Rutgers professor’s advanced analysis could let therapy start earlier and lead MS research in new directions.
The search for the cause of multiple sclerosis, a debilitating disease that affects up to two and a half million people worldwide, has confounded researchers and medical professionals for generations. But Steven Schutzer, a physician and scientist at Rutgers New Jersey Medical School, has now found an important clue why progress has been slow – it appears that most research on the origins of MS has focused on the wrong part of the brain.
Look more to the gray matter, the new findings published in the journal PLOS ONE suggest, and less to the white. That change of approach could give physicians effective tools to treat MS far earlier than ever before.
Until recently, most MS research has focused on the brain’s white matter, which contains the nerve fibers. And for good reason: Symptoms of the disease, which include muscle weakness and vision loss, occur when there is deterioration of a fatty substance called myelin, which coats nerves contained in the white matter and acts as insulation for them. When myelin in the brain is degraded, apparently by the body’s own immune system, and the nerve fiber is exposed, transmission of nerve impulses can be slowed or interrupted. So when patients’ symptoms flare up, the white matter is where the action in the brain appears to be.
But Schutzer attacked the problem from a different direction. He is one of the first scientists to analyze patients’ cerebrospinal fluid (CSF) by taking full advantage of a combination of technologies called proteomics and high-resolution mass spectrometry. “Proteins present in the clear liquid that bathes the central nervous system can be a window to physical changes that accompany neurological disease,” says Schutzer, “and the latest mass spectrometry techniques allow us to see them as never before.” In this study, he used that novel approach to compare the cerebrospinal fluid of newly diagnosed MS patients with that of longer term patients, as well as fluid taken from people with no signs of neurological disease.
What Schutzer found startled one of his co-investigators, Patricia K. Coyle of Stony Brook University in New York, one of the leading MS clinicians and researchers in the country. The proteins in the CSF of the new MS patients suggested physiological disruptions not only in the white matter of the brain where the myelin damage eventually shows up. They also pointed to substantial disruptions in the gray matter, a different part of the brain that contains the axons and dendrites and synapses that transfer signals between nerves.
Several scientists had in fact hypothesized that there might be gray matter involvement in early MS, but the technology needed to test their theories did not yet exist. Schutzer’s analysis, which Coyle calls “exquisitely sensitive,” provides the solid physical evidence for the very first time. It includes a finding that nine specific proteins associated with gray matter were far more abundant in patients who had just suffered their first attack than in longer term MS patients or in the healthy controls. “This evidence indicates gray matter may be the critical initial target in MS rather than white matter,” says Coyle. “We may have been looking in the wrong area.”
According to Coyle, that realization presents exciting possibilities. One, she says, is that patients who suffer attacks that appear related to MS could have their cerebrospinal fluid tested quickly. If proteins that point to early MS are found, helpful therapy could begin at once, before the disease can progress further.
Coyle says Schutzer’s findings may also lead one day to more effective treatments for MS with far fewer side effects. Without specific knowledge of what causes multiple sclerosis, patients now need to take medications that can broadly weaken their immune systems. These drugs slow the body’s destruction of myelin in the brain, but also degrade the immune system’s ability to keep the body healthy in other ways. By suggesting an exciting new direction for MS research, Schutzer and his team may have set the stage for more targeted treatments that attack MS while preserving other important immune functions.
Schutzer sees an even broader future for the work he is now doing. He also has used advanced analysis of cerebrospinal fluid to identify physical markers for neurological ailments that include Lyme disease, in which he has been a world leader in research for many years, as well as chronic fatigue syndrome. He says, “When techniques are refined, more medical conditions are examined, and costs per patient come down, one day there could be a broad panel of tests through which patients and their doctors can get early evidence of a variety of disorders, and use that knowledge to treat them both more quickly and far more effectively than is possible now.”
This research was funded by the National Institutes of Health.
Source: Newsfix.ca Copyright 2013 NewsFix.ca (20/11/13)
White-matter lesions drive deep gray-matter atrophy in early multiple sclerosis: support from structural MRI(13/03/13)
Summary: The researchers looked at the relationship between lesions within the cerebral white matter (WM) and atrophy within the deep grey matter (GM) in MS. In this cross-sectional study, they carried out a 3T MRI on 249 patients with clinically-isolated syndrome or RRMS and in 49 healthy controls. They looked for a spatial relationship between WM lesions and deep GM atrophy using WM lesion probability maps by voxel-wise multiple regressions, including four variables derived from regional deep GM atrophy.
The researchers found that WM lesions and deep grey matter atrophy are spatially related, with atrophy of each deep GM region explained by ipsilateral WM lesion probability. From this they hypothesise that WM lesions contribute to deep GM atrophy through axonal pathology.
BACKGROUND: In MS, the relationship between lesions within cerebral white matter (WM) and atrophy within deep gray matter (GM) is unclear.
OBJECTIVE: To investigate the spatial relationship between WM lesions and deep GM atrophy.
METHODS: We performed a cross-sectional structural magnetic resonance imaging (MRI) study (3 Tesla) in 249 patients with clinically-isolated syndrome or relapsing-remitting MS (Expanded Disability Status Scale score: median, 1.0; range, 0-4) and in 49 healthy controls. Preprocessing of T1-weighted and fluid-attenuated T2-weighted images resulted in normalized GM images and WM lesion probability maps. We performed two voxel-wise analyses: 1. We localized GM atrophy and confirmed that it is most pronounced within deep GM; 2. We searched for a spatial relationship between WM lesions and deep GM atrophy; to this end we analyzed WM lesion probability maps by voxel-wise multiple regression, including four variables derived from maxima of regional deep GM atrophy (caudate and pulvinar, each left and right).
RESULTS: Atrophy of each deep GM region was explained by ipsilateral WM lesion probability, in the area most densely connected to the respective deep GM region.
CONCLUSION: We demonstrated that WM lesions and deep GM atrophy are spatially related. Our results are best compatible with the hypothesis that WM lesions contribute to deep GM atrophy through axonal pathology.
Authors: Mühlau M, Buck D, Förschler A
Sources: MultScler. 2013 Mar 5 & Pubmed PMID: 23462349 (13/03/13)
University of Adelaide scientists have revealed breakthrough research that has the potential to help prevent the progression of multiple sclerosis.
The researchers successfully halted the autoimmune disease in mice.
They hold great hope the same results can be reproduced among humans. MS Research Australia research development manager Dr Lisa Melton said the study results were "extremely exciting".
MS is a progressive disease where the body attacks its own central nervous system, causing nerve inflammation and scarring. It results in the impairment of motor, sensory and cognitive function.
Dr Melton said it provided fresh hope for the 23,000 MS sufferers in Australia.
"It won't be a cure but it's another avenue by which we can reduce the inflammation which damages the brain and spinal cord," she said.
"If this approach works in humans, it would stop the inflammation," she said.
"But it won't undo any damage to the nerves which has already occurred."
In animal trials, Dr Iain Comerford and colleagues at the university successfully prevented the progression of MS by inhibiting the molecule, known as PI3Kgamma, which activates the cells that cause the immune system to attack itself and cause the nerve damage.
The same molecule has been successful in other autoimmune disorder trials.
Human trials were underway in other labs around the world, but any drug would be at least five years away, Dr Comerford said.
"In the animal model, it was preventive and also we could reverse the disease, but it remains to be seen whether that also happens in human beings," he said.
He said the damage in MS patients was caused by white blood cells moving into and attacking the central nervous system.
"We've inhibited an enzyme, PI3Kgamma, which is involved in the activation and migration of white blood cells," Dr Comerford said.
"The white blood cells have to move from the blood into the nervous system to do damage in MS.
"By doing that, we reduce the activation of the white blood cells and reduce the migration of the cells into the central nervous system."
Dr Comerford and his team found that when PI3Kgamma was present, severe damage to myelin, which insulates the nerves, was evident, resulting in inflammation in the spinal cord and myelin loss.
The patient's immune system would still function and provide immune responses which protect against infection.
He said that none of the existing drugs for MS patients was completely effective.
Dr Comerford's research, which was published in the journal PLOS One, was completed under a three-year fellowship from MS Research Australia.
Dr Melton said the research delivered a more targeted approach, than existing drugs used to treat MS.
"We've got drugs that do really well at reducing the relapses which occur in MS but nothing is perfect," she said. "They all have side-effects," she said.
Source: Herald Sun © Herald & Weekly Times Pty Limited (03/10/12)
A single protein implicated in inflammatory brain diseases, including multiple sclerosis and Alzheimer’s disease, could lead to novel treatments and better diagnoses.
Scientists at the Australian Nuclear Science and Technology Organisation (ANSTO) are using a technique called neutron reflectometry to study the translocator protein, which is responsible for transporting molecules across mitochondrial membranes.
The translocator protein is found in cells throughout mammal tissue and is believed to play a number of important roles, including in stress regulation. Its presence in the brain, however, is a sign of inflammation, which can be caused by injury or a number of diseases such as multiple sclerosis and Alzheimer’s disease.
"Virtually not there in healthy brains"
“[The translocator protein] is virtually not there in healthy brains, but then suddenly it appears when there’s brain inflammation, which implies it could be quite important,” explained Claire Hatty, a biophysicist who is involved with the ANSTO research for her PhD.
A paper on the research – which is still in its preliminary stages – will be published in ANSTO Research Selections 2012, due for publication within the next month.
Neutron reflectometry involves firing neutrons at an object, in this case a synthetic cell membrane embedded with the protein. The technique allows researchers to non-invasively penetrate the surface of the cell membrane and closely study its structure.
“We’re using techniques that have traditionally been used in physics, so I find it interesting how we can apply them to biology,” added Hatty.
As part of her PhD research, Hatty hopes to get a closer look at how the translocator protein interacts with drugs on the molecular scale.
New drugs, better imaging for brain inflammation
“Because this protein appears during the inflammatory process that contributes to diseases such as multiple sclerosis, if we can better understand what it is doing and how it’s contributing to that process, we might eventually be able to create drugs that can modulate the process and even reduce the inflammation,” she said. “It’s far-reaching, but it’s what we’re hoping for.”
Other ANSTO researchers are also using the protein for its imaging potential, to scan for brain inflammation. This could be useful as a marker for diseases such as Alzheimer’s, and to scan inflammation caused by brain injuries.
“Processes of neuro-degeneration, such as Alzheimer’s disease, are accompanied by inflammation, so the protein has been used to track brain inflammation before there’s any loss of neurons,” said Hatty.
The result could be earlier diagnosis – and ideally treatment – of Alzheimer’s disease, before symptoms set in.
“Almost all brain diseases have an inflammatory component and the translocator protein is thought to play an important role in this process,” commented Steve Meikle, a medical imaging physicist at the University of Sydney, who was not involved with the ANSTO research.
“This research is providing new insights into the structure and function of this important protein, which will ultimately help the developers of new drugs in their quest to produce more effective treatments for brain diseases such as multiple sclerosis,” he said.
“It will also help the development of new imaging tools that detect inflammation in the brain during the very early stages, when treatment can be most effective.”
Source: Cosmos ©2006-12 Luna Media Pty Ltd (30/08/12)