Posts tagged schizophrenia
Articles and news from the latest research reports.
Stem Cell Research Helps to Identify Origins of Schizophrenia
New University at Buffalo research demonstrates how defects in an important neurological pathway in early development may be responsible for the onset of schizophrenia later in life.
The UB findings, published in Schizophrenia Research, test the hypothesis in a new mouse model of schizophrenia that demonstrates how gestational brain changes cause behavioral problems later in life – just like the human disease.
Partial funding for the research came from New York Stem Cell Science (NYSTEM).
The genomic pathway, called the Integrative Nuclear FGFR 1 Signaling (INFS), is a central intersection point for multiple pathways of as many as 160 different genes believed to be involved in the disorder.
“We believe this is the first model that explains schizophrenia from genes to development to brain structure and finally to behavior,” says lead author Michal Stachowiak, PhD, professor in the Department of Pathology and Anatomical Sciences in the UB School of Medicine and Biomedical Sciences. He also is director of the Stem Cell Engraftment & In Vivo Analysis Facility at the Western New York Stem Cell Culture and Analysis Center at UB.
A key challenge with the disease is that patients with schizophrenia exhibit mutations in different genes, he says.
“How is it possible to have 100 patients with schizophrenia and each one has a different genetic mutation that causes the disorder?” asks Stachowiak. “It’s possible because INFS integrates diverse neurological signals that control the development of embryonic stem cell and neural progenitor cells, and links pathways involving schizophrenia-linked genes.
“INFS functions like the conductor of an orchestra,” explains Stachowiak. “It doesn’t matter which musician is playing the wrong note, it brings down the conductor and the whole orchestra. With INFS, we propose that when there is an alteration or mutation in a single schizophrenia-linked gene, the INFS system that controls development of the whole brain becomes untuned. That’s how schizophrenia develops.”
Using embryonic stem cells, Stachowiak and colleagues at UB and other institutions found that some of the genes implicated in schizophrenia bind the FGFR1 (fibroblast growth factor receptor) protein, which in turn, has a cascading effect on the entire INFS.
New findings on mortality of individuals with schizophrenia
A new study from Lund University in Sweden shows that the average life expectancy of men and women with schizophrenia is 15 years and 12 years shorter respectively than for those who do not suffer from the disease. The study has been carried out in collaboration with Stanford University in the US.
The reasons why people with schizophrenia have a shorter life expectancy have previously been unknown, but have been much discussed in recent years. The research report that has now been published shows that individuals with schizophrenia are more likely to die of two major diseases.
The study followed over six million individuals from 2003 to 2009, of whom 8,277 had schizophrenia, by analysing the Swedish population and health registers.
The results show that people with schizophrenia had contact with the health service over twice as often as people without the condition, but they were no more likely to be diagnosed with cardiovascular disease or cancer.
“Yet we saw an opposing pattern of death from these diseases. It is clear that the health service is failing to diagnose cardiovascular disease and cancer in these patients”, says Jan Sundquist, general practitioner and professor at the Centre for Primary Health Care Research at Lund University.
Women with schizophrenia were 3.3 times more likely to die of cardiovascular disease and men 2.2 times more likely. Women with schizophrenia were 1.7 times more likely to die of cancer while men were 1.4 times more likely, compared with those without schizophrenia. Only 26.3% of the men with schizophrenia who died of cardiovascular disease had been diagnosed before their deaths, compared with 43.7% of the men who did not have schizophrenia.
“It is unacceptable that such a vulnerable group of people, who also have extensive documented contact with the health service, should die prematurely of conditions such as cardiovascular disease and cancer – diseases that should be preventable”, says Professor Sundquist. “A much greater degree of diagnostic and preventive measures could be put in place for this vulnerable group in our society.”
Professor Discovers New Information in the Understanding of Autism and Genetics
Research out of the George Washington University (GW), published in the journal Proceedings of the National Academy of Sciences (PNAS), reveals another piece of the puzzle in a genetic developmental disorder that causes behavioral diseases such as autism. Anthony-Samuel LaMantia, Ph.D., professor of pharmacology and physiology at the GW School of Medicine and Health Sciences (SMHS) and director of the GW Institute for Neuroscience, along with post-doctoral fellow Daniel Meechan, Ph.D. and Thomas Maynard, Ph.D., associate research professor of pharmacology and physiology at GW SMHS, authored the study titled “Cxcr4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome.”
For the past nine years, LaMantia and his colleagues have been investigating how behavioral disorders such as autism, attention deficit hyperactivity disorder (ADHD), and schizophrenia arise during early brain development. His work published in PNAS focuses specifically on the effects diminished 22q11.2 gene dosage has on cortical circuit development.
This research shows for the first time that genetic lesions known to be associated with autism and other behavioral diseases disrupt cellular and molecular mechanisms that ensure normal development of a key type of cortical neuron: the interneuron. LaMantia and his colleagues had found previously that one type of cortical neuron, the projection neuron, is not generated in appropriate numbers during development in a mouse model of 22q11 Deletion Syndrome. In the current study published in PNAS, LaMantia found that interneurons, while made in the right numbers at their birthplace outside of the cortex, are not able to move properly into the cortex where they are needed to control cortical circuit activity. The research shows that the main reason they don’t move properly is due to diminished expression of activity of a key regulatory pathway for migration, the Cxcr4 cytokine receptor.
“This gives us two pieces of the puzzle for this genetic developmental disorder,” said LaMantia. “These two pieces tell us that in very early development, those with 22q11.2 deletion syndrome do not make enough cells in one case, and do not put the other cells in the right place. This occurs not because of some degenerative change, but because the mechanisms that make these cells and put them in the right place during the first step of development have gone awry due to mutation.”
The next step in LaMantia’s research is to probe further into the molecular mechanisms that disrupt the proliferation of projection neurons and migration of interneurons. “If we understand that better and understand its consequences, we can go about fixing it,” said LaMantia. “We want to understand why cortical circuits don’t get built properly due to the genetic deletion of chromosome 22.”
LaMantia recently received the latest installment of a 10-year RO1 grant from the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health & Human Development for his project, titled “Regulation of 22q11 Genes in Embryonic and Adult Forebrain.” This will allow him to further his research.
(Image: iStockphoto)
Risk Genes for Alzheimer’s and Mental Illness Linked to Brain Changes at Birth
Some brain changes that are found in adults with common gene variants linked to disorders such as Alzheimer’s disease, schizophrenia, and autism can also be seen in the brain scans of newborns.
“These results suggest that prenatal brain development may be a very important influence on psychiatric risk later in life,” said Rebecca C. Knickmeyer, PhD, lead author of the study and assistant professor of psychiatry in the University of North Carolina School of Medicine. The study was published by the journal Cerebral Cortex on Jan. 3, 2013.
The study included 272 infants who received MRI scans at UNC Hospitals shortly after birth. The DNA of each was tested for 10 common variations in 7 genes that have been linked to brain structure in adults. These genes have also been implicated in conditions such as schizophrenia, bipolar disorder, autism, Alzheimer’s disease, anxiety disorders and depression.
For some polymorphisms – such as a variation in the APOE gene which is associated with Alzheimer’s disease – the brain changes in infants looked very similar to brain changes found in adults with the same variants, Knickmeyer said. “This could stimulate an exciting new line of research focused on preventing onset of illness through very early intervention in at-risk individuals.”
But this was not true for every polymorphism included in the study, said John H. Gilmore, MD, senior author of the study and Thad & Alice Eure Distinguished Professor and Vice Chair for Research and Scientific Affairs in the UNC Department of Psychiatry.
For example, the study included two variants in the DISC1 gene. For one of these variants, known as rs821616, the infant brains looked very similar to the brains of adults with this variant. But there was no such similarity between infant brains and adult brains for the other variant, rs6675281.
“This suggests that the brain changes associated with this gene variant aren’t present at birth but develop later in life, perhaps during puberty,” Gilmore said.
“It’s fascinating that different variants in the same gene have such unique effects in terms of when they affect brain development,” said Knickmeyer.
Brain & Behavior Research Foundation Announces 10 Major Research Achievements of 2012
In 2012, the Brain & Behavior Research Foundation funded more than 200 new promising ideas through its NARSAD Grants to identify the causes, improve treatments and develop prevention strategies for mental illness. Many research projects also came to fruition in 2012, and the Foundation highlights ten significant findings.
Research may explain why some people with schizophrenia do not respond to treatment
New research suggests that the molecular mechanism leading to schizophrenia may be different in patients who fail to respond to anti-psychotic medication compared to patients who do respond.
The research, from King’s College London’s Institute of Psychiatry may help explain why up to one third of patients with schizophrenia do not respond to traditional anti-psychotic medication.
Schizophrenia is known to be associated with an overactive dopamine system, meaning that the brain processes abnormally high levels of dopamine. Traditional dopamine-blocking anti-psychotic medication attempts to normalise this process. However, approximately one third of patients with schizophrenia do not respond to this treatment, and until now, no study has examined whether dopamine abnormality is present in patients resistant to antipsychotic treatment.
The study was led by Dr Arsime Demjaha, Dr Oliver Howes, Professor Shitij Kapur, Professor Sir Robin Murray and Professor Philip McGuire from King’s Institute of Psychiatry and published in the American Journal of Psychiatry.
Dr Arsime Demjaha and co-authors, say: ‘Despite considerable scientific and therapeutic progress over the last 50 years, we still do not know why some patients with schizophrenia respond to treatment whilst others do not. Treatment resistance in such a disabling condition is one of the greatest clinical and therapeutic challenges to psychiatry, significantly affecting patients, their families and society in general.’
The authors conclude: ‘Our findings suggest that there may be a different molecular mechanism leading to schizophrenia in patients who do not respond to anti-psychotic medication. Identifying the precise molecular pathway particularly in these patients is of utmost importance and will help inform the development of much-needed novel treatments.’
Researchers used PET scan imaging to investigate dopamine synthesis capacity in 12 patients with schizophrenia who did not respond to treatment, 12 who did, and 12 healthy controls. They found that schizophrenia patients whose illness was resistant to antipsychotic treatment have relatively normal levels of dopamine synthesis capacity which would explain why the dopamine blocking anti-psychotic medication was not effective in this group.
However, the authors add that the findings need to be replicated in larger samples before the research can affect clinical practice. They add that future research will need to focus on long-term prospective studies of patients who have never taken anti-psychotics to determine whether presynaptic dopamine synthesis capacity was normal in patients in the treatment-resistant group at the onset of their illness, and predates antipsychotic exposure.
(Source: kcl.ac.uk)
Is schizophrenia more than one disease?
Schizophrenia wrecks the lives of millions worldwide – and has defeated researchers looking for a single cause. Time for complex new thinking.
PAUL is 21. He thinks the voices started a couple of years ago, but it’s hard to remember exactly because they just seemed to fade in. They whisper insistently, commenting on his actions, trying to control his thoughts and feelings. Living with them is a constant battle, causing him to drop out of college and stop seeing friends. He has been treated in hospital and is being prescribed antipsychotic drugs, but he sees all this as part of a conspiracy.
Paul’s world view is informed by psychosis. This mental state disrupts perception and the interpretation of reality, and is characterised by hallucinations and delusions. Doctors recognise psychosis as a marker for many medical conditions ranging from those caused by electrolyte disturbance to epilepsy, dementia and rare autoimmune disorders.
In Paul’s case these conditions are rapidly excluded. After other short-lived, mood or drug-related causes are also excluded, Paul is diagnosed with schizophrenia - one of a group of disorders characterised by psychosis. But schizophrenia also affects Paul’s emotional and verbal responsiveness, motivation and insight. And it is these functional symptoms that are its most disabling features because they erode the ability to interact with others, maintain social contacts and work.
So what is schizophrenia? In the late 19th century German psychiatrist Emil Kraepelin identified the symptoms and presentation of a disease later called schizophrenia by Eugen Bleuler, a Swiss psychiatrist. Bleuler saw it as an umbrella term for a collection of diseases. Despite attempts to define subtypes or identify specific forms, schizophrenia is still treated broadly as a single disease, and it affects around 1 per cent of adults.
So a shorter, more honest answer to the question of what schizophrenia is would be that we won’t really know until we can define its neurobiological basis. For now, psychosis represents a major frontier in neuroscience because it shakes our certainties about the way we see the world - and understand the brain.
Could poor sleep contribute to symptoms of schizophrenia?
Neuroscientists studying the link between poor sleep and schizophrenia have found that irregular sleep patterns and desynchronised brain activity during sleep could trigger some of the disease’s symptoms. The findings, published in the journal Neuron, suggest that these prolonged disturbances might be a cause and not just a consequence of the disorder’s debilitating effects.
The possible link between poor sleep and schizophrenia prompted the research team, led by scientists from the University of Bristol, the Lilly Centre for Cognitive Neuroscience and funded by the Medical Research Council (MRC), to explore the impact of irregular sleep patterns on the brain by recording electrical brain activity in multiple brain regions during sleep.
For many people, sleep deprivation can affect mood, concentration and stress levels. In extreme cases, prolonged sleep deprivation can induce hallucinations, memory loss and confusion all of which are also symptoms associated with schizophrenia.
Dr Ullrich Bartsch, one of the study’s researchers, said: “Sleep disturbances are well-documented in the disease, though often regarded as side effects and poorly understood in terms of their potential to actually trigger its symptoms.”
Using a rat model of the disease, the team’s recordings showed desynchronisation of the waves of activity which normally travel from the front to the back of the brain during deep sleep. In particular the information flow between the hippocampus — involved in memory formation, and the frontal cortex — involved in decision-making, appeared to be disrupted. The team’s findings reported distinct irregular sleep patterns very similar to those observed in schizophrenia patients.
Dr Matt Jones, the lead researcher from the University’s School of Physiology and Pharmacology, added: “Decoupling of brain regions involved in memory formation and decision-making during wakefulness are already implicated in schizophrenia, but decoupling during sleep provides a new mechanistic explanation for the cognitive deficits observed in both the animal model and patients: sleep disturbances might be a cause, not just a consequence of schizophrenia. In fact, abnormal sleep patterns may trigger abnormal brain activity in a range of conditions.”
Cognitive deficits — reduced short term memory and attention span, are typically resistant to medication in patients. The findings from this study provide new angles for neurocognitive therapy in schizophrenia and related psychiatric diseases.
(Source: eurekalert.org)
Schizophrenia Genetic Networks Identified; Connection to Autism Found
Although schizophrenia is highly genetic in origin, the genes involved in the disorder have been difficult to identify. In the past few years, researchers have implicated several genes, but it is unclear how they act to produce the disorder. A new study by researchers at Columbia University Medical Center identifies affected gene networks and provides insight into the molecular causes of the disease.
The paper was published in the online edition of the journal Nature Neuroscience.
Using an unbiased collection of hundreds of mutations associated with schizophrenia, the Columbia researchers applied a sophisticated computational approach to uncover hidden relationships among seemingly unrelated genes. The analysis revealed that many of the genes mutated in schizophrenia are organized into two main networks, which take part in a few key processes, including axon guidance, synapse function, neuron mobility, and chromosomal modification.
The study also uncovered an intriguing connection between schizophrenia and autism. “If we hadn’t known that these were two different diseases, and had put all the mutations into a single analysis, it would have come up with very similar networks,” said the study’s senior author, Dennis Vitkup, PhD, associate professor in the Department of Biomedical Informatics, the Center for Computational Biology and Bioinformatics, and the Columbia Initiative in Systems Biology at Columbia University Medical Center. “It shows how closely the autism and schizophrenia genetic networks are intertwined,” he added.
Inflammation and Cognition in Schizophrenia
There are a growing number of clues that immune and inflammatory mechanisms are important for the biology of schizophrenia. In a new study in Biological Psychiatry, Dr. Mar Fatjó-Vilas and colleagues explored the impact of the interleukin-1β gene (IL1β) on brain function alterations associated with schizophrenia.
Fatjó-Vilas said that “this study is a contribution to the relatively new field of ‘functional imaging genetics’ which appears to be potentially powerful for the study of schizophrenia, where genetic factors are of established importance and cognitive impairment – affecting particularly executive function and long-term memory – is increasingly recognized as a core feature of the disorder.”
To conduct this study, they recruited patients with schizophrenia and healthy volunteers, all of whom completed a working memory task while undergoing a functional magnetic resonance imaging scan in the laboratory. This allowed the researchers to determine which areas of the brain became activated during the task. Each participant was also genotyped to determine which allelic combination of the -511C/T polymorphism at the promoter region of the IL1β gene they carry: CC, TT, or CT.
Patients who were homozygous for the C allele (CC) showed reduced prefrontal cortex activation associated with working memory than patients who had at least one copy of the T allele. Among the healthy volunteers, frontal brain activation did not differ according to genotype.
“The analyzed genetic variant exerts an influence on prefrontal cortex function and this influence is different in healthy subjects and patients with schizophrenia,” summarized Fatjó-Vilas.
An important issue is that the -511C/T seems to have a role in regulating the levels of IL1B expression, in which case it would influence neuronal activity dependent on the protein availability. This means that the T allele has been reported to be more active than the C allele, suggesting that a tendency for greater expression of IL1β is associated with greater compromise of frontal cortical functions underlying cognition.
Interleukin-1β is released in the blood under stressful conditions and its release is one of the ways that stress promotes inflammation. IL-1β levels in the blood are altered, for example, in patients with depression and other neuropsychiatric disorders.
Apart from having a role in the immune system, interleukins are also involved in a variety of developmental and functioning processes of the central nervous system. Thus, this study provides further clues for identifying specific biological mechanisms of the disorder associated with both neurodevelopmental processes and immunological and stress response functions.
Dr. John Krystal, Editor of Biological Psychiatry, commented, “We are just beginning to explore the functional impact of inflammatory mechanisms in schizophrenia and the current findings increase our curiosity about these novel mechanisms.”
(Source: alphagalileo.org)