June 29th, 2012

Researchers shed light on molecular cause of childhood’s worst conditions as first step toward developing more effective treatments.

A research team led by Seattle Children’s Research Institute has discovered new gene mutations associated with markedly enlarged brain size, or megalencephaly.  Mutations in three genes, AKT3, PIK3R2 and PIK3CA, were also found to be associated with a constellation of disorders including cancer, hydrocephalus, epilepsy, autism, vascular anomalies and skin growth disorders.  The study, “De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes,” was published online June 24 in Nature Genetics.

The discovery offers several important lessons and hope for the future in medicine.  First, the research team discovered additional proof that the genetic make-up of a person is not completely determined at the moment of conception.  Researchers previously recognized that genetic changes may occur after conception, but this was believed to be quite rare.  Second, discovery of the genetic causes of these human diseases, including developmental disorders, may also lead directly to new possibilities for treatment.

Researchers discovered new gene mutations associated with markedly enlarged brain size, or megalencephaly. Mutations in three genes, AKT3, PIK3R2 and PIK3CA, were also found to be associated with a constellation of disorders including cancer, hydrocephalus, epilepsy, autism, vascular anomalies and skin growth disorders. Image adapted from an image by Dr. Laughlin Dawes of an 18 month old with demyelinating disorder.

AKT3, PIK3R2 and PIK3CA are present in all humans, but mutations in the genes are what lead to conditions including megalencephaly, cancer and other disorders.  PIK3CA is a known cancer-related gene, and appears able to make cancer more aggressive.  Scientists at Boston Children’s Hospital recently published similar findings related to PIK3CA and a rare condition known as CLOVES syndrome in the American Journal of Human Genetics.

Physician researcher James Olson, MD, PhD, a pediatric cancer expert at Seattle Children’s and Fred Hutchinson Cancer Research Center who was not affiliated with the study, acknowledged the two decades-worth of work that led to the findings.  “This study represents ideal integration of clinical medicine and cutting-edge genomics,” he said.  “I hope and believe that the research will establish a foundation for successfully using drugs that were originally developed to treat cancer in a way that helps normalize intellectual and physical development of affected children.  The team ‘knocked it out of the park’ by deep sequencing exceptionally rare familial cases and unrelated cases to identify the culprit pathway.”  The genes— AKT3, PIK3R2 and PIK3CA—all encode core components of the phosphatidylinositol-3-kinase (P13K)/AKT pathway, the “culprit pathway” referenced by Olson.

The research provides a first, critical step in solving the mystery behind chronic childhood conditions and diseases.  At the bedside, children with these conditions could see new treatments in the next decade.  “This is a huge finding that provides not only new insight for certain brain malformations, but also, and more importantly, provides clues for what to look for in less severe cases and in conditions that affect many children,” said William Dobyns, MD, a geneticist at Seattle Children’s Research Institute.  “Kids with cancer, for example, do not have a brain malformation, but they may have subtle growth features that haven’t yet been identified.  Physicians and researchers can now take an additional look at these genes in the search for underlying causes and answers.”

Researchers at Seattle Children’s Research Institute will now delve more deeply into the findings, with an aim to uncover even more about the potential medical implications for children.  “Based on what we’ve found, we believe that we can eventually reduce the burden of and need for surgery for kids with hydrocephalus and change the way we treat other conditions, including cancer, autism and epilepsy,” said  Jean-Baptiste Rivière, PhD, at Seattle Children’s Research Institute.  “This research truly helps advance the concept of personalized medicine.”

Drs. Dobyns, Rivière and team made this discovery through exome sequencing, a strategy used to selectively sequence the coding regions of the genome as an inexpensive but effective alternative to whole genome sequencing.  An exome is the most functionally relevant part of a genome, and is most likely to contribute to the phenotype, or observed traits and characteristics, of an organism.

Source: Neuroscience News

ScienceDaily (June 29, 2012) — Cognitive skills such as learning and memory diminish with age in everyone, and the drop-off is steepest in Alzheimer’s disease. Texas scientists seeking a way to prevent this decline reported exciting results this week with a drug that has Polynesian roots.

Easter Island statues. (Credit: © Celsius / Fotolia)

The researchers, appointed in the School of Medicine at The University of Texas Health Science Center San Antonio, added rapamycin to the diet of healthy mice throughout the rodents’ life span. Rapamycin, a bacterial product first isolated from soil on Easter Island, enhanced learning and memory in young mice and improved these faculties in old mice, the study showed.

"We made the young ones learn, and remember what they learned, better than what is normal," said Veronica Galvan, Ph.D., assistant professor of physiology at the Barshop Institute for Longevity and Aging Studies, part of the UT Health Science Center. "Among the older mice, the ones fed with a diet including rapamycin actually showed an improvement, negating the normal decline that you see in these functions with age."

The drug also lowered anxiety and depressive-like behavior in the mice, Dr. Galvan said. Anxiety and depression are factors that impair human cognitive performance. Lead author Jonathan Halloran conducted scientifically reliable tests to accurately measure these cognitive components in the rodents.

Venturing into the open

Mice are burrowers that prefer tunnels with walls. To observe behavior, Halloran used an elevated maze of tunnels that led to a catwalk. “All of a sudden the mice are in open space,” Halloran said. “It’s pretty far from the floor for their size, sort of like if a person is hiking and suddenly the trail gets steep. It’s pretty far down and not so comfortable.”

Mice with less anxiety were more curious to explore the catwalk. “We observed that the mice fed with a diet containing rapamycin spent significantly more time out in the open arms of the catwalk than the animals fed with a regular diet,” Halloran said.

The second test measured depressive-like behavior in the rodents. Mice do not like to be held by their tails, which is the way they are moved from cage to cage. Inevitably they struggle to find a way out. “So we can measure how much and how often they struggle as a measure of the motivation they have to get out of an uncomfortable situation,” Dr. Galvan said.

Rapamycin acts like an antidepressant

Some mice barely struggle to get free, but if an antidepressant is administered they struggle a lot more. This behavior is very sensitive to the action of antidepressants and is a reliable measure of whether a drug is acting like an antidepressant, Dr. Galvan said.

"We found rapamycin acts like an antidepressant — it increases the time the mice are trying to get out of the situation," she said. "They don’t give up; they struggle more."

The reductions of anxiety and depressive-like behavior in rapamycin-treated mice held true for all ages tested, from 4 months of age (college age in human years) to 12 months old (the equivalent of middle age) to 25 months old (advanced age).

Feel-good chemicals elevated

The researchers measured levels of three “happy, feel-good” neurotransmitters: serotonin, dopamine and norepinephrine. All were significantly augmented in the midbrains of mice treated with rapamycin. “This is super-interesting, something we are going to pursue in the lab,” Dr. Galvan said.

Dr. Galvan and her team published research in 2010 showing that rapamycin rescues learning and memory in mice with Alzheimer’s-like deficits. The elevation of the three neurotransmitters, which are chemical messengers in the brain, may explain how rapamycin accomplished this, Dr. Galvan said.

Rapamycin is an antifungal agent administered to transplant patients to prevent organ rejection. The drug is named for Rapa Nui, the Polynesian title for Easter Island. This island, 2,000 miles from any population centers, is the famed site of nearly 900 mysterious monolithic statues.

Source: Science Daily

ScienceDaily (June 28, 2012) — Johns Hopkins researchers, working with an international consortium, say they have generated stem cells from skin cells from a person with a severe, early-onset form of Huntington’s disease (HD), and turned them into neurons that degenerate just like those affected by the fatal inherited disorder.

By creating “HD in a dish,” the researchers say they have taken a major step forward in efforts to better understand what disables and kills the cells in people with HD, and to test the effects of potential drug therapies on cells that are otherwise locked deep in the brain.

Although the autosomal dominant gene mutation responsible for HD was identified in 1993, there is no cure. No treatments are available even to slow its progression.

The research, published in the journal Cell Stem Cell, is the work of a Huntington’s Disease iPSC Consortium, including scientists from the Johns Hopkins University School of Medicine in Baltimore, Cedars-Sinai Medical Center in Los Angeles and the University of California, Irvine, as well as six other groups. The consortium studied several other HD cell lines and control cell lines in order to make sure results were consistent and reproducible in different labs.

The general midlife onset and progressive brain damage of HD are especially cruel, slowly causing jerky, twitch-like movements, lack of muscle control, psychiatric disorders and dementia, and — eventually — death. In some cases (as in the patient who donated the material for the cells made at Johns Hopkins), the disease can strike earlier, even in childhood.

"Having these cells will allow us to screen for therapeutics in a way we haven’t been able to before in Huntington’s disease," saysChristopher A. Ross, M.D., Ph.D., a professor of psychiatry and behavioral sciences, neurology, pharmacology and neuroscience at the Johns Hopkins University School of Medicine and one of the study’s lead researchers. "For the first time, we will be able to study how drugs work on human HD neurons and hopefully take those findings directly to the clinic."

Ross and his team, as well as other collaborators at Johns Hopkins and Emory University, are already testing small molecules for the ability to block HD iPSC degeneration.These small molecules have the potential to be developed into novel drugs for HD.

The ability to generate from stem cells the same neurons found in Huntington’s disease may also have implications for similar research in other neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

To conduct their experiment, Ross took a skin biopsy from a patient with very early onset HD.When seen by Ross at the HD Center at Hopkins, the patient was just seven years old. She had a very severe form of the disease, which rarely appears in childhood, and of the mutation that causes it. Using cells from a patient with a more rapidly progressing form of the disease gave Ross’ team the best tools with which to replicate HD in a way that is applicable to patients with all forms of HD.

Her skin cells were grown in culture and then reprogrammed by the lab of Hongjun Song, Ph.D., a professor at Johns Hopkins’ Institute for Cell Engineering, into induced pluripotent stem cells. A second cell line was generated in an identical fashion in Dr. Ross’s lab from someone without HD. Simultaneously, other HD and control iPS cell lines were generated as part of the NINDS funded HD iPS cell consortium.

Scientists at Johns Hopkins and other consortium labs converted those cells into generic neurons and then into medium spiny neurons, a process that took three months. What they found was that the medium spiny neurons deriving from HD cells behaved just as they expected medium spiny neurons from an HD patient would. They showed rapid degeneration when cultured in the lab using basic culture medium without extensive supporting nutrients. By contrast, control cell lines did not show neuronal degeneration.

"These HD cells acted just as we were hoping," says Ross, director of the Baltimore Huntington’s Disease Center. "A lot of people said, ‘You’ll never be able to get a model in a dish of a human neurodegenerative disease like this.’ Now, we have them where we can really study and manipulate them, and try to cure them of this horrible disease. The fact that we are able to do this at all still amazes us."

Specifically, the damage caused by HD is due to a mutation in the huntingtin gene (HTT), which leads to the production of an abnormal and toxic version of the huntingtin protein. Although all of the cells in a person with HD contain the mutation, HD mainly targets the medium spiny neurons in the striatum, part of the brain’s basal ganglia that coordinates movement, thought and emotion. The ability to work directly with human medium spiny neurons is the best way, researchers believe, to determine why these specific cells are susceptible to cell stress and degeneration and, in turn, to help find a way to halt progression of HD.

Much HD research is conducted in mice. And while mouse models have been helpful in understanding some aspects of the disease, researchers say nothing compares with being able to study actual human neurons affected by HD.

For years, scientists have been excited about the prospect of making breakthroughs in curing disease through the use of stem cells, which have the remarkable potential to develop into many different cell types. In the form of embryonic stem cells, they do so naturally during gestation and early life. In recent years, researchers have been able to produce induced pluripotent stem cells (iPSCs), which are adult cells (like the skin cells used in Ross’s experiments) that have been genetically reprogrammed back to the most primitive state. In this state, under the right circumstances, they can then develop into most or all of the 200 cell types in the human body.

Source: Science Daily

ScienceDaily (June 28, 2012) — We’ve all heard that eating fish is good for our brains and memory. But what is it about DHA, an omega-3 fatty acid found in fish, that makes our memory sharper?

Researchers with the Faculty of Medicine & Dentistry discovered a possible explanation and just published their findings in the peer-reviewed journal Applied Physiology, Nutrition, and Metabolism.

Principal investigator Yves Sauve and his team discovered lab models fed a high-DHA diet had 30 per cent higher levels of DHA in the memory section of the brain, known as the hippocampus, when compared to animal models on a regular, healthy diet.

"We wanted to find out how fish intake improves memory," says Sauve, a medical researcher at the University of Alberta who works in the department of physiology, the department of ophthalmology and the Centre for Neuroscience.

"What we discovered is that memory cells in the hippocampus could communicate better with each other and better relay messages when DHA levels in that region of the brain were higher. This could explain why memory improves on a high-DHA diet."

Sauve noted it is a key finding that when a diet is supplemented with DHA, that additional stores of the omega-3 fatty acid are deposited in the brain. His team confirmed this finding, a discovery other labs have noted as well.

Supplementing your diet with DHA, such as increasing fish intake or taking supplements, could prevent declining DHA levels in the brain as we age, says Sauve.

This research was funded by Alberta Innovates — Health Solutions.

Earlier this year, Sauve and other colleagues discovered DHA prevents the accumulation of a toxic molecule at the back of the eye that causes age-related vision loss. He is continuing his research in this area.

Source: Science Daily

June 28, 2012

Researchers have come up with a device that may enable people who are completely unable to speak or move at all to nevertheless manage unscripted back-and-forth conversation. The key to such silent and still communication is the first real-time, brain-scanning speller, according to the report published online on June 28 in Current Biology.

Researchers have come up with a device that may enable people who are completely unable to speak or move at all to nevertheless manage unscripted back-and-forth conversation. The key to such silent and still communication is the first real-time, brain-scanning speller, according to the report published online on June 28 in Current Biology.

The new technology builds on groundbreaking earlier uses of fMRI brain scans to assess consciousness in people described as being in an unconscious, vegetative state and to enable them to answer yes and no questions. fMRI (or functional magnetic resonance imaging) is typically used for clinical and research purposes to track brain activity by measuring blood flow.

"The work of Adrian Owen and colleagues led me to wonder whether it might even become possible to use fMRI, mental tasks, and appropriate experimental designs to freely encode thoughts, letter-by-letter, and therewith enable back-and-forth communication in the absence of motor behavior,” said Bettina Sorger of Maastricht University in The Netherlands.

[Video]
This video shows mental task-related brain activation patterns. Video (c) Current Biology

The new evidence shows that the answer to that thought question is yes. Sorger’s team came up with a letter-encoding technique that requires almost no pre-training. Participants in their study voluntarily selected letters on a screen, which guided the letter encoding; for each specific character, participants were asked to perform a particular mental task for a set period of time. That produced 27 distinct brain patterns corresponding to each letter of the alphabet and the equivalent of a space bar, which could be automatically decoded in real-time using newly developed data analysis methods.

In each communication experiment, participants held a mini-conversation consisting of two open questions and answers. Everyone the researchers tested was able to successfully produce answers within a single one-hour session.

The results substantially extend earlier uses of fMRI, which allowed individuals to answer the equivalent of multiple-choice questions having four or fewer possible answers, by enabling free-letter spelling. That could make all the difference for people who are completely paralyzed and unable to benefit from other means of alternative communication, Sorger says.

Ultimately, she says their goal is to transfer the fMRI technology they’ve developed to a more portable and affordable method for measuring blood flow, such as functional near-infrared spectroscopy (fNIRS).

Source: medicalxpress.com

ScienceDaily (June 28, 2012) — Mayo Clinic researchers have successfully used smaller, folded DNA molecules to stimulate regeneration and repair of nerve coatings in mice that mimic multiple sclerosis (MS). They say the finding, published June 28 in the journal PLoS ONE, suggests new possible therapies for MS patients.

Laboratory mouse. (Credit: iStockphoto)

"The problem has been to find a way to encourage the nervous system to regenerate its own myelin (the coating on the nerves) so nerve cells can recover from an MS attack," says L. James Maher III, Ph.D., Mayo Clinic biochemist and senior author on the paper. "We show here that these small molecules, called aptamers, can stimulate repair in the mice we are studying."

More than 200,000 people have multiple sclerosis. There is no cure and no effective therapy to stop progression or repair damage to the myelin sheath that surrounds and protects the nerves. Without that protection, nerve fibers will be damaged, leading to declining mobility and cognitive function, and other debilitating complications.

MS researchers, including Mayo neurologist Moses Rodriguez, M.D., a co-author on this paper, have focused on monoclonal antibodies in mice to stimulate myelin repair. The Rodriguez and Maher teams, working together, have determined that the aptamers are not only effective, but they are easy and cheap to synthesize — an important point for drug developers. They also are stable and not likely to cause an immune response. This new approach must be validated in other mouse models to see if it might be a candidate for human clinical trials.

The monoclonal antibodies used in earlier research are large and complex, but were shown to promote both cell signaling and remyelination of central nervous system lesions in mice. The aptamers used in this study are less than one-tenth the size of antibodies and are single-strands of DNA containing only 40 nucleotide units.

Source: Science Daily

June 28, 2012

In a genome-wide association (GWA) study, researchers from Boston University Schools of Medicine (BUSM) and Public Health (BUSPH) have identified several genes which influence degeneration of the hippocampus, the part of the brain most associated with Alzheimer disease (AD). The study, which currently appears online as a Rapid Communication in the Annals of Neurology, demonstrates the efficacy of endophenotypes for broadening the understanding of the genetic basis of and pathways leading to AD.

AD is a progressive neurodegenerative disorder for which there are no prevention methods. Available drugs only marginally affect disease severity and progression, making AD effectively untreatable.

GWA studies using very large samples have increased the number of robust associations to 10 genes, including APOE. However, these genes account for no more than 35 percent of the inherited risk of AD and most of the genetic underpinning of the disorder remains unexplained. According to the researchers, magnetic resonance imaging (MRI) of the brain provides in vivo quantitative measures of neurodegenerative and cerebrovascular brain injury that may represent AD-related changes long before clinical symptoms appear. These measures are more powerful than comparisons of individuals with AD with cognitively healthy persons because they avoid misclassification of normal persons who will develop disease in the future.

BUSM researchers conducted a two-stage GWA study for quantitative measures of hippocampal volume (HV), total cerebral volume (TCV) and white matter hyperintensities (WMH). Brain MRI measures of HV, TCV and WMH were obtained from 981 Caucasian and 419 African-American AD cases and their cognitively normal siblings in the MIRAGE (Multi Institutional Research in Alzheimer’s Genetic Epidemiology) Study. In addition, similar MRI measures were obtained from 168 AD cases, 336 individuals with mild cognitive impairment and 188 controls (all Caucasian) in the AD Neuroimaging Initiative (ADNI) Study. The MIRAGE Caucasian families and ADNI subjects were included in the first stage and the MIRAGE African American families were added in stage two. Results from the two Caucasians data sets were combined by meta-analysis.

In stage two, one genetic marker (i.e. single nucleotide polymorphism or SNP) from each of the gene regions that were most significantly associated with AD in the Caucasian data sets was evaluated in the African-American data set.

Novel genome-wide significant associations were observed for HV with SNPs in the APOE, F5/SELP, LHFP, and GCFC2 gene regions. All of these associations were supported by evidence in each data set.

"Our two-stage GWAS identified highly significant associations between a measure of degeneration in the brain region most strongly correlated with AD and several genes in both Caucasian and African American samples containing AD, cognitively impaired and cognitively healthy subjects. One of these associations was with the ε4 variant of APOE which is the most well-established genetic risk factor for AD.

Other associations were demonstrated with markers in F5/SELP, LHFP, and GCFC2, genes not previously implicated in this disease” explained senior author Lindsay Farrer, PhD, chief of biomedical genetics at BUSM. He also noted, “previous studies showed that blood level of P-selectin (the protein encoded by SELP) has been correlated with rate of cognitive decline in AD patients.”

Farrer believes it is very likely that the number and specificity of these associations will increase in future studies using larger samples and focused on additional precise structural and functional MRI measures. “These findings will inform experiments designed to increase our understanding of disease-causing mechanism and may lead to new therapeutics targets,” added Farrer.

Provided by Boston University Medical Center

Source: medicalxpress.com