A report of recent research progress in MS
The National Multiple Sclerosis Society
An international team of investigators has found an unexpected role for a brain molecule, and if further research confirms and expands their laboratory findings, this work may provide a new lead for developing better therapies for multiple sclerosis.
The molecule in question is Nogo, a protein normally found in the brain, especially in the myelin coating that insulates nerve fibers. Nogo is known to inhibit nerve regeneration, and may be a key player in a long-known phenomenon: Nerve fibers in the brain and spinal cord do not easily repair themselves the way they can in the peripheral nervous system.
Investigators hope to unlock Nogo’s secrets to discover ways to stimulate nerve repair in the brain — a vital quest for restoring function in persons with MS, spinal cord injury, stroke and other conditions.
One of several teams around the world focusing on Nogo, Drs. Claude C. A. Bernard, Tara Karnezis (La Trobe University, Bundoora, Australia) and colleagues have now successfully reduced the severity and duration of MSlike disease in mice by vaccinating them with Nogo.
While this might seem to be a contradictory result, they determined that the vaccinations caused the mice’s immune systems to produce their own antibodies that neutralized Nogo’s inhibitory activity in the nervous system. The vaccinations might also have reduced inflammation.
This pathbreaking research, described in a report published online in June 2004 in Nature Neuroscience (slated for the July 7, 2004 print issue), was partially funded by the National Multiple Sclerosis Society.
In a logical succession of controlled experiments, the investigators were able to show that mice that received weekly, subcutaneous injections of Nogo were less prone to laboratory-induced EAE, an experimental disease involving an autoimmune attack against brain and spinal cord tissues. This disease model is thought to reflect many features of MS in people.
Compared to mice that did not get the Nogo vaccinations, the treated mice showed significant reductions in the incidence and severity of EAE. Their brain and spinal cord tissues also showed reductions of inflammatory lesions (damaged areas), and decreases in the amount and extent of myelin and nerve fiber damage.
Subsequent experiments showed that mice bred to be deficient in Nogo also had some protection against EAE, having delayed onset, shorter duration and milder symptoms of the disease, compared to regular laboratory mice.
How Does It Work?
The investigators conducted experiments aimed at discovering how Nogo vaccinations altered the course of EAE. In addition to inducing antibodies that neutralized Nogo activity, Nogo vaccinations altered other immune responses underlying EAE, taming a normally aggressive immune attack. They found no evidence that in these mice, the Nogoblocking vaccinations fostered nerve regeneration.
These findings, suggested the authors in their report, “…indicate that this molecule may have a far more complex role than... previously anticipated.” Further research is ongoing to decipher that role, and to determine whether Nogo or any similar molecule holds promise in the development of a new treatment for people with MS.
Society funding for this work included a research grant to Claude Bernard, DSc, PhD, and a postdoctoral fellowship to collaborator Wim Mandemakers, PhD (Stanford University Medical Center), whose project was paid in full by the Alan Buegeleisen Research Fund, in honor of National MS Society founder Sylvia Lawry.
First Publication from the Society’s Sonya Slifka Longitudinal MS Study
The first publication from the Sonya Slifka Longitudinal Multiple Sclerosis Study points to challenges facing persons who are aging with MS. This first pass, which explores baseline responses and does not look at changes over time, only skims the surface of the wealth of information beginning to accumulate from this effort. That wealth is now being made available to qualified investigators seeking clues to the impact of MS over time.
One of the National MS Society’s targeted research initiatives begun in 1999, the Slifka study is following a sample of the MS population in the U.S. over a long period of time. The seven-year, $3.3 million grant was supported in part by a gift from the Society’s Past Chair Richard Slifka, and named in honor of his mother.
Sarah Minden, MD, and colleagues (Abt Associates, Inc., Cambridge, MA) collect information from participants every six months via phone interviews. Questions cover a broad range of topics, including demographics and clinical characteristics, health care utilization, social and family issues, and more.
The recently published study (NeuroRehabilitation 2004;19(1):55-67) compared the 2,156 persons participating in the Slifka Study, splitting them for the purposes of this study into those older than, or younger than, 65. Findings included:
• Older individuals tended to have progressive disease and to be more severely disabled, and more likely to need help with daily activities. Although 85% reported having such help, only 40% received professional home care services. The investigators hope to explore this further in terms of the quality of care and unmet needs.
• Almost all in the older group had health insurance and 75% had prescription drug coverage.
• Persons in the older group were less likely to have a regular source of MS care or to be using a disease-modifying drug.
• On average, income was lower in the older group, and they were more likely than those under 65 to live alone.
• Despite levels of disability and care needs, many older individuals viewed their health status and quality of life positively.
Over time, because a wide variety of information is being tracked, the Slifka Study will permit scientists to pose a wide range of questions, and allow investigators to tease out factors that may influence disease course. Qualified investigators may apply to the Society to gain access to the data; for information, visit our Web site: http://www.nationalmssociety.org/%5Cresources_Slifka.asp.
MS Researcher Jeffrey Mason, PhD:Hits the Ground Running with a Career Transition Fellowship
One way to attract new minds to the search for a cure for MS is identify the promising young scientists and cement their dedication to the disease. One way the National MS Society does that is through the new Career Transition Fellowship, offering the best postdoctoral fellows – young scientists who have earned their doctoral degrees ( PhDs, MDs, DOs, DVMs, etc.) but are still undergoing hands-on lab training – a leg up in finding faculty positions to begin their careers as independent MS researchers.
This award provides up to $550,000 over five years to support up to two years of advanced, mentored postdoctoral training and then the first three years of research support in a new faculty appointment.
Here we meet one of the Society’s inaugural Career Transition Fellows, Jeffrey L. Mason, PhD, whose award allowed him to make a speedy transition from a postdoctoral fellow at Columbia Presbyterian Medical Center in New York to a faculty position at Thomas Jefferson University in Philadelphia. Dr. Mason is interviewed by Society Science Writer Sara Bernstein.
SB: How did you become interested in doing research related to MS?
JM: I majored in psychology at San Diego State University. The more I learned about the brain, the more I became interested in the biologic processes at work. I moved on to do graduate work in neurobiology at the University of North Carolina at Chapel Hill, where there was a wealth of accomplished scientists working on MS.
As I learned more about this disease, I realized that it often first attacked people my own age. This struck a cord and drew me in even more.
SB: What are some challenges facing a person beginning a career in scientific research?
JM: You have to be able to accept failure – we’re lucky if we’re right 30 percent of the time. As soon as you realize a misstep, you have to be able to adjust your thinking, and move on.
For example, when I began in MS research, most scientists were approaching the disease by trying to shut down the immune attack. I started with the same thought process, and worked with a mouse model in which damage to nerve-insulating myelin is caused by a toxic agent called cuprizone. In some studies, we found that one immune messenger protein thought to be involved in MS, called interleukin-1 beta, seemed to promote myelin repair in these mice by promoting the development of immature myelin-making cells. So, we changed direction, and began investigating whether an immune attack also had some beneficial effect.
SB: Has the Career Transition Fellowship helped you to meet the challenges of a young scientist?
JM: Yes! This award has given me a lot of flexibility. Usually, when you start a faculty position, it can take a while to gather the resources necessary to begin your studies. With this award, I was able to bring people into my lab right away, and was engaged in actual science within a few months, rather than having to wait to obtain my first research grants. My research has not slowed down at all. Also, this award has helped stay focused on MS.
This award shows that the Society is willing to provide tremendous assistance to young scientists developing careers in MS research, and that means a lot.
A Glimpse at Dr. Mason’s Work
Can a natural growth factor prevent the damage and loss of myelinmaking cells and nerve fibers in MS? With a Career Transitional Fellowship from the National MS Society, Jeffrey Mason, PhD (see page 4) hopes to find out.
Cells known as oligodendrocytes produce the myelin sheath that covers nerve fibers, or axons, in the brain and spinal cord. In MS, this sheath is the target of an immune attack.
At some point, oligodendrocytes and axons are also damaged, preventing the re-formation of myelin and recovery of normal function. When and how this damage to oligodendrocytes and axons in MS occurs is still not understood.
Evidence from previous studies conducted in cell cultures suggests that specific chemicals produced during the immune attack cause the death of oligodendrocytes and axons. Mason is studying a natural growth factor produced by the body, called IGF-1 (insulin-like growth factor one), to determine whether it can protect these tissues from damage and promote myelin repair in mice. IGF-1 appears to be stimulated by the immune messenger called interleukin- 1 beta, which has been implicated in the immune attack involved in MS.
In 2003, Mason and colleagues published a report describing early results related to IGF (Journal of Neuroscience 2003 Aug. 20;23(20):7710-8.) The investigators disrupted the gene that encodes manufacturing instructions for a protein that serves as a docking station (receptor) for IGF in mice with myelin destruction that normally repairs itself. The mice missing the IGF receptor did not adequately repair myelin, and there was a lack of proliferation of immature oligodendrocytes which would normally precede myelin repair. This offers evidence that the IGF receptor plays a crucial role in the signaling that occurs to launch myelin repair.
This and other ongoing MS research may lead to new avenues for protecting nerve tissues and stimulating myelin repair in MS.
New Studies on MS, Stress and Depression
The phrase, “Don’t sweat it!” can be particularly aggravating to someone with a chronic disease such as MS. Aside from the stress that arises in daily life for everyone, MS creates its own emotionally taxing predicaments, not the least of which is dealing with the unpredictable course of this disease. Depression is also experienced by individuals with MS more often than the general population. And just to complicate the picture, stress has been studied as a possible trigger for MS relapses. Here we describe three recent reports that explored stress and depression in MS.
In a study funded partially by National MS Society postdoctoral fellowships to Laura J. Julian, PhD, and Darcy S. Cox, PsyD, with participation from their mentor David Mohr, PhD, and other colleagues (University of California at San Francisco), the investigators searched the medical literature for papers from 1965 to February 2003 that contained the terms “stress,” “trauma,” and “multiple sclerosis.”
Three investigators independently reviewed the 20 papers identified, analyzing methods, statistics, and outcomes. Based on specific criteria, they selected 14 and conducted a “metaanalysis” (which statistically combines findings) of the 14. They noted a significant increase in the risk of MS relapse after stressful life events in 13 of the 14 studies evaluated.
However, in their report, published online in the British Medical Journal (March 19, 2004), the authors noted a number of limitations. The quality of the studies varied significantly. Many did not consider other factors that might be triggering relapses, or relied on subjects’ recall of stressful events over long periods of time, in some cases more than five years. Furthermore, an association between stress and relapse was not consistent among patients, or even in one individual over time.
While this study summarizes the existing literature concerning the possible link between stress and MS attacks, it does not resolve the issue. Rather than establishing a “causal” relationship between stress and MS, the investigators document that an association may be present. They noted that these results should encourage further research to define which stressful events might affect people with MS, what biologic processes may be at work, and how people’s individual reactions to stress may come into play.
The investigators emphasize that these data should not be used to infer that persons with MS are responsible for their relapses.
“The association between stress and exacerbation in multiple sclerosis can be conclusively confirmed only with a clinical trial of a behavioral intervention that teaches patients to reduce the occurrence and impact of stress,” concluded the authors.
Approaching the question in a different manner, Jiong Li, MD, MSc (University of Aarhus, Denmark) and colleagues investigated the association between MS and an event bound to cause major stress: the death of a child (Neurology, March 9, 2004). They gathered information from extensive nationwide registries on 21,062 parents who lost a child younger than 18 years old from 1980 to 1996 in Denmark, comparing these data with 293,745 parents who did not lose a child. The two groups were followed to track the development of MS in either parent from 1980 to 1997.
The investigators found that people who experienced the loss of a child had an increased risk of developing MS compared to individuals who, over a similar period of time, did not lose a child – an increase that was significant only eight or more years following the death of the child.
This would seem to link a significant stressful life event with development of MS. The authors noted, however, a significant limitation to their study, in that they had collected no information on lifestyle factors, physical trauma, infections, family history, or occupational exposures – factors that might also contribute to MS risk and which may have been different between the studied populations. These results, however, encourage more research on how stress may impact the biologic processes that lead to disease.
MS and Depression
On the flip side is the question of how having MS itself increases stress felt by those with the disease. A recent study that attempted to discern the causes of major depression in MS highlights the complexities of this issue.
Major depression is estimated to strike between 25 to 50 percent of individuals with MS at some point in their lives, compared with an estimated 17 percent of the general population. University of Toronto researchers investigated whether MS-related depression could be associated with structural changes in the brain caused by the disease (Neurology 2004;62:586-590).
Using magnetic resonance imaging, the investigators, led by Anthony Feinstein, MD, PhD, FRCPC, compared brain structures in 21 persons with MS and depression, compared to 19 persons with MS who did not have depression.
The researchers indeed found that specific areas of the brain were more likely to show signs of disease pathology, such as lesions or atrophy, in those with depression. However, these structural findings were not linked to depression in every case, and whether they actually caused depression or were caused by depression is still an open question. The investigators cited other possible factors that could be contributing to depression, such as coping ability, physical disability, uncertainty over the future and perceived levels of social support, all of which have been implicated in previous studies. MS researchers continue their attempts to sort out stress, depression and other psychosocial aspects of MS.
In the meantime, since it is nearly impossible to avoid stress, finding
better ways to better cope with stress can help. The National MS Society
provides suggestions in “Taming Stress in Multiple Sclerosis,” a brochure
that is available on its Web site at http://www.nationalmssociety.org/Brochures-TamingStress1.asp.
Copyright © 2004, The National Multiple Sclerosis Society