Blood-Brain Barrier Permeability of Normal Appearing White Matter in Relapsing-Remitting Multiple Sclerosis

Henrik Lund,Arnold Skimminge,Olaf B Paulson,Dan Hesse,Martin Krakauer,Ellen Garde,Finn Sellebjerg,Hartwig R Siebner,Lars G Hanson,Gaolang Gong

doi:10.1371/journal.pone.0056375

Abstract

BackgroundMultiple sclerosis (MS) affects the integrity of the blood-brain barrier (BBB). Contrast-enhanced T1 weighted magnetic resonance imaging (MRI) is widely used to characterize location and extent of BBB disruptions in focal MS lesions. We employed quantitative T1 measurements before and after the intravenous injection of a paramagnetic contrast agent to assess BBB permeability in the normal appearing white matter (NAWM) in patients with relapsing-remitting MS (RR-MS).Methodology/Principal FindingsFifty-nine patients (38 females) with RR-MS undergoing immunomodulatory treatment and nine healthy controls (4 females) underwent quantitative T1 measurements at 3 tesla before and after injection of a paramagnetic contrast agent (0.2 mmol/kg Gd-DTPA). Mean T1 values were calculated for NAWM in patients and total cerebral white matter in healthy subjects for the T1 measurements before and after injection of Gd-DTPA. The pre-injection baseline T1 of NAWM (945±55 [SD] ms) was prolonged in RR-MS relative to healthy controls (903±23 ms, p = 0.028). Gd-DTPA injection shortened T1 to a similar extent in both groups. Mean T1 of NAWM was 866±47 ms in the NAWM of RR-MS patients and 824±13 ms in the white matter of healthy controls. The regional variability of T1 values expressed as the coefficient of variation (CV) was comparable between the two groups at baseline, but not after injection of the contrast agent. After intravenous Gd-DTPA injection, T1 values in NAWM were more variable in RR-MS patients (CV = 0.198±0.046) compared to cerebral white matter of healthy controls (CV = 0.166±0.018, p = 0.046).Conclusions/SignificanceWe found no evidence of a global BBB disruption within the NAWM of RR-MS patients undergoing immunomodulatory treatment. However, the increased variation of T1 values in NAWM after intravenous Gd-DTPA injection points to an increased regional inhomogeneity of BBB function in NAWM in relapsing-remitting MS.

Highlights

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system and is one of the major neurologic diseases in the Western world
Quantitative multi-point T1 measurements revealed significantly higher mean T1 values in normal appearing white matter (NAWM) in patients with relapsing-remitting MS (RR-MS) compared to white matter in healthy controls, both before (t = 2.255, p = 0.028, df = 67) and after (t = 2.676, p = 0.009, df = 66) the injection of contrast agent (Figure 1, Table 1)
No significant differences in the response to Gd-DTPA injection could be detected between MS patients with an expanded disability status scale (EDSS) score #2 and patients with an EDSS score of

Summary

Introduction

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system and is one of the major neurologic diseases in the Western world. The local disruption of the BBB can be captured with T1 weighted MRI after intravenous injection of a Gadolinium (Gd) chelated paramagnetic contrast agent [5]. Since the contrast agent penetrates the disrupted BBB and accumulates locally in the affected brain parenchyma it causes an increase in signal intensity (i.e., contrast enhancement) on T1 weighted images. Multiple sclerosis (MS) affects the integrity of the blood-brain barrier (BBB). Contrast-enhanced T1 weighted magnetic resonance imaging (MRI) is widely used to characterize location and extent of BBB disruptions in focal MS lesions. We employed quantitative T1 measurements before and after the intravenous injection of a paramagnetic contrast agent to assess BBB permeability in the normal appearing white matter (NAWM) in patients with relapsing-remitting MS (RR-MS)

Results

Discussion

Conclusion