by Jamie Talan
NEXT MONTH, patients newly diagnosed with multiple sclerosis will make their way to Brookhaven National Laboratory to take part in a landmark exploration into their brains. Scientists there have just put the finishing touches on a new magnetic resonance scanner, the most powerful one to date, and one that promises a much more elaborate look inside the disease process.
The scientists, in collaboration with neurologists at SUNY Stony Brook, will begin scanning patients as soon as possible after the initial diagnosis and follow them monthly for three years. The aim is to track formation of lesions in the brain and determine if there is a correlation between the lesions and symptoms.
Dr. Lauren Krupp, a neurologist at Stony Brook's University Hospital and Medical Center, said the scanner is far more sensitive to what's happening biologically than what doctors can observe clinically. "It's a terrific opportunity," she said.
What scientists now know about multiple sclerosis, an autoimmune disorder that occurs twice as often in women as in men, is that the symptoms-numbness, weakness, tingling, double vision-may wax and wane even as the brain-damaging process continues. Brookhaven chemist William Rooney wants to observe the underlying biological process in action.
One of the main features of MS is an increase in the brain's water volume in the white matter, the area of brain where the long projections, or axons, of the nerves build their connections with other nerve cells. These axons are covered with an insulating substance called myelin, which allows a nerve cell's electrical signals to transmit properly. Myelin is destroyed in the disease process, and the resulting poor conduction of electrical signals leads to the symptoms. Rooney said that regions with the highest water content are at risk for developing lesions within one year, but it's not clear why.
The chemist and his colleagues have evidence from other ongoing work that MS is triggered by vascular abnormalities that lead to global shifts in water volume. "The distribution of water in white matter is increased in MS patients," Rooney explained. A contrast agent, which is injected into the patient before the MRI, works like a dye to allow visualization of the lesions and their change over time.
Rooney and others believe that the brain's protective blood barrier becomes leaky, allowing extra water and immune molecules to intrude and cause inflammation, and then the immune cells attack the myelin sheath. When lesions appear, Rooney's studies have shown, there is a corresponding increase in the brain's water content. When the blood-brain barrier reseals, the lesions begin to disappear.
Scanning patients every month will help scientists answer some questions: Do symptoms correlate with the lesions? (Recent work from the Brookhaven-Stony Brook team suggests that for every episode, there are 10 new lesions in the brain.) Do patients report feeling better when the lesions, or scars, disappear? What impact does medication have on the lesions, and the symptoms? And how is the increased water content related to a patient's symptoms? Scientists also hope to determine how well patients respond to medications, both biologically and clinically. They will be able to get initial scanning information before patients begin treatment, Krupp said.
They are recruiting 25 patients with the most common form of MS, a condition in which symptoms come and go with no apparent reason. In addition to the brain scans, patient volunteers will undergo continuous testing to measure stress, cognition, memory, mood and fatigue.
Only in recent years have scientists directed the technology deep into the brain to crack some of the mysteries of degenerative brain diseases. At the Mayo Clinic, scientists have taken tissue frozen for more than 30 years and found four different patterns of pathology. "You don't want to wait for an autopsy," Krupp said. "MRI is our living autopsy." Indeed, the results from the frozen tissue suggests that there are several types of MS: one that causes inflammation around the blood vessels; one that causes more global inflammation; another in which white blood cells produce antibodies that wind up in the brain; and yet another in which cells in the brain's white matter die.
The scanning technology also is expected to help research into women's greater susceptibility to develop MS. In a recently completed study, Rooney, Krupp and Stony Brook's Dr. Patricia Coyle enrolled 10 women, half of whom have MS, to determine whether the menstrual cycle plays a role in the formation of new lesions or symptoms. Results of the study are now being analyzed.
Additionally, the Brookhaven-Stony Brook group has received funds from a $20 million research project of the National Institutes of Health and the National Multiple Sclerosis Society for a study on the sex differences in immune diseases. Scientists say women appear to have higher levels of certain immune cells and antibodies than do men. Hormones are known to affect the body's immune response, and studies on women show that low estrogen levels trigger a more reactive immune response and high levels seem to inhibit the immune system. (It has long been known that MS symptoms decline during pregnancy, a time when estrogen levels are highest.) In other research, scientists at the University of California in Los Angeles are testing whether an estrogen-like compound, estriol, reduces the number of episodes in women with MS. In another study funded by the NIH and MS Society, researchers at Oregon Health Sciences University in Portland have vaccinated animals prone to an MS-like autoimmune disease called experimental allergic encephalomyelitis. And many labs are focusing on the genetic aspects of disease and response to treatments.
It is not clear how many people in the United States have multiple sclerosis. The federal government puts the number at 350,000, but many experts believe these numbers are far too low.
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