Caroline Helwick

February 24, 2016

NEW ORLEANS — The degree of meningeal inflammation and cortical pathology might prove useful for stratifying patients with early progressive multiple sclerosis (MS), new research suggests.

The findings are from European investigators, who evaluated gene and protein expression in cerebrospinal fluid (CSF) and correlated the profiles with cortical damage as visualized by neuropathology and by MRI.

"Different CSF molecular profiles are associated with specific levels of gray matter (GM) damage, thus suggesting that this may represent a useful approach for patient stratification at disease onset, and for individualizing therapy," said Roberta Magliozzi, MD, from the University of Verona, Italy, and Imperial College London, United Kingdom.

Dr Magliozzi and senior investigator Richard Reynolds, MD, also from Imperial College London, described the findings here at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2016.

In an interview with Medscape Medical News, Dr Reynolds explained the study. "We are trying to identify markers in the CSF of patients that will predict who will progress more rapidly."

"We started with postmortem findings in patients who did progress rapidly and had more brain damage. We saw an increase in certain immune-related molecules," he said.

"Then we came back to the patient studies, and we could already see some of those changes at an earlier stage," he continued. "We analyzed these by combining imaging measures of gray matter damage with the immune profile. We saw that with more gray matter damage, there was an increase in the same molecules we saw postmortem."

Searching for a Biomarker

In her presentation, Dr Magliozzi noted that GM damage provides the best correlate of the variable accumulation of physical and cognitive deficits and is one of the main substrates of disability progression in MS.

"The changing clinical course of MS is a matter of gray matter," she commented.

The changing clinical course of MS is a matter of gray matter. Dr Roberta Magliozzi

In addition, meningeal B-cell infiltrates have been proposed as the main source of the intrathecal inflammatory/cytotoxic milieu in the CSF that may mediate and exacerbate the gradient of tissue injury in the adjacent GM.  

Meningeal inflammation in postmortem secondary progressive MS samples has been associated with increased inflammatory gene expression in the meninges and inflammatory protein expression in the CSF, she noted.

Compartmentalized meningeal inflammation, which is associated with cortical demyelination, can be quantified by advanced imaging techniques, she added.

Putting these factors together, the investigators sought to identify specific biomarkers and imaging tools to predict and monitor GM pathology and its association with MS progression. 

"Our hypothesis was that the degree of meningeal/CSF inflammation and cortical pathology can be related, and can be used to stratify a subgroup of MS patients with rapid progression," Dr Magliozzi said.

She and her colleagues evaluated gene expression in meningeal and protein expression in CSF samples from 20 postmortem patients with secondary progressive MS and 10 controls. They also combined advanced MRI of GM damage with an extensive protein analysis of CSF from 36 patients with MS and 12 controls with other noninflammatory neurologic diseases.

Proinflammatory CSF Profile

A pronounced proinflammatory CSF profile was found to be strictly associated with increased GM pathology and disease progression in MS patients, she reported.

This included over-expression of CXCL13, CXCL12, CCL19, CCL21, IL6, IL10, APRIL, BAFF, TNF, TNFR1, LIGHT, IFN-γ, GM-CSF, and MMP2, suggesting lymphoid-neogenesis, B-cell involvement and plasmablast/plasma cell involvement, in addition to a TNF-mediated inflammatory response.

In keeping with this, increased expression of CXCL13, CXCL9, TNF, IFNγ, LTα, LTβ, IL10, IL16, and IL12p40 was detected in the meninges and CSF samples of postmortem secondary progressive MS cases with higher level of meningeal inflammation and GM demyelination.

The high levels of GM damage suggest that meningeal B-cell infiltrates may represent the main source of inflammatory/cytotoxic molecules that are released into the CSF to cause cortical tissue injury in progressive MS, she suggested.

In contrast, in patients with less GM pathology, the researchers observed a pattern of increased regulatory molecules, including IFNα, IFNβ, IFNλ, CCL22, and CCL25.

The proinflammatory CSF profile "significantly differs from that of patients with a low level of GM damage, thus confirming that this may represent a useful approach for patient stratification at disease onset," she said.

Dr Reynolds told Medscape Medical News that the investigators were surprised about the higher expression of certain molecules in patients with greater progression. He cited, for example, chemokines such as CXCL13 that are involved in attracting B lymphocytes into the meninges.

"That's a very important finding," he said. "Seeing those molecules upregulated in the spinal fluid early on might help us predict patients with rapid progression."

Would the level of these inflammatory markers fall with appropriate treatment? "Perhaps," he said. "Anti-B-cell therapy is the approach most likely to be effective."

A trial of the anti-CD20 agent ocrelizumab that incorporates these markers is being planned by Massimiliano Calabrese, MD, from the University of Verona, and colleagues.

Dr Reynolds and his team plan to follow their patients with clinical, MRI, and cognitive evaluations in an attempt to validate the correlations between the imaging and CSF profiles and clinical progression.

Jerry Wolinsky, MD, interim chair of the Department of Neurology at the University of Texas Health Science Center at Houston, commented for Medscape Medical News.

"I am very interested in this notion that we may be able to get a profile on these patients that will be partly radiologic-based and functionally based, and that may differentiate which patients are in the progressive phase, highly likely to enter a progressive phase, or not in a progressive phase and who may miss this phase altogether," he said.

"That would be phenomenal information, and this study is probably as close as anything I've heard that will get us there," he said. "These are very important observations."

The study was supported by a grant from Progressive MS Alliance. Dr Magliozzi, Dr Reynolds, and Dr Wolinsky have disclosed no relevant financial relationships.

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2016. Abstract LB1. Presented February 19, 2016.


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