Randomised controlled trial of intermittent calorie restriction in people with multiple sclerosis.

BACKGROUND: Calorie restriction (CR) ameliorates preclinical models of multiple sclerosis (MS) via multiple mechanisms. These include decreased leptin, a proinflammatory adipokine, but mechanistic studies in humans are lacking. Tests of daily and intermittent CR (iCR) in people with MS (pwMS) showed improvements in fatigue and well-being measures. This trial studied the effects of 12-week iCR on metabolic, immunological, and clinical outcomes in pwMS. METHOD: Relapsing-remitting MS participants were randomised to iCR or a control group. Study visits were conducted at baseline, 6 and 12 weeks. The primary outcome was reduction in serum leptin levels at 12 weeks. Feasibility and safety were assessed by diet adherence and adverse events (AEs). Secondary outcomes included changes in anthropometric and body composition measures, metabolic and immunologic profiling, and clinical measures. Mixed effects linear regression models were used to evaluate outcome differences between and within groups over time. RESULTS: Forty-two pwMS were randomised, 34 completed the study (17/group). Leptin serum levels at 12 weeks were significantly lower in the iCR versus the control group (mean decrease -6.98 µg/dL, 95% CI: -28.02 to 14.06; p=0.03). Adherence to iCR was 99.5% and 97.2% at 6 and 12 weeks, respectively, and no serious AEs were reported. An increase in blood CD45RO+ regulatory T-cell numbers was seen after 6 weeks of iCR. Exploratory cognitive testing demonstrated a significant improvement in the Symbol Digit Modality Test Score in the iCR group at 12 weeks. CONCLUSIONS: iCR has the potential to benefit metabolic and immunologic profiles and is safe and feasible in pwMS. TRIAL REGISTRATION NUMBER: NCT03539094 .

Incorporating non-linear alignment and multi-compartmental modeling for improved human optic nerve diffusion imaging.

In vivo human optic nerve diffusion magnetic resonance imaging (dMRI) is technically challenging with two outstanding issues not yet well addressed: (i) non-linear optic nerve movement, independent of head motion, and (ii) effect from partial-volumed cerebrospinal fluid or interstitial fluid such as in edema. In this work, we developed a non-linear optic nerve registration algorithm for improved volume alignment in axial high resolution optic nerve dMRI. During eyes-closed dMRI data acquisition, optic nerve dMRI measurements by diffusion tensor imaging (DTI) with and without free water elimination (FWE), and by diffusion basis spectrum imaging (DBSI), as well as optic nerve motion, were characterized in healthy adults at various locations along the posterior-to-anterior dimension. Optic nerve DTI results showed consistent trends in microstructural parametric measurements along the posterior-to-anterior direction of the entire intraorbital optic nerve, while the anterior portion of the intraorbital optic nerve exhibited the largest spatial displacement. Multi-compartmental dMRI modeling, such as DTI with FWE or DBSI, was less subject to spatially dependent biases in diffusivity and anisotropy measurements in the optic nerve which corresponded to similar spatial distributions of the estimated fraction of isotropic diffusion components. DBSI results derived from our clinically feasible (∼10 min) optic nerve dMRI protocol in this study are consistent with those from small animal studies, which provides the basis for evaluating the utility of multi-compartmental dMRI modeling in characterizing coexisting pathophysiology in human optic neuropathies.