Blood-brain barrier breakdown in non-enhancing multiple sclerosis lesions detected by 7-Tesla MP2RAGE ΔT1 mapping

Abstract

Although the blood-brain barrier (BBB) is altered in most multiple sclerosis (MS) lesions, gadolinium enhancement is seen only in acute lesions. In this study, we aimed to investigate gadolinium-induced changes in T1 relaxation time in MS lesions on 7-tesla (7T) MRI as a means to quantify BBB breakdown in non-enhancing MS lesions. Forty-seven participants with MS underwent 7T MRI of the brain with a magnitude-prepared rapid acquisition of 2 gradient echoes (MP2RAGE) sequence before and after contrast. Subtraction of pre- and post-contrast T1 maps was used to measure T1 relaxation time change (ΔT1) from gadolinium. ΔT1 values were interrogated in enhancing white matter lesions (ELs), non-enhancing white matter lesions (NELs), and normal appearing white matter (NAWM) and metrics were compared to clinical data. ΔT1 was measurable in NELs (median: -0.139 (-0.304, 0.174) seconds; p < 0.001) and was negligible in NAWM (median: -0.001 (-0.036, 0.155) seconds; p = 0.516). Median ΔT1 in NELs correlated with disability as measured by Expanded Disability Status Scale (EDSS) (rho = -0.331, p = 0.026). Multiple measures of NEL ΔT1 variability also correlated with EDSS. NEL ΔT1 values were greater and more variable in patients with progressive forms of MS and greater in those not on MS treatment. Measurement of the changes in T1 relaxation time caused by contrast on 7T MP2RAGE reveals clinically relevant evidence of BBB breakdown in NELs in MS. This data suggests that NEL ΔT1 should be evaluated further as a potential biomarker of persistently disrupted BBB in MS.

Although the blood-brain barrier (BBB) is altered in most multiple sclerosis (MS) lesions, gadolinium enhancement is seen only in acute lesions. In this study, we aimed to investigate gadolinium-induced changes in T1 relaxation time in MS lesions on 7-tesla (7T) MRI as a means to quantify BBB breakdown in non-enhancing MS lesions. Forty-seven participants with MS underwent 7T MRI of the brain with a magnitude-prepared rapid acquisition of 2 gradient echoes (MP2RAGE) sequence before and after contrast. Subtraction of pre- and post-contrast T1 maps was used to measure T1 relaxation time change (ΔT1) from gadolinium. ΔT1 values were interrogated in enhancing white matter lesions (ELs), non-enhancing white matter lesions (NELs), and normal appearing white matter (NAWM) and metrics were compared to clinical data. ΔT1 was measurable in NELs (median: -0.139 (-0.304, 0.174) seconds; p < 0.001) and was negligible in NAWM (median: -0.001 (-0.036, 0.155) seconds; p = 0.516). Median ΔT1 in NELs correlated with disability as measured by Expanded Disability Status Scale (EDSS) (rho = -0.331, p = 0.026). Multiple measures of NEL ΔT1 variability also correlated with EDSS. NEL ΔT1 values were greater and more variable in patients with progressive forms of MS and greater in those not on MS treatment. Measurement of the changes in T1 relaxation time caused by contrast on 7T MP2RAGE reveals clinically relevant evidence of BBB breakdown in NELs in MS. This data suggests that NEL ΔT1 should be evaluated further as a potential biomarker of persistently disrupted BBB in MS.

Fig 1. Lesion masking for ELs and NELs as seen on pre- and post-contrast T₁w images, T₁ map, and ΔT₁ map.

A: Lesioned areas (indicated by blue arrows) appeared hypointense on pre-contrast T₁-weighted image. B: EL area (indicated by a red arrow) on post-contrast T₁-weighted image while NELs remains unenhanced. C: White matter lesions seen on T₁ map (EL in red, NEL in blue). D: White matter lesions seen on ΔT₁ map (EL in red, NEL in blue, units: s). The color bar displays the full range of ΔT₁ (units: s) values only in this participant. EL = enhancing lesion; NEL = non-enhancing lesion; T₁w = T₁-weighted.

Fig 2. Magnitude of ΔT₁ in non-enhanced lesion areas.

Shown are images from three separate participants (A: SPMS/female/53, B: RRMS/female/52, C: SPMS/female/61). Color maps of ΔT₁ (units: s) in NEL’s were overlaid upon T₁-weighted images. Each color bar (not scaled) displays the full range of ΔT₁ only within NEL of the corresponding participant. Three representative participants shown for display purposes (analysis was in all subjects). Each row shows three consecutive image slices of a single participant. SPMS = secondary progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis; BBB = blood-brain barrier; NEL = non-enhancing lesion.

Fig 3. ΔT₁ and Pre-contrast T₁ in NEL, NAWM, cGM of entire cohort.

A: Overlaid kernel density estimations (KDEs) of ΔT₁ in NEL. Each colored line represents the smoothed histogram using KDE for all voxels in one subject. Blue vertial line indicates voxel-wise mean ΔT₁ value (-0.116 s), and green line denotes voxel-wise median ΔT₁ value (-0.105 s). B: Per voxel Spearman’s rho coefficient for the relationship of pre-contrast T₁ and ΔT₁ of all NEL voxels of the entire cohort shows a weak correlation, which indicates that observed ΔT₁ is not solely driven by initial T₁ before contrast agent administration. C: Overlaid KDEs of pre-contrast T₁ in NEL D: Overlaid KDEs of ΔT₁ in NAWM. E: Per voxel Spearman’s rho coefficient in NAWM shows a stronger correlation than NEL (blue line, mean ΔT₁ of 0.011 s; green line, median ΔT₁ of 0.002 s). F: Overlaid KDEs of pre-contrast T₁ in NAWM. G: Overlaid KDE of ΔT₁ in cGM (blue line, mean ΔT₁ of -0.107 s; green line, median ΔT₁ of -0.091 s). H: Per voxel Spearman’s rho coefficient in cGM also shows a stronger correlation than NEL. I: Overlaid KDEs of pre-contrast T₁ in cGM. NEL = non-enhancing lesion, NAWM = normal-appearing white matter, cGM = cortical gray matter.

Fig 4. Group differences in median ΔT₁ in non-enhancing white matter lesions.

A: NEL median ΔT₁ comparison for EDSS scores that were > median (3.0) vs. ≤ median. Gadolinium induced greater changes in T₁ in MS participants with higher EDSS scores. B: NEL median ΔT₁ comparison for MS Type, PMS vs. RRMS. Gadolinium induced greater changes in T₁ in participants with PMS. C: NEL median ΔT₁ comparison for multiple sclerosis immunomodulatory treatment, Yes vs. No. Gadolinium induced greater changes in T₁ in participants not on MS treatment. Per subject median ΔT₁ values were used in the Mann-Whitney U-test. NEL = non-enhancing lesion; EDSS = Expanded Disability Status Scale; MS = multiple sclerosis; PMS = progressive multiple sclerosis (PPMS + SPMS); PPMS = primary progressive multiple sclerosis; SPMS = secondary progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis.