in the identification and treatment of anxiety disorders, Michigan State University scientists say the brains of anxious girls work much harder than those of boys.

This electrode cap was worn by participants in an MSU experiment that measured how people responded to mistakes. Female subjects who identified themselves as big worriers recorded the highest brain activity. (Credit: G.L. Kohuth)

The finding stems from an experiment in which college students performed a relatively simple task while their brain activity was measured by an electrode cap. Only girls who identified themselves as particularly anxious or big worriers recorded high brain activity when they made mistakes during the task.

Jason Moser, lead investigator on the project, said the findings may ultimately help mental health professionals determine which girls may be prone to anxiety problems such as obsessive compulsive disorder or generalized anxiety disorder.

"This may help predict the development of anxiety issues later in life for girls," said Moser, assistant professor of psychology. "It’s one more piece of the puzzle for us to figure out why women in general have more anxiety disorders."

The study, reported in the International Journal of Psychophysiology, is the first to measure the correlation between worrying and error-related brain responses in the sexes using a scientifically viable sample (79 female students, 70 males).

Participants were asked to identify the middle letter in a series of five-letter groups on a computer screen. Sometimes the middle letter was the same as the other four (“FFFFF”) while sometimes it was different (“EEFEE”). Afterward they filled out questionnaires about how much they worry.

Although the worrisome female subjects performed about the same as the males on simple portions of the task, their brains had to work harder at it. Then, as the test became more difficult, the anxious females performed worse, suggesting worrying got in the way of completing the task, Moser said.

"Anxious girls’ brains have to work harder to perform tasks because they have distracting thoughts and worries," Moser said. "As a result their brains are being kind of burned out by thinking so much, which might set them up for difficulties in school. We already know that anxious kids — and especially anxious girls — have a harder time in some academic subjects such as math."

Currently Moser and other MSU researchers are investigating whether estrogen, a hormone more common in women, may be responsible for the increased brain response. Estrogen is known to affect the release of dopamine, a neurotransmitter that plays a key role in learning and processing mistakes in the front part of the brain.

"This may end up reflecting hormone differences between men and women," Moser said.

In addition to traditional therapies for anxiety, Moser said other ways to potentially reduce worry and improve focus include journaling — or “writing your worries down in a journal rather than letting them stick in your head” — and doing “brain games” designed to improve memory and concentration.

Source: Science Daily

ScienceDaily (June 5, 2012) — Mothers who use marijuana as teens — long before having children — may put their future children at a higher risk of drug abuse, new research suggests.

Researchers in the Neuroscience and Reproductive Biology section at the Cummings School of Veterinary Medicine conducted a study to determine the transgenerational effects of cannabinoid exposure in adolescent female rats. For three days, adolescent rats were administered the cannabinoid receptor agonist WIN-55, 212-2, a drug that has similar effects in the brain as THC, the active ingredient in marijuana. After this brief exposure, they remained untreated until being mated in adulthood.

The male offspring of the female rats were then measured against a control group for a preference between chambers that were paired with either saline or morphine. The rats with mothers who had adolescent exposure to WIN-55,212-2 were significantly more likely to opt for the morphine-paired chamber than those with mothers who abstained. The results suggest that these animals had an increased preference for opiate drugs.

The study was published in the Journal of Psychopharmocology and funded by the National Institutes of Health.

"Our main interest lies in determining whether substances commonly used during adolescence can induce behavioral and neurochemical changes that may then influence the development of future generations," said Research Assistant Professor John J. Byrnes, the study’s lead author, "We acknowledge that we are using rodent models, which may not fully translate to the human condition. Nevertheless, the results suggest that maternal drug use, even prior to pregnancy, can impact future offspring."

Byrnes added that much research is needed before a definitive connection is made between adolescent drug use and possible effects on future children.

The study builds on earlier findings by the Tufts group, most notably a study published last year in Behavioral Brain Research by Assistant Professor Elizabeth Byrnes that morphine use as adolescent rats induces changes similar to those observed in the present study.

Other investigators in the field have previously reported that cannabinoid exposure during pregnancy (in both rats and humans) can affect offspring development, including impairment of cognitive function, and increased risk of depression and anxiety.

Source: Science Daily

ScienceDaily (June 5, 2012) — Using a noninvasive test on maternal blood that deploys a novel biochemical assay and a new algorithm for analysis, scientists can detect, with a high degree of accuracy, the risk that a fetus has the chromosomal abnormalities that cause Down syndrome and a genetic disorder known as Edwards syndrome. The new approach is more scalable than other recently developed genetic screening tests and has the potential to reduce unnecessary amniocentesis or CVS.

Two studies evaluating this approach are available online in advance of publication in the April issue of the American Journal of Obstetrics & Gynecology (AJOG).

Diagnosis of fetal chromosomal abnormalities, or aneuploidies, relies on invasive testing by chorionic villous sampling or amniocentesis in pregnancies identified as high-risk. Although accurate, the tests are expensive and carry a risk of miscarriage. A technique known as massively parallel shotgun sequencing (MPSS) that analyzes cell-free DNA (cfDNA) from the mother’s plasma for fetal conditions has been used to detect trisomy 21 (T21) pregnancies, those with an extra copy of chromosome 21 that leads to Down syndrome, and trisomy 18 (T18), the chromosomal defect underlying Edwards syndrome. MPSS accurately identifies the conditions by analyzing the entire genome, but it requires a large amount of DNA sequencing, limiting its clinical usefulness.

Scientists at Aria Diagnostics in San Jose, CA developed a novel assay, Digital Analysis of Selected Regions (DANSR™), which sequences loci from only the chromosomes under investigation. The assay requires 10 times less DNA sequencing than MPSS approaches.

In the current study, the researchers report on a novel statistical algorithm, the Fetal-fraction Optimized Risk of Trisomy Evaluation (FORTE™), which considers age-related risks and the percentage of fetal DNA in the sample to provide an individualized risk score for trisomy. Explains author Ken Song, MD, “The higher the fraction of fetal cfDNA, the greater the difference in the number of cfDNA fragments originating from trisomic versus disomic [normal] chromosomes and hence the easier it is to detect trisomy. The FORTE algorithm explicitly accounts for fetal fraction in calculating trisomy risk.”

To test the performance of the DANSR/FORTE assay, Dr. Song and his colleagues evaluated a set of subjects consisting of 123 normal, 36 T21, and 8 T18 pregnancies. All samples were assigned FORTE odd scores for chromosome 18 and chromosome 21. The combination of DANSR and FORTE correctly identified all 36 cases of T21 and 8 cases of T18 as having a greater than 99% risk for each trisomy in a blinded analysis. There was at least a 1,000 fold magnitude separation in the risk score between trisomic and disomic samples.

In a related study, researchers from the Harris Birthright Research Centre for Fetal Medicine, Kings College Hospital, University of London and the University College London Hospital, University College London, provided 400 maternal plasma samples to Aria for analysis using the DANSR assay with the FORTE algorithm. The subjects were all at risk for aneuploidies, and they had been tested by chorionic villous sampling. The analysis distinguished all cases of T21 and 98% of T18 cases from euploid pregnancies. In all cases of T21, the estimated risk for this aneuploidy was greater than or equal to 99%, whereas in all normal pregnancies and those with T18, the risk score for T21 was less than or equal to 0.01%.

"Combining the DANSR assay with the FORTE algorithm provides a robust and accurate assessment of fetal trisomy risk," says Dr. Song. "Because DANSR allows analysis of specific genomic regions, it could be potentially used to evaluate genetic conditions other than trisomy. The incorporation of additional risk information, such as from ultrasonography, into the FORTE algorithm warrants investigation."

Kypros H. Nicolaides, MD, senior author of the University of London study, suggests that fetal trisomy evaluation with cfDNA testing will inevitably be introduced into clinical practice. “It would be useful as a secondary test contingent upon the results of a more universally applicable primary method of screening. The extent to which it could be applied as a universal screening tool depends on whether the cost becomes comparable to that of current methods of sonographic and biochemical testing.”

Dr. Nicolaides also notes that the plasma samples were obtained from high-risk pregnancies where there is some evidence of impaired placental function. It would also be necessary to demonstrate that the observed accuracy with cfDNA testing obtained from the investigation of pregnancies at high-risk for aneuploidies is applicable to the general population where the prevalence of fetal trisomy 21 is much lower. “This may well prove to be the case because the ability to detect aneuploidy with cfDNA is dependent upon assay precision and fetal DNA percentage in the sample rather than the prevalence of the disease in the study population,” he concludes.

Source: Science Daily

ScienceDaily (June 5, 2012) — In an early study, UCLA researchers found that the immune cells of patients with amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, may play a role in damaging the neurons in the spinal cord. ALS is a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement.

In the ALS spinal cord, a patient’s own immune cells called macrophages (green) impact neurons (live neurons =red, which are also marked by an asterisk (*), and dead neurons = magenta that are marked by an arrow. (Credit: University of California, Los Angeles)

Specifically, the team found that inflammation instigated by the immune system in ALS can trigger macrophages — cells responsible for gobbling up waste products in the brain and body — to also ingest healthy neurons. During the inflammation process, motor neurons, whether healthy or not, are marked for clean-up by the macrophages.

In addition, the team found that a lipid mediator called resolvin D1, which is made in the body from the omega-3 fatty acid DHA, was able to “turn off” the inflammatory response that made the macrophages so dangerous to the neurons. Resolvin D1 blocked the inflammatory proteins being produced by the macrophages, curbing the inflammation process that marked the neurons for clean-up. It inhibited key inflammatory proteins like IL-6 with a potency 1,100 times greater than the parent molecule, DHA. DHA has been shown in studies to be neuroprotective in a number of conditions, including stroke and Alzheimer’s disease.

For the study, the team isolated macrophages from blood samples taken from both ALS patients and controls and spinal cord cells from deceased donors.

The study findings on resolvin D1 may offer a new approach to attenuating the inflammation in ALS. Currently, there is no effective way of administering resolvins to patients, so clinical research with resolvin D1 is still several years away. The parent molecule, DHA, is available in stores, although it has not been tested in clinical trials for ALS. Studies with DHA are in progress for Alzheimer’s disease, stroke and brain injury and have been mostly positive.

Source: Science Daily

June 5, 2012

The brain receives information from the ear in a surprisingly orderly fashion, according to a University at Buffalo study scheduled to appear June 6 in the Journal of Neuroscience.

Light microscope image of a bushy neuron in the cochlear nucleus, with a glass microelectrode for recording electrical activity inside the cell. The cell is about 12 micrometers in diameter. New research, published in the Journal of Neuroscience, shows that the synapses onto these cells are sorted according to their plasticity. Credit: Dr. L. Pliss

The research focuses on a section of the brain called the cochlear nucleus, the first way-station in the brain for information coming from the ear. In particular, the study examined tiny biological structures called synapses that transmit signals from the auditory nerve to the cochlear nucleus.

The major finding: The synapses in question are not grouped randomly. Instead, like orchestra musicians sitting in their own sections, the synapses are bundled together by a key trait: plasticity.

Plasticity relates to how quickly a synapse runs down the supply of neurotransmitter it uses to send signals, and plasticity can affect a synapse’s sensitivity to different qualities of sound. Synapses that unleash supplies rapidly may provide good information on when a sound began, while synapses that release neurotransmitter at a more frugal pace may provide better clues on traits like timbre that persist over the duration of a sound.

UB Associate Professor Matthew Xu-Friedman, who led the study, said the findings raise new questions about the physiology of hearing. The research shows that synapses in the cochlear nucleus are arranged by plasticity, but doesn’t yet explain why this arrangement is beneficial, he said.

"It’s clearly important, because the synapses are sorted based on this. What we don’t know is why," said Xu-Friedman, a member of UB’s Department of Biological Sciences. "If you look inside a file cabinet and find all these pieces of paper together, you know it’s important that they’re together, but you may not know why."

In the study, Xu-Friedman and Research Assistant Professor Hua Yang used brain slices from mice to study about 20 cells in the cochlear nucleus called bushy cells, which receive information from synapses attached to auditory nerve fibers.

The experiments revealed that each bushy cell was linked to a network of synapses with similar plasticity. This means that bushy cells themselves may become specialized, developing unique sensitivities to particular characteristics of a sound, Xu-Friedman said.

The study hints that the cochlear nucleus may not be the only part of the brain where synapses are organized by plasticity. The researchers observed the phenomenon in the excitatory synapses of the cerebellum as well.

"One reason this may not have been noticed before is that measuring the plasticity of two different synapses onto one cell is technically quite difficult," Xu-Friedman said.

Provided by University at Buffalo

Source: medicalxpress.com

June 5, 2012

(Medical Xpress) — Using transcranial magnetic stimulation (TMS), an international team led by French researchers from the Centre de Recherche de l’Institut du Cerveau (CNRS) has succeeded in enhancing the visual abilities of a group of healthy subjects. Following stimulation of an area of the brain’s right hemisphere involved in perceptual awareness and in orienting spatial attention, the subjects appeared more likely to perceive a target appearing on a screen. This work, published in the journal PLoS ONE, could lead to the development of novel rehabilitation techniques for certain visual disorders. In addition, it could help improve the performance of individuals whose tasks require very high precision.

TMS is a non-invasive technique that consists in sending a magnetic pulse into a given area of the brain. This results in an activation of the cortical neurons located within the range of the magnetic field, which modifies their activity in a painless and temporary manner. For several years, scientists have been looking at the possibility of using this technique to enhance certain brain functions in healthy subjects.

In this respect, the team led by Antoni Valero-Cabré has carried out research involving the stimulation of a region of the right cerebral hemisphere known as the frontal eye field. Strictly speaking, this is not a primary visual area but it participates in the planning of ocular movements and the orientation of each individual’s attention in the visual space. In a first experiment, a group of healthy subjects tried to distinguish a very low contrast target appearing on a screen for just 30 ms. In some of the tests, the subjects received a magnetic pulse lasting between 80 and 140 ms on this frontal region before the target appeared. The researchers found that the success rate was higher when using TMS. The visual sensitivity of healthy subjects was temporarily increased by around 12%. In a second experiment, the subjects were shown a fleeting visual cue indicating the spot where the target could appear. In this configuration, the enhancement of visual sensitivity, which remained of the same order, was only apparent when the cue indicated the correct location of the target.

Although cerebral functions such as conscious vision are highly optimized in healthy adults, these results show that there is a significant margin for improvement, which can be “enhanced” by TMS. This technique could be tested for the rehabilitation of patients suffering from cortical damage, due for example to a cardiovascular accident, and for that of patients with retinal disorders. The second experiment suggests that rehabilitation based on both TMS and visual cues could be more selective than the use of stimulation alone. The researchers want to further explore this possibility using repetitive TMS, which, in this case, could make it possible to obtain long-lasting modification of cerebral activity.

Furthermore, according to the researchers, TMS could be used in the near future to increase the attentional abilities of individuals performing tasks that require good visual skills.

Provided by CNRS

Source: medicalxpress.com