Exploratory analysis of biological age measures in a remyelination clinical trial

Enhancing CNS myelin repair (remyelination) is a promising strategy to prevent neurodegeneration and associated progressive disability in multiple sclerosis. Remyelination becomes inefficient with older chronological age, but the relationship between measures of biological age and remyelination has not been previously described in a clinical cohort. Here, we investigated two measures of biological age amongst participants of the Cambridge Centre for Myelin Repair One trial of bexarotene: MRI brain age (BA_MRI) and a blood-based biological age (BA_Blood). In people with radiologically stable multiple sclerosis (n = 44 of 49 total participants), we found that treatment with bexarotene, along with promoting remyelination, was associated with significant decrease in MRI brain age [-1.98 years, 95% confidence interval (CI) [-3.75, -0.21 years] versus placebo over 6 months, P = 0.034]. Whilst BA_MRI increased as expected during the trial in the placebo group (+0.92 years, CI [-0.41, 2.26]), the brain MRIs of participants treated with bexarotene appeared on average 11 months younger at the end compared to the start of the trial (-0.93 years, CI [-2.02, 0.17]). The effect of bexarotene on BA_MRI was associated with its remyelinating activity in cortical grey matter lesions (β = 0.25% units (pu)/year, CI [0.03, 0.46], P = 0.023) and brainstem lesions (β = 0.24 pu/year, CI [0.09, 0.39], P = 0.003). We also observed some regional trends that the remyelinating response to bexarotene was linked with measures of biological age at baseline. For example, after adjustment for chronological age, remyelination of brainstem lesions assessed by magnetization transfer ratio was reduced by 0.06 pu for each year increase in BA_MRI (CI [0.00, 0.13], P = 0.058) and 0.02 pu for each year increase in BA_Blood (CI [-0.01, 0.05], P = 0.17). This is, to the best of our knowledge, the first demonstration that MRI brain age can be therapeutically modulated by a drug in people with a neurological disorder. Overall, these findings highlight that beyond chronological age, biological age may also influence the potential for repair and should be considered when developing treatments for multiple sclerosis.