Telomere Length Is Associated with Disability Progression in Multiple Sclerosis

Abstract

Objective: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS).

Methods: Adults with MS/clinically isolated syndrome in the University of California, San Francisco EPIC cohort study were included. LTL was measured on DNA samples by quantitative polymerase chain reaction and expressed as telomere to somatic DNA (T/S) ratio. Expanded Disability Status Scale (EDSS) and 3-dimensional T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up. Associations of baseline LTL with cross-sectional and longitudinal outcomes were assessed using simple and mixed effects linear regression models. A subset (n = 46) had LTL measured over time, and we assessed the association of LTL change with EDSS change with mixed effects models.

Results: Included were 356 women and 160 men (mean age = 43 years, median disease duration = 6 years, median EDSS = 1.5 [range = 0-7], mean T/S ratio = 0.97 [standard deviation = 0.18]). In baseline analyses adjusted for age, disease duration, and sex, for every 0.2 lower LTL, EDSS was 0.27 higher (95% confidence interval [CI] = 0.13-0.42, p < 0.001) and brain volume was 7.4mm³ lower (95% CI = 0.10-14.7, p = 0.047). In longitudinal adjusted analyses, those with lower baseline LTL had higher EDSS and lower brain volumes over time. In adjusted analysis of the subset, LTL change was associated with EDSS change over 10 years; for every 0.2 LTL decrease, EDSS was 0.34 higher (95% CI = 0.08-0.61, p = 0.012).

Interpretation: Shorter telomere length was associated with disability independent of chronological age, suggesting that biological aging may contribute to neurological injury in MS. Targeting aging-related mechanisms is a potential therapeutic strategy against MS progression. ANN NEUROL 2019;86:671-682.

FIGURE 1:

Proposed causal diagram of the association between telomere length and disability (A) and between age and disability mediated by telomere length (B). (A) Cumulative number of cell divisions, telomerase activity, genetic factors, and environmental factors affect telomere length, which is a marker of biological age, and we assess its association with disability. Chronological age and sex are considered confounders, whereas disease duration is hypothesized to be a mediator. (B) The same relationships are shown, but the association between chronological age and disability is the primary focus, with mediation by telomere length. Black arrows represent the relationships of interest. MS = multiple sclerosis.

FIGURE 2:

Predicted trajectory of Expanded Disability Status Scale (EDSS; A, B), brain volume (C, D), and cortical gray matter volume (E, F) over 10 years by baseline telomere length with longitudinal analyses in the entire cohort with unadjusted and adjusted mixed models. Predictions are based on longitudinal mixed effects models of the entire cohort for outcomes of EDSS (A, unadjusted; B, adjusted), total brain volume (C, unadjusted; D, adjusted), and cortical gray matter volume (E, unadjusted; F, adjusted). Leukocyte telomere length (LTL) was treated as continuous in the models, but key LTL values including the approximate mean value (1), and 2 standard deviations below (0.6) and above (1.4) the mean are shown graphically to display model results. Shaded areas represent 95% confidence limits. EDSS increased and brain volume decreased over time regardless of baseline LTL, with similar trajectories despite baseline LTL, and no relevant interaction between LTL and time since enrollment. T/S ratio = telomere to somatic DNA ratio. Adjusted models were adjusted for baseline age, sex, and disease duration. Year 7 was excluded from the models due to very few participants completing this visit.