Objective To evaluate alterations in apparent axon diameter and axon density obtained by high‐gradient diffusion MRI in the corpus callosum of MS patients and the relationship of these advanced diffusion MRI metrics to neurologic disability and cognitive impairment in MS. Methods Thirty people with MS (23 relapsing‐remitting MS [RRMS], 7 progressive MS [PMS]) and 23 healthy controls were scanned on a human 3‐tesla (3T) MRI scanner equipped with 300 mT/m maximum gradient strength using a comprehensive multishell diffusion MRI protocol. Data were fitted to a three‐compartment geometric model of white matter to estimate apparent axon diameter and axon density in the midline corpus callosum. Neurologic disability and cognitive function were measured using the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Minimal Assessment of Cognitive Function in MS battery. Results Apparent axon diameter was significantly larger and axon density reduced in the normal‐appearing corpus callosum (NACC) of MS patients compared to healthy controls, with similar trends seen in PMS compared to RRMS. Larger apparent axon diameter in the NACC of MS patients correlated with greater disability as measured by the EDSS ( r = 0.555, P = 0.007) and poorer performance on the Symbol Digits Modalities Test ( r = ‐0.593, P = 0.008) and Brief Visuospatial Memory Test–Revised ( r = −0.632, P < 0.01), tests of interhemispheric processing speed and new learning and memory, respectively. Interpretation Apparent axon diameter in the corpus callosum obtained from high‐gradient diffusion MRI is a potential imaging biomarker that may be used to understand the development and progression of cognitive impairment in MS.

Strong gradient systems can improve the signal-to-noise ratio of diffusion MRI measurements and enable a wider range of acquisition parameters that are beneficial for microstructural imaging. We present a comprehensive diffusion MRI dataset of 26 healthy participants acquired on the MGH-USC 3 T Connectome scanner equipped with 300 mT/m maximum gradient strength and a custom-built 64-channel head coil. For each participant, the one-hour long acquisition systematically sampled the accessible diffusion measurement space, including two diffusion times (19 and 49 ms), eight gradient strengths linearly spaced between 30 mT/m and 290 mT/m for each diffusion time, and 32 or 64 uniformly distributed directions. The diffusion MRI data were preprocessed to correct for gradient nonlinearity, eddy currents, and susceptibility induced distortions. In addition, scan/rescan data from a subset of seven individuals were also acquired and provided. The MGH Connectome Diffusion Microstructure Dataset (CDMD) may serve as a test bed for the development of new data analysis methods, such as fiber orientation estimation, tractography and microstructural modelling.

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