Estriol-mediated neuroprotection in multiple sclerosis localized by voxel-based morphometry

Abstract

Introduction: Progressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairment has been observed in 40%-70% of MS patients and has been linked to GM atrophy. In a phase 2 trial of estriol treatment in women with relapsing-remitting MS (RRMS), higher estriol levels correlated with greater improvement on the paced auditory serial addition test (PASAT) and imaging revealed sparing of localized GM in estriol-treated compared to placebo-treated patients. To better understand the significance of this GM sparing, the current study explored the relationships between the GM sparing and traditional MRI measures and clinical outcomes.

Methods: Sixty-two estriol- and forty-nine placebo-treated RRMS patients underwent clinical evaluations and brain MRI. Voxel-based morphometry (VBM) was used to evaluate voxelwise GM sparing from high-resolution T1-weighted scans.

Results: A region of treatment-induced sparing (TIS) was defined as the areas where GM was spared in estriol- as compared to placebo-treated groups, localized primarily within the frontal and parietal cortices. We observed that TIS volume was directly correlated with improvement on the PASAT. Next, a longitudinal cognitive disability-specific atlas (DSA) was defined by correlating voxelwise GM volumes with PASAT scores, that is, areas where less GM correlated with less improvement in PASAT scores. Finally, overlap between the TIS and the longitudinal cognitive DSA revealed a specific region of cortical GM that was preserved in estriol-treated subjects that was associated with better performance on the PASAT.

Conclusions: Discovery of this region of overlap was biology driven, not based on an a priori structure of interest. It included the medial frontal cortex, an area previously implicated in problem solving and attention. These findings indicate that localized GM sparing during estriol treatment was associated with improvement in cognitive testing, suggesting a clinically relevant, disability-specific biomarker for clinical trials of candidate neuroprotective treatments in MS.

Keywords: atrophy; brain; estriol; magnetic resonance imaging; multiple sclerosis; voxel-based morphometry.

Figure 1

Trial profile

Figure 2

Change in paced auditory serial addition test at 3 s (PASAT3) scores in all patients at baseline month 0 and on treatment at months 3, 6, 12, 18, and 24. Change in mean absolute scores at each time point as compared to baseline is shown in red for the estriol + glatiramer acetate group and in black for the placebo + glatiramer acetate group. Values are expressed as means ± standard error of the mean. Positive change in absolute scores from baseline indicates improvement

Figure 3

Estriol treatment‐induced sparing of gray matter. Surface renderings (top) and maximum intensity projections (bottom) of regions of significant gray matter preservation in the estriol + glatiramer acetate group as compared to the placebo + glatiramer acetate group at month 12 superimposed on the statistical parametric mapping standard glass brain. Results were corrected for multiple comparisons by controlling the false discovery rate at p ≤ 0.05

Figure 4

Heat map showing positive and negative correlations and their clustering in each treatment group. A graphical representation of relationship among treatment‐induced sparing volume (TIS vol), traditional MRI measures (gray matter volume (GM vol), cortical gray matter volume (cGM vol), fluid‐attenuated inversion recovery lesion volume (FLAIR vol), gadolinium‐enhancing lesion volume (Gd vol), white matter volume (WM vol), cerebrospinal fluid volume (CSF vol)), and clinical measures (paced auditory serial addition test at 3 s (PASAT3), paced auditory serial addition test at 2 s (PASAT2), timed 25‐foot walk (T25FW), nine‐hole peg test (9HPT), multiple sclerosis functional composite (MSFC), expended disability status score (EDSS)). In the heat map, yellow indicates a positive (direct) correlation and red indicates a negative (indirect) correlation between the values. (a) Heat map for the estriol + glatiramer acetate group. (b) Heat map for the placebo + glatiramer acetate group

Figure 5

Longitudinal cognitive disability‐specific atlas. Surface renderings (top) and maximum intensity projections (bottom) of regions of statistically significant correlation between gray matter volume change and paced auditory serial addition test at 2‐s performance change in all patients and across all time points superimposed on the statistical parametric mapping standard glass brain. All results were corrected for multiple comparisons by controlling the false discovery rate at p ≤ 0.05

Figure 6

Overlap of the region of treatment‐induced sparing and the longitudinal cognitive disability‐specific atlas. Surface renderings (top) and maximum intensity projections (bottom) superimposed on the statistical parametric mapping standard glass brain