Category: Multiple Sclerosis

Teenage women who are obese may be more than twice as likely to develop multiple sclerosis (MS) as adults compared to female teens who are not obese, according to a study published in the November 10, 2009, print issue of Neurology®, the medical journal of the American Academy of Neurology.

The research involved 238,371women from the Nurses' Health Study and Nurses' Health Study II who were 25 to 55 years old. The women answered a questionnaire about their health behavior and medical information every two years. Over the course of 40 years, 593 developed MS.

Participants reported their weight and height at age 18. Scientists then calculated their body mass index (BMI). The women were also asked to choose one of nine body silhouettes, ranging from very thin to extremely obese, to describe their body size at five, 10 and 20 years old.

The study found that women who had a BMI of 30 or larger at age 18 had more than twice the risk of developing MS compared to those with a BMI between 18.5 and 20.9. A woman with a BMI of 25 to 29.9 kilograms per meter squared was considered overweight whereas a woman who was considered obese had a BMI of 30 or more kilograms per meter squared. The disease risk among women who were overweight but not obese at age 18 was only somewhat increased. The results were the same after accounting for smoking status and physical activity level.

Women who had a larger body size at 20 years of age, represented by the use of silhouettes in the study, also had twice the risk of MS compared to women who reported a thinner body size. Larger body sizes at ages 5 and 10 were not associated with MS risk.

"Our results suggest that weight during adolescence, rather than childhood or adulthood, is critical in determining the risk of MS," said study author Kassandra Munger, ScD, of Harvard School of Public Health in Boston. "Teaching and practicing obesity prevention from the start, but especially during teenage years, may be an important step in reducing the risk of MS later in life for women."

Munger said there are two possible explanations why obesity may affect MS risk. Higher levels of vitamin D in the body are thought to reduce disease risk. People who are obese tend to have lower vitamin D levels compared to people who are not obese. In addition, fatty tissue produces substances that affect the immune system and certain types of cell activities that are thought to be associated with MS.

The study was supported by the National Institute of Neurological Disorders and Stroke.

— In diseases such as multiple sclerosis, cells of the immune system infiltrate the brain tissue, where they cause immense damage. For many years, it was an enigma as to how these cells can escape from the bloodstream. This is no trivial feat, given that specialized blood vessels act as a barrier between the nervous system and the bloodstream. Until now, tissue sections provided the sole evidence that the immune cells really do manage to reach the nerve cells.

Now, a team of scientists from the Max Planck Institute of Neurobiology, the University Medical Center Göttingen, and other institutes, has witnessed the movements of these cells "live" under the microscope for the very first time. In the process, they discovered several new behavioural traits of the immune cells. The consolidated findings mark a significant step forward in our understanding of this complex disease. (Nature, 14 October 2009)

The brain and the spinal cord monitor and control the functions of all body parts and co-ordinate the whole organism's movements, senses and behaviour. Adequate protection of the brain and spinal cord are therefore of the utmost importance. Physical influences and injuries are warded off by the cranial bone and the vertebral column. Dangers lurking within the body, such as viruses circulating in the bloodstream, are kept at bay by highly specialized blood vessels. The vessels' walls form a barrier that cannot be penetrated by the cells or various other small particles, thus serving to protect the delicate nerve cells.

There are, however, exceptions to the rule. In diseases such as multiple sclerosis (MS), aggressive cells in the immune system manage to break through the blood vessels' barrier. Having invaded the brain tissue, these cells wreak havoc by triggering off inflammatory reactions and attacking nerve cells. In Germany alone, the resulting adverse effects afflict over 120,000 MS-patients.

Tracking down the culprits

Since there is normally a clear division between the blood circulatory system and the central nervous system (i.e. brain plus spinal cord), scientists were baffled as to how immune cells manage to cross the blood-brain-barrier. This knowledge may aid in understanding the origins of multiple sclerosis. In the 1980s, scientists were able to prove conclusively that, under certain conditions, so called T-cells can recognize and attack components of the body's own brain cells. Thanks to tissue sections performed over the last few decades, scientists now have much better knowledge of the migration of these cells from their point of origin to their point of penetration into the brain and the damage that they cause. However, actual observations of such movements long remained impossible

Observing aggressive cells in action

Scientists at the Max Planck Institute of Neurobiology, the University Medical Center Göttingen and their colleagues have now overcome this impossibility. Using a two-photon microscope, the researchers succeeded in tracing the movements of aggressive T-cells labelled with the green fluorescent protein (GFP) in the living tissue of rats. The systematic observation of these cells during the course of the disease provided amazing new insights into the cell's behaviour.

The scientists discovered that the aggressive T-cells overcome the barrier between blood and nerve tissue in a number of steps. Outside the nervous system, the labelled cells moved just as we would expect them to; most cells were floating along with the flow of the bloodstream. Only now and again did a cell attach itself briefly onto the vascular wall. Here they rolled in the direction of the blood stream or were being carried off again by the current. Yet, once the cells reached the blood vessels of the nervous system, they began to act in a completely different manner. The scientists observed here far more cells clinging to the vascular walls. "Things got really exciting when we observed that the cells can actually creep, a behaviour so far unheard of for T-cells," Ingo Bartholomäus relates his observations. Here, "creeping" describes an active cell movement, usually against the flow of the bloodstream. The scientists watched T-cells as they took anything between a few minutes and several hours to creep along the vessels' walls. At the end of such a search movement, the cells were either swept away again by the bloodstream or they managed to squeeze through the vascular wall.

Ominous encounters

Having successfully penetrated the blood-brain-barrier, the cells continued their search in the vicinity of the blood vessels. It was thus only a question of time before the T-cells encountered one of the phagocytic cells abundant on the outer linings of blood vessels and on the surface of the nerve tissue. When a mobile T-cell came across such a phagocyte, the two cells formed a closely connected pair. Some of these pairs remained inseparable for several minutes.

Although the scientists already knew that T-cells must make contact with phagocytes in order to become immune-activated, they were now able to observe these interactions right where they happened, i.e. at the blood-brain-barrier. And indeed, the T-cells did not launch their attack on the nervous system by releasing their inflammatory neurotransmitters until they had bonded with the phagocytes. As a result of the T-cells' activation, more and more T-cells passed through the vascular walls. "The activation of T-cells at the border to the nerve tissue appears to be a decisive signal for the invasion of the immune cells," concludes Alexander Flügel, supervisor of the study and director of the Department of Experimental and Clinical Neuroimmunology at the University Medical Center Göttingen and Head of the MS Hertie-Institute.

Light bulb moments

Thanks to their sophisticated observation methods, the scientists also established that some of the antibodies already being used in MS-therapy cause the creeping cells to disappear. As Ingo Bartholomäus explains "Up to now, it was only known that these antibodies prevented the T-cells' escaping from the blood vessels, but as our observations now show, they actually prevent them from creeping."

Thanks to the scientists' observations, we now have a much clearer picture of how the immune cells move and obtain access to the nervous system. This knowledge is likely to also increase our knowledge of the immune system's security system functions in healthy tissue. However, as is often the case, new insights and information also give rise to many new questions. How do the immune cells manage to cling to the lining of the blood vessels and how do they recognize the weak spots, where they can slip through the barrier between the bloodstream and the nervous system? What governs the cells once they have surmounted the blood-brain-barrier? These are some of the questions the scientists will be addressing next. The long-term goal will be to develop new forms of therapy and medication for multiple sclerosis and other diseases.

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Journal Reference:

1. Ingo Bartholomäus, Naoto Kawakami, Francesca Odoardi, Christian Schläger, Djordje Miljkovic, Joachim W. Ellwart, Wolfgang EF Klinkert, Cassandra Flügel-Koch, Thomas B. Issekutz, Hartmut Wekerle, Alexander Flügel. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature, 2009; 462 (7269): 94 DOI: 10.1038/nature08478

— Stem cells isolated from the brain of adult mice (adult neural stem cells [aNSCs]) have shown very modest therapeutic effects in a mouse model of the chronic inflammatory neurodegenerative disease multiple sclerosis.

But now, Guang-Xian Zhang and colleagues, at Thomas Jefferson University, Philadelphia, have developed an approach to enhance the therapeutic effects of aNSCs in this model of multiple sclerosis.

The research is reported in the Journal of Clinical Investigation.

Specifically, the researchers genetically engineered aNSCs to express the anti-inflammatory molecule IL-10 and found that these cells induced more extensive functional and pathological recovery from ongoing disease than did nonengineered aNSCs. Importantly, the IL-10-aNSCs mediated their effects in multiple ways, suppressing immune system attack of nerve cells, promoting nerve cell repair, and promoting production of the nerve cell protective sheath.

The authors hope these results might increase the chance that aNSC-based therapies might one day be developed for clinical use.

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Journal Reference:

1. Yang et al. Adult neural stem cells expressing IL-10 confer potent immunomodulation and remyelination in experimental autoimmune encephalitis. Journal of Clinical Investigation, 2009; DOI: 10.1172/JCI37914

Neurologists at the University at Buffalo are beginning a research study that could overturn the prevailing wisdom on the cause of multiple sclerosis (MS).

The researchers will test the possibility that the symptoms of MS result from narrowing of the primary veins outside the skull, a condition called "chronic cerebrospinal venous insufficiency," or CCSVI.

CCSVI is a complex vascular condition discovered and described by Paolo Zamboni, M.D., from Italy's University of Ferrara. In the original Italian patients, CCSVI was found to be strongly associated with MS, increasing the risk of developing MS by 43 fold.

This narrowing restricts the normal outflow of blood from the brain, causing alterations in the blood flow patterns within the brain that eventually causes injury to brain tissue and degeneration of neurons.

"If we can prove our hypothesis, that cerebrospinal venous insufficiency is the underlying cause of MS," said Robert Zivadinov, M.D., Ph.D., UB associate professor of neurology, director of the Buffalo Neuroimaging Analysis Center (BNAC) and principal investigator on the study, "it is going to change the face of how we understand MS."

Michael Cain, M.D., professor and dean of the UB School of Medicine and Biomedical Sciences, said a positive outcome from this trial would have enormous implications for the treatment of MS. "Being able to identify those at risk of developing MS before symptoms take their toll could change the lives of millions of persons who now face inevitable lifestyle restrictions."

Margaret Paroski, M.D., executive vice president and chief medical officer of Kaleida Health, parent of Buffalo General Hospital where the BNAC is located, commented: "Will Rogers once said, 'It isn't what we don't know that gives us trouble, it's what we do know that ain't so'. Challenging basic assumptions about diseases has lead to some very important discoveries.

"When I was in medical school, we thought peptic ulcer disease was due to stress. We now know that 80 percent of cases are due to a bacterial infection. Dr. Zivadinov's work may lead to a whole different way of thinking about multiple sclerosis."

The preliminary findings were based on a pilot study at the BNAC headed by Zivadinov, and at the Universities of Ferrara and Bologna, Italy, directed by Zamboni and Fabrizio Salvi, M.D, respectively. The study showed that several abnormalities affecting the predominant pathways that return venous blood from the brain to the heart occurred more frequently in MS patients than in controls.

This research, supported by the Hilarescere Foundation of Italy and the BNAC, was conducted to replicate the findings of the Italian investigators.

"Results of this preliminary study, which involved 16 relapsing-remitting MS patients and eight age-and-sex-matched healthy controls, showed that all the MS patients, but none of the controls, had chronic insufficient blood flow out of the brain," said Zivadinov.

Bianca Weinstock-Guttman, M.D., UB associate professor of neurology and a co-principal investigator on the pilot study, added: "The images from this study were acquired using a method called Doppler ultrasound. The method identified anomalies in the venous blood flow associated with strictures, malformed valves and peculiar webs within the large veins of the neck and brain"

Weinstock-Guttman directs the Baird Multiple Sclerosis Center at the Jacobs Neurological Institute (JNI), UB's Department of Neurology. The JNI and BNAC are located in Buffalo General Hospital of Kaleida Health.

Advanced magnetic resonance imaging scanning (MRI) of the MS study patients conducted at the BNAC also identified distinct areas of iron deposits in the brain, and showed that those deposits may be associated with the location of MS lesions and sites of impaired drainage. The scans also revealed increased brain atrophy and changes in the flow of cerebrospinal fluid in the MS patients.

These results, which form the basis of the current larger investigation, were presented at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis held in September in Dusseldorf, Germany

The new study will involve 1,600 adults and 100 children. The cohort will be comprised of 1,100 patients who were diagnosed with possible or definite MS, 300 age-and-sex matched normal controls, and 300 patients with other autoimmune and neurodegenerative diseases. Enrollment in the study has begun and will continue for two years. MS patients from across the U.S. are eligible to participate in the study.

"The prevailing wisdom that central nervous system damage in MS is predominantly the result of abnormal immune responses against the patient's nervous tissue has been challenged by research findings, which have demonstrated a significant neurodegenerative component in MS and the progressive loss of neurons" said Zivadinov.

However, these inflammatory and neurodegenerative processes occur concurrently in MS and vary considerably among patients, making it difficult to identify the cause, or causes of the disease. Consequently, the origin and development of MS remains poorly understood, and its cause remains elusive."

To determine if these preliminary findings can be repeated, Zivadinov and Weinstock-Guttman organized the present study, which will evaluate both the velocity of blood flow through both the brain's blood vessels and the extracranial veins, using Doppler ultrasound.

The technical name of the study is "combined transcranial and extracranial venous Doppler (CTEVD) evaluation in MS and related diseases".

All study subjects will undergo a general clinical examination and a Doppler scan of the head and neck to acquire images of the direction of venous blood flow in different body postures. Participants also will provide blood samples, and complete an extensive environmental questionnaire to identify potential MS risk factors.

All MS patients will undergo MRI of the brain to measure iron deposits in lesions and surrounding areas of the brain using a method called susceptibility-weighted imaging. Iron findings on these images will be related to neuropsychological symptoms. The neuropsychological part of the study will be conducted by Ralph Benedict, Ph.D., professor of neurology and psychiatry at the JNI, UB's Department of Neurology.

A sub-cohort of 250 consecutive patients and controls will undergo MRI of the veins of the neck to confirm diagnosis of CCSVI.

Murali Ramanathan, Ph.D., associate professor in the Department of Pharmaceutical Sciences, UB School of Pharmacy and Pharmaceutical Sciences, will analyze blood samples for proteins and soluble factors associated with central nervous system injury. He also will be looking for other factors of interest in MS research, such as vitamin D metabolites and cigarette smoking, which have been linked to increased risk for developing MS as well as MS disease progression.

The data will be unblinded at three predetermined time-points, with the initial unblinding scheduled for November 2009. For more details on the study, send an email to [email protected].

Zivadinov said results of the study may lead to a larger multicenter North-American trial that will evaluate the occurrence of CCSVI in MS.

While gripping, lifting or manipulating an object such as drinking from a cup or placing a book on a shelf is usually easy for most, it can be challenging for those with neurological diseases such as multiple sclerosis or Parkinson's, or for people who had a stroke. For them, the tight gripping can cause fatigue, making everyday tasks difficult.

A team of University of Illinois at Chicago physical therapists report this month in the journal Neurorehabilitation and Neural Repair that persons with multiple sclerosis use excessive force when they are lifting objects. In an earlier finding reported in the journal Clinical Neurophysiology, they reported that regaining control and coordination may be as easy as applying a gentle touch to the affected hand from a finger of the opposite hand.

"We studied how this light touch application changes the way people apply force to an object they want to grip," said Alexander Aruin, professor of physical therapy. The study compared eight adults with multiple sclerosis to eight without the disease, gender-matched and of comparable age. "In each case, the grip force required to lift an object decreased," said Aruin.

He found similar results in an earlier study he did of people with arm weakness caused by a stroke.

Why the simple light finger touch application works so well is not fully understood, but Aruin offers a hypothesis.

"It could be due to auxiliary sensory information from the contra-lateral arm," he said. "When we use our second hand and touch the wrist of the target hand, available information to the central nervous system about the hand-object interaction may increase. Without the touch, the information needed to manipulate an object comes only through vision and sensory input from just the target arm and hand."

Aruin and his colleagues tested subjects griping and lifting a variety of objects that they moved in several different ways, directions and velocities. The gentle finger touch always helped to reduce grip force, making the task easier.

The UIC researcher said he and his colleagues plan to test the approach on those with other neurological and muscular diseases to examine the effects.

"We look forward to developing training and rehabilitation procedures on how to use this," said Aruin. "We know that MS patients are prone to fatigue and muscle weakness. This finding may enable them to perform daily activities more independently to improve their quality of life."

The papers' lead author was Veena Iyengar, a former master's student of Aruin's now at Advocate Lutheran General Hospital in Park Ridge, Ill. Other authors were Marcio Santos, a former UIC postdoctoral fellow now at Santa Catarina State University in Brazil, and Michael Ko, a neurologist with Loyola University Chicago's medical center.

Over the last 40 years, Epstein-Barr virus (EBV) has been repeatedly associated with multiple sclerosis and other autoimmune diseases. During the 2nd European Congress of Immunology ECI 2009 held in Berlin, Francesca Aloisi, Istituto Superiore di Sanità, Rome, will present new data* that further support the link. In the brain lesions of patients with multiple sclerosis her team found abnormal accumulation of EBV infected B lymphocytes. Similar findings were made in the pathological tissues of patients with other autoimmune diseases.

Multiple sclerosis is the most common inflammatory disease of the central nervous system affecting young adults. Similarly to other chronic inflammatory diseases, like rheumatoid arthritis and systemic lupus erythematosus, multiple sclerosis is thought to result from an inappropriate attack of the immune system toward selected body components, a process named autoimmunity. In the case of multiple sclerosis, the immune system is thought to attack myelin, the lipid-rich sheath coating our nerves.

To date neither the causes nor the cure of this highly disabling disease have been identified. A detailed knowledge of the cause(s) and the pathogenesis is needed to develop effective new options for therapy and prevention. Viruses have always attracted the interest of immunologists as possible triggers of autoimmune diseases due to their ability to interfere with the host’s immune system. One of the most ubiquitous viruses, EBV, which infects up to 95 % of the human population worldwide, has been repeatedly associated with multiple sclerosis through epidemiological and serological studies, but direct proof of its involvement was missing. The virus has the ability to hide in a particular population of immune cells, the B lymphocytes, remaining in a relatively dormant state for the entire life of the host. However, when not properly controlled by the immune system, EBV can reactivate causing tumours.

At the end of 2007, Aloisi and co-workers showed that EBV is present in brain lesions of patients with multiple sclerosis and that the virus is brought into the central nervous system by B lymphocytes, which behave as Trojan horses for the virus. They also showed that the infected B cells present in the brain become the target of an immune attack, thus promoting the chronic inflammation which leads to tissue destruction. „This raises the suspicion that EBV and its Trojan horses are the main cause of brain damage in multiple sclerosis“, Aloisi says.

The scientists demonstrated that abnormal accumulation of EBV infected B lymphocytes is also found in pathological tissues in other autoimmune diseases. „These findings reinforce the long-held view that EBV might be involved in several autoimmune diseases and represent a step forward in the effort to understand the mechanisms underlying the development of autoimmunity. One of the main challenges for the future will be to understand whether preventing or counteracting EBV infection will have a beneficial impact on autoimmune diseases.”

*This project is supported by the FP6 EU Programme