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Will New Data on Gray Matter Dysfunction in MS Upend Theory on Disease Demyelination?

Moran, Mark

doi: 10.1097/01.NT.0000437152.09717.01
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A new paper suggests that multiple sclerosis initiates with gray matter damage and entails brain loss.

Cerebrospinal fluid (CSF) of patients with first-episode multiple sclerosis (MS) appears to be differentially enriched with gray matter proteins — as opposed to white matter proteins — suggesting that gray matter dysfunction is involved in early MS.

That was the finding from a study using high-resolution mass spectrometry to compare CSF of first-episode patients, established patients with relapsing-remitting MS, and a group of healthy controls. The study was published in the Sept. 10 online edition of PLOS One.

The results, if replicated, upend a long-established hypothesis that MS is a disease of demyelination, and suggest that the disease initiates instead with gray matter damage and entails brain loss. Conceivably — though study authors and experts who reviewed the paper agree this is a long way off — replication could lead to the development of clinically useful biomarkers.

The marked preponderance of gray matter proteins in almost all of the first-episode — also called clinically-isolated syndrome (CIS) — patients suggests as well that the first attack in MS may not be a random occurrence, but rather orchestrated by specific, as-yet-unidentified circumstances that culminate in clinical disease expression.

“A current hypothesis is that there are random ‘hits’ or injuries occurring in the brain, and when they happen to affect an eloquent part of the brain then clinical manifestations can be seen,” lead author Steven E. Schutzer, MD, professor of medicine, and epidemiology and biostatistics at Rutgers University New Jersey Medical School, told Neurology Today. “If they do not hit that certain part, the patient does not have an outward observable manifestation of MS. The finding of gray matter-related proteins in most of the first attack patients versus just a few, raises the contrasting hypothesis that the disease process involves non-random, but rather targeted hits to those specific eloquent areas.”

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In the study, researchers collected CSF from three groups: nine first-attack patients who eventually met the criteria for MS (eight females and one male, three with optic neuritis and six with a multifocal CNS syndrome); 12 patients with established diagnosis of relapsing-remitting (RR)-MS (nine females and three males); and four female and two male control subjects without overt organic CNS disease who underwent lumbar puncture for headache or tinnitus.

CSF samples were analyzed using high-resolution mass spectrometry.

Analysis of the quantitative differences in protein abundance comparing control, first-attack, and established RR-MS samples revealed group-specific differences. There was a total of 20 CNS-specific proteins detected in CSF which showed significant quantitative differences in the first-attack CIS MS group compared with established RR-MS and controls; at least 15 of these 20 proteins affect synapse, axon, and neuron functioning (gray matter associated), as opposed to myelin (white matter), according to the report.

Nine of the proteins were significantly increased in first-attack CIS MS compared with both groups with the most striking increase in soluble Nogo receptor.

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Timothy Vollmer, MD, who reviewed the report for Neurology Today, said the study joins other imaging studies as well as pathologic studies pointing to disease in the cortex of patients with MS that clinicians don't see using traditional MRI techniques.

“This is one of a number of studies that are telling us that MS is not a disease of myelin but of the CNS, and that both can be impacted,” said Dr. Vollmer, medical director of the Rocky Mountain Multiple Sclerosis Center, director of neurology clinical research, and professor of neurology at the University of Colorado, Denver. “What this is also emphasizing is that, contrary to popular belief, the loss of neurons we see is most likely not secondary to demyelination, but is a more direct attack on neurons in the gray matter.

“This is important because we know from a number of studies that damage to gray matter predicts disability much more than damage to white matter,” he said. “Therapeutically, our goal ought to be to preserve brain volume as much as possible. That would mean selecting newer, more effective therapies early in the disease course rather than using older medications and waiting for people to fail on them before moving on to the new agents.”

Among agents, Dr. Vollmer said, those that have been shown to preserve neurons are natalizumab (Tysabri), fingolimod (Gilenya), and dimethyl fumarate (Tecfidera).

“This is an area the MS community needs to pay attention to because most clinicians are not really focused on neuronal injury, but on the number of white spots they see on MRIs,” Dr. Vollmer said.

Richard Rudick, MD, director of the Mellen Center at the Cleveland Clinic Foundation, likewise hailed the report — particularly its use of CSF to confirm gray matter involvement in early MS that has been suggestive in imaging studies. “The implication of what they have found is that neurons and axons are involved in the early stage of MS and it is not simply myelin that is targeted,” he said in an interview. “That's important.”

But he cautioned that it may be premature to assume that gray matter is either preferentially targeted in early MS or that it precedes demyelination. He noted that white matter proteins were seen in the CSF of first-episode patients, and it cannot be known conclusively whether the damage occurs simultaneously, or whether one precedes the other.

And he emphasized that patients experiencing a first clinically isolated episode are not necessarily experiencing a first episode of MS, but may actually have existing, older but “silent” damage.

That's a point echoed by Robert Lisak, MD, who also reviewed the report. “We need to remember that many first clinical episodes are not the first pathologic episodes since patients very often have lesions seen on MRI scans that are clearly older than the lesions that are responsible for the first event,” Dr. Lisak, professor of neurology at Wayne State University School of Medicine, told Neurology Today.

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Dr. Schutzer acknowledged that the findings are not conclusive, but said they could point the way to more targeted research on the pathogenesis of MS. “This discovery phase study lays the groundwork for the follow-up on verification and validation phase studies which can result in clinically useful biomarkers,” he said. “If fully verified that [gray matter damage] is closer to the starting point of the process, knowing you have the beginning of MS could prompt an earlier start-to-treat time with disease-modifying therapies approved by FDA. These disease-modifying therapies have been shown to decrease the number of attack relapses compared with placebo therapy, so the hope is that treating sooner rather than later can decrease severity of the disease.”

Dr. Schutzer added that some of the currently available therapies have significant side effects. “Proteomic studies in the compartment most relevant to brain processes — such as cerebrospinal fluid, which is akin to a liquid window to the brain — may help identify neurologically important pathways that new research can study. Parts of those pathways might be ripe for new targeted therapies that slow or halt the disease and have fewer side effects than what is currently available.”

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•. Schutzer SE, Angel TE, Liu T, et al. Gray matter is targeted in first-attack multiple sclerosis. PLoS One 2013;8(9):e66117.
•. Neurology Today archives on neuropathology of MS:
•. Neurology archive on neuropathology of MS:
© 2013 American Academy of Neurology