Gray matter, rather than myelin, may be involved in the earliest stages of multiple sclerosis (MS), according to research published September 3 in PLOS One . Gray matter components (eg, axons, neurons, and synapses) may distinguish the CSF proteome of a patient with a true first attack of MS from those of healthy controls and patients with established relapsing-remitting MS.
Nogo receptor was markedly elevated in the CSF of patients with a true first attack of MS, compared with patients with established relapsing-remitting MS and controls, said Steven E. Schutzer, MD, Professor of Medicine at Rutgers University New Jersey Medical School in Newark. Patients with a first attack of MS also had a significant increase of contactin-2/TAG-1, an axonal glycoprotein, in their CSF. Contactin-2/TAG-1 has been reported as an autoimmune target in MS.
Researchers Analyzed CSF From Three Patient Groups
Previous imaging studies have suggested that gray matter changes, and not white matter changes, occur early and predict the development of MS. Other data have conflicted with this idea, however. To determine whether gray matter is involved in early MS, Dr. Schutzer and colleagues collected CSF from three groups of patients. The first group included nine patients with clinically isolated syndrome (CIS) who eventually met diagnostic criteria for MS. The second group included 12 patients with established diagnoses of relapsing-remitting MS according to the McDonald criteria. The third group included six control subjects with no apparent CNS disease.
For the purpose of comparison, the investigators used previously published protein lists generated from two groups of persons with other neurologic diseases and more than 200 healthy controls. The researchers also analyzed a separate group of 10 patients with CIS to compare them with the CIS patients in the study. Dr. Schutzer and colleagues performed protein separation and fractionation on the CSF samples and analyzed them with direct liquid chromatography–mass spectrometry.
Quantities of 20 Proteins Differed Among the Groups
The researchers found 20 proteins that were present in significantly different quantities in patients with CIS, patients with established relapsing-remitting MS, and controls. Nine of these proteins were significantly increased in patients with first-attack CIS, compared with the other two groups. Five proteins were significantly decreased in patients with first-attack CIS, compared with the other groups. The remaining proteins were increased in patients with CIS, compared with patients with relapsing-remitting MS, but decreased compared with controls. Fifteen of the 20 proteins were associated with gray matter.
“There is an increasing literature on the importance of gray matter, neuronal, and axonal involvement in MS, even at very early time points,” said Dr. Schutzer. “Our findings support this [hypothesis] and indicate that axonal, neuronal, and synaptic involvement may be required for the initial presentation of MS. It is interesting in this disease, which is characterized by demyelination as it progresses, that gray matter components may be diagnostically more useful than myelin components at the earliest stages,” he added.
—Erik Greb
Senior Associate Editor