The effect of ibudilast on thalamic volume in progressive multiple sclerosis.

BACKGROUND: Thalamic volume loss is known to be associated with clinical and cognitive disability in progressive multiple sclerosis (PMS). OBJECTIVE: To investigate the treatment effect of ibudilast on thalamic atrophy more than 96 weeks in the phase 2 trial in progressive(MS Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS]). METHODS: A total of 231 participants were randomized to either ibudilast (n = 114) or placebo (n = 117). Thalamic volume change was computed using Bayesian Sequence Adaptive Multimodal Segmentation tool (SAMseg) incorporating T1, fluid-attenuated inversion recovery (FLAIR), and fractional anisotropy maps and analyzed with a mixed-effects repeated-measures model. RESULTS: There was no significant difference in thalamic volumes between treatment groups. On exploratory analysis, participants with primary progressive multiple sclerosis (PPMS) on placebo had a 0.004% greater rate of thalamic atrophy than PPMS participants on ibudilast (p = 0.058, 95% confidence interval (CI) = -0.008 to <0.001). Greater reductions in thalamic volumes at more than 96 weeks were associated with worsening multiple sclerosis functional composite (MSFC-4) scores (p = 0.002) and worsening performance on the symbol digit modality test (SDMT) (p < 0.001). CONCLUSION: In a phase 2 trial evaluating ibudilast in PMS, no treatment effect was demonstrated in preventing thalamic atrophy. Participants with PPMS exhibited a treatment effect that trended toward significance. Longitudinal changes in thalamic volume were related to worsening of physical and cognitive disability, highlighting this outcome's clinical importance.

Associations between corpus callosum damage, clinical disability, and surface-based homologous inter-hemispheric connectivity in multiple sclerosis.

Axonal damage in the corpus callosum is prevalent in multiple sclerosis (MS). Although callosal damage is associated with disrupted functional connectivity between hemispheres, it is unclear how this relates to cognitive and physical disability. We investigated this phenomenon using advanced measures of microstructural integrity in the corpus callosum and surface-based homologous inter-hemispheric connectivity (sHIC) in the cortex. We found that sHIC was significantly decreased in primary motor, somatosensory, visual, and temporal cortical areas in a group of 36 participants with MS (29 relapsing-remitting, 4 secondary progressive MS, and 3 primary-progressive MS) compared with 42 healthy controls (cluster level, p < 0.05). In participants with MS, global sHIC correlated with fractional anisotropy and restricted volume fraction in the posterior segment of the corpus callosum (r = 0.426, p = 0.013; r = 0.399, p = 0.020, respectively). Lower sHIC, particularly in somatomotor and posterior cortical areas, was associated with cognitive impairment and higher disability scores on the Expanded Disability Status Scale (EDSS). We demonstrated that higher levels of sHIC attenuated the effects of posterior callosal damage on physical disability and cognitive dysfunction, as measured by the EDSS and Brief Visuospatial Memory Test-Revised (interaction effect, p < 0.05). We also observed a positive association between global sHIC and years of education (r = 0.402, p = 0.018), supporting the phenomenon of "brain reserve" in MS. Our data suggest that preserved sHIC helps prevent cognitive and physical decline in MS.

Comprehensive diffusion MRI dataset for in vivo human brain microstructure mapping using 300 mT/m gradients.

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.

Corpus callosum axon diameter relates to cognitive impairment in multiple sclerosis.

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.