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Brain's Gray Matter Involved In Multiple Sclerosis

Ten years ago people with multiple sclerosis could expect little from the medical profession other than drugs to help relieve their symptoms and canes or walkers to help them get around as their physical disabilities mounted.

That, however, was before researchers were able to focus the full power of biotechnology on the disease.

Today, by using advanced MRI brain imaging methods and tapping into one of the most powerful supercomputing systems in the world, University at Buffalo researchers in the Buffalo Neuroimaging Analysis Center (BNAC) are providing insights into the disease that never before were possible.

Some researchers are creating three-dimensional images of the brain and brain structures of MS patients that show the process of atrophy under the disease's onslaught.

Others are linking stages of atrophy with physical and cognitive symptoms and are developing a "standardized" image of the caudate nucleus in brains of patients that will serve as a model for assessing disease stage and predicting progression.

Still other scientists are using advanced imaging techniques and computing power to study the amount of whole-brain shrinkage that occurs in MS and to develop accurate ways to measure brain deterioration.

But perhaps the most important development to come out of the center is the UB researchers' discovery that the brain's gray matter, where higher functioning is centered, is involved in MS.

"Traditionally, MS was thought to be strictly a 'white matter disease,'" said Rohit Bakshi, M.D., UB associate professor of neurology and director of the BNAC, located in The Jacobs Neurological Institute at Kaleida Health's Buffalo General Hospital. "We thought it only affected the 'roadways' in the brain." White matter allows various gray-matter structures to communicate with each other.

The finding about gray matter resulted from their work with a brain structure situated deep in the gray matter called the caudate nucleus, which is an important nerve center for controlling movement and cognitive processing. Other laboratories have studied the role of the caudate nucleus in Alzheimer's disease and Huntington's disease. The BNAC is the only center studying it in MS patients with
state-of-the-art MRI techniques.

"Through our computerized imaging analysis capabilities we have been able to visualize the caudate nucleus in MS patients in new ways and found it was atrophied," said Bakshi. "Moreover, the atrophy is not associated with the amount of white matter damage."

The finding is significant, he explained, because "if we are going to treat this disease, we have to know where the damage is."

MS strikes primarily between the ages of 20 and 40 and there is no cure. It is the most common cause of progressive neurologic disability in young adults. The disease is most prevalent in mid-North America and Northern Europe. Symptoms vary widely, depending on where and how much brain damage is involved.

A leap forward in treatment occurred in 1996 when a drug developed by the late Lawrence Jacobs, M.D., UB neurologist, was approved by the Federal Drug Administration (FDA) after several years of clinical trials supervised by Jacobs. The drug, interferon beta-1a (Avonex), slows progression of disability of the relapsing-remitting form of the disease and reduces the amount of flare-ups. It is now the most widely prescribed treatment for MS.

"Our challenge is to uncover mechanisms in the brain that could lead us to a new therapy, building on Dr. Jacob's work," said Bakshi. "One possibility might be a drug cocktail that includes interferon and a neuroprotective agent to target and preserve the gray matter."

Bakshi's own research could point to one possible drug approach. He is first author on a study published in January in Archives of Neurology that reports that brains of MS patients appear to contain excess iron deposits.

"In our imaging studies the gray-matter structures of MS patients appear very dark on one type of MRI scan," Bakshi said. "This evidence points to high levels of iron in the brain, which suggests iron could be causing cell damage. The brain's mechanism to regulate iron could be impaired or shutdown in MS.

"We've been able to correlate gray matter hypointensity with brain atrophy and physical impairment," he said. "This leads us to think that hypointensity in the deep gray matter is a strong predictor of disability, progression of the disease and subsequent brain atrophy."

If these findings hold up through longitudinal studies, a treatment designed to prevent iron build-up could prove beneficial.

While Bakshi analyzed several gray-matter structures, Robert Bermel, a third-year medical student working in his lab, is concentrating on the caudate nucleus. Specialists in UB's Center for Computational Research (CCR) are taking data from high-resolution MRI scans of the structure in MS patients and converting them into three-dimensional images that can be displayed on a computer monitor and rotated in any direction interactively. The studies are aimed at looking at how disease of the gray matter is detected in the brain and how it relates to MS progression.

"Until we had the ability to create three-dimensional images, we were able to use computers to obtain only quantitative data, such as the structure's volume and dimensions," said Bermel. "Now we are able to visualize structures, to actually see where atrophy is occurring."

Bermel presented a poster in April at the American Academy of Neurology meeting detailing his findings, which showed that caudate nuclei in MS patients were smaller than in healthy controls. The atrophy of this brain structure wasn't associated with any other measures of disease progression, such as whole-brain atrophy, duration of disease or extent of brain lesions.

"This suggests that another undetermined mechanism may play a role in gray matter disease," Bermel said. "The study also demonstrated that new computer-assisted imaging capabilities can show gray-matter disease, which previous MRIs could not detect. It opens a new window into the brain."

Bermel and his CCR colleagues now are establishing a database of three-dimensional images of caudate nuclei from MS patients and correlating each image with each patient's ability to function. This will allow researchers to track the association between atrophy and MS symptoms, and by matching images from new patients to the database, to predict their disease stage and progress.

The center's funding -- more than $1 million in its two years of existence -- and its research agenda, is multidisciplinary. UB provided a grant to purchase computers. The Juvenile Diabetes Foundation, the National Multiple Sclerosis Society and the National Institutes of Health provided research funding.

Bakshi has gathered a group of energetic student researchers from various disciplines to work with senior neurologists on several projects. Among the researchers is Andrew Fabiano, a second-year UB medical student, who is analyzing diffusion-weighted MRI scans of gray-matter structures in MS patients. This type of scan measures the amount of water that passes through a brain structure: the higher the diffusion rate, the less dense the tissue.

Fabiano is assessing the diffusion rates of two different categories of disease, relapsing-remitting and secondary-progressive, and comparing them to patient's symptoms.

In results presented at the American Academy of Neurology meeting in April, Fabiano reported that the diffusion rate was higher in secondary-progressive patients than in relapsing-remitting. In the caudate nucleus, a higher diffusion rate was linked to greater physical disability.

His findings suggest that this type of scan could be used as a noninvasive method to determine and monitor gray-matter tissue damage in MS patients. Fabiano has been awarded a prestigious research grant from the Alpha Omega Alpha Medical Honor Society to continue this work this summer in Bakshi's lab.

Jitendra Sharma, M.D., a graduate student at Roswell Park Cancer Institute, is collaborating with a researcher at the University of Trieste to develop a highly reliable measure of whole-brain atrophy. Jin Kuwata, a UB psychology graduate, is administering cognitive tests to MS patients and comparing their performance with the amount of atrophy shown on their brain scans, making the connection between gray matter damage and mental function.

Christopher Tjoa, a computer science and pre-med major at UB, is conducting brain mapping in an effort to develop a standardized image of a healthy brain, against which MS brain images can be compared.

While current work at the center will continue to concentrate on MS, in the future researchers will be analyzing brain scans of juvenile diabetes patients and persons with other conditions, such as lupus, stroke, dementia and epilepsy.

"Our main thrust," said Bakshi, "is to determine, through MRI analysis, the sites and mechanisms of disease in the brain and provide new information about how diseases progress. The applications of this work include a more accurate diagnosis of neurologic disorders, and the ability to accurately predict the disease course at the time of the earliest symptoms.

"Also, through studying diseases with sophisticated MRI analysis, we begin to untangle the great mystery of how the brain functions. Ultimately, this information could result in new treatments and, in the best scenario, to possible cures for a variety of brain disorders. This is what we all work toward." - By Lois Baker

[Contact: Lois Baker]






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