Is There a Cerebral Lymphatic System?

Abstract

The brain is unique among virtually all somatic organs in its lack of a conventional lymphatic vasculature.1–3 In the periphery, the lymphatic circulation facilitates the clearance of extracellular proteins and excess fluid from the interstitium, a role critical to tissue homeostasis and function.4,5 Yet within the brain, despite its complex architecture and high metabolic activity and neural cells’ sensitivity to changes in the extracellular environment, no specialized organ-wide anatomic structure has yet been identified that facilitates the efficient lymphatic clearance of extracellular solutes and fluid from the brain parenchyma. For small molecules and hydrophobic compounds, efflux across the blood–brain barrier is relatively unrestricted. Molecules that are substrates for specific blood–brain barrier transporters are also readily cleared from the brain.6,7 Other compounds must be cleared from the brain interstitium to the cerebrospinal fluid (CSF) compartment, where they are ultimately eliminated to the blood stream via arachnoid granulations or to peripheral lymphatics along cranial nerves.1,8,9 However, the distances between much of the brain tissue and the CSF compartments are too great for efficient clearance by simple diffusion, particularly for large molecules (such as peptides and proteins) with low diffusion coefficients.6 Rather, the clearance of these interstitial solutes from the brain is attributed to bulk flow, by which convective currents of interstitial fluid (ISF) sweep solutes along at a high rate that is largely independent of molecular size.1,2,6,7 In a controversial series of studies, Grady et al10,11 suggested that brain ISF may exchange with CSF along paravascular routes surrounding cerebral blood vessels. Because these findings seemed to be subsequently refuted by Cserr et al,12,13 such retrograde movement of CSF into the brain parenchyma is now thought to …