Antioxidant May Influence Brain Changes in Multiple Sclerosis, Study Suggests

— N-acetylcysteine linked to functional connectivity, cerebral glucose metabolism

N-acetylcysteine (NAC) treatment led to changes in functional connectivity and cerebral glucose metabolism in people with multiple sclerosis (MS), a small randomized trial suggested.

The study aimed to assess oxidative stress in MS after treatment with NAC, an antioxidant that increases brain glutathione. People with mild to moderate MS were randomized to either NAC plus standard of care, or to standard of care only (the control group).

Blood oxygen level dependent (BOLD) functional MRI (fMRI) showed significant connectivity alterations in the inferior frontal region, cerebellum, and parts of the temporal and parietal lobes in the NAC group compared with the control group, reported Sahar Darabi Monadi, MD, of Thomas Jefferson University in Philadelphia, at the American Society of Functional Neuroradiologyopens in a new tab or window meeting in Newport Beach, California.

Fluorodeoxyglucose (FDG) PET revealed that the NAC group had corresponding increases in cerebral glucose metabolism in several of these areas, including the inferior frontal and inferior temporal gyri. Self-reported improvements in cognition and attention correlated with these changes.

The findings were published in IBRO Neuroscience Reportsopens in a new tab or window.

"Multiple sclerosis affects 2.8 million people worldwide, and 40 to 70% experience cognitive impairment, which is the result of both inflammation and oxidative stress. Yet, the majority of the approved treatments target only inflammation and almost none address oxidative stress, which is a key driver of neurodegeneration," Monadi said.

An antioxidant approach could complement existing MS therapies, she suggested. "That's the gap that N-acetylcysteine targets."

"NAC boosts antioxidant capacity, which increases glutathione and reduces oxidative stress," Monadi pointed out. "A few other studies have shown that NAC can increase cerebral glucose metabolism and improve fatigue in MS, but those effects have never been characterized simultaneously at the level of functional connectivity and metabolism. Our study was the first to do that."

NAC treatment has been investigated in other neurologic disorders, noted co-author Andrew Newberg, MD, also of Thomas Jefferson University.

In a recent study of people with Parkinson's diseaseopens in a new tab or window, "we showed changes in dopamine function and in functional connectivity in response to receiving N-acetylcysteine," Newberg told MedPage Today. Other work suggested that NAC may have an effect on resting-state functional MRI and cognitive performance in people with chronic mild traumatic brain injuryopens in a new tab or window.

"NAC has an interesting place in terms of therapeutics. As an oral supplement, it is something anybody can get. As an intravenous infusion, it's used for several different purposes. One of the most commonly known ones is to protect the liver from oxidative damage when someone takes an overdose of Tylenol [acetaminophen]," Newberg observed.

"This afforded us an opportunity to use a combination of intravenous and oral NAC in our studies," he noted. "We were interested in doing that because prior data suggested oral NAC is variable and may not be well absorbed."

The current trialopens in a new tab or window randomized 36 patients with mild to moderate MS -- 18 to the NAC treatment group and 18 to the control group. Those in the treatment group received 50 mg/kg of intravenous NAC once a week and 500 mg of oral NAC twice a day on the other 6 days each week.

Participants in both groups were evaluated initially and after 4 months (plus or minus 2 months) on an integrated PET-MRI platform with resting BOLD fMRI and FDG PET. They also completed clinical symptom questionnaires at both time points.

Clinical improvements emerged in the NAC group only, where participants reported better scores on pain (P=0.015), fatigue (P=0.016), cognition (P=0.036), and attention (P=0.010) after treatment.

The study may offer new insights into the neurophysiology of MS, Newberg noted. "The imaging findings seemed to correspond to some of the clinical improvements people were reporting," he said.

"This was an initial evaluation in MS patients," he acknowledged. "We hope it opens an opportunity to explore the use of NAC in a more detailed way, clarifying appropriate dosing regimens and duration as well as timing."