Neuroscience

A novel test that measures proteins from nerve damage that are deposited in blood and spinal fluid reveals the rate of progression of amyotrophic lateral sclerosis (ALS) in patients, according to researchers from Mayo Clinic’s campus in Florida, Emory University and the University of Florida.

Their study, which appears online in the Journal of Neurology, Neurosurgery & Psychiatry, suggests this test, if perfected, could help physicians and researchers identify those patients at most risk for rapid progression. These patients could then be offered new therapies now being developed or tested.

ALS — also known as Lou Gehrig’s disease — is a progressive neurodegenerative disease caused by deterioration of motor neurons (nerve cells) that control voluntary muscle movement. The rate of progression varies widely among patients, and survival from the date of diagnosis can be months to 10 years or more, says Kevin Boylan, M.D., medical director of the ALS Clinic at Mayo Clinic in Florida.

"In the care of our ALS patients there is a need for more reliable ways to determine how fast the disease is progressing," says Dr. Boylan, who is the study’s lead investigator. "Many ALS researchers have been trying to develop a molecular biomarker test for nerve damage like this, and we are encouraged that this test shows such promise. Because blood samples are more readily collected than spinal fluid, we are especially interested in further evaluating this test in peripheral blood in comparison to spinal fluid."

There are no curative or even significantly beneficial therapies in clinics now for ALS treatment, but many are in development, Dr. Boylan says. A test like this could help identify those patients who are at risk for faster progression of weakness. With experimental treatments that primarily slow progression of ALS, detecting a treatment response in patients with faster progression may be easier to detect, says Dr. Boylan. Now, patients with varying rates of progression participate together in clinical studies, which can make analysis of a drug’s benefit difficult, he says.

"If there were a way to identify people who are likely to have relatively faster progression, it should be possible to conduct therapeutic trials with smaller numbers of patients in less time than is required presently," Dr. Boylan says.

A longer-range goal is to develop tests of this kind to gauge how well a patient is responding to experimental therapies, he adds.

The test measures neurofilament heavy form in blood and spinal fluid. These are proteins that provide structure to motor neurons, and when these nerves are damaged by the disease, the proteins break down and float free in blood serum and in the spinal fluid. Earlier research in this area was conducted by Gerry Shaw, Ph.D., a neuroscientist at the University of Florida, who is the study’s senior investigator and the developer of the neurofilament assay used in the study.

The researchers measured neurofilament heavy form in blood and spinal fluid samples from patients at Mayo Clinic and at Emory University, and correlated levels of the protein with rate of progression. “We demonstrated a solid association between higher levels of this protein and a faster progression of muscle weakness,” Dr. Boylan says. There was also evidence suggesting that ALS patients with higher protein levels may have shorter survival, he adds.

Deciphering what causes the brain cell degeneration of Parkinson’s disease has remained a perplexing challenge for scientists. But a team led by scientists from The Scripps Research Institute (TSRI) has pinpointed a key factor controlling damage to brain cells in a mouse model of Parkinson’s disease. The discovery could lead to new targets for Parkinson’s that may be useful in preventing the actual condition.

The team, led by TSRI neuroscientist Bruno Conti, describes the work in a paper published online ahead of print on November 19, 2012 by the Journal of Immunology.

Parkinson’s disease plagues about one percent of people over 60 years old, as well as some younger patients. The disease is characterized by the loss of dopamine-producing neurons primarily in the substantia nigra pars compacta, a region of the brain regulating movements and coordination.

Among the known causes of Parkinson’s disease are several genes and some toxins. However, the majority of Parkinson’s disease cases remain of unknown origin, leading researchers to believe the disease may result from a combination of genetics and environmental factors.

Neuroinflammation and its mediators have recently been proposed to contribute to neuronal loss in Parkinson’s, but how these factors could preferentially damage dopaminergic neurons has remained unclear until now.

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Researchers at McMaster University have discovered new genetic evidence about why some people are happier than others.

McMaster scientists have uncovered evidence that the gene FTO – the major genetic contributor to obesity – is associated with an eight per cent reduction in the risk of depression. In other words, it’s not just an obesity gene but a “happy gene” as well.

The research appears in a study published in the journal Molecular Psychiatry. The paper was produced by senior author David Meyre, associate professor in clinical epidemiology and biostatistics at the Michael G. DeGroote School of Medicine and a Canada Research Chair in genetic epidemiology; first author Dr. Zena Samaan, assistant professor, Department of Psychiatry and Behavioural Neurosciences, and members of the Population Health Research Institute of McMaster University and Hamilton Health Sciences.

“The difference of eight per cent is modest and it won’t make a big difference in the day-to-day care of patients,” Meyre said. “But, we have discovered a novel molecular basis for depression.”

In the past, family studies on twins, and brothers and sisters, have shown a 40 per cent genetic component in depression. However, scientific studies attempting to associate genes with depression have been “surprisingly unsuccessful” and produced no convincing evidence so far, Samaan said.

The McMaster discovery challenges the common perception of a reciprocal link between depression and obesity: That obese people become depressed because of their appearance and social and economic discrimination; depressed individuals may lead less active lifestyles and change eating habits to cope with depression that causes them to become obese.

“We set out to follow a different path, starting from the hypothesis that both depression and obesity deal with brain activity. We hypothesized that obesity genes may be linked to depression,” Meyre said.

The McMaster researchers investigated the genetic and psychiatric status of patients enrolled in the EpiDREAM study led by the Population Health Research Institute, which analyzed 17,200 DNA samples from participants in 21 countries.

In these patients, they found the previously identified obesity predisposing genetic variant in FTO was associated with an eight per cent reduction in the risk of depression. They confirmed this finding by analyzing the genetic status of patients in three additional large international studies.

Meyre said the fact the obesity gene’s same protective trend on depression was found in four different studies supports their conclusion. It is the “first evidence” that an FTO obesity gene is associated with protection against major depression, independent of its effect on body mass index, he said.

This is an important discovery as depression is a common disease that affects up to one in five Canadians, said Samaan.

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.

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Researchers at the University of Copenhagen have found that a protein, known for causing cancer cells to spread around the body, is also one of the molecules that trigger repair processes in the brain. These findings are the subject of a paper, published this week in Nature Communications. They point the way to new avenues of research into degenerative brain diseases like Alzheimer’s.

How to repair brain injuries is a fundamental question facing brain researchers. Scientists have been familiar with the protein S100A4 for some time as a factor in metastasis, or how cancer spreads. However it’s the first time the protein has been shown to play a role in brain protection and repair.

“This protein is not normally in the brain, only when there’s trauma or degeneration. When we deleted the protein in mice we discovered that their brains were less protected and able to resist injury. We also discovered that S100A4 works by activating signalling pathways inside neurons,” says Postdoc Oksana Dmytriyeva, who worked on the research in a team at the Protein Laboratory in the Department of Neuroscience and Pharmacology at the University of Copenhagen.

The villain turns out to be the hero

This research stands on the shoulders of many years of work on S100A4 in its deadlier role in cancer progression. The discovery represents a significant development for the new Neuro-Oncology Group that moved to the University of Copenhagen’s Protein Laboratory Group from the Danish Cancer Society in October.

“We were surprised to find this protein in this role, as we thought it was purely a cancer protein. We are very excited about it and we’re looking forward to continuing our research in a practical direction. We hope that the findings will eventually benefit people who need treatment for neurodegenerative disorders like Alzheimer’s disease, although obviously we have a long way to go before we get to that point,” says Oksana Dmytriyeva.

A team of cognitive neuroscientists has identified the areas of the brain responsible for processing specific words meanings, bringing us one step closer to developing multilingual mind reading machines.

Presenting the findings at the Society for the Neurobiology of Language Conference in San Sebastián, Spain, Joao Correia of Maastricht University explained that his team decided to answer one central question: “how do we represent the meaning of words independent of the language we are listening to?”

Past studies have focused on identifying areas of the brain that generate and hear general terms or feelings. However, if we can locate where the actual concept of a word — which transcends language — is processed, we would be able to read the mind of any individual. The recent case of 39-year-old Scott Routley letting doctors know he is not in pain, just by thinking, is a prime example of where this could be extremely effective in the future. After not responding to any stimulation for more than a decade, Routley was thought to be in a persistent vegetative state. However, by studying fMRI scans in real time neurologists could identify that Routley was in fact responding to their questions — they asked him to think about playing tennis or walking around at home to indicate yes or no. These two actions are processed in different areas of the brain, so answers could be extracted by reading scans. With Correia’s approach, we would need no signifier for yes or no — we could go straight to the source where the processing of the meaning of positive and negative takes place; the “hub”, as he puts it.

"This fMRI study investigates the neural network of speech processing responsible for transforming sound to meaning, by exploring the semantic similarities between bilingual wordpairs," explains an abstract of the study. To achieve this, they needed bilingual volunteers, so worked with eight Dutch candidates all fluent in English. First off, the team monitored the volunteers’ neural activity while saying the words "bull", "horse", "shark" and "duck" in English. All the words chosen had one syllable, were from a similar group and were probably learnt round the same period — this ensured that any differences would specifically relate to meaning. Different brain activity patterns appeared in the left anterior temporal cortex, and each of these were then fed into an algorithm so it would be able to flag up when one of the words was uttered again.

The hypothesis was, if the algorithm could still correctly identify the words when they were spoken in Dutch, these patterns would hold the key to where the word concepts are derived. The algorithm did exactly that. It demonstrates that words are encoded in the same way in the brain, regardless of language.

There is one pretty major drawback to the process, which quashes any visions of a full-on real-time mind translation machine hitting stores anytime soon — the neural activity patterns differed slightly from person to person. Our neurons learn and identify in unique ways, and understanding these pathway patterns through machine learning would be a long process. “You would have to scan a person as they thought their way through a dictionary,” said Matt Davis of the MRC Cognition and Brain Sciences Unit in Cambridge. It would be difficult to translate a mind now without this concept map. However, we are only at the beginning of this line of study, and an algorithm could potentially be devised to aggregate hundreds of neural activity patterns to help indicate what the brain activity of an individual unable to communicate represents.

Researchers and patients look forward to the day when stem cells might be used to replace dying brain cells in Alzheimer’s disease and other neurodegenerative conditions. Scientists are currently able to make neurons and other brain cells from stem cells, but getting these neurons to properly function when transplanted to the host has proven to be more difficult. Now, researchers at Sanford-Burnham Medical Research Institute have found a way to stimulate stem cell-derived neurons to direct cognitive function after transplantation to an existing neural network. The study was published November 7 in the Journal of Neuroscience.

“We showed for the first time that embryonic stem cells that we’ve programmed to become neurons can integrate into existing brain circuits and fire patterns of electrical activity that are critical for consciousness and neural network activity,” said Stuart A. Lipton, M.D., Ph.D., senior author of the study. Lipton is director of Sanford-Burnham’s Del E. Webb Neuroscience, Aging, and Stem Cell Research Center and a clinical neurologist.

The trick turned out to be light. Lipton and his team—including Juan Piña-Crespo, Ph.D., D.V.M., Maria Talantova, M.D., Ph.D., and other colleagues at Sanford-Burnham and Stanford University—transplanted human stem cell-derived neurons into a rodent hippocampus, the brain’s information-processing center. Then they specifically activated the transplanted neurons with optogenetic stimulation, a relatively new technique that combines light and genetics to precisely control cellular behavior in living tissues or animals.

To determine if the newly transplanted, light-stimulated human neurons were actually working, Lipton and his team measured high-frequency oscillations in existing neurons at a distance from the transplanted ones. They found that the transplanted neurons triggered the existing neurons to fire high-frequency oscillations. Faster neuronal oscillations are usually better—they’re associated with enhanced performance in sensory-motor and cognitive tasks.

To sum it up, the transplanted human neurons not only conducted electrical impulses, they also roused neighboring neuronal networks into firing—at roughly the same rate they would in a normal, functioning hippocampus.

The therapeutic outlook for this technology looks promising. “Based on these results, we might be able to restore brain activity—and thus restore motor and cognitive function—by transplanting easily manipulated neuronal cells derived from embryonic stem cells,” Lipton said.