Quantification of subtle blood-brain barrier disruption in non-enhancing lesions in multiple sclerosis: a study of disease and lesion subtypes

Abstract

Few attempts have been made to detect subtle blood-brain barrier (BBB) leakage in visibly non-enhancing MRI lesions in multiple sclerosis (MS). For 19 patients, longitudinal relaxation time (T1) maps were generated from MRI scans obtained before, and at 20, 40 and 60 minutes after injection of gadolinium (Gd)-DTPA (0.3 mmol/kg). Regions of interest (ROI) were placed around non-enhancing lesions, and in paired contralateral normal appearing brain tissue (NABT). Post-Gd rate of R1 (=1/T1) rise (ΔR1/Δt), was used to quantify leakage. ΔR1/Δt was greater in lesions than paired NABT (P ≤ 0.001 at all post-Gd timepoints). ΔR1/Δt was greater in T1 hypointense than isointense lesions (P = 0.001 and 0.01 for first and second timepoints respectively), and negatively related to lesion cross sectional area (P ≤ 0.001 at all post-Gd timepoints). Relapsing remitting (RRMS) lesions had a greater initial ΔR1/Δt than secondary progressive (SPMS) lesions ( P = 0.04), but this was not seen in subsequent timepoints. ΔR1/Δt in visibly enhancing lesions was significantly greater than in visibly non-enhancing lesions, with no overlap in the normal ranges of the two populations. Subtle BBB leakage is a consistent feature in non-enhancing lesions, and is distinct from the overt BBB leakage observed in visibly enhancing lesions. It is detectable using quantitative contrast-enhanced MRI. It is apparent in all clinical and lesion subtypes studied, and greater in T1 hypointense and smaller lesions. Larger initial ΔR1/Δt in RRMS than SPMS lesions may reflect differences in blood volume rather than BBB leakage. Multiple Sclerosis 2007; 13: 884—894. http://msj.sagepub.com

Keywords

blood brain barrier multiple sclerosis non-enhancing lesions T1 maps

Get full access to this article

View all access options for this article.

References

de Vries HE , Kuiper J. , de Boer AG , van Berkel TJ , Breimer DD The blood-brain barrier in neuroinflammatory diseases. Pharmacol Rev 1997; 49: 143—55.

Clawson CC , Hartmann JF , Vernier RL Electron microscopy of the effect of gram-negative endotoxin on the blood-brain barrier. J Comp Neurol 1966; 127: 183—98.

Davies DC Blood-brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 2002; 200: 639—46.

Kuroiwa T. , Shibutani M. , Okeda R. Blood-brain barrier disruption and exacerbation of ischemic brain edema after restoration of blood flow in experimental focal cerebral ischemia. Acta Neuropathol (Berl) 1988; 76: 62—70.

Broman T. Blood-brain barrier damage in multiple sclerosis. Supravital test observations . Acta Neurol Scand 1964; 40(Suppl): 4.

Adams CW , Poston RN , Buk SJ , Sidhu YS , Vipond H. Inflammatory vasculitis in multiple sclerosis. J Neurol Sci 1985; 69: 269—83.

Gay D. , Esiri M. Blood-brain barrier damage in acute multiple sclerosis plaques. An immunocytological study. Brain 1991; (Pt1B): 557—572.

Claudio L. , Raine CS , Brosnan CF Evidence of persistent blood-brain barrier abnormalities in chronic-progressive multiple sclerosis. Acta Neuropathol (Berl) 1995; 90: 228—38.

Kwon EE , Prineas JW Blood-brain barrier abnormalities in longstanding multiple sclerosis lesions. An immunohistochemical study. J Neuropathol Exp Neurol 1994; 53: 625—36.

10.

Hawkins CP , Munro PM , MacKenzie F. , Kesselring J. , Tofts PS , du Boulay EP et al. Duration and selectivity of blood-brain barrier breakdown in chronic relapsing experimental allergic encephalomyelitis studied by gadolinium-DTPA and protein markers. Brain 1990; 113: 365—78.

11.

Bruck W. , Bitsch A. , Kolenda H. , Bruck Y. , Stiefel M. , Lassmann H. Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol 1997; 42: 783—93.

12.

Grossman RI , Gonzalez-Scarano F. , Atlas SW , Galetta S. , Silberberg DH Multiple sclerosis: gadolinium enhancement in MR imaging. Radiology 1986; 161: 721—25.

13.

Katz D. , Taubenberger JK , Cannella B. , McFarlin DE , Raine CS , McFarland HF Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis. Ann Neurol 1993; 34: 661—69.

14.

Miller DH , Rudge P. , Johnson G. , Kendall BE , MacManus DG , Moseley IF et al. Serial gadolinium enhanced magnetic resonance imaging in multiple sclerosis. Brain 1988; 111: 927—39.

15.

Lai M. , Hodgson T. , Gawne-Cain M. , Webb S. , MacManus D. , McDonald WI et al. A preliminary study into the sensitivity of disease activity detection by serial weekly magnetic resonance imaging in multiple sclerosis . J Neurol Neurosurg Psychiatry 1996; 60: 339—41.

16.

Harris NG , Gauden V. , Fraser PA , Williams SR , Parker GJ MRI measurement of blood-brain barrier permeability following spontaneous reperfusion in the starch microsphere model of ischemia. Magn Reson Imaging 2002; 20: 221—30.

17.

Zhu XP , Li KL , Kamaly-Asl ID , Checkley DR , Tessier JJ , Waterton JC et al. Quantification of endothelial permeability, leakage space, and blood volume in brain tumors using combined T1 and T2* contrast-enhanced dynamic MR imaging. J Magn Reson Imaging 2000; 11: 575—85.

18.

Silver NC , Tofts PS , Symms MR , Barker GJ , Thompson AJ , Miller DH Quantitative contrast-enhanced magnetic resonance imaging to evaluate blood-brain barrier integrity in multiple sclerosis: a preliminary study. Mult Scler 2001; 7: 75—82.

19.

Kappos L. , Moeri D. , Radue EW , Schoetzau A. , Schweikert K. , Barkhof F. et al. 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 1999; 353: 964—69.

20.

The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 1995; 45: 1277—85.

21.

van Walderveen MA , Kamphorst W. , Scheltens P. , van Waesberghe JH , Ravid R. , Valk J. et al. Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology 1998; 50: 1282—88.

22.

van Walderveen MA , Lycklama Ang , Ader HJ , Jongen PJ , Polman CH , Castelijns JA et al. Hypointense lesions on T1-weighted spin-echo magnetic resonance imaging: relation to clinical characteristics in subgroups of patients with multiple sclerosis. Arch Neurol 2001; 58: 76—81.

23.

Kurtzke JF Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33: 1444—52.

24.

Poser CM , Paty DW , Scheinberg L. , McDonald WI , Davis FA , Ebers GC et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227—31.

25.

Studholme C. , Hill Dlg , Hawkes DJ An overlap invariant entropy measure of 3D medical image alignment. Pattern Recognition 1999; 32: 71—86.

26.

Woods RP , Cherry SR , Mazziotta JC Rapid automated algorithm for aligning and reslicing PET images. J Comput Assist Tomogr 1992; 16: 620—33.

27.

Parker GJ , Barker GJ , Tofts PS Accurate multislice gradient echo T(1) measurement in the presence of non-ideal RF pulse shape and RF field nonuniformity. Magn Reson Med 2001; 45: 838—45.

28.

Plummer DL Dispimage: a display and analysis tool for medical images. Rivista di Neuroradiologia 1992; 5: 489—95.

29.

Tofts PS , Kermode AG Measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging. 1. Fundamental concepts. Magn Reson Med 1991; 17: 357—67.

30.

Tofts PS , Brix G. , Buckley DL , Evelhoch JL , Henderson E. , Knopp MV et al. Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols . J Magn Reson Imaging 1999; 10: 223—32.

31.

Baltagi BH Econometric analysis of panel data. John Wiley and Sons , 1995.

32.

Carpenter J. , Bithell J. Bootstrap confidence intervals: when, which, what? A practical guide for medical statisticians. Stat Med 2000; 19: 1141—64.

33.

Tofts PS , Berkowitz BA Measurement of capillary permeability from the Gd enhancement curve: a comparison of bolus and constant infusion injection methods. Magn Reson Imaging 1994; 12: 81—91.

34.

Haselhorst R. , Kappos L. , Bilecen D. , Scheffler K. , Mori D. , Radu EW et al. Dynamic susceptibility contrast MR imaging of plaque development in multiple sclerosis: application of an extended blood-brain barrier leakage correction. J Magn Reson Imaging 2000; 11: 495—505.

35.

Wuerfel J. , Bellmann-Strobl J. , Brunecker P. , Aktas O. , McFarland H. , Villringer A. et al. Changes in cerebral perfusion precede plaque formation in multiple sclerosis: a longitudinal perfusion MRI study. Brain 2004; 127: 111—19.

36.

Hiehle JF Jr , Grossman RI , Ramer KN , Gonzalez-Scarano F. , Cohen JA Magnetization transfer effects in MR-detected multiple sclerosis lesions: comparison with gadolinium-enhanced spin-echo images and nonenhanced T1-weighted images. AJNR Am J Neuroradiol 1995; 16: 69—77.

37.

Rashid W. , Parkes LM , Ingle GT , Chard DT , Toosy AT , Altmann DR et al. Abnormalities of cerebral perfusion in multiple sclerosis. J Neurol Neurosurg Psychiatry 2004; 75: 1288—93.

38.

Ge Y. , Law M. , Johnson G. , Herbert J. , Babb JS , Mannon LJ et al. Dynamic susceptibility contrast perfusion MR imaging of multiple sclerosis lesions: characterizing hemodynamic impairment and inflammatory activity. AJNR Am J Neuroradiol 2005; 26: 1539—47.

39.

Tan IL , van Schijndel RA , Pouwels PJ , van Walderveen MA , Reichenbach JR , Manoliu RA et al. MR venography of multiple sclerosis 7. AJNR Am J Neuroradiol 2000; 21: 1039—42.

40.

Fernando KT , McLean MA , Chard DT , MacManus DG , Dalton CM , Miszkiel KA et al. Elevated white matter myo-inositol in clinically isolated syndromes suggestive of multiple sclerosis. Brain 2004; 127: 1361—69.

41.

Kidd D. , Barker GJ , Tofts PS , Gass A. , Thompson AJ , McDonald WI et al. The transverse magnetisation decay characteristics of longstanding lesions and normal-appearing white matter in multiple sclerosis. J Neurol 1997; 244: 125—30.

42.

Werring DJ , Clark CA , Barker GJ , Thompson AJ , Miller DH Diffusion tensor imaging of lesions and normal-appearing white matter in multiple sclerosis. Neurology 1999; 52: 1626—32.