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Published: 18 May 2011

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Researchers including members from the Niels Bohr Institute at the University of Copenhagen have developed a new method for making detailed X-ray images of brain cells. The method, called SAXS-CT, can map the myelin sheaths of nerve cells, which are important for conditions such as multiple sclerosis and Alzheimer's disease. The results have been published in the scientific journal, NeuroImage.

The myelin sheaths of nerve cells are lamellar membranes surrounding the neuronal axons. The myelin layers are important to the central nervous system as they ensure the rapid and uninterrupted communication of signals along the neuronal axons. Changes in the myelin layers are associated with a number of neurodegenerative disorders such as cerebral malaria, multiple sclerosis, and Alzheimer's disease.

The development of these diseases are still not fully understood, but are thought to be related to the damage of the myelin layers, so that messages from the brain reach the various parts of the body poorly or not at all. It is like an electric cord where the insulating material has been damaged and the current short circuits. In order to find methods to prevent or treat the diseases it is important to understand the connection between the diseases and the changes in the myelin.

Getting 3-D X-ray images

"We have combined two well-known medical examination methods: SAXS (Small-Angle X-ray Scattering) and CT-scanning (computed tomography scanning). Combined with a specially developed programme for data processing, we have been able to examine the variations of the myelin sheaths in a rat brain all the way down to the molecular level without surgery", explains PhD Torben Haugaard Jensen, Niels Bohr Institute at the University of Copenhagen. The method is called 'Molecular X-ray CT', because you use X-ray CT to study myelin at the molecular level.

The research has been carried out in collaboration with researchers in Switzerland, France and Germany. The experiments took place at the Paul Scherrer Institute in Switzerland, where they have a powerful X-ray source that can measure Small-Angle X-Ray Scattering, SAXS at a high resolution. Normally such experiments would give two-dimensional X-ray images that are sharp and precise, but without information on depth. But by incorporating the method from CT-scanning, where you image from different angles, the researchers have managed to get 3D X-ray images.

This has not only required the development of new X-ray methods and experiments, but has also required the development of new methods for processing data. The extremely detailed measurements of cross sections from different angles meant that there were 800,000 images to be analysed. So the researchers have also developed an image-processing programme for the SAXS-CT method. The result is that they can see all of the detailed information from SAXS in spatially resolved.

From point samples to total samples

"We can see the myelin sheaths of the neuronal axons and we can distinguish the layers which have a thickness of 17.6 nanometers", explains Torben Haugaard Jensen. "Up until now, you had to cut out a little sample in order to examine the layers in one area and get a single measuring point. With the new method we can examine 250,000 points at once without cutting into the sample. We can get a complete overview over the concentration and thickness of the myelin and this gives of the ability to determine whether the destruction of the myelin is occurring in spots or across the entire sample", he explains.

The research provides new opportunities for collaboration with doctors at Copenhagen University Hospital and the Panum Institute, who they already have close contact with. The method cannot be used to diagnose living persons. But the doctors can obtain new knowledge about the diseases, what kind of damage is taking place? - and where? They will be able to follow the development of the diseases and find out how the brain is being attacked. This knowledge could perhaps be used to develop a treatment.

Source:
Gertie Skaarup
University of Copenhagen

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Published: 20 April 2011

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Researchers from the CHUM Research Centre (CRCHUM) have identified a new gene that predisposes people to both autism and epilepsy.

Led by the neurologist Dr. Patrick Cossette, the research team found a severe mutation of the synapsin gene (SYN1) in all members of a large French-Canadian family suffering from epilepsy, including individuals also suffering from autism. This study also includes an analysis of two cohorts of individuals from Quebec, which made it possible to identify other mutations in the SYN1 gene among 1% and 3.5% of those suffering respectively from autism and epilepsy, while several carriers of the SYN1 mutation displayed symptoms of both disorders. 

"The results show for the first time the role of the SYN1 gene in autism, in addition to epilepsy, and strengthen the hypothesis that a deregulation of the function of synapse because of this mutation is the cause of both diseases," notes Cossette, who is also a professor with the Faculty of Medicine at the Université de Montréal. He adds that "until now, no other genetic study of humans has made this demonstration."

The different forms of autism are often genetic in origin and nearly a third of people with autism also suffer from epilepsy. The reason for this comorbidity is unknown. The synapsin gene plays are crucial role in the development of the membrane surrounding neurotransmitters, also referred to as synaptic vesicles. These neurotransmitters ensure communication between neurons. Although mutations in other genes involved in the development of synapses (the functional junction between two neurons) have previously been identified, this mechanism has never been proved in epilepsy in humans until the present study.

The results of the present study were published in the latest online edition of Human Molecular Genetics.They provide the key to a common cause of epilepsy and autism and will make it possible to gain a better understanding of the pathophysiology of these devastating diseases that seriously perturb brain development. They will also contribute to the development of new treatment strategies.

Facts and figures relating to autism and epilepsy in Canada

Invasive development disorders, also called the autism spectrum, include five diagnoses: autism, the most well known; RETT syndrome; childhood disintegrative disorder; Asperger syndrome; and unspecified pervasive developmental disorder. It is estimated that 60 to 70 people (including 10 children) out of every 10,000 people are affected by pervasive development disorders in Canada.

Epilepsy affects around 85 out 10,000 people in Canada. There are several kinds of epileptic seizures and syndromes.

About the study

SYN1 loss-of-function mutations in ASD and partial epilepsy cause impaired synaptic function. Anna Fassio, Lysanne Patry, Sonia Congia, Franco Onofi, Amélie Piton, Julie Gauthier, Davide Pozzi, Mirko Messa, Enrico Defranci, Manuela Fadda, Anna Corradi, Pietro Baldelli, Line Lapointe, Judith St-Onge, Caroline Meloche, Laurent Mottron, Flavia Valtorta, Dang Khoa Nguyen, Guy A. Rouleau, Fabio Benfenati. Human Molecular Genetics.

Source:
Centre hospitalier de l'Université de Montréal

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Published: 13 April 2011

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Researchers have now discovered a potential mechanism that may contribute to the link between epilepsy and fragile X syndrome.

The protein that is missing in fragile X syndrome, FMRP, controls the production of a protein that regulates electrical signals in brain cells, scientists at Emory University School of Medicine have found. The results were published April 13 in the Journal of Neuroscience. 

Individuals with fragile X syndrome tend to have a hyperexcitable nervous system, which can be displayed in several ways: hyperactivity, anxiety, increased sensory sensitivity, and epileptic seizures in 20 percent of all cases. The Emory team's findings suggest that a therapeutic strategy against fragile X syndrome now being tested in clinical trials could also address this aspect of the disease. 

"The link between fragile X syndrome and epilepsy was not well understood," says senior author Gary Bassell, PhD, professor of cell biology and neurology at Emory University School of Medicine. "This finding might provide a molecular explanation that could also give some clues on therapeutic strategies." 

The co-first authors of the paper are postdoctoral fellow Christina Gross and PhD candidate Xiaodi Yao. They and their colleagues found that in mice missing FMRP - a model for humans with fragile X syndrome - brain cells produce less of a protein called Kv4.2. 

FMRP is known to regulate several genes, and it's possible that changes in others besides Kv4.2 contribute to the development of epilepsy. For many of the genes that FMRP controls, it normally acts as a brake, by interfering with the step in which RNA is made into protein. In FMRP's absence, this leads to runaway protein production at synapses the junctions between brain cells where chemical communication occurs. Kv4.2 appears to be an exception, because in FMRP's absence, less Kv4.2 protein is produced. 

The protein Kv4.2 is an ion channel, which allows electrical charge to flow out of neurons when they are stimulated. Kv4.2 is the major ion channel regulating the excitability of neurons in the hippocampus, a region of the brain important for learning and memory. A mutation of the gene encoding Kv4.2 leads to temporal lobe epilepsy in humans. 

In laboratory tests, drugs that tamp down glutamate signaling could partially restore levels of the Kv4.2 protein in mice missing the fragile X protein. This suggests that drugs that act against glutamate signaling, which are now in clinical trials, could reduce hyperexcitability in humans with fragile X syndrome. 

Another strategy could be to identify drugs that target the Kv4.2 protein's function directly, Bassell says. 

Not all individuals with fragile X syndrome develop epilepsy. The loss of FMRP doesn't shut Kv4.2 production off completely, and other genetic variations and environmental factors probably contribute to the development of epilepsy in individuals with fragile X syndrome, Bassell says. 

The research was supported by the National Institutes of Health and the National Fragile X Foundation. 

Reference: 

C. Gross*, X. Yao*, D.L. Pong, A. Jeromin and G.J. Bassell. Fragile X Mental Retardation Protein Regulates Protein Expression and mRNA Translation of the Potassium Channel Kv4.2. J. Neurosci,31, pa. 

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Published: 05 April 2011

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Three review articles in the May 2011 issue of Pediatrics (published online April 4) examine the scientific evidence behind medical, behavioral and developmental interventions for autism spectrum disorders (ASD). The studies, funded by the Agency for Healthcare Research and Quality, examined research published between 2000 and May 2010 on ASD interventions for children ages 12 and younger. Researchers found strong evidence for a few treatments, but also a critical need for additional studies to pinpoint specific approaches that are most effective for individual children. 

In "A Systematic Review of Medical Treatments for Children with Autism Spectrum Disorders ," researchers found strikingly little evidence of benefit for most medications used to treat ASDs. Medications that address challenging behavior had the strongest evidence to support their use. The antipsychotic medications risperidone and aripiprazole each have at least two randomized controlled trials that found improvements in challenging behavior, hyperactivity and repetitive behavior. However, both medications also cause significant side effects, including weight gain and sedation, which limit their use to patients with severe impairment. Insufficient evidence is available to judge the potential benefits and adverse effects of all other medications used to treat autism, including serotonin-reuptake inhibitors and stimulant medications. 

In a companion article, "A Systematic Review of Secretin for Children With Autism Spectrum Disorders," researchers examined evidence for treating children with autism with secretin, a gastrointestinal polypeptide used to treat peptic ulcers. Study authors found strong evidence that secretin is not effective for children with ASDs, and that further studies are not warranted. 

The study, "A Systematic Review of Early Intensive Intervention for Autism Spectrum Disorders," examined 34 studies of early intensive behavioral and developmental interventions for young children with ASDs. Gains were seen in studies of intensive interventions emphasizing both specific behavioral (e.g., UCLA/Lovaas approach) and developmental principles (e.g., the Early Start Denver Model). Such interventions resulted in improved cognitive performance, language skills and adaptive behavior skills in some young children with ASDs. However, few research studies were rated of good quality and the existing evidence did not provide strong evidence in favor of any single early intervention approach. Study authors conclude these early intensive intervention approaches have significant potential but need further research to determine which interventions are most likely to benefit specific children. 

Source: 
American Academy of Pediatrics