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Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions.

ABSTRACT: OBJECTIVE:Multiple sclerosis (MS) lesions develop around small, inflamed veins. New lesions enhance with gadolinium on magnetic resonance imaging (MRI), reflecting disruption of the blood-brain barrier (BBB). Single time point results from pathology and standard MRI cannot capture the spatiotemporal expansion of lesions. We investigated the development and expansion of new MS lesions, focusing on the dynamics of BBB permeability. METHODS:We performed dynamic contrast-enhanced (DCE) MRI in relapsing-remitting MS. We obtained data over 65 minutes, during and after gadolinium injection. We labeled spatiotemporal enhancement dynamics as centrifugal when initially central enhancement expanded outward and centripetal when initially peripheral enhancement gradually filled the center. RESULTS:We detected 34 enhancing lesions in 200 DCE-MRI scans. In 65%, enhancement first appeared as a closed ring; in 18%, as a nodule; and in 18%, as an open ring. Lesions with initially nodular enhancement were smaller than those initially enhancing as rings (p < 0.0001). All initially nodular lesions enhanced centrifugally, whereas initially ringlike lesions enhanced centripetally, becoming nodular if small (82%) or nearly nodular if larger (18%). Open-ring lesions were periventricular or juxtacortical and enhanced centripetally. Centrifugally enhancing lesions evolved into centripetally enhancing lesions over several days. INTERPRETATION:The rapid change of enhancement dynamics from centrifugal to centripetal reflects the outward growth of MS lesions around their central vein and suggests that factors mediating lesion growth and tissue repair derive from different locations at different times. We propose a model of new lesion growth that unites our imaging observations with existing pathology data.

SUBMITTER: Gaitan MI

PROVIDER: S-EPMC3143223 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions.

Gaitán María I MI Shea Colin D CD Evangelou Iordanis E IE Stone Roger D RD Fenton Kaylan M KM Bielekova Bibiana B Massacesi Luca L Reich Daniel S DS

Annals of neurology 20110627 1

<h4>Objective</h4>Multiple sclerosis (MS) lesions develop around small, inflamed veins. New lesions enhance with gadolinium on magnetic resonance imaging (MRI), reflecting disruption of the blood-brain barrier (BBB). Single time point results from pathology and standard MRI cannot capture the spatiotemporal expansion of lesions. We investigated the development and expansion of new MS lesions, focusing on the dynamics of BBB permeability.<h4>Methods</h4>We performed dynamic contrast-enhanced (DCE ...[more]

PMID: 21710622

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Project description: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.

Project description:Neuroinflammatory processes occurring during multiple sclerosis cause disseminated softening of brain tissue, as quantified by in vivo magnetic resonance elastography (MRE). However, inflammation-mediated tissue alterations underlying the mechanical integrity of the brain remain unclear. We previously showed that blood-brain barrier (BBB) disruption visualized by MRI using gadolinium-based contrast agent (GBCA) does not correlate with tissue softening in active experimental autoimmune encephalomyelitis (EAE). However, it is unknown how confined BBB changes and other inflammatory processes may determine local elasticity changes. Therefore, we aim to elucidate which inflammatory hallmarks are determinant for local viscoelastic changes observed in EAE brains. Hence, novel multifrequency MRE was applied in combination with GBCA-based MRI or very small superparamagnetic iron oxide particles (VSOPs) in female SJL mice with induced adoptive transfer EAE (n = 21). VSOPs were doped with europium (Eu-VSOPs) to facilitate the post-mortem analysis. Accumulation of Eu-VSOPs, which was previously demonstrated to be sensitive to immune cell infiltration and ECM remodeling, was also found to be independent of GBCA enhancement. Following registration to a reference brain atlas, viscoelastic properties of the whole brain and areas visualized by either Gd or VSOP were quantified. MRE revealed marked disseminated softening across the whole brain in mice with established EAE (baseline: 3.1 ± 0.1 m/s vs. EAE: 2.9 ± 0.2 m/s, p < 0.0001). A similar degree of softening was observed in sites of GBCA enhancement i.e., mainly within cerebral cortex and brain stem (baseline: 3.3 ± 0.4 m/s vs. EAE: 3.0 ± 0.5 m/s, p = 0.018). However, locations in which only Eu-VSOP accumulated, mainly in fiber tracts (baseline: 3.0 ± 0.4 m/s vs. EAE: 2.6 ± 0.5 m/s, p = 0.023), softening was more pronounced when compared to non-hypointense areas (percent change of stiffness for Eu-VSOP accumulation: -16.81 ± 16.49% vs. for non-hypointense regions: -5.85 ± 3.81%, p = 0.048). Our findings suggest that multifrequency MRE is sensitive to differentiate between local inflammatory processes with a strong immune cell infiltrate that lead to VSOP accumulation, from disseminated inflammation and BBB leakage visualized by GBCA. These pathological events visualized by Eu-VSOP MRI and MRE may include gliosis, macrophage infiltration, alterations of endothelial matrix components, and/or extracellular matrix remodeling. MRE may therefore represent a promising imaging tool for non-invasive clinical assessment of different pathological aspects of neuroinflammation.

Dataset Information

Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions.

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Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions.

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