A dysfunctional blood-brain barrier and cerebral small vessel disease.

In molecular terms, the blood–brain barrier (BBB) indicates tight junction complexes between adjacent endothelial cells that, combined with endothelial transporters (both influx and efflux), make brain endothelia different from other endothelia. While highly advantageous as a protective barrier against cerebrovascular permeability, shielding sensitive brain elements from blood-borne agents, it also poses a problem for those who seek to develop brain therapeutics such as designer antibodies targeted to amyloid deposits or tau protein derivatives. Recent evidence from human studies indicates variation in barrier efficacy among patient populations. In this issue ofNeurology®, Zhang et al. used quantitative MRI measures (dynamic contrast-enhanced [DCE]– MRI) to study cerebrovascular barrier function. They studied 116 older people, either with clinical and MRI evidence of cerebral small vessel disease or with no overt cerebrovascular disease. They used DCE-MRI to follow the time course of injected gadolinium-based contrast agent in each voxel of a brain MRI scan. They then used a standard analysis to derive 2 measures related to BBB function. These are the rate constant for gadolinium (Gd) transfer from blood to brain (variously called Ki or Ktrans) and the extent of brain tissue containing contrast agent (vL, the so-called fractional volume of leaky brain tissue), each derived for areas of white matter hyperintensity, for nonhyperintense white matter, for cortical gray matter, and for deep gray nuclei. They observed modest permeability, reflected in the Ki and vL values, in all brain regions (highest in cortical gray matter) and across both participant groups. They found that older people with small vessel disease had a greater fraction of Gdpositive tissue (observed as greater vL) relative to control individuals without small vessel disease. This held true within white matter hyperintensities, neighboring nonhyperintense white matter, and cortical gray matter (1.2to 1.4-fold difference, depending on the tissue type). This picture agrees—broadly—with previous studies of older people with manifestations of small vessel disease (lacunar stroke, white matter hyperintensities, or vascular cognitive impairment). It may be a mistake to assume that a dysfunctional cerebrovascular barrier indicates breach of the tight junctions between endothelial cells. For many years, we have known about the trafficking of plasma substrates across the endothelial cytoplasm, known as transcytosis. Traditional emphasis on efflux transporters, which limit CNS concentration of penetrating drugs, has shifted to include analyses of influx mechanisms capable of enhancing drug delivery. Interest has recently increased with discovery of Mfsd2a, a 60 KDa transmembrane protein greatly enriched in brain endothelium (.70-fold relative to peripheral endothelia). Mice genetically engineered to have no Mfsd2a gene exhibit increased BBB permeability due to increased transcytosis in brain endothelia. This pathway may be an entry route for therapeutic antibodies recently shown to reduce brain amyloid load. The current study leaves unclear the relative roles of paracellular vs transcellular barrier dysfunction. Then again, is the demonstrated dysfunctional cerebrovascular barrier really an indication of endothelial disturbances at all? The ongoing assumption is that the barrier changes occur at the capillary level, but this remains an assumption. Arterioles, the vessels immediately upstream from capillaries, have layers of smooth muscle cells that normally provide barrier protection in addition to other arteriolar constituents. But small vessel disease, either hereditary or sporadic, is typically characterized by substantial loss of smooth muscle cells. Given that smooth muscle cells of arterioles may be no more than one layer thick, some arterioles in small vessel disease could contribute to loss of cerebrovascular barrier protection, a subject for further investigation. The nature of the relationship between a dysfunctional cerebrovascular barrier and the pathogenesis of cerebral small vessel disease remains the critical question. The possible relationships, especially cause vs consequence, are complex and largely speculative at this point. Any unified model or fully developed theory linking white matter hyperintensities, microinfarcts, and cerebral microbleeds will need to incorporate conceptually a dysfunctional BBB.