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

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

doi:10.1371/journal.pone.0056375

Cited by 28 publications

(22 citation statements)

References 46 publications

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“…Second, ADMA and ET1 plasma levels in MS were independent of DD, so their increase had to be in the very early stages of the disease (Figure 2C and D). This is coherent with the hypothesis that their overproduction may be a response to the initial, altered integrity of the BBB 29. Also, as there is abundant evidence that the production of NO is significantly raised within MS lesions,30 the possibility that NO-induced vasodilation was a trigger for ET1 and ADMA overproduction cannot be discarded (see below).…”

Section: Discussionsupporting

confidence: 59%

Influence of Circulating Endothelin-1 and Asymmetric Dimethylarginine on Whole Brain Circulation Time in Multiple Sclerosis

et al. 2017

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Blood-brain barrier (BBB) breakdown, inflammatory and immune cell activation, and chronic cerebral hypoperfusion are features of multiple sclerosis (MS). The aim is to determine the influence of endothelin-1 (ET1) and asymmetric dimethylarginine (ADMA) on cerebral circulation time (CCT) in patients with MS. In all, 64 patients with MS (39 relapsing-remitting [RR]-MS; 25 secondary progressive [SP]-MS subtype) and 37 controls (C) were studied. Cerebral circulation time was obtained by angiography. Plasmatic ET1 and ADMA were measured by enzyme-linked immunosorbent assay. Lesion load (LL) and brain volume (BV) were obtained by magnetic resonance imaging. Cerebral circulation time was correlated to ET1, ADMA, LL, BV, disease duration (DD), and Expanded Disability Status Scale (EDSS). In MS, both ET1 and ADMA were significantly higher than C (P < .0001); CCT was approximately 2 times lower than C (P < .0001) and significantly slower in SP than in RR-MS (P = .0215). Cerebral circulation time significantly correlated with ET1 in SP-MS (r = 0.38), whereas in RR-MS CCT significantly correlated with DD (r = 0.75). The LL, BV, and EDSS did not correlate with CCT. Endothelin-1 significantly influences CCT delay in SP-MS. Diversely, CCT in RR-MS is independent of ET1 and correlates significantly with DD. We conclude that in RR-MS, DD responds to neurovascular damage accumulation. It is supposed that high ET1 and ADMA levels stem from a protective response to early insults, aimed at opposing nitric oxide overproduction, whereas persistent pathological ET1 and ADMA levels translate into detrimental long-term effects, due to increased brain micro-vessel resistance.

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Section: Discussionsupporting

confidence: 59%

Influence of Circulating Endothelin-1 and Asymmetric Dimethylarginine on Whole Brain Circulation Time in Multiple Sclerosis

et al. 2017

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“…In healthy controls, the finding of low grade leakage seems in good agreement with the previously estimated PET value of 0.03 mL/100 g/min (SD 0.008) (K i = 0.0003 min − 1 ) reported by Iannotti et al (1987). Although previous studies using ∆R1 / ∆t after gadolinium administration to compare leakage in MS NAWM and white matter in healthy controls have not found significant differences, they report a non-significant trend for elevated signal (Silver et al, 2001) and a higher coefficient of variation (Lund et al, 2013) in NAWM in MS patients. First of all, both studies included a relatively low number of healthy controls (Silver, n = 5; Lund, n = 9) and secondly, all patients in the study by Lund and colleagues received immunomodulatory treatment.…”

Section: Discussionmentioning

confidence: 92%

Abnormal blood–brain barrier permeability in normal appearing white matter in multiple sclerosis investigated by MRI

Cramer

Simonsen

Frederiksen

et al. 2014

NeuroImage: Clinical

182

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ObjectivesTo investigate whether blood–brain barrier (BBB) permeability is disrupted in normal appearing white matter in MS patients, when compared to healthy controls and whether it is correlated with MS clinical characteristics.MethodsDynamic contrast-enhanced MRI was used to measure BBB permeability in 27 patients with MS and compared to 24 matched healthy controls.ResultsPermeability measured as Ktrans was significantly higher in periventricular normal appearing white matter (NAWM) and thalamic gray matter in MS patients when compared to healthy controls, with periventricular NAWM showing the most pronounced difference. Recent relapse coincided with significantly higher permeability in periventricular NAWM, thalamic gray matter, and MS lesions. Immunomodulatory treatment and recent relapse were significant predictors of permeability in MS lesions and periventricular NAWM. Our results suggest that after an MS relapse permeability gradually decreases, possibly an effect of immunomodulatory treatment.ConclusionsOur results emphasize the importance of BBB pathology in MS, which we find to be most prominent in the periventricular NAWM, an area prone to development of MS lesions. Both the facts that recent relapse appears to cause widespread BBB disruption and that immunomodulatory treatment seems to attenuate this effect indicate that BBB permeability is intricately linked to the presence of MS relapse activity. This may reveal further insights into the pathophysiology of MS.

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“…We generated maps of T1‐relaxation time from IR‐magnitude data, with a fixed likelihood estimate for the goodness of the inversion pulse (F‐factor), accounting for the incomplete longitudinal relaxation at the next excitation. To remove noise from the slight enhancement of the normal‐appearing tissue reported in both patients and controls , we scaled the qT1 and T1w pre‐ and post contrast relative to the mean in a control region in the normal‐appearing white matter.…”

Section: Methodsmentioning

confidence: 99%

Quantitative T1‐mapping detects cloudy‐enhancing tumor compartments predicting outcome of patients with glioblastoma

et al. 2016

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Contrast enhancement of glioblastomas (GBM) is caused by the decrease in relaxation time, T1. Here, we demonstrate that the quantitative measurement of T1 (qT1) discovers a subtle enhancement in GBM patients that is invisible in standard MRI. We assessed the volume change of this “cloudy” enhancement during radio‐chemotherapy and its impact on patients’ progression‐free survival (PFS). We enrolled 18 GBM patients in this observational, prospective cohort study and measured 3T‐MRI pre‐ and post contrast agent with standard T1‐weighted (T1w) and with sequences to quantify T1 before radiation, and at 6‐week intervals during radio‐chemotherapy. We measured contrast enhancement by subtracting pre from post contrast contrast images, yielding relative signal increase ∆T1w and relative T1 shortening ∆qT1. On ∆qT1, we identified a solid and a cloudy‐enhancing compartment and evaluated the impact of their therapy‐related volume change upon PFS. In ∆qT1 maps cloudy‐enhancing compartments were found in all but two patients at baseline and in all patients during therapy. The qT1 decrease in the cloudy‐enhancing compartment post contrast was 21.64% versus 1.96% in the contralateral control tissue (P < 0.001). It was located at the margin of solid enhancement which was also seen on T1w. In contrast, the cloudy‐enhancing compartment was visually undetectable on ∆T1w. A volume decrease of more than 21.4% of the cloudy‐enhancing compartment at first follow‐up predicted longer PFS (P = 0.038). Cloudy‐enhancing compartment outside the solid contrast‐enhancing area of GBM is a new observation which is only visually detectable with qT1‐mapping and may represent tumor infiltration. Its early volume decrease predicts a longer PFS in GBM patients during standard radio‐chemotherapy.

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

Cited by 28 publications

References 46 publications

Influence of Circulating Endothelin-1 and Asymmetric Dimethylarginine on Whole Brain Circulation Time in Multiple Sclerosis

Influence of Circulating Endothelin-1 and Asymmetric Dimethylarginine on Whole Brain Circulation Time in Multiple Sclerosis

Abnormal blood–brain barrier permeability in normal appearing white matter in multiple sclerosis investigated by MRI

Quantitative T1‐mapping detects cloudy‐enhancing tumor compartments predicting outcome of patients with glioblastoma

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