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OBJECTIVE: Cognitive slowing is a core neuropsychological symptom of Multiple Sclerosis (MS). We aimed to assess the extent to which cognitive slowing in MS was predicted by changes in dorsolateral prefrontal networks. METHOD: We assessed patients with relapsing-remitting MS and healthy controls (HCs) on measures of processing speed. Participants underwent a functional MRI while performing a processing speed task to allow assessment of task-based connectivity. RESULTS: Patients were slower than HCs on the processing speed tasks. Patients showed attenuated connectivity between right and left dorsolateral prefrontal cortex (DLPFC) and task-relevant brain regions compared to HCs during processing speed task performance. Patients' connectivity with DLPFC in these group-disparate networks accounted for significant variability in their performance on processing speed measures administered both in and out of the imaging environment. Specifically, patients who had stronger functional connections with DLPFC in group-disparate networks performed faster than patients with weaker connections with DLPFC in group-disparate networks. CONCLUSION: Results suggest that MS-related cognitive slowing can be accounted for by systemic alterations in executive functional networks.

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For the first time, we obtained direct intra-neural measurements of muscle sympathetic nerve activity (MSNA) in relapsing-remitting multiple sclerosis (MS) patients to test the hypothesis that spontaneous resting MSNA is reduced in MS patients compared to age, sex-matched healthy controls. Spontaneous MSNA (microneurography; peroneal nerve), plasma norepinephrine, arterial blood pressure (finger photoplethysmography), and heart rate were measured at rest in three groups: 1) relapsing-remitting MS patients on disease modifying therapy only (MS-DT; n=6); 2) relapsing-remitting MS patients on disease modifying therapy and medications for MS-related symptoms that are known to effect the central nervous system (MS-DT/ST; n=5), and 3) healthy age and sex-matched controls (CON; n=6). Compared to the CON group, MSNA burst frequency (bursts/min) was significantly lower in both MS-DT (P=0.027) and MS-DT/ST groups (P=0.003). Similarly, MSNA burst incidence (bursts/100 heartbeats) was significantly reduced in both MS-DT (P=0.049) and MS-DT/ST groups (P=0.004) compared to the CON group. Burst frequency and burst incidence were not different between MS-DT and MS-DT/ST groups. Resting plasma norepinephrine was also significantly lower in both MS-DT (P=0.039) and MS-DT/ST groups (P=0.021) compared to the CON group. Reduced MSNA may signify an important dysfunction in autonomic control of cardiovascular function in patients with MS.

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BACKGROUND: Mycophenolate mofetil (MMF) is an oral DNA base synthesis inhibitor with immunomodulatory effects on B cells, T cells, and macrophages. OBJECTIVE: To conduct a safety and tolerability pilot study of interferon beta-1a (IFN-b1a) in combination with either placebo or oral MMF in multiple sclerosis (MS). METHODS: Twenty-four treatment-naïve R-RMS patients participated in a one-year prospective, placebo-controlled, blinded, safety pilot clinical trial. Every patient injected weekly intramuscular interferon beta-1a. The cohort was then randomized (1 : 1) to either active oral MMF or identical-appearing placebo tablets. Clinical evaluations were assessed every 3 months, along with brain MRI scans performed at baseline and repeated every 60 days for one year. Comprehensive laboratory assessments were monitored for safety, along with adverse events. RESULTS: In this small pilot investigation, no differences were identified between the two treatment groups with respect to patient-reported adverse events, MRI metrics, or laboratory abnormalities. Notwithstanding these observations, and the limited number of patients treated, trends appeared to favor the combination therapy regimen. CONCLUSIONS: The combination treatment regimen of interferon beta-1a and MMF appeared to be well tolerated in this pilot study. Despite the small sample size, therapeutic trends were observed in favor of combination therapy. An adequately powered controlled trial of MMF in MS appears warranted.