Neuroscience

A research team led by Robert Nagele, PhD, of the New Jersey Institute for Successful Aging (NJISA) at the University of Medicine and Dentistry of New Jersey (UMDNJ)-School of Osteopathic Medicine, has demonstrated that the anti-atherosclerosis drug darapladib can significantly reduce leaks in the blood brain barrier. This finding potentially opens the door to new therapies to prevent the onset or the progression of Alzheimer’s disease. Writing in the Journal of Alzheimer’s Disease (currently in press), the researchers describe findings involving the use of darapladib in animal models that had been induced to develop diabetes mellitus and hypercholesterolemia (DMHC), which are considered to be major risk factors for Alzheimer’s disease.

“Diabetes and hypercholesterolemia are associated with an increased permeability of the blood-brain barrier, and it is becoming increasingly clear that this blood-brain barrier breakdown contributes to neurodegenerative diseases such as Alzheimer’s,” Nagele said. “Darapladib appears to be able to reduce this permeability to levels comparable to those found in normal, non-DMHC controls, and suggests a link between this permeability and the deposition of amyloid peptides in the brain.”

The study involved 28 animal (pig) models that were divided into three groups – DMHC animals treated with a 10 mg/day dose of darapladib; DMHC animals that received no treatment; and non-DMHC controls. Post-mortem analysis of the brains of the darapladib-treated animals showed significant decreases in blood-brain barrier leakage and in the density of amyloid-positive neurons in the cerebral cortices. Interestingly, the amyloid peptides that leaked into the brain tissue were found almost exclusively in the pyramidal neurons of the cerebral cortex, one of the earliest pathologies of the development of Alzheimer’s disease.

“Because our results suggest that these metabolic disorders can trigger neurodegenerative changes through blood-brain barrier compromise, therapies – such as darapladib – that can reduce vascular leaks have great potential for delaying the onset or slowing the progression of diseases like Alzheimer’s,” said the study’s lead author, Nimish Acharya, PhD, of the NJISA and the UMDNJ-Graduate School of Biomedical Sciences. “The clinical, caregiving and financial impact of such an effect cannot be overestimated.”

The British astrophysicist Stephen Hawking is likely to be the world’s most famous person living with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. ALS is a progressive disease affecting motor neurons, nerve cells that control muscle function, and nearly always leads to death. Researchers at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) in Vienna have now identified a completely new mechanism in the onset of motor neuron diseases. Their findings could be the basis for future treatments for these presently incurable diseases.

A new principle on motor neuron death
The IMBA scientists, working with an international team of researchers under the leadership of Josef Penninger and Javier Martinez, discovered a completely new fundamental mechanism that triggers the death of motor neurons. Motor neurons are nerve cells responsible for stimulating muscles. The loss of these motor neurons in mice with a genetic mutation in a gene named CLP11 leads to severe and progressive muscular paralysis and, in some cases, to death.
"We’ve been working on resolving the function of the CLP1 gene in a living organism for a long time. To do that, we developed model mice in which the function of CLP1 was genetically inactivated. To our utter surprise we discovered that deactivating CLP1 increases the sensitivity of cell die when exposed to oxidative stress2. That leads to enhanced activity of the p53 protein3 and then to the permanent destruction of motor neurons," says Toshikatsu Hanada, a postdoctoral researcher working in the lab of Josef Penninger and first author of the study along with Stefan Weitzer.

Stephen Hawking - a most renowned patient
Motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are chronic disorders of the neuromuscular system. These diseases are caused by damage in the motor nerve cells in the brain and spinal cord, and the nerves can no longer stimulate motion in the muscles. The primary symptoms are muscular weakness, muscular dystrophy, and problems swallowing or speaking. Stephen Hawking was diagnosed with ALS 50 years ago. But not all ALS patients live so long with the disease: so far there are no treatments for ALS. Nearly all ALS patients die of paralysis of respiratory muscles within a few years.

Completely new disease mechanism
Javier Martinez, an IMBA team leader and co-author of the study, is a specialist in the field of ribonucleic acid (RNA) research. His research group had discovered the CLP1 gene in an earlier study, published in Nature in 2007. Until now, the exact essential function of CLP1 in RNA biology was unclear. “By deactivating CLP1, we have discovered a previously unknown new species of RNA,” says Javier Martinez about the scientific relevance of the work. “The accumulation of this RNA is a consequence of increased oxidative stress in the cell. We see this as one of the triggers for the loss of motor neurons that occurs in ALS and other neuromuscular diseases. Thus our findings describe a completely new mechanism of motor neuron diseases.”

Seminal findings
Josef Penninger, scientific director at the IMBA and last-author of the study, is excited about the researchers’ findings: “This surprising discovery of a role of CLP1 in the onset of motor neuron diseases is an entirely new principle in how RNA talks to oxidative stress. Nearly all genetic mutations found in ALS patients affect either RNA metabolism or oxidative stress, suggesting a possibly unifying principle for these diseases. Our work may have revealed the ‘missing link’ in how these two biological systems communicate and trigger incurable diseases like ALS.”

Stefan Weitzer sees tremendous potential for these findings: “We’ve discovered a new mechanism that leads to the death of motor neurons. If this holds true for other neuronal disease, our results could be one day used to drive the development of treatments for previously incurable diseases. In our work we also describe how the p53 protein regulates the loss of motor neurons. Removing p53 saves mice with CLP1 mutations from certain death.” If scientists are successful in applying these findings to people, the researchers may have discovered a treatment approach to cure ALS and similar diseases. The authors, however, caution that more studies will be needed to translate their findings to human medicine.

This study was performed in collaboration with research groups from the Medical Universities of Vienna and Innsbruck, the University Medical Center at Hamburg-Eppendorf in Germany, the Harvard Medical School, the Harvard Stem Cell Institute, the Boston Children’s and Massachusetts General Hospitals, the Keio University School of Medicine in Tokyo, Oita University in Japan, and the Weizmann Institute of Science in Rehovot in Israel.

Their work, “CLP1 links tRNA metabolism to progressive motor-neuron loss”, was published on March 10, 2013 in “Nature”, an internationally renowned journal.

People with multiple sclerosis (MS) who have cognitive problems, or problems with memory, attention, and concentration, have more damage to areas of the brain involved in cognitive processes than people with MS who do not have cognitive problems, according to a study published in the March 6, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.

The study used a type of MRI brain scan called diffusion tensor imaging along with regular MRI scans to compare brain measurements in 20 people with MS who had related cognitive problems, 35 people with MS who did not have cognitive problems and 30 healthy participants.

The diffusion tensor images showed that, compared to the healthy control participants, 49 percent of the investigated brain white matter had impaired integrity in those with MS and no cognitive problems, while impaired integrity was evident in 76 percent of the investigated white matter of those with MS and related cognitive problems. In the people with MS-related cognitive problems, the extra white matter dysfunction was particularly seen in areas important for cognitive skills, such as the thalamus.

“This state-of-the-art imaging technology confirms that cognitive symptoms in MS have a biological basis,” said study author Hanneke E. Hulst, MSc, of VU University Medical Center in Amsterdam, the Netherlands. “The consequence of this discovery is that imaging can now be used to capture a wider spectrum of changes in the brains of people with MS, and will therefore help determine more accurately whether new treatments are helping with all aspects of the disease.” Cognitive problems are common in MS, affecting up to 65 percent of people with the disease.

For the first time, an international team of researchers has found that a combination of a particular virus in the mother and a specific gene variant in the child increases the risk of the child developing schizophrenia.

Viruses and genes interact in a way that may increase the risk of developing schizophrenia significantly. This happens already in the developing foetus.

An international team of scientists led by Aarhus University, Denmark, has made this discovery. As the first in the world, they scanned the entire genome of hundreds of sick and healthy people to see if there is an interaction between genes and a very common virus - cytomegalovirus - and to see whether the interaction influences the risk of developing schizophrenia.

And it does.

Women that have been infected by the virus - and around 70% has - will have a statistically significant increased risk of giving birth to a child who later develops schizophrenia if the child also has the aforementioned gene variant. This variant is found in 15 percent. The risk is five times higher than usual, the researchers report in Molecular Psychiatry.

No cause for alarm

People infected with cytomegalovirus most often do not know it, as the infection by the virus, which belongs to the herpes virus family, is usually very mild. But the researchers stress that there is no cause for alarm - even if both risk factors are present in mother and child, there may be a variety of other factors that prevents disease development in the child.

But as schizophrenia affects 1 per cent of the global population, this new knowledge is very important.

"In the longer term, the development of an effective vaccine against cytomegalovirus may help to prevent many cases of schizophrenia," says Professor of Medical Genetics at Aarhus University, Anders Børglum.

"And our discovery emphasizes that mental disorders such as schizophrenia may arise in the context of an interaction between genes and biological environmental factors very early in life."

Every year thousands of people in Europe are paralysed by a spinal cord injury. Many are young adults, facing the rest of their lives confined to a wheelchair. Although no medical cure currently exists, in the future they could be able to walk again thanks to a mind-controlled robotic exoskeleton being developed by EU-funded researchers.

The system, based on innovative ‘Brain-neural-computer interface’ (BNCI) technology - combined with a light-weight exoskeleton attached to users’ legs and a virtual reality environment for training - could also find applications in the rehabilitation of stroke victims and in assisting astronauts rebuild muscle mass after prolonged periods in space.

In the United Kingdom, every eight hours someone suffers a spinal cord injury, often leading to partial or full lower-body paralysis. In the United States, more than 250.000 people are living with paralysis as a result of damage to their spinal cord, usually because of a traffic accident, fall or sporting injury. Many are under the age of 50, and with no known medical cure or way of repairing damaged spinal nerves they face the rest of their lives in a wheelchair.

But by bypassing the spinal cord entirely and routing brain signals to a robotic exoskeleton, they should be able to get back on their feet. That is the ultimate goal of researchers working in the ‘Mind-controlled orthosis and VR-training environment for walk empowering' (Mindwalker) project, a three-year initiative supported by EUR 2.75 million in funding from the European Commission.

'Mindwalker was proposed as a very ambitious project intended to investigate promising approaches to exploit brain signals for the purpose of controlling advanced orthosis, and to design and implement a prototype system demonstrating the potential of related technologies,' explains Michel Ilzkovitz, the project coordinator at Space Applications Services in Belgium.

The team’s approach relies on an advanced BNCI system that converts electroencephalography (EEG) signals from the brain, or electromyography (EMG) signals from shoulder muscles, into electronic commands to control the exoskeleton.

The Laboratory of Neurophysiology and Movement Biomechanics at the Université Libre de Bruxelles (ULB) focused on the exploitation of EEG and EMG signals treated by an artificial neural network, while the Foundation Santa Lucia in Italy developed techniques based on EMG signals modelled by the coupling of neural and biomechanical oscillators.

One approach for controlling the exoskeleton uses so-called ‘steady-state visually evoked potential’, a method that reads flickering visual stimuli produced at different frequencies to induce correlated EEG signals. Detection of these EEG signals is used to trigger commands such as ‘stand’, ‘walk’, ‘faster’ or ‘slower’.

A second approach is based on processing EMG signals generated by the user’s shoulders and exploits the natural arm-leg coordination in human walking: arm-swing patterns can be perceived in this way and converted into control signals commanding the exoskeleton’s legs.

A third approach, ‘ideation’, is also based on EEG-signal processing. It uses the identification and exploitation of EEG Theta cortical signals produced by the natural mental process associated with walking. The approach was investigated by the Mindwalker team but had to be dropped due to the difficulty, and time needed, in turning the results of early experiments into a fully exploitable system.

Regardless of which method is used, the BNCI signals have to be filtered and processed before they can be used to control the exoskeleton. To achieve this, the Mindwalker researchers fed the signals into a ‘Dynamic recurrent neural network’ (DRNN), a processing technique capable of learning and exploiting the dynamic character of the BNCI signals.

'This is appealing for kinematic control and allows a much more natural and fluid way of controlling an exoskeleton,' Mr Ilzkovitz says.

The team adopted a similarly practical approach for collecting EEG signals from the user’s scalp. Most BNCI systems are either invasive, requiring electrodes to be placed directly into brain tissue, or require users to wear a ‘wet’ capon their head, necessitating lengthy fitting procedures and the use of special gels to reduce the electrical resistance at the interface between the skin and the electrodes. While such systems deliver signals of very good quality and signal-to-noise ratio, they are impractical for everyday use.

The Mindwalker team therefore turned to a ‘dry’ technology developed by Berlin-based eemagine Medical Imaging Solutions: a cap covered in electrodes that the user can fit themselves, and which uses innovative electronic components to amplify and optimise signals before sending them to the neural network.

'The dry EEG cap can be placed by the subject on their head by themselves in less than a minute, just like a swimming cap,' Mr Ilzkovitz says.

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According to a 2012 World Health Organization report, over 35 million people worldwide currently have dementia, a number that is expected to double by 2030 (66 million) and triple by 2050 (115 million). Alzheimer’s disease, the most common form of dementia, has no cure and there are currently only a handful of approved treatments that slow, but do not prevent, the progression of symptoms.

New drug development, no matter the disease, is a slow, expensive, and risky process. Thus, innovative techniques to study and assess the possibilities of already-existing drugs for different diseases can be used to alleviate the traditional burdens of cost and time. Detailed in their new article in Biological Psychiatry, researchers from the University of Washington, led by Dr. Brian Kraemer, have developed an exciting new approach to screening potential new treatments for Alzheimer’s disease using C. elegans, a small transparent worm.

Their focus was on tau, a protein involved in maintaining brain cell structure. In Alzheimer’s disease and related disorders, tau protein becomes abnormally modified and forms clumps of protein called aggregates. These aggregates are a hallmark of the dying nerve cells in Alzheimer’s disease and other related disorders. Diseases with abnormal tau are called tauopathies.

Dr. Kraemer’s lab previously developed a worm model for tauopathy by expressing human tau in C. elegans nerve cells. This model has behavioral abnormalities, accumulates abnormal tau protein, and exhibits loss of nerve cells—all of which are general features of Alzheimer’s disease.

Using their worm model for this study, they screened a library of 1,120 drugs approved for human use and tested each at three different concentrations to identify compounds that suppress the effects of abnormal tau aggregation.

“We have identified six compounds capable of reliably alleviating tau induced behavioral abnormalities in our C. elegans model for tauopathy. In a human cultured cell model for abnormal tau protein, we have also seen that azaperone treatment can decrease the amount of abnormal tau,” said Kraemer.

Azaperone, an antipsychotic drug, normally binds to certain dopamine receptors found in nerve cells. They demonstrated that removing those receptors in either C. elegans or human cells has the same effect as azaperone treatment, indicating that azaperone and related drugs should alter abnormal tau accumulation. Other antipsychotic drugs also have a similar effect to azaperone.

Tests of these compounds for anti-tau properties are now underway in existing mouse models of Alzheimer’s disease.

“This study is an exemplary instance of how a simple C. elegans model system may be used to rapidly screen drugs for diseases and evaluate mechanism of action,” said Drs. Sangeetha Iyer and Jonathan Pierce-Shimomura, authors of a commentary that accompanies this article.

Dr. John Krystal, Editor of Biological Psychiatry, agrees and added: “Studying the worm, C. elegans, has already provided us with fundamental insights into how the brain develops. The new approach described by McCormick and colleagues suggests that this animal model may be a powerful new approach to studying novel treatments that prevent its decline.”

Last month, the National Institutes of Health announced a new collaborative initiative that aims to accelerate the search for biomarkers — changes in the body that can be used to predict, diagnose or monitor a disease — in Parkinson’s disease, in part by improving collaboration among researchers and helping patients get involved in clinical studies. As part of this program, launched by the National Institute of Neurological Disorders and Stroke (NINDS), part of the NIH, Clemens Scherzer, MD, a neurologist and researcher at Brigham and Women’s Hospital (BWH), was awarded $2.6 million over five years to work on the development of biomarkers and facilitate NINDS-wide access to one of the largest data and biospecimens bank in the world for Parkinson’s available at BWH. This NINIDS initiative is highlighted in an editorial in the March issue of Lancet Neurology.

"There is a critical gap in the research that leads to lack of treatment for diseases like Parkinson’s," said Scherzer. "Biomarkers are desperately needed to make clinical trials more efficient, less expensive and to monitor disease and treatment response. We are hopeful that this initiative will fast track new discoveries in this area."

According to Scherzer, most of our knowledge of the human brain is based on the analysis of just 1.5 percent of the human genome that encodes proteins. The first part of Scherzer’s project will examine the function of the remaining 98.5 percent of the genome that, so far, has been unexplored in the human brain. While this remainder had been previously dismissed as “junk”, it is now becoming clearer that parts of it actively regulate cell biology.  Scherzer and colleagues believe that “dark matter” RNA transcribed from stretches of so called “junk” DNA is active in brain cells and contributes to the complexity of normal dopamine neurons and, when corrupted, Parkinson’s disease.

"This offers a potentially ground breaking opportunity for biomarker development. Initially, the team will search for these RNAs associated in brain tissue of individuals at earliest stages of the disease. Then, this team will look for related biomarkers in the bloodstream and cerebrospinal fluid in both healthy brains and those with Parkinson’s," Scherzer said.

Scherzer’s lab has been spearheading biomarker research in this field since 2004 and the team already has 2,000 patients enrolled and being followed in a longitudinal study with rich clinical data and one of the largest biobanks in the world for Parkinson’s tissue with support from the Harvard NeuroDiscovery Center. The biobank was designed as an incubator for Parkinson’s research and until now was chiefly available for research collaborations within the Harvard-affiliated community. As part of this new project, this vast resource will be open to all NIH-funded investigators.

"Our ultimate goal is to personalize treatment for our patients with Parkinson’s." said Scherzer. "By opening up this vast collection of specimens, we are exploding the resources that are available to NIH-funded investigators looking at this disease. We hope to harness the power of collaboration to speed up biomarkers discovery."