New lesion formation is associated with accelerated brain aging in multiple sclerosis
- 1Windreich Department of Artificial Intelligence and Human Health & Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Abstract
BackgroundBrain age is a biomarker of brain tissue integrity associated with disability in multiple sclerosis. While new lesion formation is central to MS diagnosis and treatment monitoring, its direct relationship to brain aging has not been established.
MethodsWe analyzed 163 people with MS with clinical and MRI assessments at baseline and years 3, 6, and 8. Brain age was estimated using BrainAgeNeXt. Annualized brain age acceleration was modeled as a function of radiological activity using generalized estimating equations, adjusting for age, sex, disease duration, baseline T2 lesion volume, normalized brain volume (NBV), brain age difference (BAD), and disease-modifying therapy. Secondary analyses examined dose-response effects, post-activity recovery, paramagnetic rim lesion (PRL) associations, and disability associations.
Results105 participants had at least one new T2 lesion over 8 years. Radiologically active intervals (138 of 333) were associated with +0.19 yr/yr greater brain age acceleration than stable intervals (95% CI: 0.03-0.37; p=0.022), scaling with lesion count ({beta}=+0.18; p=0.001) and volume. Older age, greater baseline BAD, and NBV were independently associated with reduced brain age acceleration. Brain age acceleration in individuals with new lesions normalized during subsequent stable intervals (0.41 vs -0.06 yr/yr; p=0.001). Both PRLs and non-PRL lesions were associated with greater brain age acceleration than stable intervals. Baseline BAD, but not annualized acceleration, predicted Expanded Disability Status Scale (EDSS) and Nine-Hole Peg Test (9HPT) worsening.
ConclusionsNew focal lesion formation is associated with a quantifiable, dose-response acceleration of brain aging in MS that normalizes once lesion activity is suppressed.
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BibTeX
@misc{rosa2026lesion,
title = {{New lesion formation is associated with accelerated brain aging in multiple sclerosis}},
author = {F. La Rosa and J. Dos Santos Silva and E. Dereskewicz and K. Onyemeh and B. Ayci and E. Sizer and E. Shashkova and N. Garcia and R. Graney and S. Levy and I. Katz Sand and J. Sumowski and E. S. Beck},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.27.26361556},
url = {https://www.medrxiv.org/content/10.64898/2026.08.27.26361556v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - New lesion formation is associated with accelerated brain aging in multiple sclerosis
AU - F. La Rosa
AU - J. Dos Santos Silva
AU - E. Dereskewicz
AU - K. Onyemeh
AU - B. Ayci
AU - E. Sizer
AU - E. Shashkova
AU - N. Garcia
AU - R. Graney
AU - S. Levy
AU - I. Katz Sand
AU - J. Sumowski
AU - E. S. Beck
PY - 2026
DA - 2026/08/27
PB - medRxiv
DO - 10.64898/2026.08.27.26361556
UR - https://www.medrxiv.org/content/10.64898/2026.08.27.26361556v1
AB - BackgroundBrain age is a biomarker of brain tissue integrity associated with disability in multiple sclerosis. While new lesion formation is central to MS diagnosis and treatment monitoring, its direct relationship to brain aging has not been established. MethodsWe analyzed 163 people with MS with clinical and MRI assessments at baseline and years 3, 6, and 8. Brain age was estimated using BrainAgeNeXt. Annualized brain age acceleration was modeled as a function of radiological activity using generalized estimating equations, adjusting for age, sex, disease duration, baseline T2 lesion volume, normalized brain volume (NBV), brain age difference (BAD), and disease-modifying therapy. Secondary analyses examined dose-response effects, post-activity recovery, paramagnetic rim lesion (PRL) associations, and disability associations. Results105 participants had at least one new T2 lesion over 8 years. Radiologically active intervals (138 of 333) were associated with +0.19 yr/yr greater brain age acceleration than stable intervals (95% CI: 0.03-0.37; p=0.022), scaling with lesion count ({beta}=+0.18; p=0.001) and volume. Older age, greater baseline BAD, and NBV were independently associated with reduced brain age acceleration. Brain age acceleration in individuals with new lesions normalized during subsequent stable intervals (0.41 vs -0.06 yr/yr; p=0.001). Both PRLs and non-PRL lesions were associated with greater brain age acceleration than stable intervals. Baseline BAD, but not annualized acceleration, predicted Expanded Disability Status Scale (EDSS) and Nine-Hole Peg Test (9HPT) worsening. ConclusionsNew focal lesion formation is associated with a quantifiable, dose-response acceleration of brain aging in MS that normalizes once lesion activity is suppressed.
ER -