Abnormal blood–brain barrier permeability in normal appearing white matter in multiple sclerosis investigated by MRI
Open accessAbstract
OBJECTIVES: To 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. METHODS: Dynamic contrast-enhanced MRI was used to measure BBB permeability in 27 patients with MS and compared to 24 matched healthy controls. RESULTS: Permeability measured as K(trans) 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. CONCLUSIONS: Our 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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In multiple sclerosis patients, increased blood-brain barrier permeability has been shown by DCE-MRI in the cortex and adjacent white matter, corpus callosum and internal capsule, and thalamic gray matter.
“More recently, an increase in BBB permeability has been shown in MS patients by DCE-MRI in the cortex and adjacent white matter (392), corpus callosum and internal capsule (121-123, 421, 574), as well as thalamic gray matter (123).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [123]
The Results (page not provided) report significantly higher BBB permeability in thalamic gray matter in MS patients than in healthy controls, measured by DCE-MRI. The Methods describe regions of interest in periventricular white matter and thalamic gray matter, but the paper does not report separate findings for the corpus callosum or internal capsule. The cortex and adjacent white matter are attributed to a different citation in the citing sentence. (LLM, conf=0.86)
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Cites
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“Relapsewasdefined as new or worsening symptoms that lasted 24 h and occurred in the absence of fever or infection (Schumacher et al., 1965).”
BackgroundProgressive multiple sclerosis: pathology and pathogenesis
Lassmann, H., van Horssen, J., & Mahad, D. (2012) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.168 · Cited by 1,033 · cited 5× · see citing works
“…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…”
BackgroundInfluentialBlood-brain barrier disruption in multiple sclerosis
Minagar, A., & Alexander, J. S. (2003) · Multiple Sclerosis · doi:10.1191/1352458503ms965oa · Cited by 685 · cited 2× · see citing works
“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.”
BackgroundKERMODE, A. G., THOMPSON, A. J., TOFTS, P., MACMANUS, D. G., KENDALL, B. E., KINGSLEY, D. P. E., MOSELEY, I. F., RUDGE, P., & MCDONALD, W. I. (1990) · Brain · doi:10.1093/brain/113.5.1477 · Cited by 578 · cited 1× · see citing works
“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…”
BackgroundHow do immune cells overcome the blood-brain barrier in multiple sclerosis?
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“On the other hand, activated leukocytes themselves are capable of altering BBB permeability through expression and secretion of inflammatory cytokines (Larochelle et al., 2011).”
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“…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.”
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“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…”
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“…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.”
BackgroundEpstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain.
Willis, S., Stadelmann, C., Rodig, S., Caron, T. J., Gattenloehner, S., Mallozzi, S. S., Roughan, J. E., Almendinger, S. E., Blewett, M. M., Brück, W., et al. (2009) · Brain : a journal of neurology · doi:10.1093/brain/awp200 · Cited by 304 · cited 1× · see citing works
“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).”
BackgroundPlumb, J., McQuaid, S., Mirakhur, M., & Kirk, J. (2002) · Brain Pathology · doi:10.1111/j.1750-3639.2002.tb00430.x · Cited by 274 · cited 2× · see citing works
“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…”
BackgroundThe risk of relapses in multiple sclerosis during systemic infections
Correale, J. D., Fiol, M. P., & Gilmore, W. (2006) · Neurology · doi:10.1212/01.wnl.0000233834.09743.3b · Cited by 273 · cited 1× · see citing works
“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).”
BackgroundLarsson, H., Courivaud, F., Rostrup, E., & Hansen, A. E. (2009) · Magnetic Resonance in Medicine · doi:10.1002/mrm.22136 · Cited by 236 · cited 1× · see citing works
“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).”
MethodSelf-citationPathogenesis of multiple sclerosis
ffrench‐Constant, C. (1994) · The Lancet · doi:10.1016/s0140-6736(94)91118-5 · Cited by 227 · see citing works
A serial study of new MS lesions and the white matter from which they arise
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“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).”
BackgroundVos, C. M. P., Geurts, J. J. G., Montagne, L., van Haastert, E. S., Bö, L., van der Valk, P., Barkhof, F., & de Vries, H. E. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.06.012 · Cited by 188 · cited 2× · see citing works
“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…”
BackgroundPakpoor, J., Disanto, G., Gerber, J. E., Dobson, R., Meier, U., Giovannoni, G., & Ramagopalan, S. (2013) · Multiple Sclerosis · doi:10.1177/1352458512449682 · Cited by 179 · cited 2× · see citing works
“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.”
ResultIngrisch, M., Sourbron, S., Morhard, D., Ertl-Wagner, B., Kümpfel, T., Hohlfeld, R., Reiser, M., & Glaser, C. (2012) · Investigative Radiology · doi:10.1097/rli.0b013e31823bfc97 · Cited by 106 · cited 4× · see citing works
“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).”
BackgroundMethodResultInfluentialMR properties of rat sciatic nerve following trauma
Stanisz, G. J., Midha, R., Munro, C. A., & Henkelman, R. M. (2001) · Magnetic Resonance in Medicine · doi:10.1002/1522-2594(200103)45:3 · Cited by 95 · see citing works
Casiraghi, C., Dorovini‐Zis, K., & Horwitz, M. S. (2010) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2010.08.003 · Cited by 87 · cited 2× · see citing works
“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).”
BackgroundResultLarsson, H., Hansen, A. E., Berg, H., Rostrup, E., & Haraldseth, O. (2008) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.21328 · Cited by 84 · cited 1× · see citing works
“The DCE MRI data was analyzed with a semi-automatic procedure (Larsson et al., 2008) using in-house MatLab-based software.”
MethodSelf-citationSimplified, noninvasive PET measurement of blood-brain barrier permeability.
Iannotti, F., Fieschi, C., Alfano, B., Picozzi, P., Mansi, L., Pozzilli, C., Punzo, A., del Vecchio, G., Lenzi, G. L., & Salvatore, M. (1987) · Journal of computer assisted tomography · doi:10.1097/00004728-198705000-00004 · Cited by 80 · cited 1× · see citing works
“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).”
ResultInfluentialNgono, A. E., Pettré, S., Salou, M., Bahbouhi, B., Soulillou, J., Brouard, S., & Laplaud, D. A. (2012) · Clinical Immunology · doi:10.1016/j.clim.2012.05.009 · Cited by 77 · see citing works
Silver, N., Tofts, P., Symms, M., Barker, G. J., Thompson, A., & Miller, D. (2001) · Multiple Sclerosis · doi:10.1177/135245850100700201 · Cited by 76 · cited 5× · see citing works
“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).”
BackgroundResultInfluentialMultiple sclerosis. Observations and reflections--a personal memoir.
Poser, C. (1992) · Journal of Neurological Sciences · doi:10.1016/0022-510x(92)90280-x · Cited by 75 · cited 1× · see citing works
“The large body of evidence supporting BBB dysfunction in MS is reviewed in detail elsewhere (Poser, 1986, 1992, 2004) with two main points.”
BackgroundThe effects of blood–brain barrier disruption on glial cell function in multiple sclerosis
McQuaid, S., Cunnea, P., McMahon, J. M., & FitzGerald, U. (2009) · Biochemical Society Transactions · doi:10.1042/bst0370329 · Cited by 69 · cited 2× · see citing works
“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…”
BackgroundInitial clinical evaluation of gadolinium DTPA for contrast-enhanced magnetic resonance imaging.
Runge, V. M., Schoerner, W., Niendorf, H., Laniado, M., Koehler, D., Claussen, C., Felix, R., & James, A. E. (1985) · Magnetic Resonance Imaging · doi:10.1016/0730-725x(85)90006-2 · Cited by 62 · cited 1×
“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).”
BackgroundOwens, G. P., & Bennett, J. L. (2012) · Multiple Sclerosis Journal · doi:10.1177/1352458512448109 · Cited by 58 · cited 3× · see citing works
“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.”
BackgroundResultHansen, A. E., Pedersen, H., Rostrup, E., & Larsson, H. (2009) · Magnetic Resonance in Medicine · doi:10.1002/mrm.22098 · Cited by 50 · see citing works
Self-citationKraus, J., Voigt, K., Schuller, A., Scholz, M., Kim, K., Schilling, M., Schäbitz, W., Oschmann, P., & Engelhardt, B. (2008) · Multiple Sclerosis · doi:10.1177/1352458508088940 · Cited by 50 · cited 1× · see citing works
“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).”
BackgroundThe role of trauma in the pathogenesis of multiple sclerosis: a review.
Poser, C. (1994) · Clinical neurology and neurosurgery (Dutch-Flemish ed. Print) · doi:10.1016/0303-8467(94)90042-6 · Cited by 50 · cited 1× · see citing works
“Even trauma and certain chemical effects seem to be able to initiate the plaque forming process in some MS cases (Poser, 1994).”
BackgroundDetection of viral DNA sequences in the cerebrospinal fluid of patients with multiple sclerosis
Mancuso, R., Hernis, A., Cavarretta, R., Caputo, D., Calabrese, E., Nemni, R., Ferrante, P., Delbue, S., & Clerici, M. (2010) · Journal of Medical Virology · doi:10.1002/jmv.21764 · Cited by 49 · cited 1×
“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).”
BackgroundTofts, P. (1996) · Magnetic Resonance Imaging · doi:10.1016/0730-725x(96)00023-9 · Cited by 38 · cited 1× · see citing works
“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).”
ResultSoon, D., Altmann, D., Fernando, K., Giovannoni, G., Barkhof, F., Polman, C., O'Connor, P., Gray, B., Panzara, M., & Miller, D. H. (2007) · Journal of Neurology · doi:10.1007/s00415-006-0356-z · Cited by 34 · cited 1× · see citing works
“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).”
ResultLund, H., Krakauer, M., Skimminge, A., Sellebjerg, F. T., Garde, E., Siebner, H. R., Paulson, O. B., Hesse, D., & Hanson, L. G. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056375 · Cited by 32 · cited 5× · see citing works
“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).”
BackgroundResultInfluentialMultiple sclerosis trait: the premorbid stage of multiple sclerosis. A hypothesis
Poser, C. (2004) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.2004.00277.x · Cited by 24 · cited 1×
“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).”
Background
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Research works printed but not linked: 2
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- van Osch M.J. Vonken E.J. Bakker C.J. Viergever M.A. Correcting partial volume artifacts of the arterial input function in quantitative cerebral perfusion MRI Magn. Reson. Med. 45 2001 477 485 11241707
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Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders
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Blood-Brain Barrier: From Physiology to Disease and Back
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“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).”
The role of brain vasculature in neurodegenerative disorders
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“…(Starr et al., 2003), vascular cognitive impairment (Taheri et al., 2011a), normal-appearing and lesion tissue in multiple sclerosis patients (Cramer et al., 2014; Taheri et al., 2011b), mild cognitive impairment (Taheri et al., 2011b), zinc de fi ciency (Noseworthy and Bray, 2000) and small…”
InfluentialRole of the Blood–Brain Barrier in Multiple Sclerosis
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“According to one major theory proposed by Poser in 1986 (10), four elements are required in order to develop MS: a) genetic susceptibility, b) environmental and probably viral immune-mediated event, c) alteration of the BBB function d) myelinoclastic plaqueforming capability in the CNS (19).”
BackgroundRajeev, V., Fann, D. Y., Dinh, Q. N., Kim, H. A., Silva, T. M. D., Lai, M. K. P., Chen, C., Drummond, G. R., Sobey, C. G., & Arumugam, T. V. (2022) · Theranostics · doi:10.7150/thno.68304 · Cited by 314 · see citing works
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“…2015; Taheri et al., 2011a), healthy subjects (Cramer and Larsson, 2014), and in the normalappearing tissue of patients with multiple sclerosis (Cramer et al., 2014), primary brain tumours (Larsson et al., 2009; Sourbron et al., 2009) and acute stroke (Thornhill et al., 2010), involving a…”
BackgroundPatel, J. P., & Frey, B. N. (2015) · Neural Plasticity · doi:10.1155/2015/708306 · Cited by 182 · see citing works
“periventricular normal appearing white matter (NAWM) in patients with MS [63].”
BackgroundCurrent Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis
Lovelace, M. D., Varney, B., Sundaram, G., Franco, N. F., Ng, M. L., Pai, S., Lim, C. K., Guillemin, G. J., & Brew, B. J. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00246 · Cited by 154 · see citing works
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“There is also strong evidence that in diseases such as stroke, brain trauma (17), AD (18, 19), PD (20, 21), and MS (22), peripheral leukocytes, including monocytes, infiltrate the brain and differentiate into effector cells such as macrophages that are found at the site of pathology.”
BackgroundChronic inflammation in multiple sclerosis - seeing what was always there
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“More recent studies acquired at higher field strengths and using more sophisticated kinetic modeling have determined that the Ktrans of healthy BBB is low but not zero and detected differences in MS patients compared to controls (19,26,28) as well as increases during normal aging and in MCI patients(20).”
BackgroundInfluentialCerebral Cavernous Malformation: From Mechanism to Therapy
Snellings, D., Hong, C. C., Ren, A. A., Lopez-Ramirez, M., Girard, R., Srinath, A., Marchuk, D., Ginsberg, M., Awad, I., & Kahn, M. (2021) · Circulation Research · doi:10.1161/circresaha.121.318174 · Cited by 113
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Self-citationCai, Y., Zhang, Y., Leng, S., Ma, Y., Jiang, Q., Wen, Q., Ju, S., & Hu, J. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106426 · Cited by 111 · see citing works
“DCE-MRI studies have similarly established the presence of increased BBB permeability in white matter in MS (Montagne et al., 2015; Cramer et al., 2015; Cramer et al., 2014; Taheri et al., 2011), particularly in active MS lesions (Cramer et al., 2015; Gaitan et al., 2011).”
Blood-brain barrier imaging as a potential biomarker for bipolar disorder progression
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“However, DCE-MRI studies have been used to identify BBB dysfunction in disorders such as multiple sclerosis (Ingrisch et al., 2012; Cramer et al., 2014; Varatharaj, 2019; Haider et al., 2019), stroke (Merali et al., 2017; Kassner et al., 2009; Serlin et al., 2019), brain tumors (Bergamino et al.,…”
MethodBlood brain barrier: A review of its anatomy and physiology in health and disease
Sharif, Y., Jumah, F., Coplan, L., Krosser, A., Sharif, Κ., & Tubbs, R. S. (2018) · Clinical Anatomy · doi:10.1002/ca.23083 · Cited by 143 · see citing works
“These effects could be due to the disease itself or to side effects of immunomodulatory treatments (Cramer et al. 2014).”
Blood-brain barrier hyperpermeability precedes demyelination in the cuprizone model
Berghoff, S. A., Düking, T., Spieth, L., Winchenbach, J., Stumpf, S. K., Gerndt, N., Kusch, K., Ruhwedel, T., Möbius, W., & Saher, G. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0497-6 · Cited by 100 · see citing works
“MS is an acquired inflammatory demyelinating disease of the CNS in which BBB permeability is increased in both newly forming demyelinating lesions and even in normal appearing white matter [18, 59].”
Approaches to CNS Drug Delivery with a Focus on Transporter-Mediated Transcytosis
Razzak, R. A., Florence, G. J., & Gunn‐Moore, F. J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20123108 · Cited by 115 · see citing works
Cramer, S. P., Modvig, S., Simonsen, H. J., Frederiksen, J. L., & Larsson, H. B. W. (2015) · Brain · doi:10.1093/brain/awv203 · Cited by 94 · see citing works
“We used an axial T2weighted MRI sequence [five slices, echo time = 100 ms, repetition time = 3000 ms, acquired voxel-size 0.57/0.76/8 mm3 (interpolated to 0.45/0.45/8 mm3), field of view = 230 119 mm2] with same orientation and slice thickness (8 mm) as our DCE-MRI sequence, in order to manually…”
BackgroundMethodInfluentialSelf-citationMiller, E. D., Dziedzic, A., Saluk, J., & Bijak, M. (2019) · Nutrients · doi:10.3390/nu11071528 · Cited by 103 · see citing works
“, endothelial cells, microglia, astrocytes, and pericytes) [9].”
Advances in the immunopathogenesis of multiple sclerosis
Yadav, S. K., Mindur, J. E., Ito, K., & Dhib-Jalbut, S. S. (2015) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000205 · Cited by 166 · see citing works
Vascular Permeability in Cerebral Cavernous Malformations
Mikati, A., Khanna, O., Zhang, L.-J., Girard, R., Shenkar, R., Guo, X., Shah, A., Larsson, H., Tan, H., Li, L., et al. (2015) · Journal of Cerebral Blood Flow and Metabolism · doi:10.1038/jcbfm.2015.98 · Cited by 90
Self-citationDosSantos, M. F. H., Afonso, R. C. D. H., de Lima, R. L., DaSilva, A. F. M., & Moura‐Neto, V. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00302 · Cited by 94 · see citing works
“…a concept that is supported not only by experimental (Morrissey et al., 1996; Morgan et al., 2007; Kooij et al., 2009; Reijerkerk et al., 2012) but also clinical data (Plumb et al., 2002; Kirk et al., 2003; Minagar and Alexander, 2003; Leech et al., 2007; Padden et al., 2007; Cramer et al., 2014).”
BackgroundWang, Y., Wu, J., Wang, J.-X., He, L.-X., Lai, H., Zhang, T., Wang, X., & Li, W. (2023) · Mitochondrion (Amsterdam. Print) · doi:10.1016/j.mito.2023.01.007 · Cited by 80 · see citing works
Varatharaj, A., Liljeroth, M., Darekar, A., Larsson, H. B. W., Galea, I., & Cramer, S. P. (2018) · The Journal of Physiology · doi:10.1113/jp276887 · Cited by 88 · see citing works
“Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a newer technique which can measure all levels of BBB leakiness, including levels invisible to conventional imaging (Cramer et al. 2014).”
BackgroundResultInfluentialSelf-citationCladribine: mechanisms and mysteries in multiple sclerosis
Jacobs, B., Ammoscato, F., Giovannoni, G., Baker, D., & Schmierer, K. (2018) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2017-317411 · Cited by 78 · see citing works
Uchida, Y., Kan, H., Sakurai, K., Oishi, K., & Matsukawa, N. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1111448 · Cited by 70 · see citing works
“, 2013), multiple sclerosis (Gaitán et al., 2011; Jelescu et al., 2011; Shinohara et al., 2011; Ingrisch et al., 2012; Cramer et al., 2014), and ischemic strokes (Kassner et al.”
BackgroundFrom Neurodevelopmental to Neurodegenerative Disorders: The Vascular Continuum
Ouellette, J., & Lacoste, B. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.749026 · Cited by 87 · see citing works
In vivo methods for imaging blood–brain barrier function and dysfunction
Harris, W. J., Asselin, M., Hinz, R., Parkes, L. M., Allan, S. M., Schießl, I., Boutin, H., & Dickie, B. (2022) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-022-05997-1 · Cited by 87 · see citing works
Antipsychotic drugs counteract autophagy and mitophagy in multiple sclerosis
Patergnani, S., Bonora, M., Ingusci, S., Previati, M., Marchi, S., Zucchini, S., Perrone, M., Wieckowski, M. R., Castellazzi, M., Pugliatti, M., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2020078118 · Cited by 77 · see citing works
“We found that this marker was increased in MS patients in the active phase of the disease (13, 14), identified on response to Gadolinium (Gd) (28).”
BackgroundYang, H. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17081041 · Cited by 70 · see citing works
“Similarly, neuroinflammation in multiple sclerosis and PD increases BBB permeability through inflammatory mediator release [37,38].”
Advanced Neuroimaging of Cerebral Small Vessel Disease
Blair, G. W., Hernandez, M. V., Thrippleton, M., Doubal, F., & Wardlaw, J. (2017) · Current Treatment Options in Cardiovascular Medicine · doi:10.1007/s11936-017-0555-1 · Cited by 70 · see citing works
“Several groups have reported on the pitfalls and limitations of the technique, and the results of which should be interpreted with caution [78, 82 – 84].”
BackgroundKamintsky, L., Beyea, S., Fisk, J., Hashmi, J., Omisade, A., Calkin, C., Bardouille, T., Bowen, C., Quraan, M., Mitnitski, A., et al. (2020) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2020-218004 · Cited by 69 · see citing works
Li, Y., Li, M., Zuo, L., Shi, Q.-L., Qin, W., Yang, L., Jiang, T., & Hu, W.-L. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00221 · Cited by 68 · see citing works
“Regions of Interest We used an axial T2 FLAIR MRI sequence with the same orientation and slice thickness as our DCE sequence to manually draw ROIs in the NAWM, WMH, CGM, and DGM in both hemispheres (Figure 1) (16).”
MethodIntact blood−brain barrier during spontaneous attacks of migraine without aura: a 3T DCE‐MRI study
Amin, F., Hougaard, A., Cramer, S., Christensen, C., Wolfram, F., Larsson, H., & Ashina, M. (2017) · European Journal of Neurology · doi:10.1111/ene.13341 · Cited by 66 · see citing works
“The standard deviation (30%) for the Ki in our power calculation was based on results from three previous studies using the same DCE-MRI method including a total of 125 subjects (healthy controls and patients with multiple sclerosis and optic neuritis) [11,17,18].”
BackgroundMethodInfluentialSelf-citationYu, Z., Xue, F., Liu, W., Sun, R. X., Zhou, J., Pu, Y., Zhao, M., Sun, D., Xiang, Z., Liu, P., et al. (2022) · Advanced Science · doi:10.1002/advs.202105442 · Cited by 68 · see citing works
Uher, T., Horáková, D., Týblová, M., Zeman, D., Krasulová, E., Mrázová, K., Seidl, Z., Vaněčková, M., Krásenský, J., Weinstock‐Guttman, B., et al. (2015) · Multiple Sclerosis Journal · doi:10.1177/1352458515601903 · Cited by 56 · see citing works
How does neurovascular unit dysfunction contribute to multiple sclerosis?
Cashion, J. M., Young, K. M., & Sutherland, B. A. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106028 · Cited by 57 · see citing works
“It is well established that the BBB becomes compromised and leaky in multiple sclerosis, resulting in immune cell infiltration into the brain parenchyma (Cramer et al., 2014; Montagne et al., 2015).”
Remyelination in multiple sclerosis: Cellular mechanisms and novel therapeutic approaches
Olsen, J. A., & Akirav, E. M. (2014) · Journal of Neuroscience Research · doi:10.1002/jnr.23493 · Cited by 48 · see citing works
“, 2011) as a result of increased permeabilization of the blood–brain barrier, observable by dynamic contrastenhanced magnetic resonance imaging (MRI; Cramer et al., 2013), and produce an autoimmune response to various myelin and nonmyelin antigens (Kerlero de Rosbo et al.”
BackgroundRegulatory T cell therapy for multiple sclerosis: Breaching (blood-brain) barriers
Verreycken, J., Baeten, P., & Broux, B. (2022) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2022.2153534 · Cited by 58 · see citing works
“This leads to a compromised migration of these Th1 cells in the CNS. Additionally, with the expansion of Tregs, the BBB was limitedly damaged and remained more intact, indicating a Treg-driven protective effect on the BBB. Enhancement of Tregs also decreases the migration of mast cells through the BBB via a down-regul…”
BackgroundInfluentialInsulin Resistance and Blood-Brain Barrier Dysfunction Underlie Neuroprogression in Bipolar Disorder
Calkin, C., McClelland, C., Cairns, K., Kamintsky, L., & Friedman, A. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.636174 · Cited by 46 · see citing works
“Recent advances in MRI techniques have allowed direct assessment of BBB functionality in living patients, demonstrating BBBD in pathological conditions such as traumatic and ischemic injuries (86, 87), epilepsy (77), dementia (78) multiple sclerosis (79), and systemic lupus erythematosus (SLE) (75).”
BackgroundHouston, Z., Bunt, J., Chen, K.-S., Puttick, S., Howard, C. B., Fletcher, N., Fuchs, A., Cui, J.-W., Ju, Y., Cowin, G., et al. (2020) · ACS Central Science · doi:10.1021/acscentsci.9b01299 · Cited by 47 · see citing works
Role of proteoglycans in neuro-inflammation and central nervous system fibrosis
Heindryckx, F., & Li, J. (2018) · Matrix Biology · doi:10.1016/j.matbio.2018.01.015 · Cited by 50 · see citing works
Bester, M., Forkert, N., Stellmann, J., Aly, L., Drabik, A., Young, K., Heesen, C., Fiehler, J., & Siemonsen, S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119356 · Cited by 46 · see citing works
“Cramer et al [44] investigated the integrity of the BBB and describe a gradual decrease of permeability after an MS relapse.”
Loss of corticospinal tract integrity in early MS disease stages
Pawlitzki, M., Neumann, J. H. L., Kaufmann, J., Heidel, J., Stadler, E., Sweeney‐Reed, C. M., Sailer, M., & Schreiber, S. (2017) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000000399 · Cited by 48 · see citing works
“FA andMD values could thus serve as alternative markers of inflammation, probably indicating ongoing demyelination(24) and predicting new relapses.(25) DTI measures could thus have the potential to serve as a biomarker disclosing ongoing (inflammatory) disease activity, especially in secondary or primary progressive M…”
BackgroundCGRP and Brain Functioning: Cautions for Migraine Treatment
Borkum, J. (2019) · Headache · doi:10.1111/head.13591 · Cited by 43 · see citing works
“This might be relevant clinically for people with MS, a condition in which the prevalence of migraines is three times greater than in the general population,(129) and in which the BBB is compromised for up to several months after a flare-up.(77) As we have seen, CGRP, injected into a cerebral ventricle, reduces diseas…”
BackgroundXu, Z., Zeng, W., Sun, J., Chen, W., Zhang, R., Yang, Z., Yao, Z., Wang, L., Song, L., Chen, Y., et al. (2016) · NeuroImage · doi:10.1016/j.neuroimage.2016.07.017 · Cited by 46 · see citing works
Imaging blood–brain barrier disruption in neuroinflammation and Alzheimer’s disease
Lee, R., & Funk, K. E. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1144036 · Cited by 40 · see citing works
Direct Estimation of Tracer-Kinetic Parameter Maps from Highly Undersampled Brain DCE-MRI
Guo, Y., Lingala, S., Zhu, Y.-H., Lebel, R., & Nayak, K. (2016) · Magnetic Resonance in Medicine · doi:10.1002/mrm.26540 · Cited by 41 · see citing works
Hecker, M., Bühring, J., Fitzner, B., Rommer, P. S., & Zettl, U. K. (2021) · Biomolecules · doi:10.3390/biom11101510 · Cited by 48 · see citing works
“Key steps in the pathogenesis of MS are presumably the peripheral expansion of autoreactive immune cells, the breakdown of the blood–brain barrier [56], the infiltration of activated cells into the CNS and the subsequent generation of”
BackgroundSphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation
Roggeri, A., Schepers, M., Tiane, A., Rombaut, B., van Veggel, L., Hellings, N., Prickaerts, J., Pittaluga, A., & Vanmierlo, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207537 · Cited by 40 · see citing works
“Alterations of tight junction proteins [35–37] and the consequent increased BBB permeability, ease the passage of autoreactive T-cells towards the CNS [35,38].”
BackgroundPro-Thrombotic Activity of Blood Platelets in Multiple Sclerosis
Saluk, J., Dziedzic, A., & Bijak, M. (2019) · Cells · doi:10.3390/cells8020110 · Cited by 42 · see citing works
Charabati, M., Zandee, S., Fournier, A. P., Tastet, O., Thai, K., Zaminpeyma, R., Lécuyer, M., Bourbonnière, L., Larouche, S., Klément, W., et al. (2022) · Brain · doi:10.1093/brain/awac389 · Cited by 45 · see citing works
“Its junctional integrity is disturbed and it becomes permeable to circulating macromolecules.(2,4,5) In the clinic, CNS vascular breakdown is”
BackgroundKluge, A., Lukas, M., Tóth, V., Pyka, T., Zimmer, C., & Preibisch, C. (2016) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2015.12.015 · Cited by 37 · see citing works
“Previous studies with dynamic contrast-enhanced MRI [15,22] suggest that even in healthy tissue a small amount of leakage can occur.”
BackgroundResultCommon comorbidities and survival in MS: Risk for stroke, type 1 diabetes and infections.
Murtonen, A., Kurki, S., Hänninen, K., Soilu-Hänninen, M., & Sumelahti, M. (2018) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2017.10.019 · Cited by 37 · see citing works
Morel, A., Miller, E. D., Bijak, M., & Saluk, J. (2016) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-016-2770-6 · Cited by 40 · see citing works
“MS is considered as a heterogeneous neurological disease with various pathophysiological mechanisms and multiple clinical course, but closely related to the damage of intracerebral blood vessels, mainly as a result of increased permeability of blood–brain barrier (BBB) as well vessel occlusion [2].”
BackgroundBlood-brain barrier and bilirubin: clinical aspects and experimental data.
Brito, M., Palmela, I., Cardoso, F., Sá-Pereira, I., & Brites, D. (2014) · Archives of Medical Research · doi:10.1016/j.arcmed.2014.11.015 · Cited by 36 · see citing works
Wengler, K., Bangiyev, L., Canli, T., Duong, T., Schweitzer, M., & He, X. (2019) · NeuroImage · doi:10.1016/j.neuroimage.2019.01.035 · Cited by 34 · see citing works
“This could lead to a better understanding of the pathogenesis of some diseases, such as multiple sclerosis and Alzheimer's disease, where females show higher prevalence than males (Janelidze et al., 2017; Wilson et al., 2008; Cramer et al., 2014).”
Aspirin and multiple sclerosis
Tsau, S., Emerson, M. R., LYNCH, S. G., & LeVine, S. M. (2015) · BMC Medicine · doi:10.1186/s12916-015-0394-4 · Cited by 31 · see citing works
“However, the slight risk of increased intracerebral bleeding observed in stroke patients given ASA [79] is troubling, since MS patients have a compromised BBB [7, 8] and ASA treatment could further disrupt the BBB (Table 2).”
BackgroundInfluentialMa, X.-X., Zhang, L., Huang, D.-H., Lyu, J., Fang, M., Hu, J.-X., Zang, Y.-L., Zhang, D.-K., Shao, H., Ma, L., et al. (2018) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.26287 · Cited by 33 · see citing works
“Lesions were selected if the lesion diameter was greater than 3 mm in the slice with the largest cross-section, and if the lesion was in the periventricular, juxtacortical, or infratentorial regions, or the subcortical white or deep gray matter.(28) Axial T1WI and coronal T2 FLAIR imaging were used to identify and del…”
MethodEisen, A., Greenberg, B., Bowen, J., Arnold, D., & Caggiano, A. (2017) · Multiple Sclerosis Journal - Experimental, Translational and Clinical · doi:10.1177/2055217317743097 · Cited by 33 · see citing works
Therapeutic perspective on vascular cognitive impairment
Toyama, K., Spin, J. M., Mogi, M., & Tsao, P. S. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104266 · Cited by 31 · see citing works
Hemostasis biomarkers in multiple sclerosis
Ziliotto, N., Bernardi, F., Jakimovski, D., Baroni, M., Marchetti, G., Bergsland, N., Ramasamy, D., Weinstock-Guttman, B., Schweser, F., Zamboni, P., et al. (2018) · European Journal of Neurology · doi:10.1111/ene.13681 · Cited by 32 · see citing works
“The pathogenesis of MS involves blood–brain barrier (BBB) breakdown, extravasation of immune cells, inflammation and neurodegeneration in the CNS, which results in the formation of lesions and development of brain atrophy [2].”
BackgroundInflammation-induced TRPV4 channels exacerbate blood–brain barrier dysfunction in multiple sclerosis
Hansen, C. E., Kamermans, A., Mol, K., Berve, K., Rodriguez-Mogeda, C., Fung, W. K., Hof, B. V. H., Fontijn, R. D., van der Pol, S. M. A., Michalick, L., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03069-9 · Cited by 33 · see citing works
“Hence, BBB dysfunction and inflammation are driving events in MS lesion formation, which presents a mandate for elucidating the underlying mechanisms of these processes [16, 17].”
BackgroundKim, Y. S., Kim, M., Choi, S.-H., You, S.-H., Yoo, R.-E., Kang, K. M., Yun, T., Lee, S.-T., Moon, J., & Shin, Y. (2019) · Radiology · doi:10.1148/radiol.2019182566 · Cited by 31
Kamrava, M., Sepahdari, A., Leu, K., Wang, P.-C., Roberts, K., Demanes, D., Mccannel, T., & Ellingson, B. (2015) · Neuroradiology · doi:10.1007/s00234-015-1546-0 · Cited by 31
Bäumer, P., Reimann, M., Decker, C., Radbruch, A., Bendszus, M., Heiland, S., & Pham, M. (2014) · Investigative Radiology · doi:10.1097/rli.0000000000000046 · Cited by 31
Wei, Z., Liu, H., Lin, Z., Yao, M., Li, R., Liu, C., Li, Y., Xu, J., Duan, W., & Lu, H. (2023) · NeuroImage · doi:10.1016/j.neuroimage.2023.119870 · Cited by 36 · see citing works
Huang, J., Han, S. H., Sun, Q., Zhao, Y., Liu, J., Yuan, X., Mao, W., Peng, B., Liu, W., Yin, J., et al. (2017) · Cell & Bioscience · doi:10.1186/s13578-017-0158-2 · Cited by 33 · see citing works
“Increased BBB permeability is the hallmark of acute inflammatory lesions in MS patients [12], and appears in the periventricular normal-appearing white matter of MS patients using dynamic contrast-enhanced MRI imaging [32].”
Larsson, H. B. W., Vestergaard, M. B., Lindberg, U., Iversen, H. K., & Cramer, S. P. (2016) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.25488 · Cited by 31 · see citing works
“It has previously been demonstrated that subtle leakage can be measured in healthy subjects, and a higher but still small leakage can be measured in periventricular normal appearing white matter in patients with multiple sclerosis and patients with optic neuritis.(10,26) In patients with brain tumors, leakage is often…”
BackgroundSelf-citationGuo, Y., Lebel, R., Zhu, Y.-H., Lingala, S., Shiroishi, M., Law, M., & Nayak, K. (2016) · Medical Physics (Lancaster) · doi:10.1118/1.4944736 · Cited by 29 · see citing works
Novel MRI and PET markers of neuroinflammation in multiple sclerosis
Hagens, M. H. J., van Berckel, B. N. M., & Barkhof, F. (2016) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000326 · Cited by 29 · see citing works
Bakhtiari, A., Vestergaard, M. B., Benedek, K., Fagerlund, B., Mortensen, E. L., Osler, M., Lauritzen, M., Larsson, H. B. W., & Lindberg, U. (2022) · GeroScience · doi:10.1007/s11357-022-00712-2 · Cited by 25 · see citing works
Self-citationFang, K., Wang, Z., Li, Z.-Q., Wang, B.-J., Han, G., Cheng, Z.-W., Chen, Z.-H., Lan, C., Zhang, Y., Zhao, P., et al. (2020) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.27495 · Cited by 27 · see citing works
“3 As the contrast agent (CA) enters and subsequently leaves the tissue, different tissues produce unique intensity time curves.”
BackgroundMethodNatural products: Potential therapeutic agents in multiple sclerosis
Yu, S., Liu, M., & Hu, K. (2018) · International Immunopharmacology · doi:10.1016/j.intimp.2018.11.036 · Cited by 31 · see citing works
Popa, A., Stan, G. E., Beşleagă, C., Ion, L., Maraloiu, V., Tulyaganov, D. U., & Ferreira, J. M. F. (2016) · ACS Applied Materials and Interfaces · doi:10.1021/acsami.6b00606 · Cited by 27 · see citing works
Nichols, P., Urriola, J., Miller, S., Bjorkman, T., Mahady, K., Vegh, V., Nasrallah, F., & Winter, C. (2021) · NeuroImage: Clinical · doi:10.1016/j.nicl.2021.102741 · Cited by 26 · see citing works
“It has been shown that in normal-appearing GM and WM, the K value is low but not zero [26-28].”
Safety and efficacy of cladribine in multiple sclerosis: a systematic review and meta-analysis
Nabizadeh, F., Mohamadi, M., Rahmani, S., Rajabi, R., Afrashteh, F., Najdaghi, S., & Mirmosayyeb, O. (2023) · Neurological Sciences · doi:10.1007/s10072-023-06794-w · Cited by 25
“However, with blood–brain barrier (BBB) disruption as a common pathological finding at all MS disease stages, cladribine can penetrate better to the CNS of MS patients [55–57].”
Mokhtarzade, M., Motl, R., Negaresh, R., Zimmer, P., Khodadoost, M., Baker, J., Patel, D. I., Majdinasab, N., & Ranjbar, R. (2018) · Neuropeptides · doi:10.1016/j.npep.2018.05.010 · Cited by 25 · see citing works
Elevated plasma fibrinogen levels in multiple sclerosis patients during relapse
Acuña, J. A. S., de la Cruz, M. H., Ros, A. L., Prasca, S., Ginés, M. L. M., & Frutos, C. D. D. A. (2017) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2017.09.033 · Cited by 23 · see citing works
Li, H.-P., Liu, X., Wang, R., Lu, A.-L., Ma, Z., Wu, S., Lu, H.-J., Du, Y., Deng, K., Wang, L.-X., et al. (2023) · Epilepsia · doi:10.1111/epi.17576 · Cited by 23 · see citing works
Developing a transwell millifluidic device for studying blood–brain barrier endothelium
Harding, I. C., O’Hare, N. R., Vigliotti, M., Caraballo, A., Lee, C. I., Millican, K., Herman, I. M., & Ebong, E. E. (2022) · Lab on a Chip · doi:10.1039/d2lc00657j · Cited by 27 · see citing works
Hanly, J., Legge, A., Kamintsky, L., Friedman, A., Hashmi, J., Beyea, S., Fisk, J., Omisade, A., Calkin, C., Bardouille, T., et al. (2022) · Lupus Science and Medicine · doi:10.1136/lupus-2022-000668 · Cited by 22 · see citing works
Choi, S., Saxena, N., Dhammu, T. S., Khan, M., Singh, A. K., Singh, I., & Won, J. (2018) · Nitric Oxide · doi:10.1016/j.niox.2018.12.007 · Cited by 20 · see citing works
“Brain imaging studies have shown that patients with relapsing-remitting MS (RRMS), the most common type of MS (> 80 %), have generally increase in BBB permeability [60; 61].”
BackgroundNotch signaling is impaired during inflammation in a Lunatic Fringe-dependent manner
Troletti, C. D., Pinheiro, M. A. L., Charabati, M., Gowing, E., Hof, B. V. H., van der Pol, S. M. A., Geerts, D., Prat, A., Fontijn, R. D., Unger, W. W. J., et al. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.12.016 · Cited by 25 · see citing works
“In addition, reduced brain endothelial cell-cell contacts and BBB dysfunction have been suggested to result in the leakage of serum components into the CNS thereby contributing to MS pathogenesis (Cramer et al., 2014; Kirk et al., 2003; Leech et al., 2007; Plumb et al., 2002).”
Guo, Y., Lingala, S., Bliesener, Y., Lebel, R., Zhu, Y.-H., & Nayak, K. (2017) · Magnetic Resonance in Medicine · doi:10.1002/mrm.26904 · Cited by 22 · see citing works
Ingrisch, M., Sourbron, S., Herberich, S., Schneider, M., Kümpfel, T., Hohlfeld, R., Reiser, M., & Ertl-Wagner, B. (2016) · Investigative Radiology · doi:10.1097/rli.0000000000000320 · Cited by 22 · see citing works
“These results are not in line with previous reports that studied NAWMperfusion in MS. Early nuclear medicine studies1–3 have found a significantly reduced CBF in patients with MS.”
ResultInfluentialRicciardelli, A., Robledo, A., Fish, J. E., Kan, P. T. M., Harris, T. H., & Wythe, J. D. (2023) · Biomedicines · doi:10.3390/biomedicines11112876 · Cited by 22 · see citing works
“…hypoperfusion) can precede cognitive decline and clinical symptoms in numerous neurological pathologies [106], including aging, multiple sclerosis [107–109], stroke, Alzheimer’s [110–114], and epilepsy, with the disruption of vascular function in the CNS causing ion disturbance, edema, and…”
BackgroundPansieri, J., Hadley, G., Lockhart, A., Pisa, M., & DeLuca, G. C. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1199491 · Cited by 20 · see citing works
Kovbasyuk, Z., Tefera, E., Li, C., Baete, S. H., & Steriade, C. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03598-x · Cited by 23 · see citing works
“Reports of higher K i in NAWM of RRMS patients compared to WM from HCs, suggests that DCE-MRI can detect subtle BBB abnormalities typically identified only histologically [2, 106].”
The blood–brain barrier as a treatment target for neurodegenerative disorders
Rust, R., Sagare, A. P., Zhang, M., Zloković, B. V., & Kisler, K. (2025) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2025.2480654 · Cited by 20 · see citing works
“Likewise, changes in BBB permeability and incidence of cerebral microbleeds (brain vascular microhemorrhages) have been reported in patients with HD [51,52], PD [53–55], and MS [56–58].”
- Authors
- Cramer, S. P., Simonsen, H., Frederiksen, J. L., Rostrup, E., & Larsson, H. B. W.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Cramer, S.P.
- Venue
- NeuroImage: Clinical
- Publisher
- Elsevier BV
- Published
- 2014
- Volume
- 4
- Pages
- 182-189
- ISSN
- 2213-1582 (ISSN-L)
- PMC
- PMC3872721
- OpenAlex
- W2039561850
- Cited by
- 232
- References
- 37
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 16 · 2023: 20 · 2022: 24 · 2021: 16 · 2020: 14 · 2019: 20 · 2018: 26 · 2017: 13 · 2016: 16 · 2015: 21 · 2014: 9 · 2012: 1
- FWCI
- 11.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- NeuroImage Clinical (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- BIBSYS Brage (BIBSYS (Norway)) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by-nc-sa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Biogen
- Scleroseforeningen (14588)
- Multiple Sclerosis Society (14588)
- Region Hovedstaden
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- multiple sclerosis, blood-brain barrier permeability, normal-appearing white matter, periventricular white matter, dynamic contrast-enhanced MRI, MS relapse, immunomodulatory therapy, MS lesions, blood-brain barrier disruption
- MeSH terms
- Adult, Blood-Brain Barrier, Capillary Permeability, Contrast Media, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Severity of Illness Index, Imaging, Three-Dimensional, Perfusion Imaging, White Matter
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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