Research

The main strategy in treating MS so far has been to dampen inflammation in hopes of limiting damage to oligodendrocytes and neurons. A complementary approach would be to protect these cells by making them more resistant to damage or more capable of repair. The latest research indicates that both of these goals can be addressed at the same time -- several MS therapies seem to reduce inflammation while simultaneously promoting neuroprotection. In past studies, glatiramer acetate (Copaxone) has been reported to stimulate production of nerve growth factors such as brain-derived neurotrophic factor (BDNF). These factors are produced in the nervous system but can also be expressed by immune cells. Now two new studies suggest similar effects for interferon-beta and for the experimental drug alemtuzumab.

The IFN-beta results come from a study done in Japan that analyzed serum BDNF levels and T cell BDNF production over time in people with MS and controls. Previous studies have examined the effect of IFN-beta on neurotrophic factors and have produced mixed results, but this question had not been studied in Asian people before. The research team found that BDNF levels in serum are higher in people with MS compared with healthy controls, are highest in the youngest people with MS who have low disease activity, and decline with age in people with MS (whereas they increase with age in healthy controls). A few of the MS subjects went on IFN-beta during the study. Treatment was accompanied by an increase in serum BDNF levels in the subjects deemed "responders" based on relapses and progression. The two non-responders had the lowest post-treatment serum BDNF levels and one of these even had a lower level post-treatment than pre-treatment. BDNF production by T cells was similar in MS and control subjects, but significantly higher in IFN-beta treated MS subjects than untreated ones. The size of the study was small, but the results support the idea that IFN-beta can have a beneficial neuroprotective effect, at least in some people.

Likewise, a study of Campath (alemtuzumab) showed that this drug also appears to boost the production of neurotrophic factors. Alemtuzumab wipes out T and B immune cells, thereby decreasing the potential for inflammatory attacks. However, scientists analyzing clinical trial results noticed that even subjects who had no sign of inflammatory activity at the start of the trial had a reduction in disability after starting the drug. They speculated that alemtuzumab may also have an effect on nerve growth factor production, perhaps because the population of immune cells that regenerate after the initial depletion has a more neuroprotective profile. The scientists took immune cells from people treated with alemtuzumab and stimulated the cells by exposure to myelin basic protein. These cells did indeed begin producing higher levels of BDNF and other growth factors such as ciliary neurotrophic factor. Furthermore, cultured neurons that were exposed to secretions from these stimulated cells had better growth and survival, and oligodendrocyte precursor cells were also more likely to mature and produce myelin.

Both of these studies reinforce the dual role (inflammatory and neuroprotective) of the immune system in MS. It would be interesting to find out whether yet another possible approach to treating MS would be to enhance nerve growth factor production directly in the brain. Drugs that induce the production of neurotrophic factors are in development for other neurologic diseases -- for example, a drug called Cogane that crosses the blood-brain barrier and boosts production of BDNF and glial-derived neurotrophic factor (GDNF) is being explored for use in Parkinson's. Perhaps this approach will someday put another type of weapon in our MS arsenal.

The prevalence of MS differs among racial groups -- for instance, it is higher in Caucasians, lower in Asians and lower still in native Africans. In addition to affecting the chance of getting MS in the first place, racial factors may also affect the clinical aspects of MS once someone has developed the disease. In North America, this concept has motivated several studies comparing clinical characteristics of MS in African-Americans and Caucasian-Americans.

In general, these studies have found that while African-Americans have a lower risk of developing MS, they tend to have a worse outcome over time than Caucasian-Americans. For example, they may need a cane sooner or require nursing home care at a younger age. A study from the New York State MS Consortium (NYSMSC) reported a few years ago that although the EDSS scores of their registry participants did not significantly vary between these two groups, race did appear to affect outcome over time. In order to further explore the influence of race on MS outcome in a large population, the NYSMSC decided to reanalyze their data using a tool called the MS Severity Scale.

The MSSS is a 10-point scale that is based on EDSS but also takes into account disease duration. If two people with MS have the same EDSS but different disease durations, the one who has had the disease longer will have a lower MSSS, and vice versa. The scoring was based on a reference population of Europeans with MS, so someone with an MSSS of 1 or less would have a disease severity equivalent to the least severely affected 10% of that reference population. The concept of benign and malignant MS can also be studied using MSSS. In this study, benign MS was defined as MSSS < 0.45 (e.g., EDSS <=3.5 after 30 years) and malignant was defined as MSSS >= 9.6 (e.g., EDSS >= 6.0 at 7 years). MSSS scores can also be divided into 6 different severity grades (1 = least severe, 6 = most severe).

The NYSMSC group identified everyone in their registry who had a recorded EDSS score and disease duration of 1-30 years. This resulted in a study population of 5,809 Caucasian-Americans and 419 African-Americans. Each subject's earliest recorded EDSS was used to assign their MSSS number. African-Americans had a higher median MSSS score than Caucasian-Americans (6.0 vs. 4.8). African-Americans were also more likely to have MSSS scores in the top two severity grades and less likely to be in the bottom two grades than Caucasian-Americans. Similarly, African-Americans were more likely to have malignant MS and less likely to have benign MS. These differences were stronger in women than in men, because there were only a small number of African-American men in the analysis.

The findings held up even when adjusted for factors like age, disease subtype, disease duration, or whether the person was using a disease-modifying therapy at enrollment. It should be noted though that the length of time someone had been on a therapy was not analyzed, which might have skewed the results if it differed between the two groups.

This study supports the idea that race can affect MS outcome, and in particular strengthens the conclusion that African-American ancestry is correlated with greater severity. Which factors underlie this correlation are not yet known, but further study may provide some leads that could then be translated into strategies or therapies to halt or delay progression.

The International Society for Stem Cell Research, an independent, nonprofit organization that fosters the exchange of information on stem cell research, recently launched a website to help consumers/patients evaluate the claims being made by stem cell treatment clinics. Clinics have been set up around the world to treat various conditions, including MS, but not all of their claims are based on solid research and not all of these clinics may be operating in the best interest of the patient.

The ISSCR's website, A Closer Look at Stem Cell Treatments, aims to help people figure out whether a particular clinic is being truthful and whether its treatment approaches are well-founded based on the existing evidence. The website offers a number of resources, such as a list of things to know about stem cell therapy and questions to ask a clinic when considering being treated there. The ISSCR is also developing a list of stem cell clinics and will be reviewing the claims of the clinics on this list. They are currently soliciting names of clinics to be reviewed, so if there are any that you'd like to have checked out, just click this link and fill out the form.

Although clinical research in MS seems to be at an all-time high level of activity, this activity remains heavily concentrated on relapsing-remitting MS as opposed to progressive forms of MS. This is understandable -- relapses can be reduced by manipulating cells circulating in the immune system, and there are many ideas for ways to manipulate these cells. However, the need for therapies is much more urgent for people with progressive MS.

Recognizing this need, a team of researchers at the Multiple Sclerosis Research Center of New York recently conducted a treatment study involving methotrexate administered intrathecally (in the spine). Methotrexate is one of many cancer-fighting agents that have been investigated in MS because of their effect on immune cells. Usually it is taken orally, but an intrathecal version is available to treat leukemia in cerebrospinal fluid. Injecting methotrexate intrathecally gets it past the blood-brain barrier and closer to the scene of disease activity.

In this study, 87 subjects with secondary progressive MS and 34 with primary progressive MS received up to 8 treatments given every 8 to 11 weeks. Each subject was evaluated a year after their last treatment using the EDSS scale. The SPMS group had a lower average EDSS score at the end of the study compared with their starting score, with 89% of the subjects either improving or staying the same. In addition, 82% of the PPMS subjects had no significant progression. Importantly, no serious side effects were observed.

There are several drugs in the MS pipeline that are thought to have neuroprotective effects and thus may improve the health of people with progressive MS. While we wait for those drugs to be brought to market, perhaps intrathecal methotrexate should be studied more extensively since it's available now and has the potential to help people with progressive MS.

While traditional MRI technologies have been very useful in MS for finding and measuring lesions in the brain and spinal cord, some newer techniques are also proving useful for measuring other things, such as damage in normal-appearing (non-lesioned) tissue. One of these techniques is diffusion-weighted imaging (DWI), which analyzes how water molecules move about in a tissue. In an area of tissue that is intact and structured, such as a white matter region which contains long, ordered bundles of axons, water molecules will move around (diffuse) differently than they will in an area that has experienced damage, such as loss of myelin and severing of axons. A few DWI studies have been successfully performed in MS already but none have examined whether disease-modifying drugs affect diffusivity, so a team from the University of Buffalo conducted a small study involving MS subjects taking glatiramer acetate (Copaxone).

This study included 19 people with MS taking glatiramer acetate and 16 healthy controls for comparison. MRI scans and clinical assessments were performed at baseline, and again after one and two years. At baseline, the mean diffusivity scores were significantly higher in the MS group than the controls (1200 vs 1125 10^−6/mm2/s), reflecting more damage. However, by the end of the second year, the MS group's scores had decreased by an average of 10% while the control group's score had increased by 0.7%. A similar result was found for another DWI measure called entropy. There was no significant difference in atrophy (loss of brain volume) between the two groups over the two years.

Other studies have produced evidence that glatiramer acetate may be neuroprotective, so perhaps the decrease in diffusivity in the MS group reflects structural repair in the brain. With more study, DWI might be validated as a measure of neuroprotection -- and such measures will (hopefully) be needed as additional drugs with reparative effects are developed and tested for use in MS.

As the authors point out, this study didn't have a comparison group of MS subjects not taking glatiramer acetate, which would have been informative. The authors also hope that follow-up studies will incorporate other imaging techniques, such as MR spectroscopy which can measure quantities of different proteins used in different types of cells, or functional MRI which shows brain activation while performing tasks, and can indicate re-routing of pathways when normal pathways are damaged. Combining these different techniques will give a fuller picture of how therapies help to boost regeneration.

Hollie's Notes from the 2010 AAN Meeting in Toronto

American Academy of Neurology meeting April 10-17 Toronto, Ontario

Each year Accelerated Cure Project attends the American Academy of Neurology. We try to take notes on as many presentations as we can, write them up, and make them available on MSNews for anyone to read.

You can see our notes below. If you have any questions or comments, please click on the link labeled "Hollie" above to send a message. By the way, if you're interested in seeing the abstracts for the posters and presentations from this conference, you can do so here: http://www.abstracts2view.com/aan

continued...

A research team from the UK is gathering information on the topic of epigenetics (factors that affect the translation of genes into proteins). They are trying to obtain the birth months of people with MS, their parents and their grandparents, and need to get as many participants as possible in order for the results to be meaningful. They have designed a web-based survey that should take less than 5 minutes to complete.

If you have MS and are interested in helping out with this study, please click here for the survey. It is important that you have the birth dates of your parents (and if possible, grandparents) at hand before you start the survey.

Having been infected with Epstein-Barr virus, being positive for the DRB1*1501 gene haplotype, and having a history of smoking are all associated with an increased risk of MS. Unfortunately, nobody knows how each of these factors relates to the actual biology of the disease. However, learning more about whether these factors interact with each other could help provide some new clues to explore.

An international study exploring this question has just been published in the journal Neurology. This study made use of blood samples and smoking histories from people with MS and controls from the US, Sweden, and Australia. Data about smoking history, DRB1 status, and the levels of antibodies to an EBV protein (EBNA) were combined and analyzed to see whether these factors act independently or work together in affecting the risk of MS. The results showed that DRB1 acts independently of smoking and EBV immune response in increasing the risk of MS. However, the immune response to EBV and smoking appear to have an interactive effect on MS risk -- that is, the effect of higher EBV antibody levels is enhanced by having a history of smoking.

The study discusses possible biological mechanisms that may be shared by EBV infection/immune response and smoking that may be involved in MS. However, not much is currently known on this topic. Seems like a good area for further research. This study also highlights again the importance of not smoking for people who want to minimize their MS risk. DRB1 status can't be changed, and EBV infection is hard to avoid, but it is possible to decide not to smoke.

This Wednesday, April 14, from 12 to 1:30 pm Eastern time, the National MS Society will be hosting a webcast on the topic of CCSVI at the American Academy of Neurology meeting. A panel of experts on this topic will be presenting information and answering questions:

• Dr. Paolo Zamboni, Director, Vascular Diseases Center, University of Ferrara, Italy
• Dr. Robert Zivadinov, Associate Professor of Neurology at the University at Buffalo, State University of New York
• Dr. Andrew Common, Radiologist in Chief at St. Michaels Hospital, University of Toronto, Ontario, CA
• Dr. Aaron Miller, Professor of Neurology and Director of the MS Center at Mount Sinai, New York, member of the AAN Board of Directors, Chief Medical Officer of the National MS Society

Click here to register in advance for the webcast and make sure your computer is compatible with the webcast system. If you're interested in submitting questions ahead of time to the panelists, you can do so on Facebook or Twitter, or you can send in questions during the session via the webcast site. Click here for more information about submitting questions. By the way, it looks like submitting questions in advance can only be done on Monday 4/12 between 10 am and 2 pm Eastern.

The webcast will be archived, so if you can't watch it live, you'll still be able to see it later.

I will be attending the AAN meeting in person, so I'll do my best to bring back information from other presentations on CCSVI -- as well as new findings on other topics such as the causes of MS, disease mechanisms, treatments, epidemiology, imaging, etc.

One of the challenges that people diagnosed with MS have to deal with is deciding which (if any) disease-modifying therapy is right for them. This challenge will only get more difficult as more drugs are approved by the FDA for treating MS. Currently the process is based on trial and error, with the result that people with MS might spend months or years and lots of money on a treatment that isn't the best one for their own particular disease.

This week, new research findings were announced that may eventually help with this challenge. A collaborative team from Stanford, University of Alabama at Birmingham, and VU University Medical Center (Amsterdam) studied blood samples from people with MS who were about to start treatment with interferon-beta. The researchers had observed that mice with EAE induced by a certain type of T cell (Th1) responded well to IFN-beta, whereas mice with EAE induced by Th17 cells got worse with IFN-beta. So the MS samples were analyzed for levels of IL-17F, a protein produced by Th17 cells. Samples from the subjects whose MS hadn't responded to IFN-beta had higher pre-treatment levels of IL-17F than samples taken from responders. So perhaps IL-17 testing will provide a way to guide someone with MS to or away from IFN-beta treatment.

However, it should be noted that this study was extremely small (only 26 MS subjects were included). So these results must be confirmed in a larger study before any practical use can be made of them. If they are confirmed, it would be good to repeat this study, but this time with people who were on Copaxone, to see if that would be a helpful alternative for those with the IL-17 producing form of MS.