An international consortium has shown for the first time evidence of substantial overlap of genetic risk factors shared between bipolar disorder, major depressive disorder and schizophrenia and less overlap between those conditions and autism and attention deficit-hyperactivity disorder (ADHD), according to a study.
The root cause of psychiatric illnesses such as bipolar disorder, major depressive disorder schizophrenia, autism and ADHD is not fully understood. For more than 125 years, clinicians have based diagnosis on a collection of symptoms observed in patients.
But, scientists have since identified that the five psychiatric disorders share a common genetic link and are now moving toward understanding the molecular underpinnings of psychiatric illness. The precise degree to which these disorders share common ground has remained unknown, until now.
The project is led by the Cross-Disorder Group of the Psychiatric Genomics Consortium and is the largest genetic study of psychiatric illness to date.
The findings provide insight into the biological pathways that may predispose an individual to disease and could ultimately lead to the development of new therapeutic avenues to treat the five major psychiatric illnesses.
‘This is a very large scale study using a new, innovative statistical method,’ said study co-senior author Kenneth S. Kendler, M.D., professor of psychiatry, and human and molecular genetics in the Virginia Commonwealth University School of Medicine, and an internationally recognised psychiatric geneticist.
‘Prior to this model, we have not been able to address these questions. These results give us by far the clearest picture available to date of the degree of genetic similarity between these key psychiatric disorders. We hope that this will help us both in developing a more scientifically based diagnostic system and understanding the degree of sharing of the biological foundation these illnesses,’ he said.
The study builds on findings published earlier this year in The Lancet, which reported that specific single nucleotide polymorphisms, or SNPs, are associated with a range of psychiatric disorders that can occur during childhood or adulthood.
Next, the group will examine other disorders for which molecular genetic data is accumulating including eating disorders, obsessive compulsive disorder and drug use disorders.
Since 2007, the Cross-Disorder Group of the Psychiatric Genomics Consortium has reviewed scientific literature of genome-wide association studies, or GWAS, on psychiatric disorders. To date, GWAS data from more than 19 countries has been gathered by the consortium.
Virginia Commonwealth University
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One night when she was trying to fall asleep, a 60-year-old woman suddenly began hearing music, as if a radio were playing at the back of her head.
The songs were popular tunes her husband recognised when she sang or hummed them. But she herself could not identify them.
This is the first known case of a patient hallucinating music that was familiar to people around her, but that she herself did not recognise, according to Dr. Danilo Vitorovic and Dr. José Biller of Loyola University Medical Center.
The case raises ‘intriguing questions regarding memory, forgetting and access to lost memories,’ the authors write.
Musical hallucinations are a form of auditory hallucinations, in which patients hear songs, instrumental music or tunes, even though no such music is actually playing. Most patients realise they are hallucinating, and find the music intrusive and occasionally unpleasant. There is no cure.
Musical hallucinations usually occur in older people. Several conditions are possible causes or predisposing factors, including hearing impairment, brain damage, epilepsy, intoxications and psychiatric disorders such as depression, schizophrenia and obsessive-compulsive disorder. Hearing impairment is the most common predisposing condition, but is not by itself sufficient to cause hallucinations.
Vitorovic and Biller describe a hearing-impaired patient who initially hallucinated music when she was trying to fall asleep. Within four months, she was hearing music all the time. For example, she would hear one song over and over for three weeks, then another song would begin playing. The volume never changed, and she was able to hear and follow conversations while hallucinating the music.
The patient was treated with carbamazepine, an anti-seizure drug, and experienced some improvement in her symptoms.
The unique feature of the patient was her ability to hum parts of some tunes and recall bits of lyrics from some songs that she did not even recognise. This raises the possibility that the songs were buried in her memory, but she could not access them except when she was hallucinating.
‘Further research is necessary on the mechanisms of forgetfulness,’ Vitorovic and Biller write. ‘In other words, is forgotten information lost, or just not accessible?’
Vitorovic is a former chief neurology resident and Biller is a professor and chair in the Department of Neurology of Loyola University Chicago Stritch School of Medicine.
Loyola University Health System
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Indiana University School of Medicine researchers have found a series of RNA biomarkers in blood that may help identify who is at risk for committing suicide.
The researchers said the biomarkers were found at significantly higher levels in the blood of both bipolar disorder patients with thoughts of suicide as well in a group of people who had committed suicide.
Principal investigator Alexander B. Niculescu III, M.D., Ph.D., associate professor of psychiatry and medical neuroscience at the IU School of Medicine and attending psychiatrist and research and development investigator at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, said he believes the results provide a first ‘proof of principle’ for a test that could provide an early warning of somebody being at higher risk for an impulsive suicide act.
‘Suicide is a big problem in psychiatry. It’s a big problem in the civilian realm, it’s a big problem in the military realm and there are no objective markers,’ said Dr. Niculescu, director of the Laboratory of Neurophenomics at the Institute of Psychiatric Research at the IU School of Medicine.
‘There are people who will not reveal they are having suicidal thoughts when you ask them, who then commit it and there’s nothing you can do about it. We need better ways to identify, intervene and prevent these tragic cases,’ he said.
Over a three-year period, Niculescu and his colleagues followed a large group of patients diagnosed with bipolar disorder, completing interviews and taking blood samples every three to six months. The researchers conducted a variety of analyses of the blood of a subset of participants who reported a dramatic shift from no suicidal thoughts to strong suicidal ideation. They identified differences in gene expression between the ‘low’ and ‘high’ states of suicidal thoughts and subjected those findings to a system of genetic and genomic analysis called Convergent Functional Genomics that identified and prioritized the best markers by cross-validation with other lines of evidence.
The researchers found that the marker SAT1 and a series of other markers provided the strongest biological ‘signal’ associated with suicidal thoughts.
Next, to validate their findings, working with the local coroner’s office, they analysed blood samples from suicide victims and found that some of same top markers were significantly elevated.
Finally, the researchers analysed blood test results from two additional groups of patients and found that high blood levels of the biomarkers were correlated with future suicide-related hospitalisations, as well as hospitalisations that had occurred before the blood tests.
‘This suggests that these markers reflect more than just a current state of high risk, but could be trait markers that correlate with long term risk,’ said Dr. Niculescu.
Although confident in the biomarkers validity, Dr. Niculescu noted that a limitation is that the research subjects were all male.
‘There could be gender differences,’ he said. ‘We would also like to conduct more extensive, normative studies, in the population at large.’
In addition to extending the research to females to see if the same or other markers come into play, Dr. Niculescu and colleagues plan to conduct research among other groups, such as persons who have less impulsive, more deliberate and planned subtypes of suicide.
Indiana University School of Medicine
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A new way of screening for ovarian cancer is showing ‘potential’, according to researchers in the US. Tumours in the ovaries are hard to detect in the earliest stages meaning it can be too late to treat them effectively by the time they are found. A trial of 4,051 women showed the method could identify those needing treatment. But a huge study taking place in the UK will give a final verdict on the test when it is completed in 2015.
There is a survival rate of up to 90% when ovarian cancer is caught early, compared with less than 30% if it is discovered in the later stages. Unlike other cancers, the symptoms, such as pelvic and abdominal pain or persistent bloating, are often put down to other common ailments and the tumour can be missed. There is no mass screening programme to detect the cancer either.
Scientists already know that levels of a protein in the blood, called CA125, are often higher with ovarian cancer. However, it is too unreliable on its own. It misses some patients and tells others they have the cancer when they are actually healthy.
Researchers are now testing the idea of using the blood test to sort patients in risk groups based on levels of CA125. Instead of going straight for surgery, low-risk patients are tested again in a year, medium-risk ones after three months and high-risk patients have an ultrasound scan to hunt for tumours.
The US study, at the University of Texas, followed post-menopausal women for 11 years on average. Ten women had surgery based on their ultrasound scan and all the cancers detected were at an early stage.
Researcher Dr Karen Lu told the BBC: ‘Clinical practice definitely should not change from our study, but it gives us an insight – we didn’t get a lot of false positives.’
She said the UK study of 50,000 people would give definitive results: ‘There are two big questions – do we see cancers at an earlier stage and do we decrease the number of deaths.’
Dr Sarah Blagden, from the Ovarian Cancer Action research centre, said: ‘Relative to the trial under way in the in the UK , this is a small study, but it does show that effective ovarian screening is possible.
‘In 2015 the results of the UKCTOCs study will become available and the results are eagerly anticipated, more so now that this American study has produced such encouraging results.’
BBC
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Reversing inflammation in the fluid surrounding the brain’s cortex may provide a solution to the complex riddle of Parkinson’s, according to researchers who have found a link between pro-inflammatory biomarkers and the severity of symptoms such as fatigue, depression and anxiety in patients with the chronic disease.
Lena Brundin of Michigan State University’s College of Human Medicine was part of a research team that measured inflammatory markers found in cerebrospinal fluid samples of Parkinson’s patients and members of a control group.
‘The degree of neuroinflammation was significantly associated with more severe depression, fatigue, and cognitive impairment even after controlling for factors such as age, gender and disease duration,’ said Brundin, an associate professor in the college and a researcher with the Van Andel Institute.
‘By investigating associations between inflammatory markers and non-motor symptoms we hope to gain further insight into this area, which in turn could lead to new treatment options.’
Inflammation in the brain long has been suspected to be involved in the development of Parkinson’s disease, specifically in non-motor symptoms such as depression, fatigue and cognitive impairment. Recent research suggests inflammation could drive cell death and that developing new drugs that target this inflammation might slow disease progression.
Parkinson´s disease is the second most common degenerative disorder of the central nervous system; the causes of the disease and its development are not yet fully understood.
‘The few previous studies investigating inflammatory markers in the cerebrospinal fluid of Parkinson’s patients have been conducted on comparatively small numbers of subjects, and often without a healthy control group for comparison,’ Brundin said.
In the study, 87 Parkinson’s patients were enrolled between 2008 and 2012. For the control group, 37 individuals were recruited. Participants underwent a general physical exam and routine blood screening. Researchers looked at the following markers: C-reactive protein, interleukin-6, tumor necrosis factor-alpha, eotaxin, interferon gamma-induced protein-10, monocyte chemotactic protein-1 and macrophage inflammatory protein 1-β.
The study was carried out in collaboration with researchers from Lund University in Sweden, Skåne University Hospital in Sweden and the Mayo Clinic College of Medicine in Florida.
Michigan State University
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Researchers have tied mutations in a gene that causes amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders to the toxic build-up of certain proteins and related molecules in cells, including neurons. The research offers a new approach for developing treatments against these devastating diseases.
Scientists at St. Jude Children’s Research Hospital and the University of Colorado, Boulder, led the work.
The findings provide the first evidence that a gene named VCP plays a role in the break-up and clearance of protein and RNA molecules that accumulate in temporary structures called RNA granules. RNAs perform a variety of vital cell functions, including protein production. RNA granules support proper functioning of RNA.
In ALS and related degenerative diseases, the process of assembling and clearing RNA granules is impaired. The proteins and RNAs associated with the granules often build up in nerve cells of patients. This study shows how mutations in VCP might contribute to that process and neurodegenerative disease.
‘The results go a long way to explaining the process that links a variety of neurodegenerative diseases, including ALS, frontotemporal dementia and related diseases of the brain, muscle and bone known as multisystem proteinopathies,’ said the study’s co-corresponding author, J. Paul Taylor, M.D., Ph.D., a member of the St. Jude Department of Developmental Neurobiology. Roy Parker, Ph.D., of the University of Colorado’s Department of Chemistry and Biochemistry and the Howard Hughes Medical Institute (HHMI), is the other corresponding author.
St Jude Children’s Research Hospital
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Problems with a key group of enzymes called topoisomerases can have profound effects on the genetic machinery behind brain development and potentially lead to autism spectrum disorder (ASD), according to research. Scientists at the University of North Carolina School of Medicine have described a finding that represents a significant advance in the hunt for environmental factors behind autism and lends new insights into the disorder’s genetic causes.
‘Our study shows the magnitude of what can happen if topoisomerases are impaired,’ said senior study author Mark Zylka, PhD, associate professor in the Neuroscience Center and the Department of Cell Biology and Physiology at UNC. ‘Inhibiting these enzymes has the potential to profoundly affect neurodevelopment — perhaps even more so than having a mutation in any one of the genes that have been linked to autism.’
The study could have important implications for ASD detection and prevention.
‘This could point to an environmental component to autism,’ said Zylka. ‘A temporary exposure to a topoisomerase inhibitor in utero has the potential to have a long-lasting effect on the brain, by affecting critical periods of brain development. ‘
This study could also explain why some people with mutations in topoisomerases develop autism and other neurodevelopmental disorders.
Topiosomerases are enzymes found in all human cells. Their main function is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes.
Most of the known topoisomerase-inhibiting chemicals are used as chemotherapy drugs. Zylka said his team is searching for other compounds that have similar effects in nerve cells. ‘If there are additional compounds like this in the environment, then it becomes important to identify them,’ said Zylka. ‘That’s really motivating us to move quickly to identify other drugs or environmental compounds that have similar effects — so that pregnant women can avoid being exposed to these compounds.’
Zylka and his colleagues stumbled upon the discovery quite by accident while studying topotecan, a topoisomerase-inhibiting drug that is used in chemotherapy. Investigating the drug’s effects in mouse and human-derived nerve cells, they noticed that the drug tended to interfere with the proper functioning of genes that were exceptionally long — composed of many DNA base pairs. The group then made the serendipitous connection that many autism-linked genes are extremely long.
‘That’s when we had the ‘Eureka moment,’’ said Zylka. ‘We realised that a lot of the genes that were suppressed were incredibly long autism genes.’
Of the more than 300 genes that are linked to autism, nearly 50 were suppressed by topotecan. Suppressing that many genes across the board — even to a small extent — means a person who is exposed to a topoisomerase inhibitor during brain development could experience neurological effects equivalent to those seen in a person who gets ASD because of a single faulty gene.
The study’s findings could also help lead to a unified theory of how autism-linked genes work. About 20 percent of such genes are connected to synapses — the connections between brain cells. Another 20 percent are related to gene transcription — the process of translating genetic information into biological functions. Zylka said this study bridges those two groups, because it shows that having problems transcribing long synapse genes could impair a person’s ability to construct synapses.
‘Our discovery has the potential to unite these two classes of genes — synaptic genes and transcriptional regulators,’ said Zylka. ‘It could ultimately explain the biological mechanisms behind a large number of autism cases.’
University of North Carolina School of Medicine
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Researchers from King’s College London and the University of Nottingham have identified neuroimaging markers in the brain which could help predict whether people with psychosis respond to antipsychotic medications or not.
In approximately half of young people experiencing their first episode of a psychosis (FEP), the symptoms do not improve considerably with the initial medication prescribed, increasing the risk of subsequent episodes and worse outcome. Identifying individuals at greatest risk of not responding to existing medications could help in the search for improved medications, and may eventually help clinicians personalise treatment plans.
In a study, researchers used structural Magnetic Resonance Imaging (MRI) to scan the brains of 126 individuals – 80 presenting with FEP, and 46 healthy controls. Participants had an MRI scan shortly after their FEP, and another assessment 12 weeks later, to establish whether symptoms had improved following the first treatment with antipsychotic medications.
The researchers examined a particular feature of the brain called ‘cortical gyrification’ – the extent of folding of the cerebral cortex and a marker of how it has developed. They found that the individuals who did not respond to treatment already had a significant reduction in gyrification across multiple brain regions, compared to patients who did respond and to individuals without psychosis. This reduced gyrification was particularly present in brain areas considered important in psychosis, such as the temporal and frontal lobes. Those who responded to treatment were virtually indistinguishable from the healthy controls.
The researchers also investigated whether the differences could be explained by the type of diagnosis of psychosis (eg. with or without affective symptoms, such as depression or elated mood). They found that reduced gyrification predicted non-response to treatment independently of the diagnosis.
Dr Paola Dazzan from the Department of Psychosis Studies at King’s College London’s Institute of Psychiatry, and senior author of the paper, says: ‘Our study provides crucial evidence of a neuroimaging marker that, if validated, could be used early in psychosis to help identify those people less likely to respond to medications. It is possible that the alterations we observed are due to differences in the way the brain has developed early on in people who do not respond to medication compared to those who do.’
She continues:’There have been few advances in developing novel anti-psychotic drugs over the past 50 years and we still face the same problems with a sub-group of people who do not respond to the drugs we currently use. We could envisage using a marker like this one to identify people who are least likely to respond to existing medications and focus our efforts on developing new medication specifically adapted to this group. In the longer term, if we were able to identify poor responders at the outset, we may be able to formulate personalised treatment plans for that individual patient.’
Dr Lena Palaniyappan from the University of Nottingham adds: ‘All of us have complex and varying patterns of folding in our brains. For the first time we are showing that the measurement of these variations could potentially guide us in treating psychosis. It is possible that people with specific patterns of brain structure respond better to treatments other than antipsychotics that are currently in use. Clearly, the time is ripe for us to focus on utilising neuroimaging to guide treatment decisions.’
King’s College London
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Cancer Research UK scientists have found a gene in mice that could protect against ovarian cancer and, if faulty, may increase the chance of developing the disease, according to research.
This gene, known as Helq, helps repair any damage to DNA that happens when it is copied as cells multiply. So if the gene is missing or faulty, DNA errors could mount up, increasing the chance of cancer developing.
The team, from Cancer Research UK’s London Research Institute, found that mice without either of the two copies of the Helq gene were twice as likely to develop ovarian tumours, as well as becoming less fertile. And even losing just a single copy of the Helq gene was enough to cause a mouse to develop more tumours.
Dr Simon Boulton, senior author from Cancer Research UK’s London Research Institute, said: ‘Our findings show that if there are problems with the Helq gene in mice it increases the chance of them developing ovarian and other tumours. This is an exciting finding because this might also be true for women with errors in Helq, and the next step will be to see if this is the case.
‘If it plays a similar role in humans, this may open up the possibility that, in the future, women could be screened for errors in the Helq gene that might increase their risk of ovarian cancer.’
Dr Julie Sharp, Cancer Research UK’s senior science information manager, said: ‘This study pulls together clues from a series of experiments building a picture of cell faults that could lead to ovarian cancer in women.
‘Ovarian cancer can be hard to diagnose early and treat successfully so the more we know about the causes of the disease, the better equipped we will be to detect and treat it.’
Cancer Research UK
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Scientists from the Monell Center report the surprising finding that two proteins involved in oral taste detection also play a crucial role in sperm development.
‘This paper highlights a connection between the taste system and male reproduction,’ said lead author Bedrich Mosinger, MD, PhD, a molecular biologist at Monell. ‘It is one more demonstration that components of the taste system also play important roles in other organ systems.’
While breeding mice for taste-related studies, the researchers discovered that they were unable to produce offspring that were simultaneously missing two taste-signalling proteins.
As reported online, the critical proteins were TAS1R3, a component of both the sweet and umami (amino acid) taste receptors, and GNAT3, a molecule needed to convert the oral taste receptor signal into a nerve cell response.
Breeding experiments determined that fertility was affected only in males. Both taste proteins had previously been found in testes and sperm, but until now, their function there was unknown.
In order to explore the reproductive function of the two proteins, the research team engineered mice that were missing genes for the mouse versions of TAS1R3 and GNAT3 but expressed the human form of the TAS1R3 receptor. These mice were fertile.
However, when the human TAS1R3 receptor was blocked in the engineered mice by adding the drug clofibrate to the rodents’ diet, thus leaving the mice without any functional TAS1R3 or GNAT3 proteins, the males became sterile due to malformed and fewer sperm. The sterility was quickly reversed after clofibrate was removed from the diet.
Clofibrate belongs to a class of drugs called fibrates that frequently are prescribed to treat lipid disorders such as high blood cholesterol or triglycerides. Previous studies from the Monell team had revealed that it is a potent inhibitor of the human, but not mouse, TAS1R3 receptor.
Noting the common use of fibrates in modern medicine and also the widespread use in modern agriculture of the structurally-related phenoxy-herbicides, which also block the human TAS1R3 receptor, Mosinger speculates that these compounds could be negatively affecting human fertility, an increasing problem worldwide.
He in turn notes positive implications related to the research. ‘If our pharmacological findings are indeed related to the global increase in the incidence of male infertility, we now have knowledge to help us devise treatments to reduce or reverse the effects of fibrates and phenoxy-compounds on sperm production and quality. This knowledge could further be used to design a male non-hormonal contraceptive.’
Previous work from Monell and other groups has shown that some taste genes can be found in other parts of the body, including stomach, intestines, pancreas, lungs, and brain, where they are increasingly thought to have important physiological functions.
Monell Center
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New patterns found in the genetic relationship of five major psychiatric disorders
, /in E-News /by 3wmediaAn international consortium has shown for the first time evidence of substantial overlap of genetic risk factors shared between bipolar disorder, major depressive disorder and schizophrenia and less overlap between those conditions and autism and attention deficit-hyperactivity disorder (ADHD), according to a study.
The root cause of psychiatric illnesses such as bipolar disorder, major depressive disorder schizophrenia, autism and ADHD is not fully understood. For more than 125 years, clinicians have based diagnosis on a collection of symptoms observed in patients.
But, scientists have since identified that the five psychiatric disorders share a common genetic link and are now moving toward understanding the molecular underpinnings of psychiatric illness. The precise degree to which these disorders share common ground has remained unknown, until now.
The project is led by the Cross-Disorder Group of the Psychiatric Genomics Consortium and is the largest genetic study of psychiatric illness to date.
The findings provide insight into the biological pathways that may predispose an individual to disease and could ultimately lead to the development of new therapeutic avenues to treat the five major psychiatric illnesses.
‘This is a very large scale study using a new, innovative statistical method,’ said study co-senior author Kenneth S. Kendler, M.D., professor of psychiatry, and human and molecular genetics in the Virginia Commonwealth University School of Medicine, and an internationally recognised psychiatric geneticist.
‘Prior to this model, we have not been able to address these questions. These results give us by far the clearest picture available to date of the degree of genetic similarity between these key psychiatric disorders. We hope that this will help us both in developing a more scientifically based diagnostic system and understanding the degree of sharing of the biological foundation these illnesses,’ he said.
The study builds on findings published earlier this year in The Lancet, which reported that specific single nucleotide polymorphisms, or SNPs, are associated with a range of psychiatric disorders that can occur during childhood or adulthood.
Next, the group will examine other disorders for which molecular genetic data is accumulating including eating disorders, obsessive compulsive disorder and drug use disorders.
Since 2007, the Cross-Disorder Group of the Psychiatric Genomics Consortium has reviewed scientific literature of genome-wide association studies, or GWAS, on psychiatric disorders. To date, GWAS data from more than 19 countries has been gathered by the consortium. Virginia Commonwealth University
Unique form of musical hallucinations
, /in E-News /by 3wmediaOne night when she was trying to fall asleep, a 60-year-old woman suddenly began hearing music, as if a radio were playing at the back of her head.
The songs were popular tunes her husband recognised when she sang or hummed them. But she herself could not identify them.
This is the first known case of a patient hallucinating music that was familiar to people around her, but that she herself did not recognise, according to Dr. Danilo Vitorovic and Dr. José Biller of Loyola University Medical Center.
The case raises ‘intriguing questions regarding memory, forgetting and access to lost memories,’ the authors write.
Musical hallucinations are a form of auditory hallucinations, in which patients hear songs, instrumental music or tunes, even though no such music is actually playing. Most patients realise they are hallucinating, and find the music intrusive and occasionally unpleasant. There is no cure.
Musical hallucinations usually occur in older people. Several conditions are possible causes or predisposing factors, including hearing impairment, brain damage, epilepsy, intoxications and psychiatric disorders such as depression, schizophrenia and obsessive-compulsive disorder. Hearing impairment is the most common predisposing condition, but is not by itself sufficient to cause hallucinations.
Vitorovic and Biller describe a hearing-impaired patient who initially hallucinated music when she was trying to fall asleep. Within four months, she was hearing music all the time. For example, she would hear one song over and over for three weeks, then another song would begin playing. The volume never changed, and she was able to hear and follow conversations while hallucinating the music.
The patient was treated with carbamazepine, an anti-seizure drug, and experienced some improvement in her symptoms.
The unique feature of the patient was her ability to hum parts of some tunes and recall bits of lyrics from some songs that she did not even recognise. This raises the possibility that the songs were buried in her memory, but she could not access them except when she was hallucinating.
‘Further research is necessary on the mechanisms of forgetfulness,’ Vitorovic and Biller write. ‘In other words, is forgotten information lost, or just not accessible?’
Vitorovic is a former chief neurology resident and Biller is a professor and chair in the Department of Neurology of Loyola University Chicago Stritch School of Medicine. Loyola University Health System
Researchers identify biomarkers for possible blood test to predict suicide risk
, /in E-News /by 3wmediaIndiana University School of Medicine researchers have found a series of RNA biomarkers in blood that may help identify who is at risk for committing suicide.
The researchers said the biomarkers were found at significantly higher levels in the blood of both bipolar disorder patients with thoughts of suicide as well in a group of people who had committed suicide.
Principal investigator Alexander B. Niculescu III, M.D., Ph.D., associate professor of psychiatry and medical neuroscience at the IU School of Medicine and attending psychiatrist and research and development investigator at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, said he believes the results provide a first ‘proof of principle’ for a test that could provide an early warning of somebody being at higher risk for an impulsive suicide act.
‘Suicide is a big problem in psychiatry. It’s a big problem in the civilian realm, it’s a big problem in the military realm and there are no objective markers,’ said Dr. Niculescu, director of the Laboratory of Neurophenomics at the Institute of Psychiatric Research at the IU School of Medicine.
‘There are people who will not reveal they are having suicidal thoughts when you ask them, who then commit it and there’s nothing you can do about it. We need better ways to identify, intervene and prevent these tragic cases,’ he said.
Over a three-year period, Niculescu and his colleagues followed a large group of patients diagnosed with bipolar disorder, completing interviews and taking blood samples every three to six months. The researchers conducted a variety of analyses of the blood of a subset of participants who reported a dramatic shift from no suicidal thoughts to strong suicidal ideation. They identified differences in gene expression between the ‘low’ and ‘high’ states of suicidal thoughts and subjected those findings to a system of genetic and genomic analysis called Convergent Functional Genomics that identified and prioritized the best markers by cross-validation with other lines of evidence.
The researchers found that the marker SAT1 and a series of other markers provided the strongest biological ‘signal’ associated with suicidal thoughts.
Next, to validate their findings, working with the local coroner’s office, they analysed blood samples from suicide victims and found that some of same top markers were significantly elevated.
Finally, the researchers analysed blood test results from two additional groups of patients and found that high blood levels of the biomarkers were correlated with future suicide-related hospitalisations, as well as hospitalisations that had occurred before the blood tests.
‘This suggests that these markers reflect more than just a current state of high risk, but could be trait markers that correlate with long term risk,’ said Dr. Niculescu.
Although confident in the biomarkers validity, Dr. Niculescu noted that a limitation is that the research subjects were all male.
‘There could be gender differences,’ he said. ‘We would also like to conduct more extensive, normative studies, in the population at large.’
In addition to extending the research to females to see if the same or other markers come into play, Dr. Niculescu and colleagues plan to conduct research among other groups, such as persons who have less impulsive, more deliberate and planned subtypes of suicide. Indiana University School of Medicine
Ovarian cancer screening ‘has potential’
, /in E-News /by 3wmediaA new way of screening for ovarian cancer is showing ‘potential’, according to researchers in the US. Tumours in the ovaries are hard to detect in the earliest stages meaning it can be too late to treat them effectively by the time they are found. A trial of 4,051 women showed the method could identify those needing treatment. But a huge study taking place in the UK will give a final verdict on the test when it is completed in 2015.
There is a survival rate of up to 90% when ovarian cancer is caught early, compared with less than 30% if it is discovered in the later stages. Unlike other cancers, the symptoms, such as pelvic and abdominal pain or persistent bloating, are often put down to other common ailments and the tumour can be missed. There is no mass screening programme to detect the cancer either.
Scientists already know that levels of a protein in the blood, called CA125, are often higher with ovarian cancer. However, it is too unreliable on its own. It misses some patients and tells others they have the cancer when they are actually healthy.
Researchers are now testing the idea of using the blood test to sort patients in risk groups based on levels of CA125. Instead of going straight for surgery, low-risk patients are tested again in a year, medium-risk ones after three months and high-risk patients have an ultrasound scan to hunt for tumours.
The US study, at the University of Texas, followed post-menopausal women for 11 years on average. Ten women had surgery based on their ultrasound scan and all the cancers detected were at an early stage.
Researcher Dr Karen Lu told the BBC: ‘Clinical practice definitely should not change from our study, but it gives us an insight – we didn’t get a lot of false positives.’
She said the UK study of 50,000 people would give definitive results: ‘There are two big questions – do we see cancers at an earlier stage and do we decrease the number of deaths.’
Dr Sarah Blagden, from the Ovarian Cancer Action research centre, said: ‘Relative to the trial under way in the in the UK , this is a small study, but it does show that effective ovarian screening is possible.
‘In 2015 the results of the UKCTOCs study will become available and the results are eagerly anticipated, more so now that this American study has produced such encouraging results.’ BBC
Brain inflammation linked to more severe Parkinson’s symptoms
, /in E-News /by 3wmediaReversing inflammation in the fluid surrounding the brain’s cortex may provide a solution to the complex riddle of Parkinson’s, according to researchers who have found a link between pro-inflammatory biomarkers and the severity of symptoms such as fatigue, depression and anxiety in patients with the chronic disease.
Lena Brundin of Michigan State University’s College of Human Medicine was part of a research team that measured inflammatory markers found in cerebrospinal fluid samples of Parkinson’s patients and members of a control group.
‘The degree of neuroinflammation was significantly associated with more severe depression, fatigue, and cognitive impairment even after controlling for factors such as age, gender and disease duration,’ said Brundin, an associate professor in the college and a researcher with the Van Andel Institute.
‘By investigating associations between inflammatory markers and non-motor symptoms we hope to gain further insight into this area, which in turn could lead to new treatment options.’
Inflammation in the brain long has been suspected to be involved in the development of Parkinson’s disease, specifically in non-motor symptoms such as depression, fatigue and cognitive impairment. Recent research suggests inflammation could drive cell death and that developing new drugs that target this inflammation might slow disease progression.
Parkinson´s disease is the second most common degenerative disorder of the central nervous system; the causes of the disease and its development are not yet fully understood.
‘The few previous studies investigating inflammatory markers in the cerebrospinal fluid of Parkinson’s patients have been conducted on comparatively small numbers of subjects, and often without a healthy control group for comparison,’ Brundin said.
In the study, 87 Parkinson’s patients were enrolled between 2008 and 2012. For the control group, 37 individuals were recruited. Participants underwent a general physical exam and routine blood screening. Researchers looked at the following markers: C-reactive protein, interleukin-6, tumor necrosis factor-alpha, eotaxin, interferon gamma-induced protein-10, monocyte chemotactic protein-1 and macrophage inflammatory protein 1-β.
The study was carried out in collaboration with researchers from Lund University in Sweden, Skåne University Hospital in Sweden and the Mayo Clinic College of Medicine in Florida. Michigan State University
Scientists identify ALS disease mechanism
, /in E-News /by 3wmediaResearchers have tied mutations in a gene that causes amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders to the toxic build-up of certain proteins and related molecules in cells, including neurons. The research offers a new approach for developing treatments against these devastating diseases.
Scientists at St. Jude Children’s Research Hospital and the University of Colorado, Boulder, led the work.
The findings provide the first evidence that a gene named VCP plays a role in the break-up and clearance of protein and RNA molecules that accumulate in temporary structures called RNA granules. RNAs perform a variety of vital cell functions, including protein production. RNA granules support proper functioning of RNA.
In ALS and related degenerative diseases, the process of assembling and clearing RNA granules is impaired. The proteins and RNAs associated with the granules often build up in nerve cells of patients. This study shows how mutations in VCP might contribute to that process and neurodegenerative disease.
‘The results go a long way to explaining the process that links a variety of neurodegenerative diseases, including ALS, frontotemporal dementia and related diseases of the brain, muscle and bone known as multisystem proteinopathies,’ said the study’s co-corresponding author, J. Paul Taylor, M.D., Ph.D., a member of the St. Jude Department of Developmental Neurobiology. Roy Parker, Ph.D., of the University of Colorado’s Department of Chemistry and Biochemistry and the Howard Hughes Medical Institute (HHMI), is the other corresponding author. St Jude Children’s Research Hospital
Researchers discover a potential cause of autism
, /in E-News /by 3wmediaProblems with a key group of enzymes called topoisomerases can have profound effects on the genetic machinery behind brain development and potentially lead to autism spectrum disorder (ASD), according to research. Scientists at the University of North Carolina School of Medicine have described a finding that represents a significant advance in the hunt for environmental factors behind autism and lends new insights into the disorder’s genetic causes.
‘Our study shows the magnitude of what can happen if topoisomerases are impaired,’ said senior study author Mark Zylka, PhD, associate professor in the Neuroscience Center and the Department of Cell Biology and Physiology at UNC. ‘Inhibiting these enzymes has the potential to profoundly affect neurodevelopment — perhaps even more so than having a mutation in any one of the genes that have been linked to autism.’
The study could have important implications for ASD detection and prevention.
‘This could point to an environmental component to autism,’ said Zylka. ‘A temporary exposure to a topoisomerase inhibitor in utero has the potential to have a long-lasting effect on the brain, by affecting critical periods of brain development. ‘
This study could also explain why some people with mutations in topoisomerases develop autism and other neurodevelopmental disorders.
Topiosomerases are enzymes found in all human cells. Their main function is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes.
Most of the known topoisomerase-inhibiting chemicals are used as chemotherapy drugs. Zylka said his team is searching for other compounds that have similar effects in nerve cells. ‘If there are additional compounds like this in the environment, then it becomes important to identify them,’ said Zylka. ‘That’s really motivating us to move quickly to identify other drugs or environmental compounds that have similar effects — so that pregnant women can avoid being exposed to these compounds.’
Zylka and his colleagues stumbled upon the discovery quite by accident while studying topotecan, a topoisomerase-inhibiting drug that is used in chemotherapy. Investigating the drug’s effects in mouse and human-derived nerve cells, they noticed that the drug tended to interfere with the proper functioning of genes that were exceptionally long — composed of many DNA base pairs. The group then made the serendipitous connection that many autism-linked genes are extremely long.
‘That’s when we had the ‘Eureka moment,’’ said Zylka. ‘We realised that a lot of the genes that were suppressed were incredibly long autism genes.’
Of the more than 300 genes that are linked to autism, nearly 50 were suppressed by topotecan. Suppressing that many genes across the board — even to a small extent — means a person who is exposed to a topoisomerase inhibitor during brain development could experience neurological effects equivalent to those seen in a person who gets ASD because of a single faulty gene.
The study’s findings could also help lead to a unified theory of how autism-linked genes work. About 20 percent of such genes are connected to synapses — the connections between brain cells. Another 20 percent are related to gene transcription — the process of translating genetic information into biological functions. Zylka said this study bridges those two groups, because it shows that having problems transcribing long synapse genes could impair a person’s ability to construct synapses.
‘Our discovery has the potential to unite these two classes of genes — synaptic genes and transcriptional regulators,’ said Zylka. ‘It could ultimately explain the biological mechanisms behind a large number of autism cases.’ University of North Carolina School of Medicine
Brain scans could predict response to antipsychotic medication
, /in E-News /by 3wmediaResearchers from King’s College London and the University of Nottingham have identified neuroimaging markers in the brain which could help predict whether people with psychosis respond to antipsychotic medications or not.
In approximately half of young people experiencing their first episode of a psychosis (FEP), the symptoms do not improve considerably with the initial medication prescribed, increasing the risk of subsequent episodes and worse outcome. Identifying individuals at greatest risk of not responding to existing medications could help in the search for improved medications, and may eventually help clinicians personalise treatment plans.
In a study, researchers used structural Magnetic Resonance Imaging (MRI) to scan the brains of 126 individuals – 80 presenting with FEP, and 46 healthy controls. Participants had an MRI scan shortly after their FEP, and another assessment 12 weeks later, to establish whether symptoms had improved following the first treatment with antipsychotic medications.
The researchers examined a particular feature of the brain called ‘cortical gyrification’ – the extent of folding of the cerebral cortex and a marker of how it has developed. They found that the individuals who did not respond to treatment already had a significant reduction in gyrification across multiple brain regions, compared to patients who did respond and to individuals without psychosis. This reduced gyrification was particularly present in brain areas considered important in psychosis, such as the temporal and frontal lobes. Those who responded to treatment were virtually indistinguishable from the healthy controls.
The researchers also investigated whether the differences could be explained by the type of diagnosis of psychosis (eg. with or without affective symptoms, such as depression or elated mood). They found that reduced gyrification predicted non-response to treatment independently of the diagnosis.
Dr Paola Dazzan from the Department of Psychosis Studies at King’s College London’s Institute of Psychiatry, and senior author of the paper, says: ‘Our study provides crucial evidence of a neuroimaging marker that, if validated, could be used early in psychosis to help identify those people less likely to respond to medications. It is possible that the alterations we observed are due to differences in the way the brain has developed early on in people who do not respond to medication compared to those who do.’
She continues:’There have been few advances in developing novel anti-psychotic drugs over the past 50 years and we still face the same problems with a sub-group of people who do not respond to the drugs we currently use. We could envisage using a marker like this one to identify people who are least likely to respond to existing medications and focus our efforts on developing new medication specifically adapted to this group. In the longer term, if we were able to identify poor responders at the outset, we may be able to formulate personalised treatment plans for that individual patient.’
Dr Lena Palaniyappan from the University of Nottingham adds: ‘All of us have complex and varying patterns of folding in our brains. For the first time we are showing that the measurement of these variations could potentially guide us in treating psychosis. It is possible that people with specific patterns of brain structure respond better to treatments other than antipsychotics that are currently in use. Clearly, the time is ripe for us to focus on utilising neuroimaging to guide treatment decisions.’ King’s College London
Scientists find new gene linked to ovarian cancer
, /in E-News /by 3wmediaCancer Research UK scientists have found a gene in mice that could protect against ovarian cancer and, if faulty, may increase the chance of developing the disease, according to research.
This gene, known as Helq, helps repair any damage to DNA that happens when it is copied as cells multiply. So if the gene is missing or faulty, DNA errors could mount up, increasing the chance of cancer developing.
The team, from Cancer Research UK’s London Research Institute, found that mice without either of the two copies of the Helq gene were twice as likely to develop ovarian tumours, as well as becoming less fertile. And even losing just a single copy of the Helq gene was enough to cause a mouse to develop more tumours.
Dr Simon Boulton, senior author from Cancer Research UK’s London Research Institute, said: ‘Our findings show that if there are problems with the Helq gene in mice it increases the chance of them developing ovarian and other tumours. This is an exciting finding because this might also be true for women with errors in Helq, and the next step will be to see if this is the case.
‘If it plays a similar role in humans, this may open up the possibility that, in the future, women could be screened for errors in the Helq gene that might increase their risk of ovarian cancer.’
Dr Julie Sharp, Cancer Research UK’s senior science information manager, said: ‘This study pulls together clues from a series of experiments building a picture of cell faults that could lead to ovarian cancer in women.
‘Ovarian cancer can be hard to diagnose early and treat successfully so the more we know about the causes of the disease, the better equipped we will be to detect and treat it.’ Cancer Research UK
Inactivation of taste genes causes male sterility
, /in E-News /by 3wmediaScientists from the Monell Center report the surprising finding that two proteins involved in oral taste detection also play a crucial role in sperm development.
‘This paper highlights a connection between the taste system and male reproduction,’ said lead author Bedrich Mosinger, MD, PhD, a molecular biologist at Monell. ‘It is one more demonstration that components of the taste system also play important roles in other organ systems.’
While breeding mice for taste-related studies, the researchers discovered that they were unable to produce offspring that were simultaneously missing two taste-signalling proteins.
As reported online, the critical proteins were TAS1R3, a component of both the sweet and umami (amino acid) taste receptors, and GNAT3, a molecule needed to convert the oral taste receptor signal into a nerve cell response.
Breeding experiments determined that fertility was affected only in males. Both taste proteins had previously been found in testes and sperm, but until now, their function there was unknown.
In order to explore the reproductive function of the two proteins, the research team engineered mice that were missing genes for the mouse versions of TAS1R3 and GNAT3 but expressed the human form of the TAS1R3 receptor. These mice were fertile.
However, when the human TAS1R3 receptor was blocked in the engineered mice by adding the drug clofibrate to the rodents’ diet, thus leaving the mice without any functional TAS1R3 or GNAT3 proteins, the males became sterile due to malformed and fewer sperm. The sterility was quickly reversed after clofibrate was removed from the diet.
Clofibrate belongs to a class of drugs called fibrates that frequently are prescribed to treat lipid disorders such as high blood cholesterol or triglycerides. Previous studies from the Monell team had revealed that it is a potent inhibitor of the human, but not mouse, TAS1R3 receptor.
Noting the common use of fibrates in modern medicine and also the widespread use in modern agriculture of the structurally-related phenoxy-herbicides, which also block the human TAS1R3 receptor, Mosinger speculates that these compounds could be negatively affecting human fertility, an increasing problem worldwide.
He in turn notes positive implications related to the research. ‘If our pharmacological findings are indeed related to the global increase in the incidence of male infertility, we now have knowledge to help us devise treatments to reduce or reverse the effects of fibrates and phenoxy-compounds on sperm production and quality. This knowledge could further be used to design a male non-hormonal contraceptive.’
Previous work from Monell and other groups has shown that some taste genes can be found in other parts of the body, including stomach, intestines, pancreas, lungs, and brain, where they are increasingly thought to have important physiological functions. Monell Center