Multiple Sclerosis Newsletter

Multiple Sclerosis Newsletter
Northern Colorado Edition

August-September 2006

Research Updates

Diabetes and M.S. Linked in Danish Study
Archives of Neurology, June 2006 NEW YORK (Reuters Health)

People with type 1 diabetes are more than three times more likely to develop multiple sclerosis (MS) than are those without diabetes, new research from Denmark shows. In addition the two diseases appear to be linked, albeit to a weaker extent, within families.

Both type 1 diabetes and MS are auto-immune diseases, in which the body mounts an aberrant immune response against its own tissues – attacking insulin-producing cells in the case of diabetes, and the myelin sheath surrounding neurons in MS.

The new, population-based study is not the first to reveal an association between type 1 diabetes and MS. However, previous evidence had come from relatively small numbers of patients.

As reported in the Archives of Neurology, Dr. Nete M. Nielsen, from the Statens Serum Institut in Copenhagen, and colleagues assessed the occurrence of MS in 6078 patients with type 1 diabetes over more than a decade of follow-up. In addition, the researchers evaluated the presence of type 1 diabetes in 14,771 first-degree relatives of 11,862 MS patients.

Eleven cases of MS developed in the diabetes patients, while only 3.38 cases would be expected based on the rates in the general population. Thus, patients with type 1 diabetes had a more than three-fold increased risk of MS.

First-degree relatives of MS patients had a 63 percent increased risk of developing type 1 diabetes, the team calculated from their data. However, after accounting for the possibility of also being related to a patient with type 1 diabetes, the excess risk fell to 44 percent.

“To our knowledge, the present study is the first truly nationwide cohort study to demonstrate intraindividual and, to a lesser degree, intrafamilial co-occurrence of MS and type 1 diabetes,” the investigators write. “The underlying mechanisms remain unknown,” they say, “but may involve both genetic and environmental factors.”

Traditional Pathology of MS Challenged
MSFacts, June 7, 2006

According to researchers from Australia, recent observations in early MS lesions challenge the traditional hypothesis that MS is the result of an autoimmune process that specifically targets myelin antigens.

A new MS paradigm proposes that oligodendrocyte apoptosis, which refers to the premature death of the cells that make myelin in the brain and spinal cord in the absence of any inflammation, is the earliest change in newly forming lesions and that tissue injury is amplified by the subsequent recruitment of a systemic immune response.

Over time, the pathology of MS is transformed and the changes that accompany the late phase of the disease suggest that the inflammatory response becomes progressively “compartmentalized” and therefore largely isolated from systemic influence with time. These findings raise important questions about the etiology and pathology of MS.

A better understanding of these processes is essential and could have a major impact upon how a given immune therapy may or may not impact the disease.

TOLL-LIKE RECEPTORS: NEWLY DISCOVERED MOLECULES PLAY POSSIBLE ROLE IN MS
Nat. M.S. Society, summer-fall 2005

Much research has focused on finding an infectious agent that may trigger the immune attack on the brain and spinal cord in MS, but no single agent has been proven to trigger MS. In recent years, scientists have instead tried to understand how infection itself -regardless of the agent – may affect people whose immune systems are genetically predisposed to develop MS.

Recently, a novel type of receptor – a molecule that serves as a “docking site” to receive signals from other cells and molecules – was discovered that may help clarify this picture. Toll-like receptors (TLRs) are part of the “innate immune system,” the front line against infectious invaders. TLRs recognize components on viruses or bacteria which “tip off” or signal to the innate immune cells – antigen-presenting cells – that this substance is a “stranger.” This innate immune response then instructs the “adaptive” immune system – T and B cells, and other cells and proteins – to launch an attack to suppress the invader.

In MS, researchers still don’t know whether an infectious agent or a component of nerve-insulating myelin or other molecules trigger the immune system. Evidence is growing, however, that TLRs alerted by such “stranger” signals may play a key role in activating the immune system to attack the brain and spinal cord in MS.

TLRs and Tissue Damage in MS-Like Disease. Approximately 11 separate TLRs have been identified thus far. Timothy Vartanian, MD, PhD (Beth Israel Deaconess Medical Center, Boston) has reported important findings on TLR4. His team found high levels of this receptor on microglia, brain cells that participate in the immune attack in MS. When they administered a common component of bacteria called LPS (lipopoly-saccharide, which signals through TLR4) to mice, they found that the microglia were activated to release toxic molecules that killed myelin-making cells. However, if TLR4 function was “turned off” in mice, cell injury was prevented (The Journal of Neuroscience, April 1, 2002). Vartanian’s team then showed that nerve cells suffered the same fate in the presence of TLR4, but again, not if TLR4 was disabled (Proceedings of the National Academy of Sciences, July 8, 2003). His team has recently reported similar findings related to TLR3 (Society for Neuroscience, 2004).

These studies provide a plausible link between TLR and tissue damage such as what has been observed in MS. Now, Vartanian and colleagues are exploring other TLRs with funding from a research grant from the National MS Society.

A novel theory proposed by Polly Matzinger, PhD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD) suggests that TLRs may in fact respond to “danger” rather than “stranger” ( Science, April 12, 2002). In other words, these receptors might be activated by cellular debris from tissue damage that has already occurred in multiple sclerosis, and may then help the immune attack persist. Further study should help confirm or refute this theory.

Moving Research to Human Cells. Carolyn Jack, a graduate student in the laboratory of Jack Antel, MD (McGill University, Montreal) and colleagues examined TLR activity in human microglia, as well as astrocytes, another brain cell that gets involved in the MS attack. In microglia, TLR3 and TLR4 increased production of immune messenger proteins that rev up inflammation. In astrocytes, TLR3 increased production of certain immune proteins, but TLR4 did not. The authors conclude that TLRs are active on these cells in humans, and that their signals may contribute to shaping the course of nervous system inflammation in MS (American Academy of Neurology, 2005).

Further research will fine-tune the role of various Toll-like receptors in MS. Ultimately, these molecules may serve as targets for the development of future MS therapies that could put the brakes on the immune attack.

SLEEP STRENGTHENS MEMORY
Sound slumber essential to rain facts, researchers say
Current Biology, July 11, 2006

Sleep seems critical to memory, particularly the ability to recall recently learned fact and events, researchers report.

Known as “declarative” memories, these differ from non-declarative memories, or “how to” memories – those have already been shown to benefit from sleep. However, whether sleep has an impact on declarative memories has not been known. This new finding may be particularly important to people with mentally demanding lifestyles, such as doctors, medical residents and college students, who often do not get enough sleep, the researchers say.

“We sought to explore whether sleep has any impact on memory consolidation,” said lead researcher Dr. Jeffrey M. Ellenbogen, a postdoctoral fellow at Harvard Medical School’s Center for Sleep and Cognition. “Specifically, the type of memory for facts and events in time.” Ellenbogen’s team studied 60 people who did not use prescription drugs and did not have known sleep disorders or abnormal sleep patterns. Among these, 48 were assigned to one of four groups: sleep before testing, wake before testing, sleep before testing with interference, or wake before testing with interference. As Ellenbogen explained, “interference is the concept in memory research that learning some new piece of information leads to the forgetting of something else, particularly when that something else is very similar.”

In the study, everyone first attempted to memorize 20 paired words. They were tested 12 hours later for recall by completing a cued-recall task. However, people in the interference group were also schooled in a second list of 20 word-pairs just before testing – these were the “distracting’ or interfering words that made remembering the first bunch of word-pairs even tougher. In addition, another 12 people were placed on a longer, 24-hour program with either interference and sleep or wakefulness.

Ellenbogen’s group found that sleep did have a benefit for declarative memory. People in the non-interference groups had mean recall that was slightly higher in the sleep group compared with the wake group. Moreover, people in the interference group who were able to sleep still did significantly better on the recall than did the wake group.

“Sleep had a benefit for the consolidation and strengthening of memory,” Ellenbogen said. It actively does so; it’s not a passive process. The brain actively engages memories and leads them to be strengthened the next day, and it’s a long-lasting benefit. The benefit was even larger than we were anticipating.”

Given these findings, the researchers believe that sleep is important to building and maintaining memories. “Sleep is not an inactive state. That’s an obsolete concept,” Ellenbogen said. “The brain is doing lots of things during sleep, including consolidating memories. So you need to get sleep on a regular basis in order to maximize memory.” One expert thinks this study shows that sleep is important in learning.

“Sleep specialists still do not know the overarching purpose of sleep,” said Dr. Robert D. Vorona, an associate professor in the Division of Sleep Medicine at Eastern Virginia Medical School in Norfolk. “However, we do know that insufficient sleep is associated with negative alterations in both mood and performance.”

A number of studiers suggest that sleep plays an important role in effective memory acquisition, Vorona said. “This study suggests that parents of students would do well to recommend that their children both study hard and obtain sufficient sleep in order to maximize their academic performance,” he added.

M.S. BY THE NUMBERS: NEW INITIATIVES MAY PROVIDE CLUES TO ITS CAUSE
Sara Bernstein N.M.S.S., Winter/Spring 2006

The National MS Society estimates that some 400,000 Americans have MS. The NIH estimates 250,000 to 350,000, while others suggest there are many more. Why is it difficult to be certain how many people have MS? More importantly, why do we need to know?

The Society is seeking to answer these and other questions with the formation of the Task Force on the Epidemiology of MS (the study of who gets MS). “Our basic information on the incidence and prevalence of MS is based on 30-year-old information – an NIH-funded study from 1975,” says Nicholas LaRocca, PhD, Director of Health Care Delivery and Policy Research at the Society. “We have adjusted the results to account for better diagnostic methods and other factors over the years, but at some point this ‘tweaking’ begins to wear thin. Furthermore, the 1975 study was based on reports from healthcare providers, and the results may underestimate the geographic and ethnic distribution of Americans with MS. So although we are pretty confident of the overall number (400,000) based on a number of subsequent studies, there are many other issues that remain in doubt.”

The task force comprises experts in MS, epidemiology, health policy, and other neurological disorders. The Society is looking at this group to lend insight into the process of determining how many Americans have MS. “These people know the field, and the methods available” says LaRocca. “We want them to provide recommendations on whether it is feasible and reasonable – in terms of cost – to launch a study to determine how many Americans have MS, and how we can accomplish it.” LaRocca has completed the recruitment of task force members. Once convened, he expects the group to be able to deliver its report within one year. This report will be shared with other funding agencies, such as the NIH and Centers for Disease Control (CDC), and a scientific article base on the findings will be prepared for publication.

Determining the number of people with MS can have far-reaching effects; it’s not just about knowing the number. “In addition to the overall figures, we would have age-specific figures that could tell us what is happening to the population of people with MS,’ says LaRocca. “By seeing where these numbers are going, we can develop programs geared to ages most affected by MS. We also need to know how many people the Society is reaching. We may be missing certain areas or ethnic groups affected by MS.”

Can Numbers Help Pinpoint the Cause of MS?Perhaps the most crucial element of clarifying how many people have MS is the fact that it may help to answer why people get MS. “People call us all the time saying that they know of, for example, six people on their street who have MS,” says Dhelia Williams, PhD, an investigator for the Agency for Toxic Substances and Disease Registry (ATSDR), a sister agency to the Centers for Disease Control. “They ask if we can investigate whether there is a 'cluster' of people with MS in their area that may be related to a local environmental factor, such as a hazardous waste site. But that's too small a number of people - we need to be dealing with much larger numbers of people - hundreds, thousands - before we can determine a connection to an environmental trigger."

Williamson also cites the variability of MS prevalence estimates as a factor that makes cluster investigations impractical. The agency conducted a cluster investigation in El Paso, Texas, where 22 cases of MS were reported, all of whom had attended an elementary school near a local smelter. "We compared MS prevalence in El Paso to MS prevalence as reported in several different studies, and got conflicting results," says Williamson. "The risk for developing MS in El Paso was reported as either none, or fourfold!"

In a review published in the Journal Neuroepidemiology (2004;23;211-216), Williamson and colleague Judy P. Henry of the Texas Department of Health comment, "Citizens require and deserve a less ambiguous answer to their questions concerning an excess of disease in their communities. Public health agencies also need less ambiguous information when making a decision as to whether additional resources should be committed to pursuing an etiologic investigation." (Etiology is the study of the cause of a disease.)

The ATSDR proceeded to conduct a more extensive investigation in areas of Missouri, Ohio, and Texas. These larger studies examined MS prevalence in areas where community residents were concerned about the occurrence of MS and potential exposures from a hazardous waste site. The studies relied on information primarily from neurologist offices, but also patient advocacy groups, nursing homes, and general practitioners. Preliminary results indicate that prevalence varied greatly among these areas: 43 cases per 100,000 people in Texas; 88 cases per 100,000 in Missouri; and 112 cases per 100,000 in Ohio.

Now, the ATSDR is taking these results one step further, conducting a "case-control" study in these areas of Missouri, Ohio, and Texas. In such a study, risk factors for a disease are compared in people with the disease and those without the disease. Five hundred people with MS and 1000 people without MS are being enrolled. Participants will be asked to complete a questionnaire and provide a blood sample, which will be examined for the presence of several genes that have been identified as having possible associations with the development of MS. “This study will allow us to look at both environmental and genetic factors, and what role they may play in MS,” says Williamson.

Williamson also is developing a proposal for a national surveillance system for MS. Such systems, which exist for cancer, allow for a standardized and coordinated tracking of information at state and national levels. The ATSDR is convening a meeting to begin the process of developing such a proposal in 2006.

These efforts to track MS numbers require the collaboration of the Society with the ATSDR: Williamson is to join the Society’s task force, and the Society will play an active role in the ATSDR meeting next year. “Only with such collaboration will we be able to determine who has MS and why it develops,” says Williamson.

News | Information / Subscriptions
Programs | Smile | Archive |Contact Us

FortNet Home

*This material is provided as general medical information and is not intended as advice for individual patients;
please contact your physician for specific recommendations.

Web site design by Mes Bijoux Ltd