NAC Treatment Alters Brain Connectivity and Metabolism in Multiple Sclerosis

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, Sahar Darabi Monadi, MD, of Thomas Jefferson University in Philadelphia, said.

A small randomized trial suggested that administering N-acetylcysteine (NAC) modified cerebral glucose metabolism and functional connectivity among individuals diagnosed with multiple sclerosis. The research sought to evaluate oxidative stress in MS following administration of NAC, an antioxidant known to elevate brain glutathione levels. Individuals suffering from mild to moderate multiple sclerosis were assigned at random to receive either standard care combined with NAC or standard care alone serving as the control arm. Findings from the research were published in IBRO Neuroscience Reports.

Brain Scans Reveal Connectivity and Metabolism Changes

Compared with the control participants, individuals in the NAC arm demonstrated notable functional connectivity shifts within the cerebellum, the inferior frontal region, and selected portions of the parietal and temporal lobes, as observed via blood oxygen level dependent functional MRI. Fluorodeoxyglucose PET demonstrated that participants receiving NAC exhibited matching rises in cerebral glucose metabolism across multiple of these regions, including the inferior frontal and inferior temporal gyri. Self-reported improvements in cognition and attention correlated with these changes, according to the presentation at the American Society of Functional Neuroradiology meeting in Newport Beach, California.

NAC boosts antioxidant capacity, which increases glutathione and reduces oxidative stress, Monadi pointed out, noting that while a few other studies showed NAC could increase cerebral glucose metabolism and improve fatigue in MS, those effects had never been characterized simultaneously at the level of functional connectivity and metabolism.

Combination Intravenous and Oral Dosing Regimen Used in Trial

The trial randomized 36 patients with mild to moderate MS, splitting them evenly with 18 participants in the NAC treatment group and 18 in the control group. Patients assigned to the intervention arm were administered an intravenous dose of 50 mg/kg of NAC on a weekly basis, alongside 500 mg of oral NAC taken twice daily throughout the remaining six days of each week. Participants in both groups were evaluated initially and after four months, plus or minus two months, on an integrated PET-MRI platform with resting BOLD functional MRI and FDG PET. They also completed clinical symptom questionnaires at both time points.

Co-author Andrew Newberg, MD, also of Thomas Jefferson University, noted that NAC treatment has been investigated in other neurologic disorders, including Parkinson’s disease and chronic mild traumatic brain injury. 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, Newberg observed. He explained that researchers were interested in using a combination of intravenous and oral NAC because prior data suggested oral NAC is variable and may not be well absorbed.

Clinical Improvements Reported in Patient Questionnaires

Clinical improvements emerged in the NAC group only, where participants reported better scores on pain with a P-value of 0.015, fatigue at P=0.016, cognition at P=0.036, and attention at P=0.010 after treatment. The imaging changes appeared to mirror certain clinical gains reported by patients, Newberg pointed out. This was an initial evaluation in MS patients, he acknowledged, adding that researchers hope it opens an opportunity to explore the use of NAC in a more detailed way, clarifying appropriate dosing regimens, duration, and timing.