Nitric oxide metabolites in blood could aid diagnosis of MS: Study

Measuring levels of nitric oxide metabolites in the blood could be a diagnostic biomarker for multiple sclerosis (MS), recent research suggests.

The molecules, collectively called NOx, were elevated in the blood of people with relapsing-remitting MS (RRMS) and primary-progressive MS (PPMS) compared to people with a noninflammatory neuropsychiatric condition.

“The measurement of NOx in the serum [blood] might indeed be a valuable tool in supporting MS diagnosis,” the researchers wrote in “The Use of Nitrosative Stress Molecules as Potential Diagnostic Biomarkers in Multiple Sclerosis,” which was published in the International Journal of Molecular Science. “Further investigations in larger cohorts and with a longitudinal design will be needed to fully uncover the diagnostic and prognostic potential of this group of molecules in the context of MS.”

Nitric oxide, or NO, is a molecule that plays a number of roles in the body, including in blood vessel widening, or vasodilation. High concentrations are associated with nitrosative stress, a type of cell damage that’s implicated in MS and other neurodegenerative diseases, however.

In MS, it’s thought that NO contributes to the dysfunction of the blood-brain barrier (BBB), a tight-knit layer of cells lining the blood vessels of the brain that helps keep potentially harmful substances in the bloodstream out of the nervous system. Vasodilation caused by NO disrupts this barrier, allowing immune cells to enter that contribute to the self-reactive inflammatory attacks that mark MS.

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 NOx as MS biomarker

NOx includes nitrate and nitrite, the most stable NO metabolites that are indicators of nitrosative stress. It’s been proposed that NOx levels could serve as an MS biomarker, but study results varied and didn’t account for disease subtype, leading researchers to examine NOx levels in the blood and cerebrospinal fluid (CSF) of more well-defined patient groups at their clinic in Germany. The CSF is the fluid that surrounds the brain and spinal cord.

The retrospective analysis included 71 people with RRMS and 16 with PPMS, all untreated. Thirty people with somatic symptom disorder, a noninflammatory neuropsychiatric condition marked by physical symptoms like pain or fatigue, were included as a control group.

Both RRMS and PPMS patients had higher levels of NOx in the blood than the control group, but the levels didn’t differ between the two types of MS.

In RRMS patients, this difference from the control group remained significant in a subgroup of people who were negative for an MRZ reaction. This reaction — referring to antibodies against measles, rubella, and varicella zoster virus above a certain threshold — is common in RRMS, but not other inflammatory neurological conditions and is used to aid in its diagnosis.

NOx levels also tended to be higher in the subgroup of patients negative for oligoclonal bands, another disease biomarker commonly used as a criteria for diagnosing MS.

“This highlights the potential of NOx as a biomarker in situations where, despite using the current diagnostic standard, the diagnosis remains unclear,” the researchers wrote.

Moreover, in RRMS patients, higher NOx levels in the blood were associated with a higher CSF/serum albumin ratio, an indicator of BBB disruption.

For both RRMS and PPMS patients, NOx levels didn’t appear to be influenced by age, sex, disability levels, or clinical parameters such as inflammatory brain lesions or relapses.

Biomarker levels were also examined in the CSF of a subgroup of RRMS and control patients. No relevant differences were observed. While not affected by most clinical factors, higher NOx levels in the CSF did correlate with greater disability.

The study didn’t include people with secondary progressive MS (SPMS). The researchers said they wanted to evaluate NOx levels in untreated patients, and SPMS patients have typically already received some type of MS therapy.

“NOx in SPMS would be particularly relevant as a progression and therapy response marker, which was not the focus of our study,” they wrote.

A healthy control group was also not included, which the researchers said reflects the “clinical reality” that doctors face when a person comes to the clinic with symptoms they want explained. Nevertheless, “future studies will be necessary for clarification,” they said, noting the findings position NOx as a possible screening tool to identify patients who may need additional diagnostic tests for MS.

“A combination of NOx with other biomarkers might increase sensitivity in the future,” they wrote.