Onset of multiple sclerosis before adulthood leads to failure of age-expected brain growth

Abstract

Objective: To determine the impact of pediatric-onset multiple sclerosis (MS) on age-expected brain growth.

Methods: Whole brain and regional volumes of 36 patients with relapsing-remitting MS onset prior to 18 years of age were segmented in 185 longitudinal MRI scans (2-11 scans per participant, 3-month to 2-year scan intervals). MRI scans of 25 age- and sex-matched healthy normal controls (NC) were also acquired at baseline and 2 years later on the same scanner as the MS group. A total of 874 scans from 339 participants from the NIH-funded MRI study of normal brain development acquired at 2-year intervals were used as an age-expected healthy growth reference. All data were analyzed with an automatic image processing pipeline to estimate the volume of brain and brain substructures. Mixed-effect models were built using age, sex, and group as fixed effects.

Results: Significant group and age interactions were found with the adjusted models fitting brain volumes and normalized thalamus volumes (p < 10(-4)). These findings indicate a failure of age-normative brain growth for the MS group, and an even greater failure of thalamic growth. In patients with MS, T2 lesion volume correlated with a greater reduction in age-expected thalamic volume. To exclude any scanner-related influence on our data, we confirmed no significant interaction of group in the adjusted models between the NC and NIH MRI Study of Normal Brain Development groups.

Conclusions: Our results provide evidence that the onset of MS during childhood and adolescence limits age-expected primary brain growth and leads to subsequent brain atrophy, implicating an early onset of the neurodegenerative aspect of MS.

Figure 1. Brain and normalized thalamus growth trajectories for NIHPD and MS subjects

Measured brain volume (Aa), predicted brain volume (Ab), and brain volume mean model with confidence intervals on the mean parameters (Ac) for boys and girls of the NIH MRI Study of Normal Brain Development (NIHPD) and multiple sclerosis (MS) groups. Measured normalized thalamus (Ba), predicted normalized thalamus (Bb), and normalized thalamus mean model with confidence intervals on the mean parameters (Bc) for boys and girls of the NIHPD and MS groups. Note the heterogeneity in the MS group. The participants with an asterisk had a more striking loss of thalamic volume and a more negative slope of thalamic volume over time and were removed from the study (detailed in figure e-1) to determine if they were driving the fit. We found that the resulting parameter values changed only slightly, without changing the statistical results.

Figure 2. Estimated mean models

Estimated mean models for NIH MRI Study of Normal Brain Development (NIHPD) and multiple sclerosis (MS) groups (A) and NIHPD and normally developing controls (NC) groups (B). For the normalized brain substructures, each graph has the same range to facilitate the comparison between graphs. The MS and NIHPD models were significantly different only for the brain, thalamus, and globus pallidus. The NC and NIHPD models were not significantly different.

Figure 3. Normalized thalamus fitting models with 3 groups

The NIH MRI Study of Normal Brain Development (NIHPD) group, the multiple sclerosis (MS) group with participants who have all scans with the lesion-to-brain ratio inferior to 0.35% (minimal lesion load), and the MS group with participants who have at least one scan with the lesion-to-brain ratio superior to 0.35% (higher lesion load).