New gene variant may explain psychotic features in bipolar disorder

Researchers at Karolinska Institutet have found an explanation for why the level of kynurenic acid (KYNA) is higher in the brains of people with schizophrenia or bipolar disease with psychosis. The study, which is published in the scientific periodical Molecular Psychiatry, identifies a gene variant associated with an increased production of KYNA.

The discovery contributes to the further understanding of the link between inflammation and psychosis, and might pave the way for improved therapies. Kynurenic acid (KYNA) is a substance that affects several signalling pathways in the brain and that is integral to cognitive function. Earlier studies of cerebrospinal fluid have shown that levels of KYNA are elevated in the brains of patients with schizophrenia or bipolar diseases with psychotic features. The reason for this has, however, not been fully understood.

KMO is an enzyme involved in the production of KYNA, and the Karolinska Institutet team has now shown that some individuals have a particular genetic variant of KMO that affects its quantity, resulting in higher levels of KYNA. The study also shows that patients with bipolar disease who carry this gene variant had almost twice the chance of developing psychotic episodes.

KYNA is produced in inflammation, such as when the body is exposed to stress and infection. It is also known that stress and infection may trigger psychotic episodes. The present study provides a likely description of this process, which is more likely to occur in those individuals with the gene variant related to higher production of KYNA. The researchers also believe that the discovery can help explain certain features of schizophrenia or development of other psychotic conditions.

"Psychosis related to bipolar disease has a very high degree of heredity, up to 80 per cent, but we don’t know which genes and which mechanisms are involved," says Martin Schalling, Professor of medical genetics at Karolinska Institutet’s Department of Molecular Medicine and Surgery, also affiliated to the Center for Molecular Medicine (CMM). "This is where our study comes in, with a new explanation that can be linked to signal systems activated by inflammation. This has consequences for diagnostics, and paves the way for new therapies, since there is a large arsenal of already approved drugs that modulate inflammation."

Single gene might explain dramatic differences among people with schizophrenia

Some of the dramatic differences seen among patients with schizophrenia may be explained by a single gene that regulates a group of other schizophrenia risk genes. These findings appear in a new imaging-genetics study from the Centre for Addiction and Mental Health (CAMH).

The study revealed that people with schizophrenia who had a particular version of the microRNA-137 gene (or MIR137), tended to develop the illness at a younger age and had distinct brain features – both associated with poorer outcomes – compared to patients who did not have this version. This work, led by Drs. Aristotle Voineskos and James Kennedy, appears in the latest issue of Molecular Psychiatry.

Treating schizophrenia is particularly challenging as the illness can vary from patient to patient. Some individuals stay hospitalized for years, while others respond well to treatment.

"What’s exciting about this study is that we could have a legitimate answer as to why some of these differences occur," explained Dr. Voineskos, a clinician-scientist in CAMH’s Campbell Family Mental Health Research Institute. "In the future, we might have the capability of using this gene to tell us about prognosis and how a person might respond to treatment."

"Drs. Voineskos and Kennedy’s findings are very important as they provide new insights into the genetic bases of this condition that affects thousands of Canadians and their families," said Dr. Anthony Phillips, Scientific Director at the Canadian Institutes of Health Research Institute of Neurosciences, Mental Health and Addiction.

Also, until now, sex has been the strongest predictor of the age at which schizophrenia develops in individuals. Typically, women tend to develop the illness a few years later than men, and experience a milder form of the disease.

"We showed that this gene has a bigger effect on age-at-onset than one’s gender has," said Dr. Voineskos, who heads the Kimel Family Translational Imaging-Genetics Research Laboratory at CAMH. "This may be a paradigm shift for the field."

The researchers studied MIR137 — a gene involved in turning on and off other schizophrenia-related genes — in 510 individuals living with schizophrenia. The scientists found that patients with a specific version of the gene tended to develop the illness at a younger age, around 20.8 years of age, compared to 23.4 years of age among those without this version.

"Although three years of difference in age-at-onset may not seem large, those years are important in the final development of brain circuits in the young adult," said Dr. Kennedy, Director of CAMH’s Neuroscience Research Department. "This can have major impact on disease outcome."

In a separate part of the study involving 213 people, the researchers used MRI and diffusion tensor-magnetic resonance brain imaging (DT-MRI). They found that individuals who had the particular gene version tended to have unique brain features. These features included a smaller hippocampus, which is a brain structure involved in memory, and larger lateral ventricles, which are fluid-filled structures associated with disease outcome. As well, these patients tended to have more impairment in white matter tracts, which are structures connecting brain regions, and serving as the information highways of the brain.

Developing tests that screen for versions of this gene could be helpful in treating patients earlier and more effectively.

"We’re hoping that in the near future we can use this combination of genetics and brain imaging to predict how severe a version of illness someone might have," said Dr. Voineskos. "This would allow us to plan earlier for specific treatments and clinical service delivery and pursue more personalized treatment options right from the start."

(Image: Akelei van Dam)

Computer Model May Help Athletes and Soldiers Avoid Brain Damage and Concussions

Concussions can occur in sports and in combat, but health experts do not know precisely which jolts, collisions and awkward head movements during these activities pose the greatest risks to the brain. To find out, Johns Hopkins engineers have developed a powerful new computer-based process that helps identify the dangerous conditions that lead to concussion-related brain injuries. This approach could lead to new medical treatment options and some sports rule changes to reduce brain trauma among players.

The research comes at a time when greater attention is being paid to assessing and preventing the head injuries sustained by both soldiers and athletes. Some kinds of head injuries are difficult to see with standard diagnostic imaging but can have serious long-term consequences. Concussions, once dismissed as a short-term nuisance, have more recently been linked to serious brain disorders.

“Concussion-related injuries can develop even when nothing has physically touched the head, and no damage is apparent on the skin,” said K. T. Ramesh, the Alonzo G. Decker Jr. Professor of Science and Engineering who led the research at Johns Hopkins. “Think about a soldier who is knocked down by the blast wave of an explosion, or a football player reeling after a major collision. The person may show some loss of cognitive function, but you may not immediately see anything in a CT-scan or MRI that tells you exactly where and how much damage has been done to the brain. You don’t know what happened to the brain, so how do you figure out how to treat the patient?”

To help doctors answer this question, Ramesh led a team that used a powerful technique called diffusion tensor imaging, together with a computer model of the head, to identify injured axons, which are tiny but important fibers that carry information from one brain cell to another. These axons are concentrated in a kind of brain tissue known as “white matter,” and they appear to be injured during the so-called mild traumatic brain injury associated with concussions. Ramesh’s team has shown that the axons are injured most easily by strong rotations of the head, and the researchers’ process can calculate which parts of the brain are most likely to be injured during a specific event.

The team described its new technique in the Jan. 8 edition of the Journal of Neurotrauma. The lead author, Rika M. Wright, played a major role in the research while completing her doctoral studies in Johns Hopkins’ Whiting School of Engineering, supervised by Ramesh. Wright is now a postdoctoral research fellow at Carnegie Mellon University. Ramesh is continuing to conduct research using the technique at Johns Hopkins with support from the National Institutes of Health.

Beyond its use in evaluating combat and sports-related injuries, the work could have wider applications, such as detecting axonal damage among patients who have received head injuries in vehicle accidents or serious falls. “This is the kind of injury that may take weeks to manifest,” Ramesh said. “By the time you assess the symptoms, it may be too late for some kinds of treatment to be helpful. But if you can tell right away what happened to the brain and where the injury is likely to have occurred, you may be able to get a crucial head-start on the treatment.”

Green tea extract interferes with the formation of amyloid plaques in Alzheimer’s disease

Researchers at the University of Michigan have found a new potential benefit of a molecule in green tea: preventing the misfolding of specific proteins in the brain.

The aggregation of these proteins, called metal-associated amyloids, is associated with Alzheimer’s disease and other neurodegenerative conditions.

A paper published recently in the Proceedings of the National Academy of Sciences explained how Life Sciences Institute faculty member Mi Hee Lim and an interdisciplinary team of researchers used green tea extract to control the generation of metal-associated amyloid-β aggregates associated with Alzheimer’s disease in the lab.

The specific molecule in green tea, (—)-epigallocatechin-3-gallate, also known as EGCG, prevented aggregate formation and broke down existing aggregate structures in the proteins that contained metals—specifically copper, iron and zinc.

"A lot of people are very excited about this molecule," said Lim, noting that the EGCG and other flavonoids in natural products have long been established as powerful antioxidants. "We used a multidisciplinary approach. This is the first example of structure-centric, multidisciplinary investigations by three principal investigators with three different areas of expertise."

The research team included chemists, biochemists and biophysicists.

While many researchers are investigating small molecules and metal-associated amyloids, most are looking from a limited perspective, said Lim, assistant professor of chemistry and research assistant professor at the Life Sciences Institute, where her lab is located and her research is conducted.

"But we believe you have to have a lot of approaches working together, because the brain is very complex," she said.

The PNAS paper was a starting point, Lim said, and her team’s next step is to “tweak” the molecule and then test its ability to interfere with plaque formation in fruit flies.

"We want to modify them for the brain, specifically to interfere with the plaques associated with Alzheimer’s," she said.

Lim plans to collaborate with Bing Ye, a neurobiologist in the LSI. Together, the researchers will test the new molecule’s power to inhibit potential toxicity of aggregates containing proteins and metals in fruit flies.

Age-Related Dementia May Begin with Neurons’ Inability to Rid Themselves of Unwanted Proteins

A team of European scientists from the University Medical Center Hamburg-Eppendorf (UKE) and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) at the University of Cologne in Germany has taken an important step closer to understanding the root cause of age-related dementia. In research involving both worms and mice, they have found that age-related dementia is likely the result of a declining ability of neurons to dispose of unwanted aggregated proteins. As protein disposal becomes significantly less efficient with increasing age, the buildup of these unwanted proteins ultimately leads to the development and progression of dementia. This research appears in the March 2013 issue of the journal Genetics.

“By studying disease progression in dementia, specifically by focusing on mechanisms neurons use to dispose of unwanted proteins, we show how these are interconnected and how these mechanisms deteriorate over time,” said Markus Glatzel, M.D., a researcher involved in the work from the Institute of Neuropathology at UKE in Hamburg, Germany. “This gives us a better understanding as to why dementias affect older persons; the ultimate aim is to use these insights to devise novel therapies to restore the full capacity of protein disposal in aged neurons.”

To make this discovery, scientists carried out their experiments in both worm and mouse models that had a genetically-determined dementia in which the disease was caused by protein accumulation in neurons. In the worm model, researchers in the lab of Thorsten Hoppe, Ph.D., from the CECAD Cluster of Excellence could inactivate distinct routes used for the disposal of the unwanted proteins. Results provided valuable insight into the mechanisms that neurons use to cope with protein accumulation. These pathways were then assessed in young and aged mice. This study provides an explanation of why dementias exponentially increase with age. Additionally, neuron protein disposal methods may offer a therapeutic target for the development of drugs to treat and/or prevent dementias.

“This is an exciting study that helps us understand what’s going wrong at a cellular level in age-related dementias,” said Mark Johnston, Ph.D., Editor-in-Chief of the journal Genetics. “This research holds possibilities for future identification of substances that can prevent, stop, or reverse this cellular malfunction in humans.”

(Image: damato)

Cell death in retina helps tune our internal clocks

With every sunrise and sunset, our eyes make note of the light as it waxes and wanes, a process that is critical to aligning our circadian rhythms to match the solar day so we are alert during the day and restful at night. Watching the sun come and go sounds like a peaceful process, but Johns Hopkins scientists have discovered that behind the scenes, millions of specialized cells in our eyes are fighting for their lives to help the retina set the stage to keep our internal clocks ticking.

In a study that appeared in a recent issue of Neuron, a team led by biologist Samer Hattar has found that there is a kind of turf war going on behind our eyeballs, where intrinsically photosensitive retinal ganglion cells (ipRGCs) are jockeying for the best position to receive information from rod and cone cells about light levels. By studying these specialized cells in mice, Hattar and his team found that the cells actually kill each other to seize more space and find the best position to do their job.

Understanding this fight could one day lead to victories against several conditions, including autism and some psychiatric disorders, where neural circuits influence our behavior. The results could help scientists have a better idea about how the circuits behind our eyes assemble to influence our physiological functions, said Hattar, an associate professor of biology in the Krieger School of Arts and Sciences.

“In a nutshell, death in our retina plays a vital role in assembling the retinal circuits that influence crucial physiological functions such as circadian rhythms and sleep-wake cycles,” Hattar said. “Once we have a greater understanding of the circuit formation underlying all of our neuronal abilities, this could be applied to any neurological function.”

Hattar and his team determined that the killing among rival ipRGCs is justifiable homicide: Without this cell death, circadian blindness overcame the mice, who could no longer distinguish day from night. Hattar’s team studied mice that were genetically modified to prevent cell death by removing the Bax protein, an essential factor for cell death to occur. They discovered that if cell death is prevented, ipRGCs distribution is highly affected, leading the surplus cells to bunch up and form ineffectual, ugly clumps incapable of receiving light information from rods and cones for the alignment of circadian rhythms. To detect this, the researchers used wheel running activity measurements in mice that lacked the Bax protein as well as the melanopsin protein which allows ipRGCs to respond only through rods and cones and compared it to animals where only the Bax gene was deleted.

What the authors uncovered was exciting: When death is prevented, the ability of rods and cones to signal light to our internal clocks is highly impaired. This shows that cell death plays an essential role in setting the circuitry that allows the retinal rods and cones to influence our circadian rhythms and sleep.

(Image: Advanced Retinal Institute, Inc.)

Amputee pain linked to brain retaining picture of missing limb

Changes in the brain following amputation have been linked to pain arising from the missing limb, called ‘phantom pain’, in an Oxford University brain imaging study.

Arm amputees experiencing the most phantom limb pain were found to maintain stronger representation of the missing hand in the brain – to the point where it was indistinguishable from people with both hands.

The researchers hope their identification of brain responses correlated with the level of phantom pain can aid the development of treatment approaches, as well as increase understanding of how the brain reorganises and adapts to new situations.

The Oxford University researchers, along with Dr David Henderson-Slater of the Nuffield Orthopaedic Centre, report their findings in the journal Nature Communications.

‘Almost all people who have lost a limb have some sensation that it is still there, and it’s thought that around 80% of amputees experience some level of pain associated with the missing limb. For some the pain is so great it is hugely debilitating,’ says first author Dr Tamar Makin of the Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) at Oxford University.

Treatments for phantom limb pain tend to be limited to standard drugs for pain relief. The origin of the pain is not well understood. There may be many factors that lead to the pain, including injured nerve endings where the limb was lost and changes in the brain areas connected with the missing limb.

Lynn Ledger, a 48 year old trained therapist and advisor to charities on management training from Nottingham, took part in the study. She had her left arm amputated halfway between the elbow and shoulder in May 2009 after radiotherapy for a rare form of cancer failed to deal with an extensive tumour in her arm. She experiences severe pain as if it was coming from the missing limb.

‘I’ve pretty much tried everything to deal with the pain but nothing has worked,’ Lynn says. ‘There are no drug treatments that work because the condition is not fully understood yet. I can only use various distraction techniques, breathing exercises and mental imagery techniques, to help me manage the pain.

‘It’s very hard to describe the pain to others. I have a nonexistent limb, but I still sense it and feel pain. It’s like: imagine you are wearing a lady’s evening glove that stretches from the fingers up the arm past the elbow. But everywhere the glove covers, it’s as if it’s constantly crushing your arm. There are also shooting pains and intensely painful burning sensations that come and go, but the crushing pain is constant.

‘When I heard about this study I wanted to be involved as it was trying to improve people’s understanding of the condition.’

Kirsty Mason from Bracknell is 22 and about to start a new job as a support worker for people with mental health problems, as well as being an assessor for disabled students for their assisted technology needs. She lost her right arm four years ago just below the elbow after blacking out at a train station and falling on to the rails just ahead of a train coming in. She woke to find a wheel stopped on her arm. Since then she’s learned to write with her left hand and began driving last year. She also took part in the brain imaging study.

‘With me it’s all or nothing,’ Kirsty says of her phantom pain. ‘I get the usual pins and needles and a constant niggling pain that I can shut out by doing other things. But the worst pain is a kind of burning. It’s less frequent but it’s intense: 90-100 on the scale. It sounds silly, but the only thing I can do is stick my hand in a freezer. It numbs it.

She says: ‘I can feel my fist clenching, my fingernails digging in. I can see the hand isn’t there but the sensation is so realistic. If someone throws me a ball, I’ll move both hands to catch it. I’ll put out both hands if I fall over.’

The Oxford University team used MRI imaging to study how the phantom limb pain felt by people who have had an arm amputated is related to changes in the brain.

They compared MRI data for 18 amputees, with differing levels of phantom pain, with 11 individuals born with one hand through a limb deficiency and a control group of 22 adults with two full limbs.

The amputations had been done 18 years ago on average, but the participants still experienced sensations for the missing arm. By asking them to move the fingers of the phantom limb while in the MRI scanner, the researchers were able to look at how the missing hand is represented in the brain.

They found that the brain maintained its representation of the hand, even though the limb was no longer there. The extent to which the representation was maintained was linked to the strength and frequency of the pain the amputees felt: those feeling the greatest pain retained the strongest representation of the missing hand.

‘We were astonished to find that in amputees experiencing strong phantom pain, the brain’s response was indistinguishable from that seen in people with intact limbs,’ says Dr Makin.

The researchers found that the amount of grey matter in the phantom hand area of the brain was reduced in amputees compared to those with two hands. But again this was linked to the amount of pain amputees felt. Those experiencing stronger pain showed less structural degeneration in the missing hand area following the loss of the limb.

However, while those with strong phantom limb pain maintained the local brain structure and function for the missing hand, there was evidence that connections to other parts of the brain were disrupted more.

In particular, the representation of the missing hand was more out of synch with the area looking after the other hand on the opposite side of the brain.

Dr Makin says: ‘Most people experience “phantom” sensations in a missing limb after amputation. This disconnect between the physical world and what they are experiencing appears to be linked to a functional detachment in the brain. There seem to be reduced connections between the missing limb part of the brain and the rest of the cortex that’s involved in movement.

‘Our results may encourage rehabilitation approaches that aim to re-couple the representation of the phantom hand with the external sensory environment.’