Neurodegenerative disease mechanism and potential drug identified

Two new studies of progressive, neurodegenerative diseases linked to defects in cells’ mitochondria offer hope for developing a new biomarker for research and diagnostics, and a drug for treating such diseases, report researchers at the University of California, Davis.

Both studies, co-authored by biochemist Gino Cortopassi in the UC Davis School of Veterinary Medicine, have implications for Friedreich’s ataxia, a rare, inherited disease that affects 6,000 people in the United States.

Friedreich’s is characterized by progressive neurodegeneration in the spine, as well as muscle weakness, heart disease and diabetes.

Findings from the two studies are being published this week in the journal Human Molecular Genetics.

Mitochondrial diseases

Friedrich’s ataxia is one of several serious diseases caused by dysfunctional mitochondria — microscopic structures inside the cell that generate the cell’s chemical energy, and play a key role in cell growth, function and death.

In addition to Friedreich’s ataxia, other mitochondrial diseases include Leber’s optic neuropathy, myoneurogenic gastrointestinal encephalopathy, and myoclonic epilepsy with ragged red fibers — complex names for unusual but devastating disorders.

There are currently no Food and Drug Administration-approved therapies for treating mitochondrial diseases, including Friedreich’s ataxia.

Protein defect decreases mitochondria numbers

Inherited deficiencies in the mitochondrial protein frataxin cause Friedreich’s ataxia, but it has been unclear how the deficiency in this single protein leads to the death of neurons and degeneration of muscles.

One of the new studies shows that a loss of the frataxin protein causes a decrease in mitochondrial number in blood and skin cells from patients with Friedreich’s ataxia. Mice with a deficiency in the protein also have fewer mitochondria.

There are two main applications of the new knowledge, Professor Cortopassi said. “Knowing now that the frataxin deficiency causes a shortage of mitochondria, we and others may be able to use the number of mitochondria as a biomarker for determining the disease severity and progression in Friedreich’s ataxia patients,” he said. “Such a biomarker could also be used to evaluate the effectiveness of new drugs for treating the disease.”

MS drug shown to increase mitochondria production

In the second study, Cortopassi and colleagues focused on the drug dimethyl fumarate, or DMF, already approved by the FDA for treating adult patients with a relapsing form of multiple sclerosis as well as psoriasis, an autoimmune skin disease.

DMF is known to help prevent inflammation and protect cells from damage.

In this study, the researchers examined the effects of DMF on human fibroblast (skin) cells, mice and human patients with multiple sclerosis.

The researchers demonstrated that DMF dosing causes increased mitochondrial numbers in human skin fibroblasts, in mouse tissues and in humans. The researchers also showed that the drug enhanced mitochondrial gene expression.

“Taken together, these findings suggest that DMF, by increasing mitochondria, has the potential to lessen the symptoms of muscle diseases, which are caused at least in part by mitochondrial abnormalities,” said Cortopassi, who for 25 years has focused on better understanding “orphan” mitochondrial diseases — disorders so rare that no therapies have been developed for them.

In 2011 he established Ixchel Pharma in an effort to identify existing drugs and customize them for treating patients with Friedreich’s ataxia and other mitochondrial diseases.

What others are saying

The following comments are from researchers not involved with these two studies but knowledgeable about Friedreich’s ataxia and other mitochondrial diseases:

“The studies are highly significant for several reasons. First they identify a novel disease mechanism. While defects in mitochondrial energy production in Friedreich’s ataxia have been known for quite a long time, the loss of mitochondria associated with decreased frataxin provides a rational explanation for these observations. Second, changes in mitochondrial abundance will provide useful biomarkers to assess patients’ responses to therapeutic trials. Third, and most important, the identification of DMF as a mitochondrial stimulator in Friedreich’s ataxia is an important step forward in the search for effective therapies, providing proof of concept that modulation of the signals that tell the cell to make more mitochondria may offer unique opportunities to design effective drugs.”

Giovanni Manfredi, physician and professor, the Brain and Mind Research Institute of Cornell University’s Weill Cornell Medicine, New York City

“This represents groundbreaking work that provides an important contribution to understanding the pathology of both Friedreich’s ataxia and mitochondrial diseases. The advances in these two papers are exciting because they suggest that a current drug could be used to treat FA and mitochondrial DNA diseases, for which there are few therapies. This work also shows the value of basic research in adapting current therapies to extend their range to treat currently devastating diseases.”

Mike Murphy, principal investigator, MRC Mitochondrial Biology Unit, University of Cambridge, UK said, “DMF is a well-known drug approved by regulatory agencies in both the U.S. and Europe and clinically used worldwide for many years. Thus, the finding that it stimulates mitochondrial biogenesis in multiple sclerosis patients is very important and provides great perspectives for the treatment of patients with the many rare disorders affecting mitochondrial function, including the devastating Friedreich’s ataxia. Given the amount of time and money nowadays required for developing brand-new drugs, discovering a new use for a molecule for which detailed clinical information is already available clearly represents a major, if not the only, hope for people affected by an orphan disease.”

 

Experimental therapy for immune diseases hits Achilles heel of activated T cells

Immune diseases like multiple sclerosis and hemophagocytic lymphohistiocytosis unleash destructive waves of inflammation on the body, causing death or a lifetime of illness and physical impairment. With safe and effective treatments in short supply, scientists report in PNAS Early Edition (Proceeding of the National Academy of Sciences) discovery of an experimental treatment that targets an Achilles heel of activated immune cells — killing them off and stopping autoimmune damage.

Researchers at Cincinnati Children’s Hospital Medical Center report in a study published the week of May 22 that a treatment modality they call PPCA takes advantage of DNA damage in rapidly expanding T cells, which they show was therapeutically beneficial in mouse models of hemophagocytic lymphohistiocytosis (HLH) and multiple sclerosis (MS). And for the most part it appears to be so without harming other immune system components needed to protect the body from infection.

“We found that when T cells activate and go through extraordinarily rapid cell division during initial immune responses, it leads to an unusual level of genomic stress in the cells,” explains Michael B. Jordan, MD, lead author and physician/scientist in the divisions of Bone Marrow Transplantation and Immune Deficiency and Immunobiology.

“Because T cells are always in a race with different viruses and bacteria, they have learned how to adapt and divide rapidly to respond, but this stress on their DNA means they also are living right on the edge of death,” Jordan says. “In our experiments we selectively interrupted DNA damage repair in rapidly expanding T cells, and we threw them off balance and into a chasm of death.”

Harnessing a Guardian Angel

PPCA is a newly minted acronym for “p53 potentiation with checkpoint abrogation.” The therapeutic approach was developed by Jordan and his colleagues, including Jonathan Katz, PhD, and David Hildeman, PhD, (Division of Immunobiology). It was conceived during experiments on mouse and donated human immune cells called lymphocytes, which include the aggressively effective germ killers, T cells and B cells.

Researchers hypothesized that along with the highly adaptable and proliferative abilities of T cells came an abundance of genomic stress. They observed as T cells used DNA damage response pathways to survive while adapting and gearing up to attack lymphocytic choriomeningitis virus (LCMV) as it tried to infect cells and animal models.

A gene and its protein called p53 (also called the “guardian of the genome”) helps initiate DNA damage repair — the primary reason researchers decided to target it in T cells. They also leveraged a concept developed for the treatment of cancer called cell cycle checkpoint inhibition or abrogation — in which cells are forced to lose normal control over the mitotic cell division cycle.

Precise Targeting

In selective instances of rapid T cell expansion in mouse models of HLH and experimental autoimmune encephalomyelitis (experimental mouse MS), the researchers used a small molecule called Nutlin to alter the activities of p53. They also inhibited cell cycle checkpoint proteins known as CHK1/2 or WEE1. This prevented the T cells from pausing and repairing their DNA damage, which prompted them to die off.

In mouse models of HLH — mainly a childhood disease where the immune system overheats, attacks healthy tissues, damages organs and causes early death — PPCA reduced disease in the animals and allowed them to survive long-term.

The researchers also tested PPCA treatment in mice with experimental autoimmune encephalomyelitis (EAE) used to model multiple sclerosis. In MS, autoimmune-driven inflammation damages a protective insulating sheath on nerves called myelin. This causes disruptions in the central nervous system that disrupt signals between the brain and extremities, which can lead to paralysis and other symptoms.

In EAE mouse models of MS, PPCA treatment killed off aggressively expanding T cells, tempered autoimmune processes and either reversed or prevented paralysis in the animals, authors report in their study.

Future Steps

Jordan and his research colleagues — including first author Jonathan P. McNally (a recently graduated PhD student in the Immunology graduate program) — caution that their experimental results are early. Years of additional research are needed before knowing whether the current findings will eventually apply to clinical treatment in humans.

The authors now plan to test PPCA in laboratory models of other autoimmune disorders to see how widely applicable it might be. Jordan is listed as an inventor of PPCA in a U.S. patent filing through the Center for Technology Commercialization at Cincinnati Children’s.

Funding support for the research came in part from the National Institutes of Health (RO1DK081175, RO1AI109810, RO1AI057753 and a Research Innovation Grant from Cincinnati Children’s.

Robust, high-throughput protocol for deriving microglia from human stem cells reported

Scientists from the New York Stem Cell Foundation (NYSCF) Research Institute have developed a robust, efficient method for deriving microglia, the immune cells of the brain, from human stem cells. Microglia are increasingly implicated in neurological disorders including Alzheimer’s disease, Parkinson’s disease and multiple sclerosis, among many others. However, research into the role of human microglia in these disorders has long been hampered by the inability to obtain them from the human nervous system. This new protocol now enables scientists around the world to generate this critical cell type from individual patients and improve our understanding of the role of microglia neurological malfunction.

“NYSCF’s mission is to bring cures to patients faster,” said Susan L. Solomon, CEO and co- founder of NYSCF. “One way we work towards this goal is by developing methods and models that lift the entire field of stem cell research. This new protocol is the perfect example of the type of method that will enable researchers around the world to accelerate their work.”

Published in Stem Cell Reports, this microglia protocol is optimized for use in high-throughput experiments, such as drug screening and toxicity testing among other large-scale research applications, and has the benefit of allowing such experiments to be carried out on multiple patient samples. The scientists determined that the protocol is robust and reproducible, generating microglia from sixteen induced pluripotent stem (iPS) cell lines, stem cells that are created from individual patients.

Microglia from humans have long been a desired research model, but are difficult to obtain for laboratory experiments. The NYSCF protocol provides a new source of human microglia cells, which can be generated from disease patient samples and will complement studies in mouse models to better understand the role of microglia in health and disease. Microglia generated by the NYSCF protocol will thus provide a critical tool to investigate microglia dysfunction in central nervous system disorders and advance complex disease modeling in a dish.

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Trigger for autoimmune disease identified

Researchers at National Jewish Health have identified a trigger for autoimmune diseases such as lupus, Crohn’s disease and multiple sclerosis. The findings, published in the April 2017 issue of Journal of Clinical Investigation, help explain why women suffer autoimmune disease more frequently than men, and suggest a therapeutic target to prevent autoimmune disease in humans.

“Our findings confirm that Age-associated B Cells (ABCs) drive autoimmune disease,” said Kira Rubtsova, PhD, an instructor in biomedical science at National Jewish Health. “We demonstrated that the transcription factor T-bet inside B cells causes ABCs to develop. When we deleted T-bet inside B cells, mice prone to develop autoimmune disease remained healthy. We believe the same process occurs in humans with autoimmune disease, more often in elderly women.”

Autoimmune diseases occur when the immune system attacks and destroys the organs and tissue of its own host. Dozens of autoimmune diseases afflict millions of people in the United States. Several autoimmune diseases, including lupus, rheumatoid arthritis and multiple sclerosis strike women two to 10 times as often as men. Overall, about 80 percent of autoimmune patients are women. There is no cure for autoimmune disease.

B cells are important players in autoimmune disease. The National Jewish Health research team, led by Chair of Biomedical Science Philippa Marrack, PhD, previously identified a subset of B cells that accumulate in autoimmune patients, autoimmune and elderly female mice. They named the cells Age-associated B cells, or ABCs. Subsequent research showed that the transcription factor T-bet plays a crucial role in the appearance of ABC.

Transcription factors bind to DNA inside cells and drive the expression of one or several genes. Researchers believe that T-bet appears inside cells when a combination of receptors on B-cell surfaces — TLR7, Interferon-gamma and the B-cell receptor — are stimulated.

Through breeding and genetic techniques the research team eliminated the ability of autoimmune-prone mice to express T-bet inside their B cells. As a result, ABCs did not appear and the mice remained healthy. Kidney damage appeared in 80 percent of mice with T-bet in the B cells and in only 20 percent of T-bet-deficient mice. Seventy-five percent of mice with T-bet in their B cells died by 12 months, while 90 percent of T-bet-deficient mice survived 12 months.

“Our findings for the first time show that ABCs are not only associated with autoimmune disease, but actually drive it,” said Dr. Rubtsova.

ABCs have attracted increasing interests since their discovery in 2011. Dr. Rubtsova and her colleagues at National Jewish Health have expanded their study of ABCs beyond autoimmune disease and are looking at their involvement in sarcoidosis, hypersensitivity pneumonitis and chronic beryllium disease.

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Nose2Brain: Better therapy for multiple sclerosis

Medically active substances are normally distributed via the blood — either directly by injection into the bloodstream or indirectly, for example through the digestive tract after oral administration. In many diseases, however — for example of the central nervous system — it is of decisive importance to transport the active substance as efficiently as possible to the required target site. An example of this is the treatment of multiple sclerosis, where the pharmaceutical agents have to produce their effect above all in the central nervous system. However, this is especially difficult to achieve in the usual way via the blood due to special protective mechanisms such as the blood-brain barrier.

Through the nose direct into the brain

Within the scope of the EU-funded “N2B patch” cooperative project, Fraunhofer IGB is therefore participating in the development of a medical form of therapy that delivers the drug via the Regio olfactoria. The aim of this alternative approach is to enable an active substance to circumvent the path through the bloodstream and to reach the brain directly. Here the brain, together with the surrounding liquid, is only separated from the nasal cavity by the ethmoid bone and some cell layers. The active agent can easily penetrate this barrier and reach the brain directly taking a short route. The therapeutic system will consist of the active agent itself, of a formulation containing the active agent, a hydrogel as carrier material for the formulation, and a suitable applicator for inserting the patch in the nose. The active agent is a biomolecule that stimulates the regeneration of nerve cells.

In the project the scientists at Fraunhofer IGB are concentrating on the formulation of the particles containing the active agent, and on inserting these particles into the gel. The project consortium is developing a special applicator to introduce the gel into the nose. The device is a combination of a standard endoscope and a special mixing system. This system is necessary as the target site is difficult to reach and an already solidified gel could not be deposited in the correct place. The liquid precursors of the gel therefore have to be transported separately to the olfactory epithelium inside the nose. There the various components combine to form a gel with the required consistency, so that the patch remains securely in place.

As the olfactory epithelium is difficult to reach, the gel patch should be applied by a doctor, not by the patients themselves. The active agent will then be released over an extended period of time, so there is then no need to remove the patch again. A new one is simply inserted in the case of long-term treatment.

EU funds Nose2Brain project for four years

The N2B patch project is supported financially by the EU within the scope of the tender procedure “Biomaterials for diagnosis and treatment of demyelination disorders of the central nervous system.” A total of eleven partners from research and industry are participating in the project, which is scheduled to last four years and will be completed at the end of 2020. The special focus of the participating researchers is on the treatment of multiple sclerosis; however, they also hope to develop other fields of application for the N2B platform.

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Unravelling a mystery cause of multiple sclerosis

A new study has made a major new discovery towards finding the cause of multiple sclerosis (MS), potentially paving the way for research to investigate new treatments.

Ahead of MS Awareness Week, which starts today (Monday April 24), an international team involving the University of Exeter Medical School and the University of Alberta has discovered a new cellular mechanism — an underlying defect in brain cells — that may cause the disease, and a potential hallmark that may be a target for future treatment of the autoimmune disorder.

The study was recently published in the Journal of Neuroinflammation and part funded by the Royal Devon & Exeter NHS Foundation Trust.

Professor Paul Eggleton, of the University of Exeter Medical School, said: “Multiple sclerosis can have a devastating impact on people’s lives, affecting mobility, speech, mental ability and more. So far, all medicine can offer is treatment and therapy for the symptoms — as we do not yet know the precise causes, research has been limited. Our exciting new findings have uncovered a new avenue for researchers to explore. It is a critical step, and in time, we hope it might lead to effective new treatments for MS.”

Multiple sclerosis affects around 2.5 million people around the world. Typically, people are diagnosed in their 20s and 30s, and it is more common in women than men.

Although the cause has so far been a mystery, the disease causes the body’s own immune system to attack myelin — the fatty “sheaths” that protect nerves in the brain and spinal cord. This leads to brain damage, a reduction in blood supply and oxygen and the formation of lesions in the body. Symptoms can be wide-ranging, and can include muscle spasms, mobility problems, pain, fatigue, and problems with speech.

Scientists have long suspected that mitochondria, the energy-creating “powerhouse” of the cell, plays a link in causing multiple sclerosis.

The joint Exeter-Alberta research team was the first to combine clinical and laboratory experiments to explain how mitochondria becomes defective in people with MS. Using human brain tissue samples , they found that a protein called Rab32 is present in large quantities in the brains of people with MS, but is virtually absent in healthy brain cells.

Where Rab32 is present, the team discovered that a part of the cell that stores calcium (endoplasmic reticulum or ER) gets too close to the mitochondria. The resulting miscommunication with the calcium supply triggers the mitochondria to misbehave, ultimately causing toxicity for brain cells people with MS.

Researchers do not yet know what causes an unwelcome influx of Rab32 but they believe the defect could originate at the base of the ER organelle.

The finding will enable scientists to search for effective treatments that target Rab32 and embark on determining whether there are other proteins that may pay a role in triggering MS.

Dr David Schley, Research Communications Manager at the MS Society, said, “No one knows for sure why people develop MS and we welcome any research that increases our understanding of how to stop it. There are currently no treatments available for many of the more than 100,000 people in the UK who live with this challenging and unpredictable condition. We want people with MS to have a range of treatments to choose from, and be able to get the right treatment at the right time.”

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Preliminary study suggests possible new treatment for MS

A small, preliminary study may show promise of a new type of treatment for progressive multiple sclerosis (MS). Results from the first six people enrolled in the phase 1 study, a study designed to enroll 10 people, are being presented at the American Academy of Neurology’s 69th Annual Meeting in Boston, April 22 to 28, 2017.

Phase 1 studies are designed to evaluate the safety of a treatment and identify side effects, using a small number of participants. While it was not the goal of this study to measure how effective the treatment was, symptoms improved for three of the six participants.

“While these results are very preliminary and much more research is needed, we are excited there were no serious side effects,” said study author Michael Pender, MD, PhD, of The University of Queensland in Brisbane, Australia.

The study investigates the relationship between MS and the Epstein-Barr virus (EBV), a herpes virus that is extremely common but causes no symptoms in most people. However, when a person contracts the virus as a teenager or adult, it often leads to mononucleosis. Previous research has shown a link between the virus and MS.

The study involved six people with progressive MS with moderate to severe disability. People with progressive MS have a severe condition with slow, steady worsening of symptoms.

In MS, the body’s immune system attacks the nerves in the central nervous system. As part of the normal immune response, immune cells called T cells and B cells work together to protect the body against infectious agents. In some people with MS, the immune response may be altered and T cells may be unable to control EBV-infected B cells, which accumulate in the brain and produce antibodies that attack and destroy myelin, the protective layer that insulates nerves in the brain and spinal cord. This in turns leads to neurologic dysfunction and symptoms. Elimination of the EBV-infected B cells may reduce the destruction of myelin in MS.

For the study, researchers removed the participants’ own T cells and stimulated them to boost their ability to recognize and destroy cells infected with Epstein-Barr virus. They then injected participants with infusions of escalating doses of T cells every two weeks for six weeks. They followed the patients through 26 weeks to look for evidence of side effects and possible improvement of symptoms.

Three of the participants showed improvement, starting two to eight weeks after the first infusion.

“One person with secondary progressive MS showed striking improvement,” Pender said. “This participant had a significant increase in ambulation from 100 yards with a walker at the start of the study, and over the previous five years, to three quarters of a mile, and was now also able to walk shorter distances with only one sided assistance. Lower leg spasms that had persisted for 20 years resolved.”

Pender said another participant with primary progressive MS showed improved color vision and visual acuity.

All three responding participants had improvements in fatigue and ability to perform daily activities.

“The best responses were seen in the two people who received T cells with the highest amount of reactivity to the Epstein-Barr virus,” Pender said.

None of the six participants had serious side effects.

“Of course, much more research needs to be done with larger numbers of participants to confirm and further evaluate these findings,” Pender said. “But the results add to the mounting evidence for a role of the Epstein-Barr virus infection in MS and set the stage for further clinical trials.”

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Microrna treatment restores nerve insulation, limb function in mice with MS

Scientists partially re-insulated ravaged nerves in mouse models of multiple sclerosis (MS) and restored limb mobility by treating the animals with a small non-coding RNA called a microRNA.

In a study published online March 27 in Developmental Cell, researchers at Cincinnati Children’s Hospital Medical Center report that treatment with a microRNA called miR-219 restarted production of a substance called myelin in nerves of the central nervous system. Myelin forms a protective sheath around nerves, allowing them to efficiently transmit electrical impulses that stimulate movement.

Study authors administered miR-219 into the spinal columns and cerebrospinal fluid of mice with nerve coatings damaged by a chemical called lysolecithin or by autoimmune encephalomyelitis induced in the animals, which is used to model MS. Treatment with miR-219 reinvigorated the function of damaged cells called oligodendrocytes that produce myelin, which allowed the substance to reform and reinsulate nerves.

“We show that miR-219 targets multiple processes that inhibit myelin formation after nerve injury by the disease process, and that treatment with this microRNA partially restores myelination and limb function,” said Q. Richard Lu, PhD, lead investigator and scientific director of the Brain Tumor Center at Cincinnati Children’s. “It is conceivable that augmenting miR-219 treatment with other blockers of myelin regrowth may provide a multipoint treatment strategy for people with demyelinating diseases like MS.”

The authors stress that because their study was conducted in laboratory mouse models of disease, their data cannot at this stage be applied to clinical treatment in humans.

Lu’s laboratory studies how certain glial cell subtypes of the central and peripheral nervous system form, participate in regeneration and how they can transform into cancerous cells.

Molecular Silencer

MicroRNAs are short segments of RNA encoded on the chromosomes of cells. They regulate gene expression in cells by acting as molecular silencers, essentially blocking gene expression in certain situations.

A number of earlier research papers have pointed to the absence of miR-219 in the damaged nerves and tissues with certain neurodegenerative diseases like multiple sclerosis.

Lu and his colleagues tested the presence and effects of miR-219 in genetically-engineered mouse models of MS with chemically induced nerve coating damage by lysolecithin and autoimmune encephalomyelitis. They also deleted miR-219 in mice to test the impact this had on myelin-forming oligodendrocyte cells.

The absence of miR-219 allowed a surge of activity by several inhibitors of nerve re-myelination — including a protein called Lingo1. Further testing revealed that miR-219 is an essential part of a network that targets and blocks molecules that inhibit the ability of oligodendrocytes to form myelin.

This prompted the researchers to test treatment with miR-219 in their animal models. For this they used a miR-219 mimic — essentially a synthesized version of the microRNA. After administering the mimic to their mouse models, the researchers noted improved limb function and regeneration of the myelin coating on nerves.

Next steps

Lu and his colleagues are now trying to develop additional mimics of miR-219 and therapeutically effective formulations of the microRNA to ease its delivery — particularly into brain tissue. The researchers also continue to test the potential effectiveness of miR-219 treatment in different models of neurodegenerative disease.

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Researchers find new gene interaction associated with increased MS risk

A person carrying variants of two particular genes could be almost three times more likely to develop multiple sclerosis, according to the latest findings from scientists at The University of Texas Medical Branch at Galveston and Duke University Medical Center.

One of these variants is in IL7R, a gene previously associated with MS, and the other in DDX39B, a gene not previously connected to the disease.

The discovery could open the way to the development of more accurate tests to identify those at greatest risk of MS, and possibly other autoimmune disorders, the researchers said.

The findings are published in the latest issue of Cell.

A disease in which the body’s own immune system attacks nerve cells in the spinal cord and brain, MS is a major cause of neurological disease in younger adults, from 20 to 50 years of age, and disproportionally affects women. While treatable, there is no cure for MS, which can lead to problems with vision, muscle control, balance, basic body functions, among other symptoms, and could lead to disability.

Available treatments have adverse side effects as they focus on slowing the progression of the disease through suppression of the immune system.

Thanks to the collaboration between scientists at UTMB, Duke, University of California, Berkeley, and Case Western Reserve University, researchers found that when two particular DNA variants in the DDX39B and IL7R genes are present in a person’s genetic code, their interaction can lead to an over production of a protein, sIL7R. That protein’s interactions with the body’s immune system plays an important, but not completely understood, role in MS.

“Our study identifies an interaction with a known MS risk gene to unlock a new MS candidate gene, and in doing so, open up a novel mechanism that is associated with the risk of multiple sclerosis and other autoimmune diseases,” said Simon Gregory, director of Genomics and Epigenetics at the Duke Molecular Physiology Institute at Duke University Medical Center and co-lead author of the paper in Cell.

This new information has potentially important applications.

“We can use this information at hand to craft tests that could allow earlier and more accurate diagnoses of multiple sclerosis, and uncover new avenues to expand the therapeutic toolkit to fight MS, and perhaps other autoimmune disorders,” said Gaddiel Galarza-Muñoz, first author on the study and postdoctoral fellow at UTMB.

It can sometimes take years before an MS patient is properly diagnosed allowing the diseases to progress and resulting in further damage to the nervous system before treatment begins.

With more accurate measures of risk, health care providers would be able to screen individuals with family histories of MS or with other suspicious symptoms. It could lead those with certain genotypes to be more vigilant.

“One could envision how this type of knowledge will someday lead to diagnose multiple sclerosis sooner and, now that we have promising therapies, a doctor could start the appropriate treatment more quickly. It is not out the realm of possibility to imagine a path for screening for other autoimmune diseases such as Type 1 Diabetes,” said Dr. Mariano Garcia-Blanco, Professor and Chair of the department of biochemistry and molecular biology at UTMB, and co-lead author of the paper.

For Garcia-Blanco the fight against MS is personal. He was already working on research related to MS when in 2012 he found out his daughter, then in her late 20s, had been diagnosed with the disease. Garcia-Blanco said this refocused his efforts on his MS related work.

“I’m much more aware now of how the work we do in the lab could someday lead to something that can be used to help those who have to live with MS,” Garcia-Blanco said.

 

Researchers report first known case of CTE in patient with no known head trauma

Researchers at Toronto Western Hospital’s Canadian Concussion Centre (CCC) have discovered the presence of chronic traumatic encephalopathy (CTE) in the brain of a deceased patient with no known history of traumatic brain injury or concussion, the first known case of its kind.

The case study, published in the International Journal of Pathology and Research and presented at the CCC’s 5th annual symposium on Research on the Concussion Spectrum of Disorders, discusses the unexpected finding which resulted from an autopsy examining the brain of a patient with a seven-year history of clinically diagnosed amyotrophic lateral sclerosis (ALS) and motor neuron disease (MND), yet no history of head trauma or any participation in activities associated with risk of concussion, according to his family.

“The finding of CTE in an individual who not only had no known head trauma, but also showed no signs of dementia or cognitive impairment and was high functioning mentally until his death, highlights that the cause of CTE might be more complex than we assume,” says Dr. Lili-Naz Hazrati, neuropathologist with the CCC research team who conducted the autopsy.

“So far, we have only seen this neurodegenerative disease in the brains of people with history of brain injury or multiple concussions, and we are not questioning that a relationship may exist between repetitive head trauma and brain degeneration,” she continues. “But, at this point in time, we have more questions than answers about the definitive causes of CTE, and findings like these give us new directions to pursue and investigate.”

“Finding CTE in a patient without a history of concussion is an interesting development that opens up our understanding of this disease,” says Dr. Charles Tator, Director of the CCC and a co-author of the case study. “As researchers, we need to go where the evidence takes us, and it now seems possible that CTE affects a wider range of people. The more we know about this disease, the more likely we’ll be able to figure out how to treat it and perhaps eventually prevent it.”

To date, brain autopsies of cases where individuals reported suffering multiple concussions have yielded a wide range of results, including: no neuropathological changes in the brain, presence of CTE alone, presence of CTE and another neurodegenerative disease, or a non-CTE neurodegenerative disease only.

The majority of brains studied by the CCC and other centres have come from donations made as a result of concern over symptoms — usually of unexplained cognitive impairment — displayed while the individual was alive, though not all of these cases resulted in findings of the CTE tauopathy in the brain. However, the referral of brains of symptomatic individuals who have a history of concussions increases the chances that some form of brain degeneration — whether CTE or other — would be present, which has potential to create a sample that isn’t representative of the overall population.

“Obviously brain trauma and repetitive brain trauma can result in cognitive impairment and possibly contribute to a neurodegenerative disease,” says Dr. Hazrati. “But since we’ve seen cases of brains that experienced multiple concussions but don’t have CTE, and now a brain with CTE but absence of any head trauma, there is indication that we should be cautious about labelling trauma as the only possible cause of CTE because it looks to be more complicated than that.”

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tDCS combined with computer games at home reduces cognitive symptoms of multiple sclerosis

Patients with multiple sclerosis had better problem solving ability and response time after training with a technology called transcranial direct current stimulation (tDCS), according to a new study published February 22, 2017 in Neuromodulation: Technology at the Neural Interface.

During tDCS a low amplitude direct current is applied through electrodes placed on the scalp using a headset. The stimulation can change cortical excitability in the brain by making it easier for neurons to fire, which can help improve connections and speed up the learning that takes place during rehabilitation.

Led by researchers at NYU Langone’s Multiple Sclerosis Comprehensive Care Center, the new study reports that participants with MS who used tDCS while playing the cognitive training computer games designed to improve information processing abilities showed significantly greater gains in cognitive measures than those who played the computer games alone. Importantly, the participants completed the cognitive training and tDCS while at home.

By enabling patients to be treated without repeat visits to the clinic, which can be a major challenge for people with MS as their disease progresses, the approach may improve quality of life for this patient population, according to the study’s authors.

“Our research adds evidence that tDCS, while done remotely under a supervised treatment protocol, may provide an exciting new treatment option for patients with multiple sclerosis who cannot get relief for some of their cognitive symptoms,” says lead researcher Leigh E. Charvet, PhD, associate professor of neurology and director of research at NYU Langone’s Multiple Sclerosis Comprehensive Care Center. “Many MS medications are aimed at preventing disease flares but those drugs do not help with daily symptom management, especially cognitive problems. We hope tDCS will fill this crucial gap and help improve quality of life for people with MS.”

MS is the most common progressive neurological disorder in working age adults, nearly 70 percent of whom will experience cognitive impairment with symptoms including slower information processing and difficulties with memory and problem solving. Other common symptoms of the disease include fatigue and mood, sensory and motor problems.

In this study, the brain’s dorsolateral pre-frontal cortex, an area linked to fatigue, depression and cognitive function, was targeted for tDCS.

Twenty-five participants were provided with a tDCS system with a headset they learned to apply with guided help from the research team. In each session, a study technician would contact each participant through online video conferencing, giving him or her a code to enter into a keypad that commenced the tDCS session in order to control for dosing. Then, during the stimulation, the participant played a research version of computerized cognitive training games that challenged areas of information processing and attention and working memory systems.

Members of the tDCS group participated in 10 sessions, and the researchers compared their results to 20 participants with MS who only played cognitive training games in their 10 sessions.

Researchers found participants in the group treated with tDCS showed significantly greater improvements on sensitive, computer-based measures of complex attention and increases in their response times across trials compared to the group that did cognitive training games alone. Improvements were shown to increase over time with the number of sessions, which suggests the tDCS may have a cumulative benefit. But, more research is needed to determine how long these effects may last following culmination of sessions.

The group that participated in tDCS plus cognitive training however did not show a statistically significant difference from the group that only played cognitive training games as measured by less sensitive standard neuropsychological measures like the Brief International Cognitive Assessment in MS (BICAMS) tests or on computer-based measures of basic attention. Those findings suggest the cognitive changes brought on by tDCS may require more treatment sessions to have noticeable improvements in daily functioning, according to Dr. Charvet.

The researchers are recruiting for additional clinical trials involving 20 tDCS sessions and a randomized sham-controlled protocol, to look for additional evidence of benefits of tDCS. New research has also begun at NYU Langone to test tDCS for other neurological conditions, including Parkinson’s disease.

However, Dr. Charvet warns that some tDCS products on the market are sold straight to consumer without any clinical research behind them or information or guidance on dosing frequency, so it’s important for anyone considering these technologies outside of a controlled research environment to consult with their physician.

The device was designed in conjunction with inventor Marom Bikson, PhD, a professor of biomedical engineering at The City College of New York, and Abhishek Datta, PhD, the chief technology officer of Soterix Medical which holds a patent on the tDCS device. Dr. Charvet provided Bikson’s team with feedback from participants enrolled in the trial to help better design the device. The study was funded by the National Multiple Sclerosis Society and The Lourie Foundation, Inc.