Thalamic atrophy in multiple sclerosis: A magnetic resonance imaging marker of neurodegeneration throughout disease

Abstract

Objective: Thalamic volume is a candidate magnetic resonance imaging (MRI)-based marker associated with neurodegeneration to hasten development of neuroprotective treatments. Our objective is to describe the longitudinal evolution of thalamic atrophy in MS and normal aging, and to estimate sample sizes for study design.

Methods: Six hundred one subjects (2,632 MRI scans) were analyzed. Five hundred twenty subjects with relapse-onset MS (clinically isolated syndrome, n = 90; relapsing-remitting MS, n = 392; secondary progressive MS, n = 38) underwent annual standardized 3T MRI scans for an average of 4.1 years, including a 1mm³ 3-dimensional T1-weighted sequence (3DT1; 2,485 MRI scans). Eighty-one healthy controls (HC) were scanned longitudinally on the same scanner using the same protocol (147 MRI scans). 3DT1s were processed using FreeSurfer's longitudinal pipeline after lesion inpainting. Rates of normalized thalamic volume loss in MS and HC were compared in linear mixed effects models. Simulation-based sample size calculations were performed incorporating the rate of atrophy in HC.

Results: Thalamic volume declined significantly faster in MS subjects compared to HC, with an estimated decline of -0.71% per year (95% confidence interval [CI] = -0.77% to -0.64%) in MS subjects and -0.28% per year (95% CI = -0.58% to 0.02%) in HC (p for difference = 0.007). The rate of decline was consistent throughout the MS disease duration and across MS clinical subtypes. Eighty or 100 subjects per arm (α = 0.1 or 0.05, respectively) would be needed to detect the maximal effect size with 80% power in a 24-month study.

Interpretation: Thalamic atrophy occurs early and consistently throughout MS. Preliminary sample size calculations appear feasible, adding to its appeal as an MRI marker associated with neurodegeneration. Ann Neurol 2018;83:223-234.

FIGURE 1:

Normalized thalamic volume decline from a linear mixed effects model including both healthy controls (green line, left panel) and multiple sclerosis subjects (red line, right panel) is shown. Point estimates of normalized thalamic volume at each year ±95% standard error (blue error bars) are shown.

FIGURE 2:

Normalized thalamic volume over time in multiple sclerosis subjects divided into 5-year epochs of disease duration at study entry. Estimated decline in each epoch is shown (red lines), with point estimates of normalized thalamic volume±95% standard error at each year (blue error bars).

FIGURE 3:

Normalized thalamic volume by clinical subtypes at baseline. Estimated decline in each subtype from linear mixed effects models is shown (red lines), with point estimates of normalized thalamic volume±95% standard error at each year (blue error bars). CIS=clinically isolated syndrome; SPMS=secondary progressive multiple sclerosis; RRMS=relapsing–remitting multiple sclerosis.

FIGURE 4:

Maximal effect size concept and sample size estimations. (A) The concept of maximal effect size. The rate of thalamic volume loss, estimated from linear mixed effects models, is shown in healthy controls (green line) and multiple sclerosis (MS) subjects (red line). “Maximal effect size” refers to a hypothetical treatment that could slow the rate of thalamic atrophy in MS to that of normal aging, that is to say the MS-specific atrophy that is amenable to intervention. The dashed line represents the trajectory that would occur if there were zero atrophy in the control group, an assumption not supported by the data (marked with an X). (B) The power function from a simulation procedure estimating the total sample size that would be needed to detect the maximal effect size in clinically isolated syndrome (CIS) and relapsing–remitting MS (RRMS) subjects, assuming α=0.1. To achieve 80% power, 160 subjects total would be needed in a 24-month study (80 per arm, solid red curve) and 235 subjects total in a 12-month study (118 per arm, dashed red curve). (C) The power function from a simulation procedure estimating the total sample size that would be needed to detect the maximal effect size in CIS and RRMS subjects, assuming α=0.05. To achieve 80% power, 200 subjects total would be needed in a 24-month study (100 per arm, solid red curve) and >280 subjects total in a 12-month study (dashed red curve).