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

“Relapsewasdefined as new or worsening symptoms that lasted 24 h and occurred in the absence of fever or infection (Schumacher et al., 1965).”

“…did not include secondary progressive MS patients, where the relationship between inflammation and damage to the BBB is less obvious than in RRMS (Lassmann et al., 2012), secondly, our cohorts were all evaluated for treatment intensification, thus presumably having a high relative disease…”

“However, the MS disease process itself seems capable of modifying the permeability of the BBB (Larochelle et al., 2011; Minagar and Alexander, 2003) but we observed no correlation between permeability and age, EDSS or years sinceMS onset indicating that BBB abnormalities do not seem toworsen with disease progression.”

“All rights reser inactive MS lesions as well as normal appearing white matter (NAWM) (Kirk et al., 2003; McQuaid et al., 2009; Plumb et al., 2002; Vos et al., 2005), and serial MRI studies have indicated that structural changes (Filippi et al., 1998; Werring, 2000) and BBB dysfunction (Goodkin et…”

“On the other hand, activated leukocytes themselves are capable of altering BBB permeability through expression and secretion of inflammatory cytokines (Larochelle et al., 2011).”

“…white matter (NAWM) (Kirk et al., 2003; McQuaid et al., 2009; Plumb et al., 2002; Vos et al., 2005), and serial MRI studies have indicated that structural changes (Filippi et al., 1998; Werring, 2000) and BBB dysfunction (Goodkin et al., 1998) may precedemyelin damage and leukocyte infiltration.”

“All rights reser inactive MS lesions as well as normal appearing white matter (NAWM) (Kirk et al., 2003; McQuaid et al., 2009; Plumb et al., 2002; Vos et al., 2005), and serial MRI studies have indicated that structural changes (Filippi et al., 1998; Werring, 2000) and BBB dysfunction (Goodkin et…”

“…white matter (NAWM) (Kirk et al., 2003; McQuaid et al., 2009; Plumb et al., 2002; Vos et al., 2005), and serial MRI studies have indicated that structural changes (Filippi et al., 1998; Werring, 2000) and BBB dysfunction (Goodkin et al., 1998) may precedemyelin damage and leukocyte infiltration.”

“Only a minority of cells need be infected and express viral genes, which would serve to explain the inconsistent detection of EBV in MS brains (Willis et al., 2009) and CSF (Mancuso et al., 2010).”

“All rights reser inactive MS lesions as well as normal appearing white matter (NAWM) (Kirk et al., 2003; McQuaid et al., 2009; Plumb et al., 2002; Vos et al., 2005), and serial MRI studies have indicated that structural changes (Filippi et al., 1998; Werring, 2000) and BBB dysfunction (Goodkin et…”

“On the contrary, evidence indicates that infection with many different pathogens, either bacterial or viral, increases the risk of relapse up to twofold, gives more severe relapses and shows increased lesion activity on MRI (Correale et al., 2006).”

“Tissue concentration–time curves were evaluated using a combination of model free deconvolution and a Patlak model, as described in previous work (Larsson et al., 2009).”

“We are aware of two MRI studies describing a similar phenomenon with structural abnormalities occurring consecutively in MS lesions and in contralateral NAWM (De Stefano, 1999; Werring, 2000).”

“All rights reser inactive MS lesions as well as normal appearing white matter (NAWM) (Kirk et al., 2003; McQuaid et al., 2009; Plumb et al., 2002; Vos et al., 2005), and serial MRI studies have indicated that structural changes (Filippi et al., 1998; Werring, 2000) and BBB dysfunction (Goodkin et…”

“Recent works even suggest that Epstein–Barr virus, which has long been linked toMS (Owens and Bennett, 2012; Pakpoor et al., 2013), is capable of infecting the human endothelial cells of the BBB (Casiraghi et al.”

“A recent study using a similar MRI method to investigate only MS patients, reported a mean Ktrans of 0.04 (SD 0.03) mL/100 mL/min in periventricular NAWM (Ingrisch et al., 2012).”

“Recent works even suggest that Epstein–Barr virus, which has long been linked toMS (Owens and Bennett, 2012; Pakpoor et al., 2013), is capable of infecting the human endothelial cells of the BBB (Casiraghi et al., 2011).”

“The DCE MRI data was analyzed with a semi-automatic procedure (Larsson et al., 2008) using in-house MatLab-based software.”

“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) (Ki = 0.0003 min−1) reported by Iannotti et al. (1987).”

“This would serve to explain why some studies find no difference between healthy controls and MS patients undergoing immunomodulatory treatment (Lund et al., 2013) or having no recent relapses (Silver et al., 2001).”

“The large body of evidence supporting BBB dysfunction in MS is reviewed in detail elsewhere (Poser, 1986, 1992, 2004) with two main points.”

“All rights reser inactive MS lesions as well as normal appearing white matter (NAWM) (Kirk et al., 2003; McQuaid et al., 2009; Plumb et al., 2002; Vos et al., 2005), and serial MRI studies have indicated that structural changes (Filippi et al., 1998; Werring, 2000) and BBB dysfunction (Goodkin et…”

“A key event in MS is the formation of acute gadolinium-enhancing lesions, resulting from an overt breach of the BBB (Runge et al., 1985).”

“Recent works even suggest that Epstein–Barr virus, which has long been linked toMS (Owens and Bennett, 2012; Pakpoor et al., 2013), is capable of infecting the human endothelial cells of the BBB (Casiraghi et al.”

“At least in the case of IFN-beta-1a, it has been shown to stabilize barrier characteristics of human brain capillary endothelial cells in vitro (Kraus et al., 2008).”

“Even trauma and certain chemical effects seem to be able to initiate the plaque forming process in some MS cases (Poser, 1994).”

“Only a minority of cells need be infected and express viral genes, which would serve to explain the inconsistent detection of EBV in MS brains (Willis et al., 2009) and CSF (Mancuso et al., 2010).”

“This leakage was primarily observed to occur 20 and 40 min post-contrast, and previous work suggests that low permeating MS lesions may not reach maximum concentration of contrast agent until 2 h after injection (Tofts, 1995).”

“One earlier study by Soon and colleagues did however report a higher degree of leakage in inactive MS lesions when compared to contralateral NAWM (Soon et al., 2007).”

“This would serve to explain why some studies find no difference between healthy controls and MS patients undergoing immunomodulatory treatment (Lund et al., 2013) or having no recent relapses (Silver et al., 2001).”

“A key event in MS is the formation of acute gadolinium-enhancing lesions, resulting from an overt breach of the BBB (Runge et al., 1985).”

“Imaging studies show BBB disruption in normal-appearing white matter in MS (Cramer et al., 2014), and BBB breakdown precedes the development of new lesions (Alvarez et al., 2015).”