Microbleeding in Brain May Be Behind Senior Moments
People may grow wiser with age, but they don’t grow smarter. Many of our mental abilities decline after midlife, and now researchers say that they’ve fingered a culprit. A study presented here last week at the annual meeting of the Association for Psychological Science points to microbleeding in the brain caused by stiffening arteries. The finding may lead to new therapies to combat senior moments.
This isn’t the first time that microbleeds have been suspected as a cause of cognitive decline. “We have known [about them] for some time thanks to neuroimaging studies,” says Matthew Pase, a psychology Ph.D. student at Swinburne University of Technology in Melbourne, Australia. The brains of older people are sometimes peppered with dark splotches where blood vessels have burst and created tiny dead zones of tissue. How important these microbleeds are to cognitive decline, and what causes them, have remained open questions, however.
Pase wondered if high blood pressure might be behind the microbleeds. The brain is a very blood-hungry organ, he notes. “It accounts for only 2% of the body weight yet receives 15% of the cardiac output and consumes 20% of the body’s oxygen expenditure.” Rather than getting the oxygen in pulses, the brain needs a smooth, continuous supply. So the aorta, the largest blood vessel branching off the heart, smooths out blood pressure before it reaches the brain by absorbing the pressure with its flexible walls. But as people age, the aorta stiffens. That translates to higher pressure on the brain, especially during stress. The pulse of blood can be strong enough to burst vessels in the brain, resulting in microbleeds.
A stumbling block has been accurately measuring the blood pressure that the brain experiences. The hand-pumped armband devices commonly used in doctor’s offices measure only the local pressure of blood in the arm, known as the brachial pressure. To calculate aorta stiffness, the “central blood pressure” in the aorta is needed. A technique for measuring central blood pressure was developed in the late 1990s, called applanation tonometry (AT). It works by comparing the pressure wave of blood from the heart with the reflected pressure wave from the vessels farthest from the heart—the aorta stiffness is calculated from the difference in pressure from the two. Devices for measuring AT have appeared on the market that are fast and painless.
To see if central blood pressure and aorta stiffening are related to cognitive abilities, Pase and colleagues recruited 493 people in Melbourne, 20 to 82 years old. They made traditional blood pressure measurements and also used AT to measure central blood pressure and estimate aorta stiffness. They also measured their subjects’ cognitive abilities with a standard battery of computer tests.
Central blood pressure and aorta stiffness alone were sensitive predictors of cognitive abilities, Pase reported at the meeting. The higher the central pressure and aorta stiffness, the worse people tended to perform on tests of visual processing and memory. The traditional measures of blood pressure in the arm were correlated with only scores on one test of visual processing.
To prove that aorta stiffening causes microbleeds, the researchers will need to repeat the experiment on the same people over the course of several years, using neuroimaging as well to establish that aorta stiffening leads to both microbleeding and cognitive decline. Pase notes that other causes of microbleeding have been proposed, such as weakening of blood vessels in the brain.
"This work is so important because the problem is so pervasive," says Earl Hunt, a veteran intelligence researcher at the University of Washington, Seattle, who was not involved in the work. The individual effects of these microbleeds are probably too small to measure. "But even a trifling difference multiplied a million times is big," he says. Pase’s collaborator at Swinburne, Con Stough, is now leading a study of how to prevent microbleeding through dietary supplements. He proposes that the elasticity of the aorta could be preserved by providing fatty acids or antioxidants that help maintain its structure. The results are expected in 2015.
Filed under brain microbleeding cognitive decline blood vessels blood pressure psychology neuroscience science
Genetically engineered immune cells seem to promote healing in mice infected with a neurological disease similar to multiple sclerosis (MS), cleaning up lesions and allowing the mice to regain use of their legs and tails.
The new finding, by a team of University of Wisconsin School of Medicine and Public Health researchers, suggests that immune cells could be engineered to create a new type of treatment for people with MS. Currently, there are few good medications for MS, an autoimmune inflammatory disease that affects some 400,000 people in the United States, and none that reverse progress of the disease.
Dr. Michael Carrithers, assistant professor of neurology, led a team that created a specially designed macrophage – an immune cell whose name means “big eater.” Macrophages rush to the site of an injury or infection, to destroy bacteria and viruses and clear away damaged tissue. The research team added a human gene to the mouse immune cell, creating a macrophage that expressed a sodium channel called NaVI.5, which seems to enhance the cell’s immune response.
But because macrophages can also be part of the autoimmune response that damages the protective covering (myelin) of the nerves in people with MS, scientists weren’t sure whether the NaV1.5 macrophages would help or make the disease worse.
When the mice developed experimental autoimmune encephalomyelitis – the mouse version of MS — they found that the NaV1.5 macrophages sought out the lesions caused by the disease and promoted recovery.
“This finding was unexpected because we weren’t sure how much damage they would do, versus how much cleaning up they would do,” Carrithers says. “Some people thought the mice would get more ill, but we found that it protected them and they either had no disease or a very mild case.”
In follow-up experiments, regular mice that do not express the human gene were treated with the NaV1.5 macrophages after the onset of symptoms, which include weakness of the back and front limbs. The majority of these mice developed complete paralysis of their hindlimbs. Almost all of the mice that were treated with the Na1.5 macrophages regained the ability to walk. Mice treated with placebo solution or regular mouse macrophages that did not have NaV1.5 did not show any recovery or became more ill. In treated mice, the research team also found the NaV1.5 macrophages at the site of the lesions, and found smaller lesions and less damaged tissue in the treated mice.
Because the NaV1.5 variation is present in human immune cells, Carrithers says, “The questions are, ‘Why are these repair mechanisms deficient in patients with MS and what can we do to enhance them?’’’ He says the long-range goal is to develop the NaV1.5 enhanced macrophages as a treatment for people with MS.
The study is being published in the June issue of the Journal of Neuropathology and Experimental Neurology.
(Source: med.wisc.edu)
Filed under inflammatory diseases immune cells myelin macrophages neuroscience science
Ritalin activates specific areas of the brain in children with attention-deficit/hyperactivity disorder (ADHD), mimicking the brain activity of children without the condition, a new review says.
"This suggests that Ritalin does bring the brain [of a child with ADHD] back to the brain the typically developing kid has," said study author Constance Moore, associate director of the translational center for comparative neuroimaging at the University of Massachusetts Medical School.
Analyzing data from earlier studies that looked at how children’s brains were affected by doing certain tasks that are sometimes challenging for kids with ADHD, the researchers found that Ritalin (methylphenidate) was having a visible impact on three areas of the brain known to be associated with ADHD: the cortex, the cerebellum and the basal ganglia.
The study could be helpful in diagnosing and treating children with ADHD, Moore said. “It may be helpful to know that in certain children, Ritalin is having a physiological effect in the areas of the brain involved with attention and impulse control,” she said.
The research was published recently in the Harvard Review of Psychiatry.
Nine studies analyzed by the researchers used functional MRI to evaluate brain changes after children had taken a single dose of Ritalin. The children were involved in different types of tasks that tested their ability to focus and inhibit an impulse to act.
For example, to observe the brain’s reaction during a test of what is called “inhibitory control,” a child was told that every time he saw a zero show up on a screen, he should push the button on the right; every time he saw an X appear, he should push the left button. The children would then be asked to flip their responses, pushing the left button when they saw a zero.
"That’s hard to do," Moore said, "because you’ve developed the habit [of pushing the other button], so you have to suppress your impulse. If you do 20 zeros and keep pressing and then you see an X, most kids with ADHD will hit the wrong button."
In three out of five of the inhibitory control studies, Ritalin at least partially normalized brain activation in ADHD children.
To note how the brain reacted to a selective attention test, Moore said, children would first be asked, for example, what word they were seeing. The word would be “red,” and the color of the type also would be red. Then they would be shown the word “red,” but the color of the type would be green. In several studies, Ritalin affected activation in the frontal lobes during such inhibitory control tasks.
Most of the studies included in the review were performed in the United States or the United Kingdom. The majority of participants were adolescent boys, and all studies compared their results to healthy children of the same approximate age.
Because none of the studies looked at the correlation between ADHD symptoms and whether the child was taking Ritalin, there is no way to link the changes in brain activation with clinical improvement, Moore said. “It’s possible that kids who are not responsive to Ritalin may have brain changes too,” she said.
ADHD affects between 3 percent and 7 percent of school-aged children in the United States, according to the American Psychiatric Association. Boys are more likely to have ADHD than girls.
One expert was not surprised by the results.
"The review article shows there is a consensus of well-designed imaging studies showing that [Ritalin] has an impact on the frontal cortex of the brain, where we have long believed these patients have issues," said Dr. Andrew Adesman, chief of developmental and behavioral pediatrics at the Steven & Alexandra Cohen Children’s Medical Center of New York, in New Hyde Park. Adesman wondered if Ritalin may play a role in helping the brain mature.
"Their data provides partial support for that," he said. "But if anything, the medicine seems to help the brain look more normal and doesn’t seem to do anything bad to it."
(Source: consumer.healthday.com)
Filed under ADHD ritalin brain activity neuroimaging methylphenidate cortex neuroscience science
Circadian rhythms control body’s response to intestinal infections
Circadian rhythms can boost the body’s ability to fight intestinal bacterial infections, UC Irvine researchers have found.
This suggests that targeted treatments may be particularly effective for pathogens such as salmonella that prompt a strong immune system response governed by circadian genes. It also helps explain why disruptions in the regular day-night pattern – as experienced by, say, night-shift workers or frequent fliers – may raise susceptibility to infectious diseases.
UC Irvine’s Paolo Sassone-Corsi, one of the world’s leading researchers on circadian rhythm genetics, and microbiologist Manuela Raffatellu led the study, which appears this week in the early online edition of Proceedings of the National Academy of Sciences. Marina Bellet, a postdoctoral researcher from Italy’s University of Perugia also played a key role in the experiments.
“Although many immune responses are known to follow daily oscillations, the role of the circadian clock in the immune response to acute infections has not been understood,” said Sassone-Corsi, the Donald Bren Professor of Biological Chemistry. “What we’re learning is that the intrinsic power of the body clock can help fight infections.”
Circadian rhythms of 24 hours govern fundamental physiological functions in almost all organisms. The circadian clock is an intrinsic time-tracking system in the human body that anticipates environmental changes and adapts to the appropriate time of day. Disruption of these normal rhythms can profoundly influence people’s health.
Up to 15 percent of human genes are regulated by the day-night pattern of circadian rhythms, including those that respond to intestinal infections.
In tests on mice infected with salmonella, the researchers noted that circadian-controlled genes govern the immune response to the invading pathogen, leading to day-night differences in infection potential and in the immune system’s ability to deal with pathogens.
Mice are nocturnal, with circadian rhythms opposite those of humans. While important differences exist in the immune response of mice and humans, Sassone-Corsi said, these test results could provide clues to how circadian-controlled intestinal genes regulate daily changes in the effectiveness of the human immune system.
“Salmonella is a good pathogen to study what happens during infection,” said Raffatellu, assistant professor of microbiology & molecular genetics. “We think these findings may be broadly applicable to other infectious diseases in the gut, and possibly in other organs controlled by circadian patterns.”
Sassone-Corsi added that it’s important to understand the circadian genetics regulating immunity. “This gives us the ability to target treatments that supplement the power of the body clock to boost immune response,” he said.
(Image: Stephen Sedam / Los Angeles Times)
Filed under circadian rhythms immune system intestinal infections salmonella medicine neuroscience science
Exposure to general anaesthesia increases the risk of dementia in the elderly by 35%, says new research presented at Euroanaesthesia, the annual congress of the European Society of Anaesthesiology (ESA). The research is by Dr Francois Sztark, INSERM and University of Bordeaux, France, and colleagues.
Postoperative cognitive dysfunction, or POCD, could be associated with dementia several years later. POCD is a common complication in elderly patients after major surgery. It has been proposed that there is an association between POCD and the development of dementia due to a common pathological mechanism through the amyloid β peptide. Several experimental studies suggest that some anaesthetics could promote inflammation of neural tissues leading to POCD and/or Alzheimer’s disease (AD) precursors including β-amyloid plaques and neurofibrillary tangles. But it remains uncertain whether POCD can be a precursor of dementia.
In this new study, the researchers analysed the risk of dementia associated with anaesthesia within a prospective population-based cohort of elderly patients (aged 65 years and over). The team used data from the Three-City study, designed to assess the risk of dementia and cognitive decline due to vascular risk factors. Between 1999 and 2001, the 3C study included 9294 community-dwelling French people aged 65 years and over in three French cities (Bordeaux, Dijon and Montpellier).
Participants aged 65 years and over were interviewed at baseline and subsequently 2, 4, 7 and 10 years after. Each examination included a complete cognitive evaluation with systematic screening of dementia. From the 2-year follow-up, 7008 non-demented participants were asked at each follow-up whether they have had a history of anaesthesia (general anaesthesia (GA) or local/locoregional anaesthesia (LRA)) since the last follow-up. The data were adjusted to take account of potential confounders such as socioeconomic status and comorbidities.
The mean age of participants was 75 years and 62% were women. At the 2-year follow-up, 33% of the participants (n=2309) reported an anaesthesia over the 2 previous years, with 19% (n=1333) reporting a GA and 14% (n=948) a LRA. A total of 632 (9%) participants developed dementia over the 8 subsequent years of follow-up, among them 284 probable AD and 228 possible AD, and the remaining 120 non-Alzheimer’s dementia. The researchers found that demented patients were more likely to have received anaesthesia (37%) than non-demented patients (32%). This difference in anaesthesia was due to difference in numbers receiving general anaesthetics, with 22% of demented patients reporting a GA compared with 19% of non-demented patients. After adjustment, participants with at least one GA over the follow-up had a 35% increased risk of developing a dementia compared with participants without anaesthesia.
Dr Sztark concludes: “These results are in favour of an increased risk for dementia several years after general anaesthesia. Recognition of POCD is essential in the perioperative management of elderly patients. A long-term follow-up of these patients should be planned.”
(Source: eurekalert.org)
Filed under anaesthesia dementia amyloid plaques cognitive decline socioeconomic status neuroscience science
Scientists from the University of Sussex have revealed that men are significantly better than women at using speech ‘formants’ to compare the apparent size of the source. Formants are important phonetic elements of human speech that are used by mammals to assess the body size of potential mates and rivals. This research is the first to indicate that formant perception may have evolved through sexual selection.
Dr. Benjamin D. Charlton and his team tested 18 males and 37 females, aged between 17 and 20 years. Participants heard 60 unique stimulus pairs with different formants, representing two different animals, and their task was to decide which one sounded ‘larger’. Researchers tested the ability of listeners to detect small differences in apparent size across a wide range of formants which encompassed the range of the human speaking voice.
Speech formants, which give us our particular vowel sounds, are based on the length of the vocal tract, and thus relate directly to body size. But whereas men appear to use formants to judge the physical dominance of potential rivals, formants are not consistently found to predict how women rate the attractiveness of men’s voices. Women have been found to be more reliant on voice pitch rather than formants when rating how attractive they find a male voice.
The researchers conclude that the sex differences they report could be either innate or acquired or both. Hence, while they are compatible with the hypothesis that males rely on size assessment more than females, they do not conclusively demonstrate that these abilities arose through sexual selection. For example, it is possible that males learn this skill because this information is more important to them during their everyday social interactions. There may also be key differences across cultures, particularly in societies where gender roles differ markedly. Thus, they look forward to future studies examining the effects of training and personality as well as social and cultural factors.
(Source: royalsociety.org)
Filed under sex differences formants formant perception speech vowel sounds psychology neuroscience science
Researchers at the MRC Laboratory of Molecular Biology in the United Kingdom have determined the crystal structure of Parkin, a protein found in cells that when mutated can lead to a hereditary form of Parkinson’s disease. The results, which are published in The EMBO Journal, define the position of many of the mutations linked to hereditary Parkinson’s disease and explain how these alterations may affect the stability and function of the protein. The findings may in time reveal how the activity of Parkin is affected in patients with this rare but debilitating type of Parkinson’s disease.
Parkinson’s disease is a progressive neurodegenerative disease that affects more than seven million people worldwide. Most cases of the disease occur in older individuals and are sporadic (non-familial), but around 15% of patients develop symptoms early in life because of inherited mutations in a limited number of disease genes. Why Parkin mutations are especially detrimental in nerve cells is not fully understood, but previous research indicates that Parkin regulates the function of mitochondria, the organelles that generate energy in the cell. Some disease mutations in the PARKIN gene can be easily explained since they lead to loss or instability of the Parkin protein, but many others are more difficult to understand.
Around 50% of cases of familial recessive Parkinson’s disease are caused by mutations in the PARKIN gene, which encodes a protein that belongs to the RBR ubiquitin ligase enzyme family. Enzymes in this family couple other proteins in the cell to a molecule called ubiquitin, a step that can alter the function or stability of these target proteins. To understand how Parkin and other RBR ubiquitin ligase enzymes achieve this, EMBO Young Investigator David Komander and his coworker Tobias Wauer crystallized a form of human Parkin and used X-ray diffraction patterns to determine how the Parkin protein chain folds into a three-dimensional structure. Their experiments revealed an in-built control mechanism for Parkin activity, which is lost in the presence of some of the mutations responsible for Parkinson’s disease. Wauer and Komander pinpointed amino acids of Parkin with key functions in ubiquitin ligase activity that are sensitive to blocking by reagents previously characterized in their laboratory. “This sensitivity to inhibitors that were developed for a very different class of enzymes is particularly exciting,” Komander remarked. “We could also show that these inhibitors affect related RBR ubiquitin ligases such as HOIP, which is important for inflammatory immune responses.”
The crystal structure of Parkin is already revealing some of the secrets of this molecule, which under the right conditions can protect cells from the damage that arises during Parkinson’s disease. “In time the structure may also allow development of other compounds that alter Parkin activity, which could serve as ways to limit the progression and impact of Parkinson’s disease,” concluded Komander.
(Source: embo.org)
Filed under parkinson’s disease parkin gene neurodegeneration genetics neuroscience science
Avatar therapy helps silence voices in schizophrenia
An avatar system that enables people with schizophrenia to control the voice of their hallucinations is being developed by researchers at UCL with support from the Wellcome Trust.
The computer-based system could provide quick and effective therapy that is far more successful than current pharmaceutical treatments, helping to reduce the frequency and severity of episodes of schizophrenia.
In an early pilot of this approach involving 16 patients and up to seven, 30 minute sessions of therapy, almost all of the patients reported an improvement in the frequency and severity of the voices that they hear. Three of the patients stopped hearing voices completely after experiencing 16, 13 and 3.5 years of auditory hallucinations, respectively. The avatar does not address the patients’ delusions directly, but the study found that they do improve as an overall effect of the therapy.
The team has now received a £1.3 million Translation Award from the Wellcome Trust to refine the system and conduct a larger scale, randomised study to evaluate this novel approach to schizophrenia therapy which will be conducted at King’s College London Institute of Psychiatry.
The first stage in the therapy is for the patient to create a computer-based avatar, by choosing the face and voice of the entity they believe is talking to them. The system then synchronises the avatar’s lips with its speech, enabling a therapist to speak to the patient through the avatar in real time. The therapist encourages the patient to oppose the voice and gradually teaches them to take control of their hallucinations.
Julian Leff, Emeritus Professor in UCL Mental Health Sciences, developed the therapy and is leading the project. He said: “Even though patients interact with the avatar as though it was a real person, because they have created it, they know that it cannot harm them, as opposed to the voices, which often threaten to kill or harm them and their family. As a result the therapy helps patients gain the confidence and courage to confront the avatar, and their persecutor.
“We record every therapy session on MP3 so that the patient essentially has a therapist in their pocket which they can listen to at any time when harassed by the voices. We’ve found that this helps them to recognise that the voices originate within their own mind and reinforces their control over the hallucinations.
The larger-scale study will begin enrolling the first patients in early July. The team are currently training the therapists and research staff to deliver the avatar therapy and finalising the study set-up. The first results of this larger study are expected towards the end of 2015.
Professor Thomas Craig of King’s College London Institute of Psychiatry, who will lead the larger trial, said: “Auditory hallucinations are a very distressing experience that can be extremely difficult to treat successfully, blighting patients’ lives for many years. I am delighted to be leading the group that will carry out a rigorous randomised study of this intriguing new therapy with 142 people who have experienced distressing voices for many years.
“The beauty of the therapy is its simplicity and brevity. Most other psychological therapies for these conditions are costly and take many months to deliver. If we show that this treatment is effective, we expect it could be widely available in the UK within just a couple of years as the basic technology is well developed and many mental health professionals already have the basic therapy skills that are needed to deliver it.”
Schizophrenia affects around 1 in 100 people worldwide, the most common symptoms being delusions (false beliefs) and auditory hallucinations (hearing voices). The illness often has a devastating effect, making it impossible to work and to sustain social relationships. Even with the most effective anti-psychotic medication, around one in four people with schizophrenia continue to suffer from persecutory auditory hallucinations, severely impairing their ability to concentrate.
Current guidelines from the National Institute for Health and Care Excellence (NICE) recommend that schizophrenia is treated using a combination of medication and talking therapies, such as cognitive behavioural therapy. However, fewer than one in ten patients with schizophrenia in the UK have access to this kind of psychological therapy.
Ted Bianco, Director of Technology Transfer and Acting Director of the Wellcome Trust, said: “At a time when many companies have become wary about investing in drug discovery for mental health, we are delighted to be able to facilitate the evaluation of an alternative approach to treatment based on the fusion of a talking therapy with computer-assisted ‘training’.
“In addition to the attraction that the intervention is not reliant on development of a new medication, the approach has the benefit of being directly testable in patients. Should the results of the trial prove encouraging, we expect there may be further applications of the basic strategy worth exploring in other areas of mental health.”
Filed under avatar therapy schizophrenia auditory hallucinations psychology neuroscience science
Lead Acts to Trigger Schizophrenia
Study in Mice Points to a Synergistic Relationship Between Lead Exposure and Schizophrenia Gene
Mice engineered with a human gene for schizophrenia and exposed to lead during early life exhibited behaviors and structural changes in their brains consistent with schizophrenia. Scientists at Columbia University’s Mailman School of Public Health and the Johns Hopkins University School of Medicine say their findings suggest a synergistic effect between lead exposure and a genetic risk factor, and open an avenue to better understanding the complex gene-environment interactions that put people at risk for schizophrenia and other mental disorders.
Results appear online in Schizophrenia Bulletin.
Going back to 2004, work by scientists at the Mailman School suggested a connection between prenatal lead exposure in humans and increased risk for schizophrenia later in life. But a big question remained: How could lead trigger the disease? Based on his own research, Tomás R. Guilarte, PhD, senior author of the new study, believed the answer was in the direct inhibitory effect of lead on the N-methyl-D-aspartate receptor (NMDAR), a synaptic connection point important to brain development, learning, and memory. His research in rodents found that exposure to lead blunted the function of the NMDAR. The glutamate hypothesis of schizophrenia postulates that a deficit in glutamate neurotransmission and specifically hypoactivity of the NMDAR can explain a significant portion of the dysfunction in schizophrenia.
In the new study, Dr. Guilarte, professor and chair of the department of Environmental Health Sciences at the Mailman School, and his co-investigators focused on mice engineered to carry the mutant form of Disrupted-in-Schizophrenia-1 (DISC1), a gene that is a risk factor for the disease in humans. Beginning before birth, half of the mutant DISC1 mice were fed a diet with lead, and half were given a normal diet. A second group of normal mice not expressing the mutant DISC1 gene were also split into the two feeding groups. All mice were put through a battery of behavioral tests and their brains were examined using MRI.
Mutant mice exposed to lead and given a psychostimulant exhibited elevated levels of hyperactivity and were less able to suppress a startle in response to a loud noise after being given an acoustic warning. Their brains also had markedly larger lateral ventricles—empty spaces containing cerebrospinal fluid—compared with other mice. These results mirror what is known about schizophrenia in humans.
While the role of genes in schizophrenia and mental disorders is well established, the effect of toxic chemicals in the environment is only just beginning to emerge. The study’s results focus on schizophrenia, but implications could be broader.
“We’re just scratching the surface,” says Dr. Guilarte. “We used lead in this study, but there are other environmental toxins that disrupt the function of the NMDAR.” One of these is a family of chemicals in air pollution called polycyclic aromatic hydrocarbons or PAHs. “Similarly, any number of genes could be in play,” adds Dr. Guilarte, noting that DISC1 is among many implicated in schizophrenia.
Future research may reveal to what extent schizophrenia is determined by environmental versus genetic factors or their interactions, and what other mental problems might be in the mix. One ongoing study by Dr. Guilarte is looking at whether lead exposure alone can contribute to deficits of one specialized type of neuron called parvalbumin-positive GABAergic interneuron that is known to be affected in the brain of schizophrenia patients. Scientists are also interested to establish the critical window for exposure—whether in utero or postnatal, or both.
“The animal model provides a way forward to answer important questions about the physiological processes underlying schizophrenia,” says Dr. Guilarte.
(Image: Flickr)
Filed under schizophrenia genetics DISC1 gene lead exposure glutamate neuroscience science
The St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project has identified mutations responsible for more than half of a subtype of childhood brain tumor that takes a high toll on patients. Researchers also found evidence the tumors are susceptible to drugs already in development.
The study focused on a family of brain tumors known as low-grade gliomas (LGGs). These slow-growing cancers are found in about 700 children annually in the U.S., making them the most common childhood tumors of the brain and spinal cord. For patients whose tumors cannot be surgically removed, the long-term outlook remains bleak due to complications from the disease and its ongoing treatment. Nationwide, surgery alone cures only about one-third of patients.
Using whole genome sequencing, researchers identified genetic alterations in two genes that occurred almost exclusively in a subtype of LGG termed diffuse LGG. This subtype cannot be cured surgically because the tumor cells invade the healthy brain. Together, the mutations accounted for 53 percent of the diffuse LGG in this study. Researchers also demonstrated that one of the mutations, which had not previously been linked to brain tumors, caused tumors when introduced into the glial brain cells of mice.
The findings appear in the April 14 advance online edition of the scientific journal Nature Genetics.
“This subtype of low-grade glioma can be a nasty chronic disease, yet prior to this study we knew almost nothing about its genetic alterations,” said David Ellison, M.D., Ph.D., chair of the St. Jude Department of Pathology and the study’s corresponding author. The first author is Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology.
The Pediatric Cancer Genome Project is using next-generation whole genome sequencing to determine the complete normal and cancer genomes of children and adolescents with some of the least understood and most difficult to treat cancers. Scientists believe that studying differences in the 3 billion chemical bases that make up the human genome will provide the scientific foundation for the next generation of cancer care.
“We were surprised to find that many of these tumors could be traced to a single genetic alteration,” said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. “This is a major pathway through which low-grade gliomas develop and it provides new clues to explore as we search for better treatments.”
The study involved whole genome sequencing of 39 paired tumor and normal tissue samples from 38 children and adolescents with different subtypes of LGG and related tumors called low-grade glioneuronal tumors (LGGNTs). Although many cancers develop following multiple genetic abnormalities, 62 percent of the 39 tumors in this study stemmed from a single genetic alteration.
Previous studies have linked LGGs to abnormal activation of the MAPK/ERK pathway. The pathway is involved in regulating cell division and other processes that are often disrupted in cancer. Until now, however, the genetic alterations involved in driving this pathway were unknown for some types of LGG and LGGNT.
This study linked activation in the pathway to duplication of a key segment of the FGFR1 gene, which investigators discovered in brain tumors for the first time. The segment is called a tyrosine kinase domain. It functions like an on-off switch for several cell signaling pathways, including the MAPK/ERK pathway. Investigators also demonstrated that experimental drugs designed to block activity along two altered pathways worked in cells with theFGFR1 tyrosine kinase domain duplication. “The finding suggests a potential opportunity for using targeted therapies in patients whose tumors cannot be surgically removed,” Ellison said.
Researchers also showed that the FGFR1 abnormality triggered an aggressive brain tumor in glial cells from mice that lacked the tumor suppressor gene Trp53.
Whole-genome sequencing found previously undiscovered rearrangements in the MYB and MYBL1 genes in diffuse LGGs. These newly identified abnormalities were also implicated in switching on the MAPK/ERK pathway.
Researchers checked an additional 100 LGGs and LGGNTs for the same FGFR1, MYB and MYBL1 mutations. Overall, MYB was altered in 25 percent of the diffuse LGGs, and 24 percent had alterations in FGFR1. Researchers also turned up numerous other mutations that occurred in just a few tumors. The affected genes included BRAF, RAF1, H3F3A, ATRX, EP300, WHSC1 and CHD2.
“The Pediatric Cancer Genome Project has provided a remarkable opportunity to look at the genomic landscape of this disease and really put the alterations responsible on the map. We can now account for the genetic errors responsible for more than 90 percent of low-grade gliomas,” Ellison said. “The discovery that FGFR1 and MYB play a central role in childhood diffuse LGG also serves to distinguish the pediatric and adult forms of the disease.”
(Source: stjude.org)
Filed under brain tumors brain cells genetic alterations whole-genome sequencing genetics neuroscience science
![Microbleeding in Brain May Be Behind Senior Moments
People may grow wiser with age, but they don’t grow smarter. Many of our mental abilities decline after midlife, and now researchers say that they’ve fingered a culprit. A study presented here last week at the annual meeting of the Association for Psychological Science points to microbleeding in the brain caused by stiffening arteries. The finding may lead to new therapies to combat senior moments.
This isn’t the first time that microbleeds have been suspected as a cause of cognitive decline. “We have known [about them] for some time thanks to neuroimaging studies,” says Matthew Pase, a psychology Ph.D. student at Swinburne University of Technology in Melbourne, Australia. The brains of older people are sometimes peppered with dark splotches where blood vessels have burst and created tiny dead zones of tissue. How important these microbleeds are to cognitive decline, and what causes them, have remained open questions, however.
Pase wondered if high blood pressure might be behind the microbleeds. The brain is a very blood-hungry organ, he notes. “It accounts for only 2% of the body weight yet receives 15% of the cardiac output and consumes 20% of the body’s oxygen expenditure.” Rather than getting the oxygen in pulses, the brain needs a smooth, continuous supply. So the aorta, the largest blood vessel branching off the heart, smooths out blood pressure before it reaches the brain by absorbing the pressure with its flexible walls. But as people age, the aorta stiffens. That translates to higher pressure on the brain, especially during stress. The pulse of blood can be strong enough to burst vessels in the brain, resulting in microbleeds.
A stumbling block has been accurately measuring the blood pressure that the brain experiences. The hand-pumped armband devices commonly used in doctor’s offices measure only the local pressure of blood in the arm, known as the brachial pressure. To calculate aorta stiffness, the “central blood pressure” in the aorta is needed. A technique for measuring central blood pressure was developed in the late 1990s, called applanation tonometry (AT). It works by comparing the pressure wave of blood from the heart with the reflected pressure wave from the vessels farthest from the heart—the aorta stiffness is calculated from the difference in pressure from the two. Devices for measuring AT have appeared on the market that are fast and painless.
To see if central blood pressure and aorta stiffening are related to cognitive abilities, Pase and colleagues recruited 493 people in Melbourne, 20 to 82 years old. They made traditional blood pressure measurements and also used AT to measure central blood pressure and estimate aorta stiffness. They also measured their subjects’ cognitive abilities with a standard battery of computer tests.
Central blood pressure and aorta stiffness alone were sensitive predictors of cognitive abilities, Pase reported at the meeting. The higher the central pressure and aorta stiffness, the worse people tended to perform on tests of visual processing and memory. The traditional measures of blood pressure in the arm were correlated with only scores on one test of visual processing.
To prove that aorta stiffening causes microbleeds, the researchers will need to repeat the experiment on the same people over the course of several years, using neuroimaging as well to establish that aorta stiffening leads to both microbleeding and cognitive decline. Pase notes that other causes of microbleeding have been proposed, such as weakening of blood vessels in the brain.
"This work is so important because the problem is so pervasive," says Earl Hunt, a veteran intelligence researcher at the University of Washington, Seattle, who was not involved in the work. The individual effects of these microbleeds are probably too small to measure. "But even a trifling difference multiplied a million times is big," he says. Pase’s collaborator at Swinburne, Con Stough, is now leading a study of how to prevent microbleeding through dietary supplements. He proposes that the elasticity of the aorta could be preserved by providing fatty acids or antioxidants that help maintain its structure. The results are expected in 2015.](http://41.media.tumblr.com/94707d203b7f0098726d72268ecf4037/tumblr_mnriiiQLsd1rog5d1o1_500.jpg)
