Remyelination in humans due to a retinoid-X receptor agonist is age-dependent

Abstract

Remyelination efficiency declines with advancing age in animal models, but this has been harder to demonstrate in people with multiple sclerosis. We show that bexarotene, a putatively remyelinating retinoid-X receptor agonist, shortened the visual evoked potential latency in patients with chronic optic neuropathy aged under 42 years only (with the effect diminishing by 0.45 ms per year of age); and increased the magnetization transfer ratio of deep gray matter lesions in those under 43 years only. Addressing this age-related decline in human remyelination capacity will be an important step in the development of remyelinating therapies that work across the lifespan.

Figure 1

(A) Variation of P100 latency reduction (improvement) with patient age for eyes with a prolonged baseline latency (>118 m). Each data point represents an eye, and the model fit with 95% confidence interval is shown. (B) Treatment effect (bexarotene vs. placebo) from (A) as a function of age. The region to the left of the dashed line shows the age range at which there is a significant treatment effect with type 1 error rate (α) = 0.05. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2

(A) Variation of lesion MTR increase (improvement) with patient age for the three regions with statistically significant increases in MTR. The bexarotene group is shown in blue and placebo in red. Each data point represents a lesion, with superimposed horizontal jitter to better visualize lesions with the same patient age. The model fit with 95% confidence interval is shown. (B) Volcano plot showing the effect of age on lesion MTR improvement within the bexarotene group for the locations plotted in (A). Other brain regions are shown in gray for comparison. (C) Treatment effect (bexarotene vs. placebo) for deep gray matter lesions as a function of age. The region to the left of the dashed line shows the age range at which there is a significant treatment effect with type 1 error rate (α) = 0.05. GM = gray matter, MTR = magnetization transfer ratio. [Colour figure can be viewed at wileyonlinelibrary.com]