Background and purpose: Whole-brain atrophy is a standard outcome measure in multiple sclerosis (MS) clinical trials as assessed by various software tools. The effect of processing method on the validity of such data obtained from high-resolution 3T MRI is not known. We compared two commonly used methods of quantifying whole-brain atrophy.

Methods: Three-dimensional T1-weighted and FLAIR images were obtained at 3T in MS (n = 61) and normal control (NC, n = 30) groups. Whole-brain atrophy was assessed by two automated pipelines: (a) SPM8 to derive brain parenchymal fraction (BPF, proportional-based method); (b) SIENAX to derive normalized brain parenchymal volume (BPV, registration method). We assessed agreement between BPF and BPV, as well their relationship to Expanded Disability Status Scale (EDSS) score, timed 25-foot walk (T25FW), cognition, and cerebral T2 (FLAIR) lesion volume (T2LV).

Results: Brain parenchymal fraction and BPV showed only partial agreement (r = 0.73) in the MS group, and r = 0.28 in NC. Both methods showed atrophy in MS versus NC (BPF p < 0.01, BPV p < 0.05). Within MS group comparisons, BPF (p < 0.05) but not BPV (p > 0.05) correlated with EDSS score. BPV (p = 0.03) but not BPF (p = 0.08) correlated with T25FW. Both metrics correlated with T2LV (p < 0.05) and cognitive subscales. BPF (p < 0.05) but not BPV (p > 0.05) showed lower brain volume in cognitively impaired (n = 23) versus cognitively preserved (n = 38) patients. However, direct comparisons of BPF and BPV sensitivities to atrophy and clinical correlations were not statistically significant.

Conclusion: Whole-brain atrophy metrics may not be interchangeable between proportional- and registration-based automated pipelines from 3T MRI in patients with MS.