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.

Georgia Institute of Technology.

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 pathology. Nature Communications, 2012; 3: 1084 DOI: 10.1038/ncomms2032

Columbia University Medical Center.

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.

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

Low Dopamine in Frontal Cortex Blamed For Impulsivity

 Raising levels of the neurotransmitter dopamine in the frontal cortex of the brain significantly decreased impulsivity in healthy adults, in a study conducted by researchers at the Ernest Gallo Clinic and Research Center at the University of California, San Francisco.

"Impulsivity is a risk factor for addiction to many substances, and it has been suggested that people with lower dopamine levels in the frontal cortex tend to be more impulsive," said lead author Andrew Kayser, PhD, an investigator at Gallo and an assistant professor of neurology at UCSF. "We wanted to see if we could decrease impulsivity by raising dopamine, and it seems as if we can."

The study was published on July 4 in the Journal of Neuroscience.

In a double-blinded, placebo-controlled study, 23 adult research participants were given either tolcapone, a medication approved by the Food and Drug Administration (FDA) that inhibits a dopamine-degrading enzyme, or a placebo. The researchers then gave the participants a task that measured impulsivity, asking them to make a hypothetical choice between receiving a smaller amount of money immediately ("smaller sooner") or a larger amount at a later time ("larger later"). Each participant was tested twice, once with tolcapone and once with placebo.

Participants -- especially those who were more impulsive at baseline -- were more likely to choose the less impulsive "larger later" option after taking tolcapone than they were after taking the placebo. Magnetic resonance imaging conducted while the participants were taking the test confirmed that regions of the frontal cortex associated with decision-making were more active in the presence of tolcapone than in the presence of placebo.

"To our knowledge, this is the first study to use tolcapone to look for an effect on impulsivity," said Kayser. The study was not designed to investigate the reasons that reduced dopamine is linked with impulsivity. However, explained Kayser, scientists believe that impulsivity is associated with an imbalance in dopamine between the frontal cortex, which governs executive functions such as cognitive control and self-regulation, and the striatum, which is thought to be involved in the planning and modification of more habitual behaviors.

"Most, if not all, drugs of abuse, such as cocaine and amphetamine, directly or indirectly involve the dopamine system," said Kayser. "They tend to increase dopamine in the striatum, which in turn may reward impulsive behavior. In a very simplistic fashion, the striatum is saying 'go,' and the frontal cortex is saying 'stop.' If you take cocaine, you're increasing the 'go' signal, and the 'stop' signal is not adequate to counteract it."

Kayser and his research team plan a follow-up study of the effects of tolcapone on drinking behavior. "Once we determine whether drinkers can safely tolerate this medication, we will see if it has any effect on how much they drink while they're taking it," said Kayser.

Tolcapone is approved as a medication for Parkinson's disease, in which a chronic deficit of dopamine inhibits movement.

Co-authors of the paper are Daicia C. Allen, BS, Ana Navarro-Cebrian, PhD, Jennifer M. Mitchell, PhD and senior author Howard L. Fields, MD, PhD, of the Gallo Center and UCSF.

The study was supported by funds from the Wheeler Center for the Neurobiology of Addiction, the U.S. Army Telemedicine and Advanced Technology Research Center, the Alcoholic Beverage Medical Research Foundation/The Foundation for Alcohol Research and the State of California.

University of California - San Francisco

Journal Reference:

1. Andrew S. Kayser, Daicia C. Allen, Ana Navarro-Cebrian, Jennifer M. Mitchell, and Howard L. Fields. Dopamine, Corticostriatal Connectivity, and Intertemporal Choice.The Journal of Neuroscience, 4 July 2012, 32(27):9402-9409 DOI: 10.1523/JNEUROSCI.1180-12.2012

Actual Risk of Using Ecstasy

There has been significant debate in policy circles about whether governments have over-reacted to ecstasy by issuing warnings against its use and making it illegal. In the UK, David Nutt said ecstasy was less dangerous than horseback riding, which led to him being fired as the government's chief drug advisor. Others have argued that ecstasy is dangerous if you use it a lot, but brief use is safe.

New research published online July 25 by the scientific journal Addiction, gives some of the first information available on the actual risk of using ecstasy. It shows that even in recreational amounts over a relatively short time period, ecstasy users risk specific memory impairments. Further, as the nature of the impairments may not be immediately obvious to the user, it is possible people wouldn't get the signs that they are being damaged by drug use until it is too late.

New ecstasy users who took ten or more ecstasy pills over their first year of use showed decreased function of their immediate and short-term memory compared with their pre-ecstasy performance. These findings are associated with damage of the hippocampus, the area of the brain that oversees memory function and navigation. Interestingly, hippocampal damage is one of the first signs of Alzheimer's disease, resulting in memory loss and disorientation. (Credit: © James Steidl / Fotolia)

According to the study, new ecstasy users who took ten or more ecstasy pills over their first year of use showed decreased function of their immediate and short-term memory compared with their pre-ecstasy performance. These findings are associated with damage of the hippocampus, the area of the brain that oversees memory function and navigation. Interestingly, hippocampal damage is one of the first signs of Alzheimer's disease, resulting in memory loss and disorientation.

The study participants took an average of 32 pills each over the course of the year, or about two and a half pills per month. Some participants took as few as ten pills over the year and still showed signs of memory impairments.

Lead author Dr. Daniel Wagner says: "This study was designed to minimize the methodological limitations of earlier research, in which it was not possible to say whether cognitive impairments seen among ecstasy users were in place before drug use began. By measuring the cognitive function of people with no history of ecstasy use and, one year later, identifying those who had used ecstasy at least ten times and remeasuring their performance, we have been able to start isolating the precise cognitive effects of this drug."

Uncovering Neurodegenerative Diseases From Cellular Processes

Scientists at the University of Manchester have uncovered how the internal mechanisms in nerve cells wire the brain. The findings open up new avenues in the investigation of neurodegenerative diseases by analysing the cellular processes underlying these conditions.

Dr Andreas Prokop and his team at the Faculty of Life Sciences have been studying the growth of axons, the thin cable-like extensions of nerve cells that wire the brain. If axons don't develop properly this can lead to birth disorders, mental and physical impairments and the gradual decay of brain capacity during aging.

Axon growth is directed by the hand shaped growth cone which sits in the tip of the axon. It is well documented how growth cones perceive signals from the outside to follow pathways to specific targets, but very little is known about the internal machinery that dictates their behaviour.

Dr Prokop has been studying the key driver of growth cone movements, the cytoskeleton. The cytoskeleton helps to maintain a cell's shape and is made up of the protein filaments, actin and microtubules. Microtubules are the key driving force of axon growth whilst actin helps to regulate the direction the axon grows. Dr Prokop and his team used fruit flies to analyse how actin and microtubule proteins combine in the cytoskeleton to coordinate axon growth. They focussed on the multifunctional proteins called spectraplakins which are essential for axonal growth and have known roles in neurodegeneration and wound healing of the skin.

What the team demonstrate in this recent paper is that spectraplakins link microtubules to actin to help them extend in the direction the axon is growing. If this link is missing then microtubule networks show disorganised criss-crossed arrangements instead of parallel bundles and axon growth is hampered. By understanding the molecular detail of these interactions the team made a second important finding. Spectraplakins collect not only at the tip of microtubules but also along the shaft, which helps to stabilise them and ensure they act as a stable structure within the axon. This additional function of spectraplakins relates them to a class of microtubule-binding proteins including Tau. Tau is an important player in neurodegenerative diseases, such as Alzheimer's, which is still little understood. In support of the author's findings, another publication has just shown that the human spectraplakin, Dystonin, causes neurodegeneration when affected in its linkage to microtubules.

Talking about his research Dr Prokop said: "Understanding cytoskeletal machinery at the cell level is a holy grail of current cell research that will have powerful clinical applications. Thus, cytoskeleton is crucially involved in virtually all aspects of a cell's life, including cell shape changes, cell division, cell movement, contacts and signalling between cells, and dynamic transport events within cells. Accordingly, the cytoskeleton lies at the root of many brain disorders. Therefore, deciphering the principles of cytoskeletal machinery during the fundamental process of axon growth will essentially help research into the causes of a broad spectrum of diseases. Spectraplakins like at the heart of this machinery and our research opens up new avenues for its investigation".

What Dr Prokop's paper in the Journal of Neuroscience also demonstrates is the successful research technique using the fruit fly Drosophila. The team was able to replicate its findings regarding axon growth in mice which in turn means the findings can be translated to humans. Dr Prokop points out fruit flies provide ideal means to make sense of these findings and essentially help to unravel the many mysteries of neurodegeneration.

Dr Prokop continues: "Understanding how spectraplakins perform their cellular functions has important implications for basic as well as biomedical research. Thus, besides their roles during axon growth, spectraplakins of mice and humans are clinically important for a number of conditions and processes including skin blistering, neuro-degeneration, wound healing, synapse formation and neuron migration during brain development. Understanding spectraplakins in one biological process will instruct research on the other clinically relevant roles of these proteins."

The recently published paper represents six years of work by Dr Prokop and his dedicated team.

University of Manchester 

Journal Reference:

1. Juliana Alves-Silva, Natalia Sánchez-Soriano, Robin Beaven, Melanie Klein, Jill Parkin, Thomas H. Millard, Hugo J. Bellen, Koen J. T. Venken, Christoph Ballestrem, Richard A. Kammerer, and Andreas Prokop. Spectraplakins Promote Microtubule-Mediated Axonal Growth by Functioning As Structural Microtubule-Associated Proteins and EB1-Dependent TIPs (Tip Interacting Proteins). Journal of Neuroscience, July 4, 2012 DOI: 10.1523/%u200BJNEUROSCI.0416-12.2012

Gene Mutations Responsible For Childhood Brain Tumors

Researchers at the Stanford University School of Medicine and Lucile Packard Children's Hospital have identified several gene mutations responsible for the most common childhood brain tumor, called medulloblastoma, adding evidence to the theory that the diagnosis is a group of genetically distinct cancers with different prognoses. These and accompanying findings are likely to lead to less-toxic, better-targeted treatment approaches over the next two years, the researchers said.

"We tend to treat all medulloblastomas as one disease without taking into account how heterogeneous the tumors are at the molecular level," said Yoon-Jae Cho, MD, an assistant professor of neurology and neurological sciences at Stanford, a pediatric neurologist at Packard Children's and the senior author of the new research. "This paper represents a finer-grained view of the genetic landscape of these tumors and provides us with some leads on how to develop new therapies."

The research, which appeared online in Nature July 22, is part of a large, ongoing effort to characterize genetic errors in medulloblastoma. Two companion studies on which Cho is a co-author will be published simultaneously with his paper. The three papers came from a consortium that involves scientists at Stanford, Packard Children's, the Broad Institute, Children's Hospital Boston, the Dana-Farber Cancer Institute, the German Cancer Research Center, Brandeis University and the Hospital for Sick Children in Toronto.

Current treatment for medulloblastoma, which originates in the cerebellum and affects about 250 U.S. children each year, begins with surgery to remove as much of the tumor as possible. Patients then receive a combination of radiation and chemotherapy, but the treatments are not tailored to the tumor's genetic characteristics.

Cho's team extracted DNA from 92 medulloblastoma tumors and compared it with DNA from matched blood samples from the same patients, uncovering 12 significant "point mutations" -- single-letter errors in the genetic code -- that occurred frequently in the brain cancer. A handful of the mutations had been previously identified in smaller studies of medulloblastoma, but several mutations were novel in both medulloblastoma and in cancer.

Among the newly identified mutations was one in an RNA helicase gene, DDX3X, which Cho said is the second-most common mutation in medulloblastoma tumors. "Mutations in this gene have now also been identified in other tumor types, such as chronic lymphocytic leukemia, and head and neck tumors," he said.

However, the researchers found that it was rare for the same gene mutated in several different patients' tumors. More commonly, mutations involving a set of genes regulating a single biological pathway were found in the tumors -- a pattern that is emerging across cancer genome sequencing efforts.

Though no single tumor in the study carried all 12 mutations, the researchers were able to categorize the tumors according to which mutations they possessed. "We now understand that there are certain tumors with particular genetic signatures that are really resistant to standard treatments," Cho said. Children with medulloblastoma do not routinely have their tumors' genetic signatures characterized, but Cho believes that such characterization coupled with targeted therapies could greatly enhance tumor treatment.

About two-thirds of medulloblastoma patients now survive five years past diagnosis, but many survivors suffer lasting physical or intellectual side effects from their cancer treatments. Drugs tailored to a tumor's genetic profile have the potential to save more patients while reducing side effects, Cho said.

Several of the mutations discovered affect cellular signals that switch large groups of genes on and off. "The dysregulation of these 'epigenetic programs' is becoming a common theme not only in medulloblastoma but across cancer," Cho said. Such pathways may be good targets for cancer drugs; indeed, drugs targeting one such pathway (histone methyltransferases) are currently in pre-clinical development, while agents against another pathway (Hedgehog signaling pathway) are entering phase-2 clinical trials for medulloblastoma.

Cho is the co-chair of a committee within the Pediatric Brain Tumor Consortium that guides which drugs should be moved into clinical trials next. "Our plan is that within the next one to two years we will be able to offer kids a new set of compounds that have a clear biological rationale based on our genomic studies." Cho said. "We want to make sure we're being careful of what we move forward with, but at the same time, for some of these kids we don't have many, if any, effective and durable treatment options."

Cho's collaborators at Stanford included research associate Furong Yu; Gerald Crabtree, PhD, professor of pathology and of developmental biology and a member of the Stanford Cancer Institute; and life science research assistant Amanda Kautzman.

The research was funded by the National Institutes of Health, a St. Baldrick's Foundation Career Development Award, the Beirne Faculty Scholar endowment at Stanford University, German Cancer Aid, the BMBF ICGC-PedBrain project, the Howard Hughes Medical Institute, the Pediatric Brain Tumor Foundation, the Canadian Institutes of Health Research, the Hospital for Sick Children and the Mullarkey Research Fund. Cho consults for Novartis to help develop biomarkers for the company's clinical trial design.

Stanford University Medical Center

Journal Reference:

1. Trevor J. Pugh, Shyamal Dilhan Weeraratne, Tenley C. Archer, Daniel A. Pomeranz Krummel, Daniel Auclair, James Bochicchio, Mauricio O. Carneiro, Scott L. Carter, Kristian Cibulskis, Rachel L. Erlich, Heidi Greulich, Michael S. Lawrence, Niall J. Lennon, Aaron McKenna, James Meldrim, Alex H. Ramos, Michael G. Ross, Carsten Russ, Erica Shefler, Andrey Sivachenko, Brian Sogoloff, Petar Stojanov, Pablo Tamayo, Jill P. Mesirov, Vladimir Amani, Natalia Teider, Soma Sengupta, Jessica Pierre Francois, Paul A. Northcott, Michael D. Taylor, Furong Yu, Gerald R. Crabtree, Amanda G. Kautzman, Stacey B. Gabriel, Gad Getz, Natalie Jäger, David T. W. Jones, Peter Lichter, Stefan M. Pfister, Thomas M. Roberts, Matthew Meyerson, Scott L. Pomeroy, Yoon-Jae Cho. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature, 2012; DOI: 10.1038/nature11329