The pathophysiology of the blood-brain barrier (BBB) has been described as an important factor in central nervous system disease and continues to be a topic of great interest to many researchers from a wide range of disciplines. The award of three Nobel prizes, those in medicine (MR imaging), chemistry (aquaporins), and physics (superconductivity) highlights the relevance and timeliness of the present topic. Although the understanding of this barrier has significant implications for disease detection, it is also critical for the delivery of treatment to affected brain regions.
In the May issue of the AJNR, Law et al attempt to compare regional cerebral blood volume (rCBV) and vascular permeability (Ktrans) measurements obtained from dynamic susceptibility contrast-enhanced perfusion MR imaging with glioma grade. According to that study, rCBV demonstrated a strong correlation with tumor grade, whereas Ktrans showed a weaker correlation. Some limitations existed in the study; for example, the method used to measure permeability may require further development and correlation with histopathologic findings. Only selected cases of glioma were used rather than a randomly assigned group of tumors, thereby producing a better differentiation than expected, but compromising the usefulness and validity of the results. Although these results raise questions about the accuracy of the permeability measurements, this approach is of significant importance in evaluating tumors, since it may provide a noninvasive way to estimate leakage across the BBB and to assess the results of therapy.
Presently, the physiological mechanisms that control the brain environment are collectively known as the BBB. This barrier consists of a network of capillary endothelial cells that protect the brain tissue from toxins while supplying the brain with adequate nutrients. How circulating blood passes from arteries to veins was an absolute mystery until Marcello Malpighi explained it more than 300 years ago. But it was not until much later that Carl Ludwig and his pupil Christian Bohr evaluated the role of the capillaries in the transport of solutes between blood and tissues. In the early 1900s, Erlich and Goldman observed that dyes injected into the circulation did not stain the CSF, and this led to the idea of a blood-brain barrier, a name coined by Lewandowsky (bluthirnschranke). This concept was then expanded to include the blood-CSF barrier at the choroid plexus level. Further studies demonstrated that unique cerebral capillary endothelial cells with tight junctions comprised part of the BBB, and that these cells used specific carrier systems to transport substances required for cerebral metabolism.
MR imaging permeability studies attempt to measure the degree of disruption of the BBB by using an analysis of dynamic contrast-enhanced imaging. Tumors have a “leaky” BBB, since their endothelial cells have abnormal function and organization, with intercellular spaces and loose interconnections. But although changes in permeability affect the degree of leakiness across the BBB, other physiological parameters may also affect flow across the endothelium, including the regional hydrostatic and osmotic gradients, blood flow, and luminal surface area. The resulting flux is due to several mechanisms, including simple diffusion related to concentration gradients, diffusion facilitated by endocytosis, diffusion occurring through aqueous channels (aquaporins), and active transport by carrier protein molecules. Within tumors, the driving forces are affected by several factors, including the degree of edema and mass effect that create a “back pressure” and influence transmural pressure gradients. The interstitial fluid pressures may become elevated by leakage from adjacent blood vessels, decreased lymphatic clearance, and abnormal tissue biomechanical properties, all of which can lead to decreased hydrostatic gradients and to a greater relative role for diffusion. The region where extravasation occurs may be of a variable nature, possibly highly vascular, viable, or necrotic. The edema may be vasogenic or cytotoxic. Chemical mediators may also regulate the degree of permeability. Tumor vessels have irregular calibers and abnormal branching patterns, which create regional variations in leakage and make accurate blood flow measurements difficult.
Permeability maps thus reflect a complex interaction of a number of pathophysiological variables related to permeability and blood flow. But if the driving forces across the BBB are not known, how can algorithms based on flow measurements be sufficient to calculate the permeability of the BBB? Permeability maps may actually be more representative of leakage than leakiness, since they use flow parameters to infer the degree of permeability. This distinction may not significantly affect estimation of quantities such as inflow of administered agents, but could lead to decreased accuracy if the maps are used to predict tumor grade, which may be one of their most important clinical roles at present. Theoretically, modifications of permeability imaging techniques could be performed to account for additional factors such as the distribution and degree of regional edema, diffusion rates, etc. Increasing imaging resolution by using higher field strength magnets may also be useful to directly image the microvasculature.
What about the future? Consider this: a physician enters a “very special procedures room,” ready to treat a patient with a brain tumor. First, he selects an agent that can open the blood-brain barrier reversibly without damaging it. As he administers this agent, an automated screen displays the actual opening of the BBB in real-time mode. He then injects a medication to treat the tumor and directly observes the changes in vascular leakiness and tumor blood flow. When the procedure is completed, he closes the BBB. The patient recovers without side effects. This may seem perhaps far-fetched; nevertheless, new approaches are presently being developed that could lead to such possibilities. Present measurements of permeability are difficult to perform sequentially or continuously, since the techniques involve a single bolus injection of contrast medium. However, new techniques based on labeled perfusion agents are being evaluated to monitor the status of the BBB continuously, as may be required during one or multiple interventions. New approaches to identify and target tumor vessels for more selective therapeutic interventions, and to open and close the BBB reversibly without causing tissue damage, are also being investigated.
With the continued development of newer and more effective therapeutic approaches, there is now an increasing need to improve the methods that we use to evaluate tumor blood flow and the BBB. Our advances in the imaging of tumor characteristics should also lead to a better understanding of the mechanisms that relate tumor growth with blood vessel and BBB abnormalities.
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