Researchers co-funded by the National MS Society discover possible mechanism for MS d

Researchers funded in part by the National MS Society found evidence that a blood-clotting protein called fibrinogen may play an early role in damage to axons (nerve fibers) in a model of MS-like disease in mice. Axonal damage underlies the progressive disability experienced by people with MS. If confirmed, the findings reveal early events that may trigger nervous system damage in a mouse model of MS, and point to possible new targets for new therapies to protect against that damage in people with MS. Drs. Dimitrios Davalos, Katerina Akassoglou (University of California, San Francisco) and colleagues report their findings in Nature (advanced online publication, November 27, 2012).
Background: In a healthy immune system, brain cells called “microglia” help to keep the brain and spinal cord safe from infectious agents. For reasons that are not yet clear, microglia switch to the offense in the immune attack in MS, serving up triggering molecules to immune T cells and spurring on the attack. Early in the development of MS and in the MS-like disease EAE, there is disruption in the blood-brain barrier (a system of blood vessels that controls what can enter the brain from the bloodstream).
In previous studies, Dr. Akassoglou and colleagues have shown that fibrinogen, a blood-clotting factor, leaks into the brain during the immune attack, and directly activates microglia. By inhibiting fibrinogen after the first attack in mice with the MS-like disease EAE, they were able to decrease the activation of microglia, and subsequent damage to nerve fiber-ensheathing myelin (a main target of the MS attack) diminished dramatically.
The team integrates novel technology, for example, two-photon microscopy, a technique that uses fluorescence to provide vivid, real-time detail of living tissue in action. Dr. Akassoglou’s team, which includes current and former National MS Society postdoctoral research fellows Drs. Dimitrios Davalos, Jae Kyu Ryu, and Natacha Le Moan, developed a way to adapt two-photon microscopy to watch immune cells interacting with nervous system cells and blood cells.
The Study: The team traced early events involved in myelin and axon damage in mice with EAE, and the contributions of fibrinogen in these events. They reported evidence that leakage of fibrinogen through the blood-brain barrier early in the course of EAE correlated with sites of axon damage, and that, when stimulated with fibrinogen, microglia cluster near where the blood-brain barrier is disrupted and where myelin and axon damage are located. The team also showed evidence that fibrinogen is required for the damage to occur.
Fibrinogen is the first protein, among many that leak across the disrupted blood-brain barrier during the course of EAE, shown to stimulate microglia. The authors also noted that fibrinogen induced the release by microglia of “reactive oxygen species,” which are molecules that are active in the immune attack and have been found to directly damage axons. Finally, they identified a surface docking site on microglia, called “CD11b/CD18,” which appears to be how fibrinogen interacts with microglia to exert its nerve-damaging effects.
Comment: Taken together, the team’s studies reveal early events that may trigger nervous system damage in a mouse model of MS, and point to a crucial role for the blood clotting protein fibrinogen in stimulating inflammation that leads to that damage. If these early studies are confirmed, targeting the interaction of fibrinogen and CD11b/CD18 may prove to be a novel strategy for stopping MS damage in its tracks.
Read more about efforts to stop MS.

Cutting-Edge Imaging Study Identifies Key Biological Mechanism In Multiple Sclerosis

Scientists at the Gladstone Institutes have defined for the first time a key underlying process implicated in multiple sclerosis (MS) - a disease that causes progressive and irreversible damage to nerve cells in the brain and spinal cord. This discovery offers new hope for the millions who suffer from this debilitating disease for which there is no cure.

Researchers in the laboratory of Gladstone Investigator Katerina Akassoglou, PhD, have identified in animal models precisely how a protein that seeps from the blood into the brain sets off a response that, over time, causes the nerve cell damage that is a key indicator of MS. These findings, which are reported in the latest issue of Nature Communications, lay the groundwork for much-needed therapies to treat this disease.

MS, which afflicts more than two million people worldwide, develops when the body's immune system attacks the brain. This attack damages nerve cells, leading to a host of symptoms including numbness, fatigue, difficulty walking, paralysis and loss of vision. While some drugs can delay these symptoms, they do not treat the disease's underlying cause - which researchers are only just beginning to understand.

"To successfully treat MS, we must first identify what triggers the disease and what enables its progression," said Dr. Akassoglou, who also directs the Gladstone Center for In Vivo Imaging Research and is a professor of neurology at the University of California, San Francisco, with which Gladstone is affiliated. "Here, we have shown that the leakage of blood in the brain acts as an early trigger that sets off the brain's inflammatory response - creating a neurotoxic environment that damages nerve cells."

Dr. Akassoglou and her team reached this conclusion by using advanced imaging techniques to monitor the disease's progression in the brain and spinal cord of mice modified to mimic the signs of MS. Traditional techniques only show "snapshots" of the disease's pathology. However, this analysis allows researchers to study individual cells within the living brain - and to monitor in real-time what happens to these cells as the disease worsens over time.

"In vivo imaging analysis let us observe in real-time which molecules crossed the blood-brain barrier," said Dimitrios Davalos, PhD, Gladstone staff research scientist, associate director of the imaging center and the paper's lead author. "Importantly, this analysis helped us identify the protein fibrinogen as the key culprit in MS, by demonstrating how its entry into the brain through leaky blood vessels impacted the health of individual nerve cells."

Fibrinogen, a blood protein that is involved in coagulation, is not found in the healthy brain. In vivo imaging over different stages of disease revealed, however, that a disruption in the blood-brain barrier allows blood proteins - and specifically fibrinogen - to seep into the brain. Microglia - immune cells that act as the brain's first line of defense - initiate a rapid response to fibrinogen's arrival. They release large amounts of chemically reactive molecules called 'reactive oxygen species.' This creates a toxic environment within the brain that damages nerve cells and eventually leads to the debilitating symptoms of MS.

Importantly, the team found a strategy to halt this process by genetically modifying fibrinogen in the animal models. This strategy disrupted the protein's interaction with the microglia without affecting fibrinogen's essential role as a blood coagulant. In these models, the microglia did not react to fibrinogen's arrival and did not create a toxic environment. As a result, the mice failed to show the type of progressive nerve cell damage seen in MS.

"Dr. Akassoglou's work reveals a novel target for treating MS - which might protect nerve cells and allow early intervention in the disease process," said Ursula Utz, PhD, MBA, a program director at The National Institutes of Health's National Institute of Neurological Disorders and Stroke, which provided funding for this research.

"Indeed, targeting the fibrinogen-microglia interactions to halt nerve-cell damage could be a new therapeutic strategy," said Dr. Akassoglou. "At present we are working to develop new approaches that specifically target the damaging effects of fibrinogen in the brain. We also continue to use in vivo imaging techniques to further enhance our understanding of what triggers the initiation and progression of MS

Scientists Find Early Immune Trigger Of MS

Using advanced imaging to observe the early stages of nerve damage in mice with MS, scientists in the US believe they have found an important early trigger for the disease: the leakage of a clotting protein across the blood-brain barrier that activates an immune response and results in a toxic environment that damages nerve cells. Through genetic modification, they also found a way to stop the protein triggering the immune response without impairing its ability to clot blood.

A report of the study, led by the Gladstone Institute of Neurological Disease at the University of California - San Francisco (UCSF), was published online in Nature Communications on 27 November 2012.

Researchers Just Starting to Understand Causes and Processes of MS

There are 2 million people worldwide living with MS, a disease that develops when the body's immune system attacks the brain, spinal cord and optic nerve. The attack damages nerve cells, including the myelin sheath that ensures they can send signals to each other via connecting filaments called axons.

As the damage ensues, the nerve signals get weaker and weaker and eventually don't reach the other end, causing a host of symptoms such as numbness, fatigue, difficulty walking, paralysis and loss of vision.

There are drugs that delay the symptoms, but none that removes the underlying cause, which researchers are only just starting to understand.

A new study recently reported in Nature Biotechnology, describes how scientists used nanoparticles to stop MS in mice.

Real-Time Imaging

In this latest UCSF-led study, the team used a high-resolution, real-time imaging technique called "in vivo two-photon microscopy", to observe individual cells in the living brains and spinal cords of mice engineered to develop a disease that mimics the human form of MS.

Traditional imaging techniques only show "snapshots" of the damage that MS can do.

With their latest methods, senior author Katerina Akassoglou, a professor in neurology at UCSF, and her team could see what happens to nerve cells over different stages of the disease.

Akassoglou, who also directs the Gladstone Center for In Vivo Imaging Research, says in a press statement:

"To successfully treat MS, we must first identify what triggers the disease and what enables its progression."

Leakage of Fibrinogen Causes Neurotoxic Environment for Nerve Cells

Akassoglou and colleagues saw that when there is a disruption in the blood brain barrier, it allows blood proteins to seep into the brain.

One of these proteins is a blood-clotting protein called fibrinogen. When it arrives in the brain it immediately activates a strong immune response from microglia cells, the immune system's first line of defence.

The microglia release large amounts of chemically reactive molecules called "reactive oxygen species". These are what create a toxic environment in the brain that results in damage to nerve cells that is seen in MS.

"Here, we have shown that the leakage of blood in the brain acts as an early trigger that sets off the brain's inflammatory response - creating a neurotoxic environment that damages nerve cells," says Akassoglou.

Lead author Dimitrios Davalos, a Gladstone staff research scientist and associate director of the imaging center, says the in vivo imaging analysis let them observe in real-time which of the molecules crossed the blood-brain barrier, and notes:

"Importantly, this analysis helped us identify the protein fibrinogen as the key culprit in MS, by demonstrating how its entry into the brain through leaky blood vessels impacted the health of individual nerve cells."

Targeting Fibrinogen

The team also found a way to stop the leakage: they genetically modified the fibrinogen in the MS mice. The modified protein didn't trigger the microglia response, and so no toxic environment was created. However, the protein was still able to carry out its blood-clotting role.

The treated mice did not show the same progressive nerve cell damage seen with MS.

Akassoglou says "targeting the fibrinogen-microglia interactions to halt nerve-cell damage could be a new therapeutic strategy".

She and her team are currenlty investigating ways to specifically target the damaging effects of fibrinogen in the brain.

"We also continue to use in vivo imaging techniques to further enhance our understanding of what triggers the initiation and progression of MS," notes Akassoglou.

Funding for the study came from the National Multiple Sclerosis Society, the American Heart Association, the Howard Hughes Medical Institute, the Nancy Davis Foundation for Multiple Sclerosis, the Dana Program in Brain and Immuno-Imaging, H. Lundbeck A/S, the National Institutes of Health, and other sources.

Written by Catharine Paddock PhD
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

Basic needs left wanting for 20% people with MS

Prof Marita McCabe at Deakin University conducted the Needs Analysis

Nearly one in five Australians with multiple sclerosis (MS) struggle to have basic home modifications and equipment, including air conditioning, which is needed for them to manage their symptoms. For nearly half of them, it is due to their lack of funds to purchase and install. This is one of the key findings in the National MS Needs Analysis 2012 which surveyed nearly 2,900 people with MS; some 12% of the total group of people with MS in Australia. The next most prominent needs were assistance to manage MS in the workplace (allowing people to stay in employment) and advice on financial planning and benefits. Counseling and peer support also featured as areas of great need, particularly for the newly diagnosed.
The report, perhaps one of the most comprehensive studies of its kind, was launched (today) on the International Day of People with a Disability, Monday December 3. MS Australia, the organisation that represents people with MS across the country, says the report reinforces the desperate need for funding of the NDIS to be confirmed in order to meet the daily, basic needs of people living with disabilities like MS.
The research was undertaken by Dr Marita McCabe and colleagues at Deakin University on behalf of Multiple Sclerosis Research Australia (MSRA) and MS Australia.
It is a detailed analysis of the needs of people with MS in the categories of information, employment, transport, psychological services, peer support, equipment, other support services and respite care.
One of the Report’s recommendations included help with navigating the complex web of disability benefits and financial management needed for people with MS. Their disease-related expenses are high and their ability to work is often greatly reduced as a result of their condition. Access and reliability of transport were also highlighted as a significant issue.
“We found that when people are first diagnosed, they overwhelmingly nominated counseling and peer group support as their most important needs,” said Dr McCabe. “Even if they feel well cared for, sometimes they felt a need for a broader variety of peer support,” she said.
“I congratulate the authors of this thorough report,” said Trevor Farrell, Acting CEO of MS Australia. “People with MS & their families have helped identify the areas to address their progressive and changing needs in an environment with a growing number of MS therapies and the expectations of the National Disability Insurance Scheme. This report will provide a roadmap for MS Societies around the country to focus their efforts to ensure that government and health providers understand those needs”.
The survey, designed by Prof McCabe, was implemented through the long-running MSRA research platform, the Australian MS Longitudinal Study (AMSLS ), managed by Dr Rex Simmons at Canberra Hospital. A previous study has validated the demographic spread of the AMSLS participants as an accurate representation of MS in Australia.
‘We are grateful to everyone who took the time to participate in this study and who helped to make it such a comprehensive report that will inform the provision of services and target research into the future,’ said Jeremy Wright, CEO of MSRA.
To view the National MS Needs Analysis 2012 Report please click here

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