Quantification of individual remyelination during short-term disease course by synthetic magnetic resonance imaging

Abstract

MRI is an important diagnostic tool for evaluation of myelin content in multiple sclerosis and other CNS diseases, being especially relevant for studies investigating remyelinating pharmacotherapies. In this study, we evaluated a new synthetic MRI-based myelin estimation in methylenetetrahydrofolate reductase deficiency as a treatable primary demyelinating disorder and compared this method with established diffusion tensor imaging in both methylenetetrahydrofolate reductase deficiency patients and healthy controls. This is the first synthetic MRI-based in vivo evaluation of treatment-associated remyelination. 1.5 T synthetic MRI and 3 T diffusion MRI were obtained from three methylenetetrahydrofolate reductase deficiency patients at baseline and 6 months after therapy initiation, as well as from age-matched healthy controls (diffusion tensor imaging: n = 14, synthetic MRI: n = 9). Global and regional synthetic MRI parameters (myelin volume fraction, proton density, and relaxation rates) were compared with diffusion metrics (fractional anisotropy, mean/radial/axial diffusivity) and related to healthy controls by calculating z-scores and z-deviation maps. Whole-brain myelin (% of intracranial volume) of the index patient was reduced to 6 versus 10% in healthy controls, which recovered to a nonetheless subnormal level of 6.6% following initiation of high-dosage betaine. Radial diffusivity was higher at baseline compared with healthy controls (1.34 versus 0.79 × 10^-3 mm²/s), recovering at follow-up (1.19 × 10^-3 mm²/s). The index patient's lesion volume diminished by 58% under treatment. Regional analysis within lesion area and atlas-based regions revealed lower mean myelin volume fraction (12.7_Baseline/14.71_Follow-up%) and relaxation rates, higher proton density, as well as lower fractional anisotropy and higher radial diffusivity (1.08 × 10^-3 _Baseline/0.94 × 10^-3 _Follow-up) compared with healthy controls. The highest z-scores were observed for myelin volume fraction in the posterior thalamic radiation, with greater deviation from controls at baseline and reduced deviation at follow-up. Z-deviations of diffusion metrics were less pronounced for radial and mean diffusivity than for myelin volume fraction. Z-maps for myelin volume fraction of the index patient demonstrated high deviation within and beyond lesion areas, among others in the precentral and postcentral gyrus, as well as in the cerebellum, and partial remission of these alterations at follow-up, while radial diffusivity demonstrated more widespread deviations in supra- and infratentorial regions. Concordant changes of myelin volume fraction and radial diffusivity after treatment initiation, accompanied by dramatic clinical and paraclinical improvement, indicate the consistency of the methods, while myelin volume fraction seems to characterize remyelinated regions more specifically. Synthetic MRI-based myelin volume fraction provides myelin estimation consistent with changes of diffusion metrics to monitor short-term myelin changes on individual patient level.

Keywords: MTHFR; diffusion MRI; remyelination; synthetic MRI.

Graphical abstract

Figure 1

Temporal change of leucoencephalopathic lesion of the index patient. Raw 3D T₂-FLAIR images of the index patient at baseline [upper row; voxel coordinates in each dimension: x (left-right) 106, y (posterior-anterior) 78, z (inferior-superior) 148] and at 6 months follow-up [lower row; voxel coordinates in each dimension: x (left-right) 106, y (posterior-anterior) 84, z (inferior-superior) 164].

Figure 2

Regions of interest. Selected regions of interest with registered lesion mask of Patient 1 at baseline depicted in white. Regions are based on the JHU-ICBM-labels atlas (green = corticospinal tract, lightblue = cerebral peduncle, blue = posterior limb of internal capsule, red = posterior thalamic radiation, orange = corpus callosum, pink = superior corona radiata). Depicted range of z-axis (inferior-superior axis): 38–96.

Figure 3

Regional z-scores. Mean regional z-scores for synthetic and DTI parameters at baseline (BL) and follow-up (FU). The red horizontal line depicts the threshold of 1.96. Stars highlight marked differences between baseline and follow-up (>1 SD of HC group). (A) DTI z-scores of the index patient. (B) Synthetic MRI z-scores of the index patient. (C) Synthetic MRI z-scores of Patient 2. (D) Synthetic MRI z-scores of Patient 3. CC, corpus callosum; CP, cerebral peduncle; CST, cortical spinal tract; L, left; PLIC, posterior limb of internal capsule; PTR, posterior thalamic radiation; R, right; SCR, superior corona radiata.

Figure 4

Myelin and RD z-maps. (A) Z-deviation map for voxel-wise myelin volume fraction showing considerable decreases of the index patient’s myelin from healthy controls. Left: baseline, right: follow-up. The z-map is depicted as blue overlay on the MNI152 T1 template and displays areas in which the z-deviation exceeds 1.96. (B) Z-deviation map for radial diffusivity (RD) showing considerable increases of the index patient’s RD from healthy controls. Left: baseline, right: follow-up. The z-map is depicted as orange overlay on the MNI152 T1 template and displays areas in which the z-deviation exceeds 1.96.