Fatty acid-derived molecules tied to inflammation, disability in study

Blood levels of lipid mediators differ mostly with progressive MS

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by Steve Bryson, PhD |

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Altered blood levels of certain fat molecules implicated in inflammatory responses seem to correlate with disability status and markers of nerve damage in people with multiple sclerosis (MS), particularly in those with progressive forms of the disorder, a study reported.

Findings highlight the potential role of these fat, or lipid, mediators in the disease’s development and progression, the researchers noted.

The analysis of lipid mediators in MS was published in the journal Neurology, in the study, “Association of Arachidonic Acid-Derived Lipid Mediators With Disease Severity in Patients With Relapsing and Progressive Multiple Sclerosis.”

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Derived from fatty acids, lipid mediators regulate immune responses

Lipid mediators are fat molecules metabolically derived from fatty acids that regulate immune responses. Evidence indicates that blood levels of lipid mediators differ between people with MS and those without it, suggesting they may contribute to the chronic inflammation seen in the disease.

Still, associations between lipid mediators and markers of brain and spinal cord inflammation and damage “remain elusive,” the researchers, all in the Netherlands, noted. For this reason, the team collected and analyzed blood samples from 285 people with MS, all born in that country in 1966, and 125 age-matched healthy individuals as a control group.

Among patients, 170 had relapsing-remitting MS (RRMS), and 115 had progressive forms of MS, either primary progressive MS (PPMS) or secondary progressive MS (SPMS).

“By using a cohort of [MS patients] and [healthy controls] of the same age, we have limited the confounding effect of age, as age is known to affect [lipid mediator] concentrations,” the researchers wrote.

They focused on blood levels of lipid mediators derived from omega-3 and omega-6 fatty acids and how they related to disability, brain volume, and two biomarkers of nerve damage: serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP).

Overall, people with progressive MS forms had more advanced disability, as assessed by higher scores on the Expanded Disability Status Scale (EDSS), and significantly higher sNfL and sGFAP levels than those with RRMS.

Brain volume, measured by MRI scans, was significantly lower across MS patients than controls.  Lower gray matter volume also was evident in progressive MS relative to RRMS patients. Gray matter corresponds to regions of the brain mainly composed of nerve cell bodies.

Analyses of lipid mediator levels showed significant differences between those with progressive MS and both RRMS patients and healthy individuals. In particular, 12 lipid mediators — mainly associated with omega-6-derived arachidonic acid, including 5-, 8-, and 15-HETEs — were at significantly higher levels in progressive MS patients relative to controls. Five of these molecules also were elevated in the progressive MS group compared with RRMS patients.

In turn, molecules derived from omega-6 linoleic acid, including 9- and 13-HODE, were at lower levels among the progressive MS patients compared with controls.

No significant differences were seen between the RRMS and control groups.

High 15-HETE levels tied to greater disability, disease duration, progressive MS

Across all MS patients, worse disability and higher sNfL levels correlated with increased levels of several HETEs, and with increased levels of mediators derived from omega-6 polyunsaturated fatty acids, such as DGLA and adrenic acid.

In the progressive MS group, higher levels of 8- and 15-HETE also correlated with worse disability status, and elevated 15-HETE levels associated with high sNfL levels. In turn, low 13-HODE correlated with elevated sGFAP in the RRMS group and MS patients as a whole.

sGFAP levels also linked with certain lipid mediators derived from omega-3 fatty acids in progressive MS patients.

Regarding brain volume, elevated 15-HETE levels associated with greater brain atrophy (shrinkage) in progressive MS patients, and higher levels of adrenic acid correlated with higher lesion volume.

“To our knowledge, no direct correlations between MRI measures and 15-HETE have been described before,” the team noted.

In RRMS patients, elevated levels of a lipid mediator derived from omega-3 polyunsaturated fatty acids, called DPAn-3, correlated with lower gray matter volume and a greater lesion load. Across the entire group of patients, higher DGLA, DPAn-3, adrenic acid, and 15-HETE levels all correlated with a greater lesion volume.

Finally, adjusted statistical calculations found high 15-HETE levels associated with worse disability, longer disease duration, and progressive disease. When sNfL and sGFAP were added to the calculations, greater disability across all MS patients was related to 15-HETE, disease duration, MS subtype, sNfL, and sGFAP.

“We demonstrate that patients with [progressive forms of MS] in particular display an altered LM [lipid mediator] profile compared to RRMS and [controls],” the researchers concluded.

“This altered LM profile in [progressive MS] is mainly driven by increased levels of [arachidonic acid] and its derivatives, which correlated to volumetric MRI measures, sNfL and disability,” they added.