The University of Southampton
University of Southampton Institutional Repository

Permeability of the blood-brain barrier predicts no evidence of disease activity at two years after natalizumab or fingolimod treatment in relapsing-remitting multiple sclerosis

Permeability of the blood-brain barrier predicts no evidence of disease activity at two years after natalizumab or fingolimod treatment in relapsing-remitting multiple sclerosis
Permeability of the blood-brain barrier predicts no evidence of disease activity at two years after natalizumab or fingolimod treatment in relapsing-remitting multiple sclerosis
OBJECTIVE: To investigate if blood-brain barrier (BBB) permeability, as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), can provide early detection of sub-optimal treatment response in relapsing-remitting multiple sclerosis (RRMS).
METHODS: 35 RRMS patients starting on fingolimod or natalizumab, drugs with a common effect of decreasing lymphocyte influx into the CNS, were scanned with DCE-MRI at 3T prior to treatment and at three and six-months post-treatment. We calculated the influx constant Ki , a measure of BBB permeability, using the Patlak model. Sub-optimal treatment response was defined as loss of no evidence of disease activity (NEDA-3) status after two years of treatment.
RESULTS: Subjects with loss of NEDA status at 2 years had a 51% higher mean Ki in normal-appearing white matter (NAWM) measured after six months of treatment, compared to subjects with maintained NEDA status (mean difference 0.06 (CI 0.02-0.09) ml/100g/min; p=0.002). Ki in NAWM at 6 months was a good predictor of loss of NEDA status at two years (AUC 0.84, CI 0.70-0.99; p=0.003) and a value above 0.136 ml/100/g/min yielded an odds ratio of 12.4 for sub-optimal treatment response at 2 years, with a sensitivity of 73% and a specificity of 82%.
INTERPRETATION: Our results suggest that BBB permeability as measured by DCE-MRI reliably predicts sub-optimal treatment response and is a surrogate marker of the state of health of the BBB. We find a predictive threshold for disease activity, which is remarkably identical in clinically isolated syndrome as previously reported and established RRMS as investigated here.
0364-5134
Cramer, Stig P.
ed3fe479-8e5e-4e38-bc02-bac30263db63
Simonsen, Helle J.
9911a788-79bb-4955-8191-c0045d0f9841
Varatharaj, Aravinthan
33d833af-9459-4b21-8489-ce9c0b6a09e0
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
Frederiksen, Jette L.
05f563b8-7656-477e-a253-cdbc63d6f53a
Larsson, Henrik B.W.
e6a4213a-310b-4928-8f07-4e2e53be51ae
Cramer, Stig P.
ed3fe479-8e5e-4e38-bc02-bac30263db63
Simonsen, Helle J.
9911a788-79bb-4955-8191-c0045d0f9841
Varatharaj, Aravinthan
33d833af-9459-4b21-8489-ce9c0b6a09e0
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
Frederiksen, Jette L.
05f563b8-7656-477e-a253-cdbc63d6f53a
Larsson, Henrik B.W.
e6a4213a-310b-4928-8f07-4e2e53be51ae

Cramer, Stig P., Simonsen, Helle J., Varatharaj, Aravinthan, Galea, Ian, Frederiksen, Jette L. and Larsson, Henrik B.W. (2018) Permeability of the blood-brain barrier predicts no evidence of disease activity at two years after natalizumab or fingolimod treatment in relapsing-remitting multiple sclerosis. Annals of Neurology, 83 (5). (doi:10.1002/ana.25219).

Record type: Article

Abstract

OBJECTIVE: To investigate if blood-brain barrier (BBB) permeability, as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), can provide early detection of sub-optimal treatment response in relapsing-remitting multiple sclerosis (RRMS).
METHODS: 35 RRMS patients starting on fingolimod or natalizumab, drugs with a common effect of decreasing lymphocyte influx into the CNS, were scanned with DCE-MRI at 3T prior to treatment and at three and six-months post-treatment. We calculated the influx constant Ki , a measure of BBB permeability, using the Patlak model. Sub-optimal treatment response was defined as loss of no evidence of disease activity (NEDA-3) status after two years of treatment.
RESULTS: Subjects with loss of NEDA status at 2 years had a 51% higher mean Ki in normal-appearing white matter (NAWM) measured after six months of treatment, compared to subjects with maintained NEDA status (mean difference 0.06 (CI 0.02-0.09) ml/100g/min; p=0.002). Ki in NAWM at 6 months was a good predictor of loss of NEDA status at two years (AUC 0.84, CI 0.70-0.99; p=0.003) and a value above 0.136 ml/100/g/min yielded an odds ratio of 12.4 for sub-optimal treatment response at 2 years, with a sensitivity of 73% and a specificity of 82%.
INTERPRETATION: Our results suggest that BBB permeability as measured by DCE-MRI reliably predicts sub-optimal treatment response and is a surrogate marker of the state of health of the BBB. We find a predictive threshold for disease activity, which is remarkably identical in clinically isolated syndrome as previously reported and established RRMS as investigated here.

Text
Cramer_et_al-2017-Annals_of_Neurology - Accepted Manuscript
Download (2MB)

More information

Accepted/In Press date: 28 March 2018
e-pub ahead of print date: 31 March 2018
Published date: May 2018

Identifiers

Local EPrints ID: 419288
URI: http://eprints.soton.ac.uk/id/eprint/419288
ISSN: 0364-5134
PURE UUID: a196d86e-3479-49eb-b2e7-f8a8709dece0
ORCID for Aravinthan Varatharaj: ORCID iD orcid.org/0000-0003-1629-5774
ORCID for Ian Galea: ORCID iD orcid.org/0000-0002-1268-5102

Catalogue record

Date deposited: 10 Apr 2018 16:30
Last modified: 16 Mar 2024 06:26

Export record

Altmetrics

Contributors

Author: Stig P. Cramer
Author: Helle J. Simonsen
Author: Ian Galea ORCID iD
Author: Jette L. Frederiksen
Author: Henrik B.W. Larsson

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×