Longitudinal Assessment of Multiple Sclerosis with the Brain-Age Paradigm

Ann Neurol. 2020 Jul;88(1):93-105. doi: 10.1002/ana.25746. Epub 2020 May 6.


Objective: During the natural course of multiple sclerosis (MS), the brain is exposed to aging as well as disease effects. Brain aging can be modeled statistically; the so-called "brain-age" paradigm. Here, we evaluated whether brain-predicted age difference (brain-PAD) was sensitive to the presence of MS, clinical progression, and future outcomes.

Methods: In a longitudinal, multicenter sample of 3,565 magnetic resonance imaging (MRI) scans, in 1,204 patients with MS and clinically isolated syndrome (CIS) and 150 healthy controls (mean follow-up time: patients 3.41 years, healthy controls 1.97 years), we measured "brain-predicted age" using T1-weighted MRI. We compared brain-PAD among patients with MS and patients with CIS and healthy controls, and between disease subtypes. Relationships between brain-PAD and Expanded Disability Status Scale (EDSS) were explored.

Results: Patients with MS had markedly higher brain-PAD than healthy controls (mean brain-PAD +10.3 years; 95% confidence interval [CI] = 8.5-12.1] versus 4.3 years; 95% CI = 2.1 to 6.4; p < 0.001). The highest brain-PADs were in secondary-progressive MS (+13.3 years; 95% CI = 11.3-15.3). Brain-PAD at study entry predicted time-to-disability progression (hazard ratio 1.02; 95% CI = 1.01-1.03; p < 0.001); although normalized brain volume was a stronger predictor. Greater annualized brain-PAD increases were associated with greater annualized EDSS score (r = 0.26; p < 0.001).

Interpretation: The brain-age paradigm is sensitive to MS-related atrophy and clinical progression. A higher brain-PAD at baseline was associated with more rapid disability progression and the rate of change in brain-PAD related to worsening disability. Potentially, "brain-age" could be used as a prognostic biomarker in early-stage MS, to track disease progression or stratify patients for clinical trial enrollment. ANN NEUROL 2020 ANN NEUROL 2020;88:93-105.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aging / pathology*
  • Atrophy / diagnostic imaging
  • Atrophy / pathology
  • Brain / diagnostic imaging
  • Brain / pathology*
  • Demyelinating Diseases / diagnostic imaging
  • Demyelinating Diseases / pathology*
  • Disability Evaluation
  • Disease Progression
  • Female
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Multiple Sclerosis / diagnostic imaging
  • Multiple Sclerosis / pathology*
  • Young Adult