Figure 2.

In and out the brain: plausible biomarker exit routes and transport. (A) NVU cell disassembly causes disruption of brain homeostasis, allowing blood (red asterisks and arrow) and brain (green asterisks and arrow) components directly crossing the permeable BBB (TJ, tight junctions; A, astrocytes; P, pericytes; N, neurons). (B) Brain fluid paths regulate the movement of molecules (e.g., biomarkers) within the brain parenchyma into the blood and the CSF: (a) the CSF is produced by subarachnoid arteries and (b) the choroid plexus (blood-to-CSF barrier). By bulk flow mechanisms, the CSF diffuses at the cortical levels and in periventricular organs, constituting a possible vehicle for biomarker transport. (c) BBB damage allows biomarkers exiting (or entering) the brain. (d,e) Parenchymal bulk flow and CSF reabsorption occurs at larger veins, dural venous sinuses, and dural lymphatic vessels, sites where biomarkers could accumulate. (C) Concentration gradients (green/red Δ or arrows) between the peripheral blood and the brain parenchyma are the underpinning for pathological modifications and the driving force for biomarkers (e.g., MR contrast agent brain entry, red; protein biomarkers brain exit, green). Original images by NM.