Gray Matter Structure Shrinks in Brains of MS Patients, UB Neuroimaging Scientists Find

BUFFALO, N.Y. -- A brain structure called the caudate nucleus, which plays an important role in cognition, emotions, mood, and motor function, may shrink by nearly 20 percent in persons with multiple sclerosis (MS), researchers from the University at Buffalo have shown.

By constructing three-dimensional images from high-resolution MRI scans of the caudate nuclei of MS patients and healthy controls, UB researchers have been able to compute the volume of this portion of the brain's deep gray matter, suggesting for the first time that atrophy of the caudate nucleus occurs in MS.

Results of the research appeared in the March 3 issue of NeuroReport.

Researchers led by Rohit Bakshi, M.D., associate professor of neurology in UB's School of Medicine and Biomedical Science, showed that the volume of the caudate nucleus in 24 MS patients was on average 19 percent lower than in 10 age-matched healthy controls. This result persisted after adjusting for the amount of whole-brain atrophy known to occur in patients with MS, suggesting selective atrophy of this structure.

The work was conducted in the Buffalo Neuroimaging Analysis Center (BNAC) of the Jacobs Neurological Institute, affiliated with UB and Kaleida Health.

Martins D. Innus, scientific visualization specialist in the UB Center for Computational Research, constructed three-dimensional images of the caudate nuclei of all subjects. This allowed the researchers to see exactly where atrophy might be occurring through direct visual comparison of the structures in patients and controls.

Shrinkage of the caudate nucleus in this study was not related to any measure of MS progression, such as disease duration or extent of loss of the myelin sheath, the white matter covering nerve fibers that permits neurons to send messages properly, said Robert Bermel, a fourth-year medical student in UB's School of Medicine and Biomedical Sciences and first author on the study. Bermel presented his findings in poster format last April at the American Academy of Neurology meeting in Denver.

"White-matter lesions are the conventional marker for the existence and extent of MS," Bermel said. "Our research is the first to show that specific parts of the brain's gray matter undergo atrophy in MS. The fact that gray-matter atrophy isn't related to conventional markers of MS suggests that another direct mechanism is at work in gray-matter disease.

"The study also demonstrates that new, computer-assisted imaging capabilities can show gray-matter disease, which previous MRIs could not detect," Bermel said. "It opens a new window into the brain, and could lead to new treatments for MS."

Bakshi, Bermel and colleagues hypothesize that iron deposits in gray matter -- in this case, the caudate nucleus -- are to blame for atrophy. Bakshi said MRI scans of gray-matter structures in the brains of MS patients appear very dark, an indication of high iron levels.

"We are working to prove this theory through microscopic tissue studies, but we think this is a credible hypothesis," he said. "Similar iron deposits have shown up in MRI scans of Alzheimer's and Parkinson's patients.

"We suspect that MS patients have defective blood-brain barriers, the cell layer that prevents potentially toxic substances from entering the brain. Excessive iron entering the brain may damage the caudate nucleus through generation of free radicals and lipid peroxidation, as well as inflammation, all of which would destroy neurons."

Lower caudate nucleus volume wasn't associated with standard measures of MS physical disability or the clinical course of the disease, characterized by relapsing-remitting symptoms or progressive symptoms, the study showed. The researchers suggest that no association was found because standard disability measures are weighted heavily toward motor symptoms. Gray-matter disease in MS is more strongly associated with neuropsychological function and fatigue, Bermel noted.

Bakshi's group is continuing to study gray-matter atrophy in MS to confirm how the damage occurs and how it may relate to cognitive function and physical disability. They also are studying whether atrophy of the caudate nucleus and other gray-matter brain structures could serve as early markers of a future MS diagnosis, which could permit earlier treatment.

Christopher W. Tjoa, a student researcher in the BNAC, also contributed to the study.

The research was funded by a medical student summer research grant from Alpha Omega Alpha and a UB summer research fellowship to Bermel, and by a grant to Bakshi from the National Institutes of Health.