Volume 34, Number 22
By Lois Baker, Contributing Editor
Specialists in neuroimaging at UB have proposed a mechanism by which interferon beta-1a may limit brain atrophy in multiple sclerosis (MS) patients.
The positive effect of interferon beta-1a, a standard treatment for MS, on brain atrophy is well-known, but the process through which that occurs remains a mystery. UB scientists have shown that the treatment appears to limit atrophy by minimizing the toxic effect of pathologic iron deposits found in gray-matter structures of MS patients.
While the treatment did not diminish iron concentrations that already had accumulated, it appeared to interfere with the accumulation of iron-induced damage, said Robert A. Bermel, a fourth-year student in the School of Medicine and Biomedical Sciences and lead author on the study.
Bermel presented the research findings on April 3 at the annual meeting of the American Academy of Neurology in Hawaii. He also presented the study in March at the annual meeting of the American Society of Neuroimaging, which selected the work to receive the society's 2003 Oldendorf Award for the best research project first-authored by a trainee.
The MRI imaging work was conducted at the Buffalo Neuroimaging Analysis Center (BNAC) of the Jacobs Neurological Institute, affiliated with UB School of Medicine and Biological Sciences and Kaleida Health. This group reported previously for the first time that in addition to the characteristic white-matter lesions that are a traditional marker of the disease, MS patients show shrinkage, or atrophy, of certain structures in the brain's deep gray matter.
Their imaging studies also have shown that in MS patients, these deep gray-matter structures appear hypointense, or darker than normal, signaling the presence of iron concentrations. The researchers hypothesize that brain atrophy is linked to these iron deposits.
"We know that MS patients have defective blood-brain barriers, the filter that keeps chemicals, like iron, from leaking into the brain," said Bermel. "Our hypothesis is that this defect allows iron to accumulate in certain parts of the brain, which then can be directly neurotoxic to cells, causing atrophy."
Knowing that interferon beta-1a treatment has a positive effect on brain atrophy, Bermel and colleagues set out to determine if the pathway of action was associated with iron concentration. They followed 159 patients who were enrolled in a randomized, double-blind treatment trial for the relapsing form of the disease for two years. Eighty-one patients received treatment; 78 who received placebo served as controls.
Researchers took MRI scans of all patients to determine hypointensity and brain atrophy at baseline and at two years. Results showed that hypointensity at baseline was linked to brain atrophy over that time period in controls, but not in the treatment group. Hypointensity remained unchanged in the treatment group, but brain atrophy was significantly less.
"These findings suggest that interferon may disrupt the relationship between baseline T2H (hypointensity) and atrophy over time," Bermel said, noting that there may be several explanations for the finding.
"Interferon beta-1a is known to lower the levels of inflammatory cytokines in the blood of patients with MS. When the body is in a state without inflammation, as it is normally, its cells, including neurons, can better regulate their contents and byproducts, including iron. In untreated MS, which is characterized by brain inflammation, iron may be allowed to build up to toxic levels in certain brain structures, causing toxic chemical reactions and death of nerve cells, leading to what we see as brain atrophy on MRI scans.
"Also, interferon is known to help restore the body's natural blood-brain barrier, which would keep toxic iron from seeping into the cells," Bermel said. "This study shows for the first time that interferon treatment may result in less brain atrophy in MS through a cascade of events that interferes with the pathologic iron deposition."
Additional authors on the study from Buffalo were Srinivas R. Puli, former research associate in the BNAC; Andrew J. Fabiano, third-year medical student doing research in the BNAC; Bianca Weinstock-Guttman, assistant professor of neurology; Frederick E. Munschauer, professor and chair of the Department of Neurology, and Rohit Bakshi, associate professor of neurology and director of the BNAC.
Elizabeth Fisher and Richard A. Rudick from the Cleveland Clinic performed measurements of whole brain atrophy. Jack H. Simon from the University of Colorado performed additional analysis.
The research was funded by a grant from Alpha Omega Alpha and a scholarship
from the American Academy of Neurology to Bermel and by a grant to Bakshi
from the National Institutes of Health.
© 2003, University at Buffalo