Commentary on “Alzheimer's disease drug development and the problem of the blood‐brain barrier.” The blood‐brain barrier: A physical and conceptual challenge

The ‘‘Decade of the Brain’’ (1990–2000) witnessed remarkable advances in neuroscience, but also some not-sobrainy attempts at finding a neuroprotective drug for acute stroke. The reasons for failure were many [1], and they included a failure to assess whether a promising drug crossed the blood-brain barrier (BBB). Based on Pardridge’s review, it seems we may have not learned much from history, and may be in danger of repeating it with therapies targeting Alzheimer’s disease (AD). The BBB represents not only a physical but a conceptual challenge. The vast majority of researchers in AD do not work on the BBB, and may not perceive it as a problem at all. The BBB represents a major challenge, but a small field: a boutique enterprise compared with the Wal-Mart dimensions of the amyloid emporium. Ironically, we need to co-opt the type of research that Pardridge advocates if we are to succeed with the long list of potential anti-amyloid therapies [2]. One indispensable research tool is the quantitative assessment of BBB permeability of therapeutic drugs using noninvasive imaging methods, such that the influx of putative drugs from the blood into the brain can be serially monitored. The physiological parameter that measures BBB permeability is the product of permeability and the total surface area of the capillary endothelium in a unit mass of tissue (PS). It gives the unidirectional flux of blood-borne solutes across all capillaries into the brain under the generally valid condition that brain-blood flow is much greater than the PS [3]. Positron emission tomography [4], computed tomography [5], and magnetic resonance [6] methods for measuring PS in patients were developed for inert contrast agents that permeate the BBB via passive diffusion. In principle, these same imaging methods can be applied to agents that are transported through the BBB via carrier-mediated and receptor-mediated mechanisms. For these imaging methods to work, the newer molecularly targeted agents must be appropriately labeled for them to be detected by positron emission tomography, computed tomography, and magnetic resonance imaging [7]. Alternatively, an analogue that is transported by a specific carrier-mediated transport or receptor-mediated transport mechanism has to be identified. For example, the overexpression of multidrug-resistant P-glycoprotein can be imaged with the ligand [8–10] Ga-[3-ethoxy-ENBDMPI] and positron emission tomography [8]. Although an intact BBB impedes the delivery of bloodborne therapeutic drugs, a compromised BBB has been implicated in the pathogenesis of a number of central nervous system diseases, including AD, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and others [9,10]. The presence of amyloid-b plaques in the vicinity of the cerebral microvasculature and the association of cerebral amyloid angiopathy with AD [11] suggest that vascular disease is a significant component of AD pathology. In accordance with this concept, there is increasing evidence for BBB disruption in AD [12–14]. Barriers such as the BBB can be breached through potential openings, if we can find the keys and the means of transportation. Pardridge is showing the way, and we need to join him.