New rapid, accurate T2 quantification detects pathology in normal-appearing brain regions of relapsing-remitting MS patients

Abstract

Introduction: Quantitative T₂ mapping may provide an objective biomarker for occult nervous tissue pathology in relapsing-remitting multiple sclerosis (RRMS). We applied a novel echo modulation curve (EMC) algorithm to identify T₂ changes in normal-appearing brain regions of subjects with RRMS (N = 27) compared to age-matched controls (N = 38).

Methods: The EMC algorithm uses Bloch simulations to model T₂ decay curves in multi-spin-echo MRI sequences, independent of scanner, and scan-settings. T₂ values were extracted from normal-appearing white and gray matter brain regions using both expert manual regions-of-interest and user-independent FreeSurfer segmentation.

Results: Compared to conventional exponential T₂ modeling, EMC fitting provided more accurate estimations of T₂ with less variance across scans, MRI systems, and healthy individuals. Thalamic T₂ was increased 8.5% in RRMS subjects (p < 0.001) and could be used to discriminate RRMS from healthy controls well (AUC = 0.913). Manual segmentation detected both statistically significant increases (corpus callosum & temporal stem) and decreases (posterior limb internal capsule) in T₂ associated with RRMS diagnosis (all p < 0.05). In healthy controls, we also observed statistically significant T₂ differences for different white and gray matter structures.

Conclusions: The EMC algorithm precisely characterizes T₂ values, and is able to detect subtle T₂ changes in normal-appearing brain regions of RRMS patients. These presumably capture both axon and myelin changes from inflammation and neurodegeneration. Further, T₂ variations between different brain regions of healthy controls may correlate with distinct nervous tissue environments that differ from one another at a mesoscopic length-scale.

Keywords: AUC, area under the curve; B1 +,  transmit field; Biomarkers; Demyelination; EMC, echo modulation curve; FLAIR, fluid-attenuated inversion recovery; GM, gray matter; MPRAGE, magnetization-prepared rapid gradient-echo; MSE, multi-spin echo; MWF, myelin water fraction; Mesoscopic; Neurodegeneration; ROI, Region of Interest; RRMS, relapsing-remitting multiple sclerosis; Relaxation; SPACE, sampling perfection with application-optimized contrasts using different flip angle evolution; SSE, single spin echo; WM, white matter.

Fig. 1

Expert-drawn manual regions-of-interest for a single subject with relapsing-remitting multiple sclerosis. 5 axial slices were included for the analysis; immediately below the anterior commissure (a), at the foramen of Monro (b), 1 cm above the foramen of Monro (c), roof of the lateral ventricles (d) and 1 cm above the lateral ventricles (e).

Fig. 2

Examples of regions-of-interest for MS lesions including (a) periventricular, (b) juxtacortical and (c) subcortical white matter. ROIs were drawn on a T₂ weighted image (TE = 81 ms) synthesized based on EMC fitted T₂ map without interpolation (note, black voxels indicate non-valid fitting results). Similar ROIs were drawn for investigating normal appearing brain regions, i.e., where lesions were not visibly present to a board-certified neuroradiologist (see Fig. 1).

Fig. 3

(a) Bar graph comparing T₂ values (mean ± SD) in brain regions segmented using Freesurfer, in relapsing-remitting multiple sclerosis patients and in age-matched healthy controls (N = 27 & 38 subjects respectively). Regions that are statistically different between the two groups (p < 0.05) are denoted with “*”. (b) Representative FreeSurfer segmentation map, overlaid on an axial T₁-weighted image at the level of the internal capsule.

Fig. 4

Mean thalamic T₂ values using the manual segmentation were 8.5% higher in subjects with RRMS compared to age-matched healthy controls (p < 0.001). In controls, thalamic T₂ values were independent of subject age (a). T₂ values in RRMS patients showed minimal dependence on age (b).

Fig. 5

Manual region-of-interest T₂ values (mean ± SD, N = 38) for periventricular (PV), subcortical (SC) and juxtacortical (JC) white matter (WM) regions in healthy controls decreased in a centrifugal manner (all three groups statistically different, p < 0.05). This trend may reflect different underlying mesoscopic tissue environments such as variations in axon caliber, dispersion, packing density, myelination or even orientation with respect to the MRI main magnetic field.