Measurement of Blood-Brain Barrier Permeability in Multiple Sclerosis

  • D. Soon
  • D. Miller
Part of the Topics in Neuroscience book series (TOPNEURO)


The concept of a barrier between the blood and the brain first arose in the late nineteenth century, when German bacteriologist Paul Ehrlich, discovered that aniline dyes injected intravenously into small animals stained all their organs except for the brain. The concept was developed further by his student, Goldman, who in 1905 demonstrated that tryptan blue injected intrathecally, but not intravenously, resulted in the staining of brain tissue. In the intervening century, histopathological and radiological investigations have helped shape our understanding of the blood-brain barrier (BBB) in health and in disease. In particular, the involvement of the BBB in neuroinflammation and how its disruption contributes to pathology is the subject of considerable study. This chapter will describe some of the principles and methods employed in the ongoing research making use of gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) to investigate BBB disruption in multiple sclerosis (MS).


Multiple Sclerosis Multiple Sclerosis Patient Magn Reson Image Multiple Sclerosis Lesion Chronic Relapse Experimental Allergic Encephalomyelitis 
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  1. 1.
    Pachter JS, de Vries HE, Fabry Z (2003) The blood-brain barrier and its role in immune privilege in the central nervous system. J Neuropathol Exp Neurol 62:593–604PubMedGoogle Scholar
  2. 2.
    de Vries HE, Kuiper J, de Boer AG et al (1997) The blood-brain barrier in neuroinflammatory diseases. Pharmacol Rev 49:143–155PubMedGoogle Scholar
  3. 3.
    Butt AM, Jones HC, Abbott NJ (1990) Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study. J Physiol 429:47–62PubMedGoogle Scholar
  4. 4.
    Janzer RC, Raff MC (1987) Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325:253–257PubMedCrossRefGoogle Scholar
  5. 5.
    Sobue K, Yamamoto N, Yoneda K et al (1999) Induction of blood-brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neurosci Res 35:155–164PubMedCrossRefGoogle Scholar
  6. 6.
    Abbruscato TJ, Davis TP (1999) Protein expression of brain endothelial cell Ecadherin after hypoxia/aglycemia: influence of astrocyte contact. Brain Res 842:277–286PubMedCrossRefGoogle Scholar
  7. 7.
    Davies DC (2002) Blood-brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 200:639–646PubMedCrossRefGoogle Scholar
  8. 8.
    Povlishock JT, Becker DP, Sullivan HG et al (1978) Vascular permeability alterations to horseradish peroxidase in experimental brain injury. Brain Res 153:223–239PubMedCrossRefGoogle Scholar
  9. 9.
    Clawson CC, Hartmann JF, Vernier RL (1966) Electron microscopy of the effect of gram-negative endotoxin on the blood-brain barrier. J Comp Neurol 127:183–198PubMedCrossRefGoogle Scholar
  10. 10.
    Kuroiwa T, Shibutani M, Okeda R (1988) Blood-brain barrier disruption and exacerbation of ischemic brain edema after restoration of blood flow in experimental focal cerebral ischemia. Acta Neuropathol (Berl) 76:62–70CrossRefGoogle Scholar
  11. 11.
    Berzin TM, Zipser BD, Rafii MS et al (2000) Agrin and microvascular damage in Alzheimer’s disease. Neurobiol Aging 21:349–355PubMedCrossRefGoogle Scholar
  12. 12.
    Mooradian AD (1997) Central nervous system complications of diabetes mellitus -a perspective from the blood-brain barrier. Brain Res Brain Res Rev 23:210–218PubMedCrossRefGoogle Scholar
  13. 13.
    Long DM (1979) Capillary ultrastructure in human metastatic brain tumors. J Neurosurg 51:53–58PubMedCrossRefGoogle Scholar
  14. 14.
    Deng X, Wang X, Andersson R (1995) Endothelial barrier resistance in multiple organs after septic and nonseptic challenges in the rat. J Appl Physiol 78:2052–2061PubMedGoogle Scholar
  15. 15.
    Jeppsson B, Freund HR, Gimmon Z et al (1981) Blood-brain barrier derangement in sepsis: cause of septic encephalopathy? Am J Surg 141:136–142PubMedCrossRefGoogle Scholar
  16. 16.
    Papadopoulos MC, Lamb FJ, Moss RF et al (1999) Faecal peritonitis causes oedema and neuronal injury in pig cerebral cortex. Clin Sci (Lond) 96:461–466CrossRefGoogle Scholar
  17. 17.
    Broman T (1964) Blood-brain barrier damage in multiple sclerosis supravital testobservations. Acta Neurol Scand 40:Suppl 4Google Scholar
  18. 18.
    Adams CW, Poston RN, Buk SJ et al (1985) Inflammatory vasculitis in multiple sclerosis. J Neurol Sci 69:269–283PubMedCrossRefGoogle Scholar
  19. 19.
    Mitchell DG (1997) MR imaging contrast agents -what’s in a name? J Magn Reson Imaging 7:1–4PubMedCrossRefGoogle Scholar
  20. 20.
    Hawkins CP, Munro PM, Mackenzie F et al (1990) Duration and selectivity of blood-brain barrier breakdown in chronic relapsing experimental allergic encephalomyelitis studied by gadolinium-DTPA and protein markers. Brain 113:365–378PubMedCrossRefGoogle Scholar
  21. 21.
    Katz D, Taubenberger JK, Cannella B et al (1993) Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis. Ann Neurol 34:661–669PubMedCrossRefGoogle Scholar
  22. 22.
    Bruck W, Bitsch A, Kolenda H et al (1997) Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol 42:783–793PubMedCrossRefGoogle Scholar
  23. 23.
    Kermode AG, Tofts PS, Thompson AJ et al (1990) Heterogeneity of blood-brain barrier changes in multiple sclerosis: an MRI study with gadolinium-DTPA enhancement. Neurology 40:229–235PubMedCrossRefGoogle Scholar
  24. 24.
    Miller DH, Rudge P, Johnson G et al (1988) Serial gadolinium enhanced magnetic resonance imaging in multiple sclerosis. Brain 111:927–939PubMedCrossRefGoogle Scholar
  25. 25.
    Tortorella C, Codella M, Rocca MA et al (1999) Disease activity in multiple sclerosis studied by weekly triple-dose magnetic resonance imaging. J Neurol 246:689–692PubMedCrossRefGoogle Scholar
  26. 26.
    Cotton F, Weiner HL, Jolesz FA et al (2003) MRI contrast uptake in new lesions in relapsing-remitting MS followed at weekly intervals. Neurology 60:640–646PubMedCrossRefGoogle Scholar
  27. 27.
    Barnes D, Munro PM, Youl BD et al (1991) The longstanding MS lesion. A quantitative MRI and electron microscopic study. Brain 114:1271–1280PubMedCrossRefGoogle Scholar
  28. 28.
    Filippi M, Yousry T, Campi A et al (1996) Comparison of triple dose versus standard dose gadolinium-DTPA for detection of MRI enhancing lesions in patients with MS. Neurology 46:379–384PubMedCrossRefGoogle Scholar
  29. 29.
    Silver NC, Good CD, Barker GI et al (1997) Sensitivity of contrast enhanced MRI in multiple sclerosis. Effects of gadolinium dose, magnetization transfer contrast and delayed imaging. Brain 120:1149–1161PubMedCrossRefGoogle Scholar
  30. 30.
    Silver NC, Tofts PS, Symms MR et al (2001) Quantitative contrast-enhanced magnetic resonance imaging to evaluate blood-brain barrier integrity in multiple sclerosis: a preliminary study. Mult Scler 7:75–82PubMedGoogle Scholar
  31. 31.
    Plumb J, McQuaid S, Mirakhur M et al (2002) Abnormal endothelial tight junctions in active lesions and normal-appearing white matter in multiple sclerosis. Brain Pathol 12:154–169PubMedCrossRefGoogle Scholar
  32. 32.
    Kirk J, Plumb J, Mirakhur M et al (2003) Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination. J Pathol 201:319–327PubMedCrossRefGoogle Scholar
  33. 33.
    Niendorf (1994) Safety and risk of gadolinium-DTPA: extended clinical experience after more than 5,000,000 appliations. Magnevist. Blackwell Scientific Publications, pp5–14Google Scholar
  34. 34.
    Filippi M, Campi A, Dousset V et al (1995) A magnetization transfer imaging study of normal-appearing white matter in multiple sclerosis. Neurology 45:478–482PubMedCrossRefGoogle Scholar
  35. 35.
    Losseff NA, Wang L, Lai HM et al (1996) Progressive cerebral atrophy in multiple sclerosis. A serial MRI study. Brain 119:2009–2019Google Scholar
  36. 36.
    Kidd D, Barker GJ, Tofts PS et al (1997) The transverse magnetisation decay characteristics of longstanding lesions and normal-appearing white matter in multiple sclerosis. I Neurol 244:125–130CrossRefGoogle Scholar
  37. 37.
    Werring DJ, Brassat D, Droogan AG et al (2000) The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis: a serial diffusion MRI study. Brain 123:1667–1676PubMedCrossRefGoogle Scholar
  38. 38.
    Chard DT, Griffin CM, McLean MA et al (2002) Brain metabolite changes in cortical grey and normal-appearing white matter in clinically early relapsing-remitting multiple sclerosis. Brain 125:2342–2352PubMedCrossRefGoogle Scholar
  39. 39.
    Griffin CM, Dehmeshki J, Chard DT et al (2002) Tl histograms of normal-appearing brain tissue are abnormal in early relapsing-remitting multiple sclerosis. Mult Scler 8:211–216PubMedCrossRefGoogle Scholar
  40. 40.
    Kappos L, Moeri D, Radue EW et al (1999) Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis. Gadolinium MRI Meta-analysis Group. Lancet 353:964–969PubMedCrossRefGoogle Scholar
  41. 41.
    Thompson AJ, Kermode AG, Wicks D et al (1991) Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann Neurol 29:53–62PubMedCrossRefGoogle Scholar
  42. 42.
    Tofts PS, Kermode AG (1991) Measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging. 1. Fundamental concepts. Magn Reson Med 17:357–367PubMedCrossRefGoogle Scholar
  43. 43.
    Tofts PS, Brix G, Buckley DL et al (1999) Estimating kinetic parameters from dynamic contrast-enhanced T(l)-weighted MRI of a diffusable tracer: standardized quantities and symbols. J Magn Reson Imaging 10:223–232PubMedCrossRefGoogle Scholar
  44. 44.
    Harris NG, Gauden V, Fraser PA et al (2002) MRI measurement of blood-brain barrier permeability following spontaneous reperfusion in the starch microsphere model of ischemia. Magn Reson Imaging 20:221–230PubMedCrossRefGoogle Scholar
  45. 45.
    Zhu XP, Li KL, Kamaly-Asl ID et al (2000) Quantification of endothelial permeability, leakage space, and blood volume in brain tumors using combined Tl and T2* contrast-enhanced dynamic MR imaging. J Magn Reson Imaging 11:575–585PubMedCrossRefGoogle Scholar
  46. 46.
    Iannotti F, Fieschi C, Alfano B et al (1987) Simplified, noninvasive PET measurement of blood-brain barrier permeability. J Comput Assist Tomogr 11:390–397PubMedCrossRefGoogle Scholar
  47. 47.
    Pozzilli C, Bernardi S, Mansi L et al (1988) Quantitative assessment of blood-brain barrier permeability in multiple sclerosis using 68-Ga-EDTA and positron emission tomography. J Neurol Neurosurg Psychiatry 51:1058–1062PubMedCrossRefGoogle Scholar
  48. 48.
    Parker GJ, Barker GJ, Tofts PS (2001) Accurate multislice gradient echo T(l) measurement in the presence of non-ideal RF pulse shape and RF field nonuniformity. Magn Reson Med 45:838–845PubMedCrossRefGoogle Scholar
  49. 49.
    Ashburner J, Friston K (1997) Multimodal image coregistration and partitioning -a unified framework. Neuroimage 6:209–217PubMedCrossRefGoogle Scholar

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© Springer-Verlag Italia 2004

Authors and Affiliations

  • D. Soon
  • D. Miller

There are no affiliations available

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