Sample size requirements for one-year treatment effects using deep gray matter volume from 3T MRI in progressive forms of multiple sclerosis

Abstract

Objective: The subcortical deep gray matter (DGM) develops selective, progressive, and clinically relevant atrophy in progressive forms of multiple sclerosis (PMS). This patient population is the target of active neurotherapeutic development, requiring the availability of outcome measures. We tested a fully automated MRI analysis pipeline to assess DGM atrophy in PMS. Design/Methods: Consistent 3D T1-weighted high-resolution 3T brain MRI was obtained over one year in 19 consecutive patients with PMS [15 secondary progressive, 4 primary progressive, 53% women, age (mean §SD) 50.8 §8.0 years, Expanded Disability Status Scale (median, range) 5.0, 2.0-6.5)]. DGM segmentation applied the fully automated FSL-FIRST pipeline (http://fsl.fmrib.ox.ac.uk). Total DGM volume was the sum of the caudate, putamen, globus pallidus, and thalamus. On-study change was calculated using a random-effects linear regression model. A treatment trial for an intervention that would show a 50% reduction in DGM brain atrophy would require a sample size of 123 patients for a single-arm study (one-year run-in followed by one-year on-treatment). For a two-arm placebo-controlled one-year study, 242 patients would be required per arm. The use of DGM fraction required more patients. The thalamus, putamen, and globus pallidus, showed smaller effect sizes in their on-study changes than the total DGM; however, for the caudate, the effect sizes were somewhat larger. Conclusions: DGM atrophy may prove efficient as a short-term outcome for proof-of-concept neurotherapeutic trials in PMS.

A two-year study using cerebral gray matter volume to assess the response to fingolimod therapy in multiple sclerosis

“…In addition, more precise assessments of cerebral GM atrophy may be obtained in future studies with the availability of higher field (e.g. 3 T) high-resolution MRI acquisitions [102] (which were not available in the present study) and fully automated analysis pipelines [44,[103][104][105]. Furthermore, the availability of such higher field (e.g.…”

Whole brain and deep gray matter atrophy detection over 5 years with 3T MRI in multiple sclerosis using a variety of automated segmentation pipelines

“…The most commonly-assessed aspect of brain atrophy is whole brain volume, due to the availability of numerous highly reliable and sensitive methods for its measurement [ 1 , 4 ]. Analysis of regional brain volume also has important implications related to clinical impairment, disease progression, and therapeutic monitoring [ 5 , 6 ]. Gray matter (GM) tissue loss is of particular importance because of its functional relevance.…”

“…Furthermore, DGM injury clearly has clinical relevance in patients with MS, as several studies have shown [ 13 – 16 ]. Among the many potential uses of measuring DGM damage in people with MS, the longitudinal assessment of atrophy in these structures by automated segmentation from MRI may provide an efficient, sensitive, and reliable tool to assess neurotherapeutic effects [ 6 , 17 ].…”

The Impact of MRI T1 Hypointense Brain Lesions on Cerebral Deep Gray Matter Volume Measures in Multiple Sclerosis

“…Atrophy of deep gray matter (DGM) structures (particularly thalamus) has been shown at early stages of multiple sclerosis (MS) and it is present across all disease subtypes . Due to its relevance to disability progression and cognitive dysfunction, it has become a useful measure of therapeutic monitoring and prediction . Therefore, precise and accurate measurement of DGM atrophy is a key priority for MS researchers …”