Skip to main content
SpringerLink
Log in

Frequent Blood–Brain Barrier Disruption in the Human Cerebral Cortex

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

1. The blood–brain barrier (BBB) protects the brain from circulating xenobiotic agents. The pathophysiology, time span, spatial pattern, and pathophysiological consequences of BBB disruptions are not known.

2. Here, we report the quantification of BBB disruption by measuring enhancement levels in computerized tomography brain images.

3. Pathological diffuse enhancement associated with elevated albumin levels in the cerebrospinal fluid (CSF) was observed in the cerebral cortex of 28 out of 43 patients, but not in controls. Four patients displayed weeks-long focal BBB impairment. In 19 other patients, BBB disruption was significantly associated with elevated blood pressure, body temperature, serum cortisol, and stress-associated CSF “readthrough” acetylcholinesterase. Multielectrode electroencephalography revealed enhanced slow-wave activities in areas of focal BBB disruption. Thus, quantification of BBB disruption using minimally invasive procedures, demonstrated correlations with molecular, clinical, and physiological stress-associated indices.

4. These sequelae accompany a wide range of neurological disorders, suggesting that persistent, detrimental BBB disruption is considerably more frequent than previously assumed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

REFERENCES

  • Abbott, N. J. (2000). Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol. Neurobiol. 20: 131-147.

    Google Scholar 

  • Abbruscato, T. J., andDavis, T. P. (1999). Protein expression of brain endothelial cell E-cadherin after hypoxia/aglycemia: Influence of astrocyte contact. Brain Res. 842: 277-286.

    Google Scholar 

  • Akeson, P.,Larsson, E. M.,Kristoffersen, D. T.,Jonsson, E., andHoltas, S. (1995). Brain metastasescomparison of gadodiamide injection-enhanced MR imaging at standard and high dose, contrastenhanced CT and non-contrast-enhanced MR imaging. Acta Radiol. 36: 300-306.

    Google Scholar 

  • Bakay, L. (1976). Blood-brain barrier and its alteration in pathological states. In Vinken, P. J., andBruyn, G. W. (eds.), Handbook of Clinical Neurology, Vol. 28, Elsevier/North-Holland Biomedical Press, Amsterdam, p. 370.

    Google Scholar 

  • Belova, I., andJonsson, G. (1982). Blood-brain barrier permeability and immobilization stress. Acta Physiol. Scand. 116: 21-29.

    Google Scholar 

  • Ben-Nathan, D.,Lustig, S., andDanenberg, H. D. (1991). Stress-induced neuroinvasiveness of a neurovirulent noninvasive Sindbis virus in cold or isolation subjected mice. Life Sci. 48: 1493-1500.

    Google Scholar 

  • Boje, K. M. (1996). Inhibition of nitric oxide synthase attenuates blood-brain barrier disruption during experimental meningitis. Brain Res. 720: 75-83.

    Google Scholar 

  • Brooks, R. A. (1977). A quantitative theory of the Hounsfield unit and its application to dual energy scanning. J. Comput. Assist. Tomogr. 1: 487-493.

    Google Scholar 

  • Calingasan, N. Y.,Park, L. C.,Calo, L. L.,Trifiletti, R. R.,Gandy, S. E., andGibson, G. E. (1998). Induction of nitric oxide synthase and microglial responses precede selective cell death induced by chronic impairment of oxidative metabolism. Am. J. Pathol. 153: 599-610.

    Google Scholar 

  • Chan, S. L., andMattson, M. P. (1999). Caspase and calpain substrates: Roles in synaptic plasticity and cell death. J. Neurosci. Res. 58: 167-190.

    Google Scholar 

  • Charriaut-Marlangue, C.,Aggoun-Zouaoui, D.,Represa, A., andBen-Ari, Y. (1996). Apoptotic features of selective neuronal death in ischemia, epilepsy and gp 120 toxicity. Trends Neurosci. 19: 109-114.

    Google Scholar 

  • Cornford, E. M., andOldendorf, W.H. (1986). Epilepsy and the blood-brain barrier. Adv. Neurol. 44: 787-812.

    Google Scholar 

  • Correale, J.,Rabinowicz, A. L.,Heck, C. N.,Smith, T. D.,Loskota, W. J., andDeGiorgio, C. M. (1998). Status epilepticus increases CSF levels of neuron-specific enolase and alters the blood-brain barrier. Neurology 50: 1388-1391.

    Google Scholar 

  • Elhusseiny, A.,Cohen, Z.,Olivier, A.,Stanimirovic,D. B., andHamel, E. (1999). Functional acetylcholine muscarinic receptor subtypes inhumanbrain microcirculation: Identification and cellular localization. J. Cereb. Blood Flow Metab. 19: 794-802.

    Google Scholar 

  • Esposito, P.,Gheorghe, D.,Kandere, K.,Pang, X.,Connolly, R.,Jacobson, S., andTheoharides, T.C. (2001). Acute stress increases permeability of the blood-brain barrier through activation of brain mast cells. Brain Res. 888: 117-127.

    Google Scholar 

  • Flumerfelt, B. A.,Lewis, P. R., andGwyn, D. G. (1973). Cholinesterase activity of capillaries in the rat brain. A light and electron microscopic study. Histochem. J. 5: 67-77.

    Google Scholar 

  • Friedman, A.,Kaufer, D.,Shemer, J.,Hendler, I.,Soreq, H., andTur-Kaspa, I. (1996). Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response. Nat. Med. 2: 1382-1385.

    Google Scholar 

  • Grauer, E.,Alkalai, D.,Kapon, J.,Cohen, G., andRaveh, L. (2000). Stress does not enable pyridostigmine to inhibit brain cholinesterase after parenteral administration. Toxicol. Appl. Pharmacol. 164: 301-304.

    Google Scholar 

  • Haley, R. W.,Marshall, W. W.,McDonald, G. G.,Daugherty, M. A.,Petty, F., andFleckenstein, J. L. (2000). Brain abnormalities in GulfWar syndrome: Evaluation with 1HMRspectroscopy. Radiology 215: 807-817.

    Google Scholar 

  • Inanami, O.,Ohno, K., andSato, A. (1992). Responses of regional cerebral blood flow to intravenous administration of thyrotropin releasing hormone in aged rats. Neurosci. Lett. 143: 151-154.

    Google Scholar 

  • Jefferys, J. G. (1998). Mechanisms and experimental models of seizure generation. Curr. Opin. Neurol. 11: 123-127.

    Google Scholar 

  • Kadota, E.,Nonaka, K.,Karasuno, M.,Nishi, K.,Teramura, K., andHashimoto, S. (1997). Neurotoxicity of serum components, comparison between CA1 and striatum. Acta Neurochir. Suppl. (Wien) 70: 141-143.

    Google Scholar 

  • Kaufer, D.,Friedman, A.,Seidman, S., andSoreq, H. (1998a). Acute stress facilitates long-lasting changes in cholinergic gene expression. Nature 393: 373-377.

    Google Scholar 

  • Kaufer, D.,Friedman, A.Seidman, S., andSoreq, H. (1998b). Anticholinesterases induce multigenic transcriptional feedback response suppressing cholinergic neurotransmission. Chem. Biol. Interact. 119: 349-360.

    Google Scholar 

  • Klatzo, I. (1983). Disturbance of the blood-brain barrier in cerebrovascular disorders. Acta Neuropathol. Suppl. (Berl) 8: 81-8.

    Google Scholar 

  • Kuhn, W.,Winkel, R.,Woitalla, D.,Meves, S.,Przuntek, H., andMuller, T. (1998). High prevalence of parkinsonism after occupational exposure to lead-sulfate batteries. Neurology 50: 1885-1886.

    Google Scholar 

  • Loewenstein-Lichtenstein, Y.,Schwarz, M.,Glick, D.,Norgaard-Pedersen, B.,Zakut, H., andSoreq, H. (1995). Genetic predisposition to adverse consequences of anti-cholinesterases in ‘atypical’ BCHE carriers. Nat. Med. 1: 1082-1085.

    Google Scholar 

  • Lux, H. D. (1980). Ionic conditions and membrane behavior. Adv. Neurol. 27: 63-83.

    Google Scholar 

  • McCullough, E. C.,Baker, H. L., Jr.,Houser, O. W., andReese, D. F. (1974). An evaluation of the quantitative and radiation features of a scanning x-ray transverse axial tomograph: The EMI scanner. Radiology 111: 709-715.

    Google Scholar 

  • Meijer, O. C.,de Lange, E. C.,Breimer, D. D.,de Boer, A. G.,Workel, J. O., andde Kloet, E. R. (1998). Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology 139: 1789-1793.

    Google Scholar 

  • Meldrum, B. S. (1993). Excitotoxicity and selective neuronal loss in epilepsy. Brain Pathol. 3: 405-412.

    Google Scholar 

  • Menegon, A.,Board, P. G.,Blackburn, A. C.,Mellick, G. D., andLe Couteur, D. G. (1998). Parkinson's disease, pesticides, and glutathione transferase polymorphisms. Lancet 352: 1344-1346.

    Google Scholar 

  • Raichle,M. E.,Hartman, B. K.,Eichling, J.O., andSharpe, L.G. (1975). Central noradrenergic regulation of cerebral blood flow and vascular permeability. Proc. Natl. Acad. Sci. U.S.A. 72: 3726-3730.

    Google Scholar 

  • Rhodin, J.,Thomas, T.,Bryant, M.,Clark, L., andSutton, E. T. (1999). Animal model of vascular inflammation. J. Submicrosc. Cytol. Pathol. 31: 305-311.

    Google Scholar 

  • Robinson, J. S., andMoody, R. A. (1980). Influence of respiratory stress and hypertension upon the blood-brain barrier. J. Neurosurg. 53: 666-673.

    Google Scholar 

  • Roman-Goldstein, S.,Clunie, D. A.,Stevens, J.,Hogan, R.,Monard, J.,Ramsey, F., andNeuwelt, E. A. (1994). Osmotic blood-brain barrier disruption: CT and radionuclide imaging. AJNR Am. J. Neuroradiol. 15: 581-590.

    Google Scholar 

  • Rubin, L. L., andStaddon, J. M. (1999). The cell biology of the blood-brain barrier. Annu. Rev. Neurosci. 22: 11-28.

    Google Scholar 

  • Sapolsky, R. M. (1996). Why stress is bad for your brain. Science 273: 749-750.

    Google Scholar 

  • Schwartzkroin, P. A.,Baraban, S. C., andHochman, D. W. (1998). Osmolarity, ionic flux, and changes in brain excitability. Epilepsy Res. 32: 275-285.

    Google Scholar 

  • Senanayake, N., andSanmuganathan, P. S. (1995). Extrapyramidal manifestations complicating organophosphorus insecticide poisoning. Hum. Exp. Toxicol. 14: 600-604.

    Google Scholar 

  • Sharma, H. S.,Kretzschmar, R.,Cervos-Navarro, J.,Ermisch, A.,Ruhle, H. J., andDey, P. K. (1992). Age-related pathophysiology of the blood-brain barrier in heat stress. Prog. Brain Res. 91: 189-196.

    Google Scholar 

  • Shohami, E.,Kaufer, D.,Chen, Y.,Seidman, S.,Cohen, O.,Ginzberg, D.,Melamed-Book, N.,Yirmiya, R., andSoreq, H. (2000). Antisense prevention of neuronal damages following head injury in mice. J. Mol. Med. 78: 228-236.

    Google Scholar 

  • Siegal, T.,Rubinstein, R.,Bokstein, F.,Schwartz, A.,Lossos, A.,Shalom, E.,Chisin, R., andGomori, J. M. (2000). In vivo assessment of the window of barrier opening after osmotic blood-brain barrier disruption in humans. J. Neurosurg. 92: 599-605.

    Google Scholar 

  • Sinton, C. M.,Fitch, T. E.,Petty, F., andHaley, R.W. (2000). Stressful manipulations that elevate corticosterone reduce blood-brain barrier permeability to pyridostigmine in the rat. Toxicol. Appl. Pharmacol. 165: 99-105.

    Google Scholar 

  • Skoog, I.,Wallin A.,Fredman, P.,Hesse, C.,Aevarsson, O.,Karlsson, I.,Gottfries, C. G., andBlennow, K. (1998). A population study on blood-brain barrier function in 85-year-olds: Relation to Alzheimer's disease and vascular dementia. Neurology 50: 966-971.

    Google Scholar 

  • Soreq, H.,Kaufer, D.,Friedman, A., andGlick, D. (2000). Blood-brain barrier modulations and low-level exposure to xenobiotics. In Somani S. M., andRomano J. A. (eds.), Chemical Warefare Agents: Low Level Toxicity, CRC Press, Boca, Raton, FL, pp. 121-144.

    Google Scholar 

  • Soreq, H., andSeidman, S. (2001). Acetylcholinesterase-new roles for an old actor. Nature Neurosci. Rev. 2: 294-302.

    Google Scholar 

  • Sternfeld, M.,Shoham, S.,Klein, O.,Flores-Flores, C.,Evron, T.,Idelson, G. H.,Kitsberg, D.,Patrick, J.W., andSoreq, H. (2000). Excess “read-through” acetylcholinesterase attenuates but the “synaptic” variant intensifies neurodeterioration correlates. Proc. Natl. Acad. Sci. U.S.A. 97: 8647-8652.

    Google Scholar 

  • Tator, C. H., andSchwartz, M. L. (1971). Permeability in brain tumors. J. Neurosurg. 34: 460-462.

    Google Scholar 

  • Triguero, D.,Lopez de Pablo, A. L.,Gomez, B., andEstrada, C. (1988). Regional differences in cerebrovascular cholinergic innervation in goats. Stroke 19: 736-740.

    Google Scholar 

  • van Amsterdam, J. G., andOpperhuizen, A. (1999). Nitric oxide and biopterin in depression and stress. Psychiatry Res. 85: 33-38.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology and Neurosurgery, Soroka University Hospital, Zlotowski Center of Neuroscience, Ben-Gurion University, Beersheva, Israel

    Oren Tomkins, Akiva Korn, Eli Reichenthal & Alon Friedman

  2. Department of Biological Chemistry, Institute of Life Sciences, Roland Center for Neurodegenerative Diseases, The Hebrew University, Jerusalem, Israel

    Daniela Kaufer & Hermona Soreq

  3. Department of Radiology, Soroka University Hospital, Zlotowski Center of Neuroscience, Ben-Gurion University, Beersheva, Israel

    Ilan Shelef

  4. Department of Nuclear Medicine, Soroka University Hospital, Zlotowski Center of Neuroscience, Ben-Gurion University, Beersheva, Israel

    Haim Golan

Authors
  1. Oren Tomkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniela Kaufer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akiva Korn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ilan Shelef
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haim Golan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eli Reichenthal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hermona Soreq
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alon Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tomkins, O., Kaufer, D., Korn, A. et al. Frequent Blood–Brain Barrier Disruption in the Human Cerebral Cortex. Cell Mol Neurobiol 21, 675–691 (2001). https://doi.org/10.1023/A:1015147920283

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1015147920283

Search

Navigation