Science Daily — Researchers at the Picower Institute for Learning and Memory at MIT have, for the first time, reversed symptoms of mental retardation and autism in mice.
In Fragile X, there is a mutation in a gene called FMR1 on the X chromosome. (Credit: Image courtesy of NIH/National Human Genome Research Institute)
The work will be reported in the online early edition of the Proceedings of the National Academy of Sciences the week of June 25-29.
The mice were genetically manipulated to model Fragile X Syndrome (FXS), the leading inherited cause of mental retardation and the most common genetic cause of autism. The condition, tied to a mutated X chromosome gene called fragile X mental retardation 1 (FMR1) gene, causes mild learning disabilities to severe autism.
According to the Centers for Disease Control, FXS affects one in 4,000 males and one in 6,000 females of all races and ethnic groups. The prevalence of autism ranges from one in 500 to one in 166 children. There is no effective treatment for FXS and other types of autism.
"Our study suggests that inhibiting a certain enzyme in the brain could be an effective therapy for countering the debilitating symptoms of FXS in children, and possibly in autistic kids as well," said co-author Mansuo L. Hayashi, a former Picower Institute postdoctoral fellow currently at Merck Research Laboratories in Boston.
The study identifies a key enzyme-a chemical reaction-inducing protein-as a possible target for an FXS drug. The enzyme, called p21-activated kinase, or PAK, affects the number, size and shape of connections between neurons in the brain.
Halting PAK's enzymatic activity reversed the structural abnormality of neuronal connections found in the FXS mice, said co-author Susumu Tonegawa, 1987 Nobel laureate and Picower Professor of Biology and Neuroscience. "Strikingly, PAK inhibition also restored electrical communication between neurons in the brains of the FXS mice, correcting their behavioral abnormalities in the process," he said.
There are known chemical compounds that inhibit the enzymatic activity of PAK. These compounds or versions of them may be useful in the future development of drugs for treating FXS, he said.
"These are intriguing findings because the expression of the gene that inhibits PAK occurs in the third week after birth, which means that the neuronal abnormalities in the fragile X mouse are reversed after they appear," said Eric Klann, a professor at New York University's Center for Neural Science. "This is very exciting because it suggests that PAK inhibitors could be used for therapeutic purposes to reverse already established mental impairments in fragile X children."
Restoring neuronal connections
Tonegawa, Hayashi, MIT graduate student Bridget M. Dolan of the Department of Biology and colleagues study the molecules that govern the formation of neuronal connections in the brain. They explore how abnormalities in these molecules could interfere with an animal's behavior.
In the brain, small protrusions called dendritic spines on the branch-like dendrites of one neuron receive chemical signals from other neurons and communicate them to the main cell body. The numbers and shapes of dendritic spines are key to normal brain function.
FXS patients have higher numbers of dendritic spines in their brains, but each spine is longer and thinner, and transmits weaker electric signals, than those in non-affected individuals. When the enzymatic activity of PAK was inhibited in the FXS mice, abnormalities in their spine number and structure-as well as the weaker electrical communication between their neurons-were reversed.
Reversing behavioral symptoms
The FXS mice exhibited symptoms similar to those in FXS patients. These included hyperactivity; purposeless, repetitive movements reminiscent of autistic people; attention deficits and difficulty with learning and memory tasks.
"These behavioral abnormalities are ameliorated, partially or fully, by inhibiting the enzymatic activity of PAK," Tonegawa said. "Notably, due to an elegant genetic manipulation method employed by the Picower Institute researchers, PAK inhibition in the FXS mice did not take place until a few weeks after appearance of disease symptoms. This implies that future treatment may still be effective even after symptoms are already pronounced."
"While future studies will be necessary to further characterize the precise molecular nature of the interaction between PAK and FMR1, our findings clearly demonstrate that PAK inhibition can counteract several key cellular and behavioral symptoms of FXS," the authors noted.
In addition to Tonegawa, a Howard Hughes Medical Institute investigator, Hayashi and Dolan, authors include colleagues at the National Institute of Mental Health and Neurosciences; the Tata Institute of Fundamental Research in India; and Seoul National University in Korea.
This work was supported by the FRAXA Foundation, the Simons Foundation, the Wellcome Trust and the National Institutes of Health.
Note: This story has been adapted from a news release issued by Massachusetts Institute of Technology.
lundi 14 juillet 2008
The MMR story that wasn't
Whatever you think about Andrew Wakefield, the real villains of the MMR scandal are the media.
Ben Goldacre
Wednesday July 18, 2007
The Guardian
Whatever you think about Andrew Wakefield, the real villains of the MMR scandal are the media. Just one week before his GMC hearing, yet another factless "MMR causes autism" news story appeared: and even though it ran on the front page of our very own Observer, I am dismantling it on this page. We're all grown-ups around here.
The story made three key points: that new research has found an increase in the prevalence of autism to one in 58; that the lead academic on this study was so concerned he suggested raising the finding with public heath officials; and that two "leading researchers" on the team believe that the rise was due to MMR. Within a week the story had been recycled in several national newspapers, and the news pages of at least one academic journal.
But where did the facts come from? I contacted the Autism Research Centre in Cambridge: the study the Observer reported is not finished, and not published. The data has been collected, but it has not been analysed. Unpublished data is the antithesis of what science is about: transparency, where anyone can appraise the methods, and the results, and draw their own conclusions.
This study is the perfect example of why this is important: it was specifically designed to look at how different methods of assessing prevalence affected the final figure. So it is no surprise that one of the results from an early analysis is high, "one in 58", using techniques which deliberately cast the widest net. But even other figures in the initial analysis were less dramatic, and similar to current estimates, and the Observer admits it was aware of them. It seems it simply cherry picked the single most extreme number and made it a front page splash story.
The Observer is unrepentant: it says it has the "final report", from 2005. I can't get it to show it to me but the Cambridge team suspect the paper has seen the last of the quarterly progress reports to the funders. So how did the Observer manage to crowbar MMR into this story?
First, it claimed that the lead researcher, Professor Simon Baron Cohen, "was so concerned by the one in 58 figure that last year he proposed informing public health officials in the county." Prof Cohen is clear: this is inaccurate and scaremongering.
And the meat? The Observer claims that "two of the academics, leaders in their field, privately believe that the surprisingly high figure [one in 58] may be linked to the use of the controversial MMR vaccine." This point is repeatedly reiterated, with a couple of other scientists disagreeing to create that familiar, illusory equipoise of scientific opinion which has fuelled the MMR scare in the media for almost a decade now.
But in fact, the two "leading experts" who were concerned about MMR, the "experts", the "leaders in their field", were not professors, or fellows, or lecturers: they were research associates. I rang both, and both were very clear that they wouldn't describe themselves as "leading experts". One is Fiona Scott, a psychologist and very competent researcher at Cambridge. She said to me: "I absolutely do not think that the rise in autism is related to MMR." And: "My own daughter is getting vaccinated with the MMR jab on July 17."
She also said, astonishingly, that the Observer never even spoke to her. And in the Observer's "readers' editor" column one whole week later, where the Observer half heartedly addressed some of the criticisms of its piece, the Observer persisted in claiming she believes MMR causes autism: it believes it knows the opinions of this woman better than she knows her own mind. Despite her public protestations. The only voice that Dr Scott could find - bizarrely - was in the online comments underneath the readers' editor piece, where the Observer continued to call her an MMR "dissenter", and where she posted an impassioned and slightly desperate message, protesting her support of MMR, and threatening legal action.
That's one of the leading experts. The other is Carol Stott. She does believe that MMR causes autism (at last). However, she is no longer even a "research associate" at the Autism Research Centre.
Carol Stott works in Dr Andrew Wakefield's private autism clinic in America, which the Observer failed to mention, and she was also an adviser to the legal team which failed in seeking compensation for parents who believed that MMR caused their child's autism, which the Observer failed to mention. She was paid £100,000 of public money for her services. She says her objectivity was not affected by the sum, but even so this seems an astonishing pair of facts for the Observer to leave out.
And were Stott's views private, or secret, or new? Hardly. Stott is so committed to the cause against MMR that when the investigative journalist Brian Deer exposed the legal payouts in 2004, although she had no prior contact with him, she spontaneously fired off a long series of sweary emails titled "game on": "Try me, shit head ... Believe me, you will lose ... so go fuck yourself. Got it yet shit head. Try me ... Twathead ... waiting ... oh yes ... Stick that where it feels good. Shit head ... well, ur a bit slow on the uptake ... Give it time I s'pose. Twat." And so on.
On the phone I genuinely warmed to her, and she regrets that many people have fallen into entrenched positions on MMR on both sides. But she's not a leading expert (as she herself agrees); she's not a sombre Cambridge academic suddenly expressing a fresh concern (her views are very public); and in any case, even she is very clear that this new research reported in the Observer would tell us nothing whatsoever about MMR causing autism.
Nothing has changed, and this scare will never be allowed to die. If we had the right regulatory structures, almost every section of the media would be in the dock, alongside Wakefield.
Ben Goldacre
Wednesday July 18, 2007
The Guardian
Whatever you think about Andrew Wakefield, the real villains of the MMR scandal are the media. Just one week before his GMC hearing, yet another factless "MMR causes autism" news story appeared: and even though it ran on the front page of our very own Observer, I am dismantling it on this page. We're all grown-ups around here.
The story made three key points: that new research has found an increase in the prevalence of autism to one in 58; that the lead academic on this study was so concerned he suggested raising the finding with public heath officials; and that two "leading researchers" on the team believe that the rise was due to MMR. Within a week the story had been recycled in several national newspapers, and the news pages of at least one academic journal.
But where did the facts come from? I contacted the Autism Research Centre in Cambridge: the study the Observer reported is not finished, and not published. The data has been collected, but it has not been analysed. Unpublished data is the antithesis of what science is about: transparency, where anyone can appraise the methods, and the results, and draw their own conclusions.
This study is the perfect example of why this is important: it was specifically designed to look at how different methods of assessing prevalence affected the final figure. So it is no surprise that one of the results from an early analysis is high, "one in 58", using techniques which deliberately cast the widest net. But even other figures in the initial analysis were less dramatic, and similar to current estimates, and the Observer admits it was aware of them. It seems it simply cherry picked the single most extreme number and made it a front page splash story.
The Observer is unrepentant: it says it has the "final report", from 2005. I can't get it to show it to me but the Cambridge team suspect the paper has seen the last of the quarterly progress reports to the funders. So how did the Observer manage to crowbar MMR into this story?
First, it claimed that the lead researcher, Professor Simon Baron Cohen, "was so concerned by the one in 58 figure that last year he proposed informing public health officials in the county." Prof Cohen is clear: this is inaccurate and scaremongering.
And the meat? The Observer claims that "two of the academics, leaders in their field, privately believe that the surprisingly high figure [one in 58] may be linked to the use of the controversial MMR vaccine." This point is repeatedly reiterated, with a couple of other scientists disagreeing to create that familiar, illusory equipoise of scientific opinion which has fuelled the MMR scare in the media for almost a decade now.
But in fact, the two "leading experts" who were concerned about MMR, the "experts", the "leaders in their field", were not professors, or fellows, or lecturers: they were research associates. I rang both, and both were very clear that they wouldn't describe themselves as "leading experts". One is Fiona Scott, a psychologist and very competent researcher at Cambridge. She said to me: "I absolutely do not think that the rise in autism is related to MMR." And: "My own daughter is getting vaccinated with the MMR jab on July 17."
She also said, astonishingly, that the Observer never even spoke to her. And in the Observer's "readers' editor" column one whole week later, where the Observer half heartedly addressed some of the criticisms of its piece, the Observer persisted in claiming she believes MMR causes autism: it believes it knows the opinions of this woman better than she knows her own mind. Despite her public protestations. The only voice that Dr Scott could find - bizarrely - was in the online comments underneath the readers' editor piece, where the Observer continued to call her an MMR "dissenter", and where she posted an impassioned and slightly desperate message, protesting her support of MMR, and threatening legal action.
That's one of the leading experts. The other is Carol Stott. She does believe that MMR causes autism (at last). However, she is no longer even a "research associate" at the Autism Research Centre.
Carol Stott works in Dr Andrew Wakefield's private autism clinic in America, which the Observer failed to mention, and she was also an adviser to the legal team which failed in seeking compensation for parents who believed that MMR caused their child's autism, which the Observer failed to mention. She was paid £100,000 of public money for her services. She says her objectivity was not affected by the sum, but even so this seems an astonishing pair of facts for the Observer to leave out.
And were Stott's views private, or secret, or new? Hardly. Stott is so committed to the cause against MMR that when the investigative journalist Brian Deer exposed the legal payouts in 2004, although she had no prior contact with him, she spontaneously fired off a long series of sweary emails titled "game on": "Try me, shit head ... Believe me, you will lose ... so go fuck yourself. Got it yet shit head. Try me ... Twathead ... waiting ... oh yes ... Stick that where it feels good. Shit head ... well, ur a bit slow on the uptake ... Give it time I s'pose. Twat." And so on.
On the phone I genuinely warmed to her, and she regrets that many people have fallen into entrenched positions on MMR on both sides. But she's not a leading expert (as she herself agrees); she's not a sombre Cambridge academic suddenly expressing a fresh concern (her views are very public); and in any case, even she is very clear that this new research reported in the Observer would tell us nothing whatsoever about MMR causing autism.
Nothing has changed, and this scare will never be allowed to die. If we had the right regulatory structures, almost every section of the media would be in the dock, alongside Wakefield.
Autistic Children May Have Abnormal Functioning Of Mirror Neuron System
ScienceDaily (Nov. 29, 2007) — Using a novel imaging technique to study autistic children, researchers have found increased gray matter in the brain areas that govern social processing and learning by observation.
"Our findings suggest that the inability of autistic children to relate to people and life situations in an ordinary way may be the result of an abnormally functioning mirror neuron system," said lead author Manzar Ashtari, Ph.D., from the Children's Hospital of Philadelphia in Pennsylvania.
Mirror neurons are brain cells that are active both when an individual is performing an action and experiencing an emotion or sensation, and when that individual witnesses the same actions, emotions and sensations in others. First observed in the macaque monkey, researchers have found evidence of a similar system in humans that facilitates such functions as learning by seeing as well as doing, along with empathizing and understanding the intentions of others. Dr. Ashtari's study found the autistic children had increased gray matter in brain regions of the parietal lobes implicated in the mirror neuron system.
The study included 13 male patients diagnosed with high-functioning autism or Asperger syndrome and an IQ greater than 70 and 12 healthy control adolescents. Average age of the participants was about 11 years. Each of the patients underwent diffusion tensor imaging (DTI), a technique that tracks the movement of water molecules in the brain.
DTI is traditionally used to study the brain's white matter, as well as the brain fibers. However, Dr. Ashtari's team applied it to the assessment of gray matter by employing apparent diffusion coefficient based morphometry (ABM), a new method that highlights brain regions with potential gray matter volume changes. By adding ABM to DTI, the researchers can detect subtle regional or localized changes in the gray matter.
In addition to the gray matter abnormalities linked to the mirror neuron system, the results of this study revealed that the amount of gray matter in the left parietal area correlated with higher IQs in the control group, but not in the autistic children.
"In the normal brain, larger amounts of gray matter are associated with higher IQs," Dr. Ashtari said. "But in the autistic brain, increased gray matter does not correspond to IQ, because this gray matter is not functioning properly."
The autistic children also evidenced a significant decrease of gray matter in the right amygdala region that correlated with severity of social impairment. Children with lower gray matter volumes in this area of the brain had lower scores on reciprocity and social interaction measures.
"Impairments in these areas are the hallmark of autism spectrum disorders, and this finding may lead to greater understanding of the neurobiological underpinnings of the core features of autism," said study co-author Joel Bregman, M.D., medical director of the Fay J. Lindner Center for Autism.
Autism is the fastest growing developmental disability in the United States and typically appears during the first three years of life. Children with autism are hindered in the areas of social interaction and communication skills. According to the Centers for Disease Control and Prevention, as many as 1.5 million Americans have autism.
Results of the study conducted at the Fay J. Lindner Center for Autism, North Shore-Long Island Jewish Health System in Bethpage, N.Y., were presented November 28 at the annual meeting of the Radiological Society of North America.
Co-authors are S. Nichols, Ph.D., C. McIlree, M.S., L. Spritzer, B.S., A. Adesman, M.D., and B. Ardekani, Ph.D.
This study was supported by The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System and the National Center for Research Resources/National Institutes of Health.
Adapted from materials provided by Radiological Society of North America.
"Our findings suggest that the inability of autistic children to relate to people and life situations in an ordinary way may be the result of an abnormally functioning mirror neuron system," said lead author Manzar Ashtari, Ph.D., from the Children's Hospital of Philadelphia in Pennsylvania.
Mirror neurons are brain cells that are active both when an individual is performing an action and experiencing an emotion or sensation, and when that individual witnesses the same actions, emotions and sensations in others. First observed in the macaque monkey, researchers have found evidence of a similar system in humans that facilitates such functions as learning by seeing as well as doing, along with empathizing and understanding the intentions of others. Dr. Ashtari's study found the autistic children had increased gray matter in brain regions of the parietal lobes implicated in the mirror neuron system.
The study included 13 male patients diagnosed with high-functioning autism or Asperger syndrome and an IQ greater than 70 and 12 healthy control adolescents. Average age of the participants was about 11 years. Each of the patients underwent diffusion tensor imaging (DTI), a technique that tracks the movement of water molecules in the brain.
DTI is traditionally used to study the brain's white matter, as well as the brain fibers. However, Dr. Ashtari's team applied it to the assessment of gray matter by employing apparent diffusion coefficient based morphometry (ABM), a new method that highlights brain regions with potential gray matter volume changes. By adding ABM to DTI, the researchers can detect subtle regional or localized changes in the gray matter.
In addition to the gray matter abnormalities linked to the mirror neuron system, the results of this study revealed that the amount of gray matter in the left parietal area correlated with higher IQs in the control group, but not in the autistic children.
"In the normal brain, larger amounts of gray matter are associated with higher IQs," Dr. Ashtari said. "But in the autistic brain, increased gray matter does not correspond to IQ, because this gray matter is not functioning properly."
The autistic children also evidenced a significant decrease of gray matter in the right amygdala region that correlated with severity of social impairment. Children with lower gray matter volumes in this area of the brain had lower scores on reciprocity and social interaction measures.
"Impairments in these areas are the hallmark of autism spectrum disorders, and this finding may lead to greater understanding of the neurobiological underpinnings of the core features of autism," said study co-author Joel Bregman, M.D., medical director of the Fay J. Lindner Center for Autism.
Autism is the fastest growing developmental disability in the United States and typically appears during the first three years of life. Children with autism are hindered in the areas of social interaction and communication skills. According to the Centers for Disease Control and Prevention, as many as 1.5 million Americans have autism.
Results of the study conducted at the Fay J. Lindner Center for Autism, North Shore-Long Island Jewish Health System in Bethpage, N.Y., were presented November 28 at the annual meeting of the Radiological Society of North America.
Co-authors are S. Nichols, Ph.D., C. McIlree, M.S., L. Spritzer, B.S., A. Adesman, M.D., and B. Ardekani, Ph.D.
This study was supported by The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System and the National Center for Research Resources/National Institutes of Health.
Adapted from materials provided by Radiological Society of North America.
Missing Protein May Be Key To Autism
ScienceDaily — A missing brain protein may be one of the culprits behind autism and other brain disorders, researchers at MIT's Picower Institute for Learning and Memory report in the Dec. 6 issue of Neuron.
The protein helps synapses develop. Synapses--through which neurons communicate with one other-underlie our ability to learn and remember. Now Li-Huei Tsai, Picower Professor of Neuroscience at MIT, has uncovered an enzyme that is key to that protein's activity.
Synapses are complex structures consisting of ion channels, receptors and intricate protein complexes that all work together to send and receive signals. Improperly formed synapses could lead to mental retardation, and mutations in genes encoding certain synaptic proteins are associated with autism.
Tsai studies a kinase (kinases are enzymes that change proteins) called Cdk5. While Cdk5's best-known role is to help new neurons form and migrate to their correct positions during brain development, "emerging evidence supports an important role for Cdk5 at the synapse," she said.
To gain a better understanding of how Cdk5 promotes synapse formation, Tsai's lab looked into how Cdk5 interacts with synapse-inducing proteins-in particular, a protein called CASK. CASK--a key scaffolding protein-is one of the first proteins on the scene of a developing synapse.
Scaffolding proteins such as CASK are like site managers, supporting protein-to-protein interactions to ensure that the resulting architecture is sound. Mutations in the genes responsible for Cdk5 and CASK have been found in mental retardation patients.
"We found that Cdk5 is critical for recruiting CASK to do its job for developing synapses," Tsai said. "Without Cdk5, CASK was not in the right place at the right time, and failed to interact with essential presynaptic components. This, in turn, led to problems with calcium influx." The flow of calcium in and out of neurons affects processes central to nervous system development and plasticity--its ability to change in response to experience.
Gene mutations and/or deletions in synaptic cell surface proteins and molecules called neurexins and neuroligins have been associated with autism. The problem with CASK recruitment investigated by the Tsai laboratory creates the same result as these genetic changes.
The Picower study also provides the first molecular explanation of how Cdk5, which also may go awry in neurodegenerative diseases such as Alzheimer's, promotes synapse development.
"There are still a lot of unknowns," said Tsai, who is also a Howard Hughes Medical Institute investigator. "Causes for psychiatric disorders are still very unclear, but accumulating evidence strongly suggests that alterations in the synaptogenesis program can lead to these serious diseases."
In addition to Tsai and Picower researcher Benjamin A. Samuels, co-authors are associated with Harvard Medical School; Johns Hopkins University School of Medicine; McLean Hospital in Belmont, Mass.; and Academia Sinica in Taiwan.
This work is supported by the National Institute of Neurological Disorders and Stroke (NINDS).
Adapted from materials provided by Massachusetts Institute of Technology.
The protein helps synapses develop. Synapses--through which neurons communicate with one other-underlie our ability to learn and remember. Now Li-Huei Tsai, Picower Professor of Neuroscience at MIT, has uncovered an enzyme that is key to that protein's activity.
Synapses are complex structures consisting of ion channels, receptors and intricate protein complexes that all work together to send and receive signals. Improperly formed synapses could lead to mental retardation, and mutations in genes encoding certain synaptic proteins are associated with autism.
Tsai studies a kinase (kinases are enzymes that change proteins) called Cdk5. While Cdk5's best-known role is to help new neurons form and migrate to their correct positions during brain development, "emerging evidence supports an important role for Cdk5 at the synapse," she said.
To gain a better understanding of how Cdk5 promotes synapse formation, Tsai's lab looked into how Cdk5 interacts with synapse-inducing proteins-in particular, a protein called CASK. CASK--a key scaffolding protein-is one of the first proteins on the scene of a developing synapse.
Scaffolding proteins such as CASK are like site managers, supporting protein-to-protein interactions to ensure that the resulting architecture is sound. Mutations in the genes responsible for Cdk5 and CASK have been found in mental retardation patients.
"We found that Cdk5 is critical for recruiting CASK to do its job for developing synapses," Tsai said. "Without Cdk5, CASK was not in the right place at the right time, and failed to interact with essential presynaptic components. This, in turn, led to problems with calcium influx." The flow of calcium in and out of neurons affects processes central to nervous system development and plasticity--its ability to change in response to experience.
Gene mutations and/or deletions in synaptic cell surface proteins and molecules called neurexins and neuroligins have been associated with autism. The problem with CASK recruitment investigated by the Tsai laboratory creates the same result as these genetic changes.
The Picower study also provides the first molecular explanation of how Cdk5, which also may go awry in neurodegenerative diseases such as Alzheimer's, promotes synapse development.
"There are still a lot of unknowns," said Tsai, who is also a Howard Hughes Medical Institute investigator. "Causes for psychiatric disorders are still very unclear, but accumulating evidence strongly suggests that alterations in the synaptogenesis program can lead to these serious diseases."
In addition to Tsai and Picower researcher Benjamin A. Samuels, co-authors are associated with Harvard Medical School; Johns Hopkins University School of Medicine; McLean Hospital in Belmont, Mass.; and Academia Sinica in Taiwan.
This work is supported by the National Institute of Neurological Disorders and Stroke (NINDS).
Adapted from materials provided by Massachusetts Institute of Technology.
Inherited Retardation And Autism Corrected In Mice
ScienceDaily — Researchers at MIT's Picower Institute for Learning and Memory have corrected key symptoms of mental retardation and autism in mice. They have significantly alleviated a wide range of abnormalities due to fragile X syndrome by altering only a single gene, countering the effects of the fragile X mutation.
The work also indicates that a certain class of drugs could have the same effect. These drugs are not yet approved by the FDA, but will soon be entering into human clinical trials. There is currently no treatment or therapy for fragile X syndrome, whose symptoms include mental retardation, epilepsy, and abnormal body growth.
Fragile X syndrome (FXS), affecting 100,000 Americans, is the most common inherited cause of mental retardation and autism. The MIT researchers corrected FXS in mice modeling the disease. "These findings have major therapeutic implications for fragile X syndrome and autism," said study lead author Mark F. Bear, director of the Picower Institute and Picower Professor of Neuroscience at MIT.
The findings support the theory that many of FXS's psychiatric and neurological symptoms-learning disabilities, autistic behavior, childhood epilepsy- stem from too much activation of one of the brain's chief network managers-the metabotropic glutamate receptor mGluR5.
"Fragile X is a disorder of excess-excess synaptic connectivity, protein synthesis, memory extinction, body growth, excitability-and remarkably, all these excesses can be reduced by reducing mGluR5," said Bear, a Howard Hughes Medical Institute investigator.
Individuals with FXS have mutations in the X chromosome's FMR1 gene, which encodes the fragile X mental retardation protein, FMRP. The MIT study found that FMRP and mGluR5 are at opposite ends of a kind of molecular seesaw. They keep each other in check, and without FMRP, mGluR5 signals run rampant.
Bear and colleagues study how genes and environment interact to refine connections in the brain. Synapses are the brain's connectors and their modifications are the basis for all learning and memory. There's a growing consensus among researchers that developmental brain disorders such as FXS, autism and schizophrenia should be considered "synapsopathies"- diseases of synaptic development and plasticity (the ability to change in response to experience).
Dendritic spines--little nubs on neurons' branchlike projections-receive many of the synaptic inputs from other neurons. Abnormal spines have long been associated with various forms of human mental retardation. In FXS, spines are more numerous, longer and more spindly than they should be. Thin spines tend to form weak connections.
The research team found that a 50 percent reduction in mGluR5 fixed multiple defects in the fragile X mice. In addition to correcting dendritic spines, reduced mGluR5 improved altered brain development and memory, restored normal body growth, and reduced seizures-many of the symptoms experienced by humans with FXS.
The researchers used genetic engineering to reduce mGluR5, but the same thing could be accomplished by a drug. Although not yet approved by the FDA, mGluR5 blockers are entering into human clinical trials. "Insights gained by this study suggest novel therapeutic approaches, not only for fragile X but also for autism and mental retardation of unknown origin," Bear said.
Earlier this year, MIT Picower Institute researcher Susumu Tonegawa and colleagues reported positive results using a different approach to reversing FXS symptoms. Tonegawa and colleagues identified a key enzyme called p21-activated kinase, or PAK, that affects the number, size and shape of connections between neurons.
This research is scheduled to be published in the Dec. 20 issue of Neuron. In addition to Bear, authors include Brown University graduate student Gul Dolen; Picower Institute postdoctoral fellow Emily Osterweil, B.S. Shankaranarayana Rao of the National Institute of Mental Health and Neuroscience in India; MIT graduate students Gordon B. Smith and Benjamin D. Auerbach; and Sumantra Chattarji of the National Center for Biological Sciences and Tata Institute of Fundamental Research in India.
This work is supported by the National Institute of Mental Health; the National Institute of Child Health and Human Development; the National Fragile X Foundation; FRAXA, a Fragile X research foundation; and the Simons Foundation.
Adapted from materials provided by Massachusetts Institute of Technology.
The work also indicates that a certain class of drugs could have the same effect. These drugs are not yet approved by the FDA, but will soon be entering into human clinical trials. There is currently no treatment or therapy for fragile X syndrome, whose symptoms include mental retardation, epilepsy, and abnormal body growth.
Fragile X syndrome (FXS), affecting 100,000 Americans, is the most common inherited cause of mental retardation and autism. The MIT researchers corrected FXS in mice modeling the disease. "These findings have major therapeutic implications for fragile X syndrome and autism," said study lead author Mark F. Bear, director of the Picower Institute and Picower Professor of Neuroscience at MIT.
The findings support the theory that many of FXS's psychiatric and neurological symptoms-learning disabilities, autistic behavior, childhood epilepsy- stem from too much activation of one of the brain's chief network managers-the metabotropic glutamate receptor mGluR5.
"Fragile X is a disorder of excess-excess synaptic connectivity, protein synthesis, memory extinction, body growth, excitability-and remarkably, all these excesses can be reduced by reducing mGluR5," said Bear, a Howard Hughes Medical Institute investigator.
Individuals with FXS have mutations in the X chromosome's FMR1 gene, which encodes the fragile X mental retardation protein, FMRP. The MIT study found that FMRP and mGluR5 are at opposite ends of a kind of molecular seesaw. They keep each other in check, and without FMRP, mGluR5 signals run rampant.
Bear and colleagues study how genes and environment interact to refine connections in the brain. Synapses are the brain's connectors and their modifications are the basis for all learning and memory. There's a growing consensus among researchers that developmental brain disorders such as FXS, autism and schizophrenia should be considered "synapsopathies"- diseases of synaptic development and plasticity (the ability to change in response to experience).
Dendritic spines--little nubs on neurons' branchlike projections-receive many of the synaptic inputs from other neurons. Abnormal spines have long been associated with various forms of human mental retardation. In FXS, spines are more numerous, longer and more spindly than they should be. Thin spines tend to form weak connections.
The research team found that a 50 percent reduction in mGluR5 fixed multiple defects in the fragile X mice. In addition to correcting dendritic spines, reduced mGluR5 improved altered brain development and memory, restored normal body growth, and reduced seizures-many of the symptoms experienced by humans with FXS.
The researchers used genetic engineering to reduce mGluR5, but the same thing could be accomplished by a drug. Although not yet approved by the FDA, mGluR5 blockers are entering into human clinical trials. "Insights gained by this study suggest novel therapeutic approaches, not only for fragile X but also for autism and mental retardation of unknown origin," Bear said.
Earlier this year, MIT Picower Institute researcher Susumu Tonegawa and colleagues reported positive results using a different approach to reversing FXS symptoms. Tonegawa and colleagues identified a key enzyme called p21-activated kinase, or PAK, that affects the number, size and shape of connections between neurons.
This research is scheduled to be published in the Dec. 20 issue of Neuron. In addition to Bear, authors include Brown University graduate student Gul Dolen; Picower Institute postdoctoral fellow Emily Osterweil, B.S. Shankaranarayana Rao of the National Institute of Mental Health and Neuroscience in India; MIT graduate students Gordon B. Smith and Benjamin D. Auerbach; and Sumantra Chattarji of the National Center for Biological Sciences and Tata Institute of Fundamental Research in India.
This work is supported by the National Institute of Mental Health; the National Institute of Child Health and Human Development; the National Fragile X Foundation; FRAXA, a Fragile X research foundation; and the Simons Foundation.
Adapted from materials provided by Massachusetts Institute of Technology.
Dental Tooth Fillings Containing Mercury Don't Affect Children's Brain Development, Study Suggests
ScienceDaily (Jan. 27, 2008) — Dental amalgam tooth fillings do not adversely affect children's brain development and neurological status, researchers report in the February issue of The Journal of the American Dental Association.
The authors of the report—members of a joint team from the University of Lisbon, Portugal, and the University of Washington, Seattle—studied the possible neurological effects of dental amalgam tooth restorations. Dental amalgam contains elemental mercury combined with other metals such as silver, copper, tin and zinc to form a safe, stable alloy. Dental amalgam has been used for generations to fill decayed teeth that might otherwise have been lost.
Beginning in 1997 and continuing for seven years, the authors studied 507 Portuguese children aged 8 through 12 years who received either amalgam or resin-based composite fillings. They conducted routine clinical neurological examinations to assess two types of neurological signs: hard (indicating damage to specific neural structures) and soft (subtle signs of central nervous system dysfunction that likely point to immature sensory-motor skills rather than to any structural damage in the brain). The researchers also evaluated the children for presence of tremor.
After seven years, the two groups of children did not differ in terms of the presence or absence of hard signs or tremor. They also didn't differ in terms of the presence or absence or severity of soft signs at any point. Also, as expected in healthy children, the severity of any neurological soft signs diminished as the children aged.
"Even at the levels of amalgam exposure in this study (a mean of 7.7-10.7 amalgam surfaces per subject across the seven years of follow-up)," the authors write, "[we] conclude that exposure to mercury from dental amalgam does not adversely affect neurological status.
"These data indicate the absence of a generalized negative effect on children's nervous system functions stemming from the presence of dental amalgam," they continue, "and while we cannot rule out potential adverse reactions in individual children, we found no indications of any."
JADA, a monthly journal, is the ADA's flagship publication and the most widely read scientific journal in dentistry.
Adapted from materials provided by American Dental Association.
The authors of the report—members of a joint team from the University of Lisbon, Portugal, and the University of Washington, Seattle—studied the possible neurological effects of dental amalgam tooth restorations. Dental amalgam contains elemental mercury combined with other metals such as silver, copper, tin and zinc to form a safe, stable alloy. Dental amalgam has been used for generations to fill decayed teeth that might otherwise have been lost.
Beginning in 1997 and continuing for seven years, the authors studied 507 Portuguese children aged 8 through 12 years who received either amalgam or resin-based composite fillings. They conducted routine clinical neurological examinations to assess two types of neurological signs: hard (indicating damage to specific neural structures) and soft (subtle signs of central nervous system dysfunction that likely point to immature sensory-motor skills rather than to any structural damage in the brain). The researchers also evaluated the children for presence of tremor.
After seven years, the two groups of children did not differ in terms of the presence or absence of hard signs or tremor. They also didn't differ in terms of the presence or absence or severity of soft signs at any point. Also, as expected in healthy children, the severity of any neurological soft signs diminished as the children aged.
"Even at the levels of amalgam exposure in this study (a mean of 7.7-10.7 amalgam surfaces per subject across the seven years of follow-up)," the authors write, "[we] conclude that exposure to mercury from dental amalgam does not adversely affect neurological status.
"These data indicate the absence of a generalized negative effect on children's nervous system functions stemming from the presence of dental amalgam," they continue, "and while we cannot rule out potential adverse reactions in individual children, we found no indications of any."
JADA, a monthly journal, is the ADA's flagship publication and the most widely read scientific journal in dentistry.
Adapted from materials provided by American Dental Association.
MMR links to autism dismissed by huge study
Sarah Boseley, The Guardian
There is no evidence to link the MMR vaccination to autism in children, according to a substantial new study published today.
In the biggest review conducted to date, scientists from Guy's Hospital in London, Manchester University and the Health Protection Agency, analysed the blood from 250 children and concluded that the vaccine could not be responsible.
The study, which was funded by the Department of Health and is published in the journal Archives of Disease in Childhood, was initiated five years ago and comes a decade after a scare about the vaccination - which protects against mumps, measles and rubella - led to a big drop in the number of children given the jab.
The theory put forward by Dr Andrew Wakefield and colleagues was that the measles virus in the MMR caused bowel disorder and subsequently autism.
However, the blood samples taken from all the children in today's study did not support that analysis. The research specifically looked for traces of measles virus in the blood of 250 children who had been given the MMR vaccination, 98 of whom had an autistic spectrum disorder.
The scientists found no difference in levels of measles virus or antibodies between those who had been diagnosed with autism and those who had not.
The tests also showed no signs of bowel disorders developing either.
The children, aged about 10 years old, had been given the first MMR jab but not all had the booster. The researchers found that those with autism or learning difficulties tended not to have had the second jab, which they say is of concern.
Professor David Salisbury, director of immunisation at the Department of Health, said: "It's natural for parents to worry about the health and wellbeing of their children and I hope this study will reassure them that there is no evidence linking the MMR vaccine to autism."
Public health experts will be hoping this study can lay to rest the controversy.
The Department of Health stressed the quality of the study and in a statement said it had "linked very careful assessment and diagnosis of a child's condition, with expert analysis of blood samples".
There is no evidence to link the MMR vaccination to autism in children, according to a substantial new study published today.
In the biggest review conducted to date, scientists from Guy's Hospital in London, Manchester University and the Health Protection Agency, analysed the blood from 250 children and concluded that the vaccine could not be responsible.
The study, which was funded by the Department of Health and is published in the journal Archives of Disease in Childhood, was initiated five years ago and comes a decade after a scare about the vaccination - which protects against mumps, measles and rubella - led to a big drop in the number of children given the jab.
The theory put forward by Dr Andrew Wakefield and colleagues was that the measles virus in the MMR caused bowel disorder and subsequently autism.
However, the blood samples taken from all the children in today's study did not support that analysis. The research specifically looked for traces of measles virus in the blood of 250 children who had been given the MMR vaccination, 98 of whom had an autistic spectrum disorder.
The scientists found no difference in levels of measles virus or antibodies between those who had been diagnosed with autism and those who had not.
The tests also showed no signs of bowel disorders developing either.
The children, aged about 10 years old, had been given the first MMR jab but not all had the booster. The researchers found that those with autism or learning difficulties tended not to have had the second jab, which they say is of concern.
Professor David Salisbury, director of immunisation at the Department of Health, said: "It's natural for parents to worry about the health and wellbeing of their children and I hope this study will reassure them that there is no evidence linking the MMR vaccine to autism."
Public health experts will be hoping this study can lay to rest the controversy.
The Department of Health stressed the quality of the study and in a statement said it had "linked very careful assessment and diagnosis of a child's condition, with expert analysis of blood samples".
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