Extracellular Fluid Movement and Clearance in the Brain: The Glymphatic Pathway

Diffusion and Bulk Flow

In principal, ISF and solutes move through the brain through two different processes: diffusion and bulk flow (convection) ( Fig. 71.1A–B ). Diffusion is movement of particles down a concentration gradient that occurs because of random thermal motion and is influenced by the size of the molecule, the geometry of the extracellular space, and the chemical interactions among the particles and their surroundings (see Fig. 71.1C–D ). Bulk flow is the movement of fluid under the influence of hydrostatic or osmotic pressure. Associated solutes are carried along largely at the rate of the fluid and independent of molecular size, like boats of different sizes drifting together in the current of a river. This principle is limited, naturally, in the case of molecules and particles whose size approaches the dimensions of the extracellular space itself.

Solutes are cleared from the brain interstitium by three principle routes. Nonpolar solvents are cleared to the blood by diffusing directly across the BBB, whereas for many polar molecules, specific BBB transporters facilitate clearance across the BBB. Because diffusion is highly efficient within cellular dimensions (the tens of microns that separate neurons and astrocytes from the nearest BBB surface), the efflux of such solutes across the BBB is dependent primarily on diffusion and is constrained by the factors that influence diffusion. Solutes that do not cross the BBB are cleared from the brain interstitium to the CSF of the ventricular, subarachnoid, and cisternal spaces. ^, However, within the anatomic dimensions of the wider brain (the millimeters and centimeters that may separate a volume of brain interstitium from the nearest CSF space), the efficiency of diffusion drops off precipitously, particularly for macromolecules such as peptides and proteins, and cannot account for the rapid clearance from the brain interstitium. Rather, these interstitial solutes are proposed to be cleared from the brain by the bulk flow of interstitial fluid to the CSF compartments.

The Extracellular Space

The extracellular space makes up 15% to 20% of the total brain volume. It is a tortuous space filled with the complex gel of the extracellular matrix and composed of dead ends and branching connections (see Fig. 71.1C ). Thus diffusion in the brain extracellular space is an order of magnitude slower than in free solution. The characteristics of the extracellular space that influence diffusion can be quantified experimentally, resulting in two commonly used parameters: the extracellular volume fraction (volume of extracellular space divided by total tissue volume) and the extracellular tortuosity (a composite parameter that encompasses the shape of the space, the presence of cul-de-sacs, and the characteristics of the matrix itself). Reductions in extracellular volume fraction and increases in tortuosity both decrease the rate of diffusion, whereas changes in the opposite direction increase the rate of diffusion (see Fig. 71.1E ).

These parameters represent global measurements of the brain extracellular space and their influence on diffusion. However, the local architecture of brain tissue can have profound effects on both diffusion and bulk flow. Two clear examples of this are white matter tracts and perivascular spaces within the brain parenchyma ( Fig. 71.2 ). Because axon bundles within a white matter tract tend to orient along a single axis, diffusion within the white matter extracellular spaces exhibits anisotropy, the tendency to move more freely along one axis than along orthogonal axes. Similar effects on bulk flow are observed: bulk flow along white matter tracts is more rapid than through gray matter. Bulk flow through the extracellular spaces surrounding large intraparenchymal blood vessels (perivascular spaces) is also more rapid than through the bulk extracellular space. ^, These local architectural features exert important influences on the movement of ISF and solutes through different brain regions and the brain as a whole by providing an interconnected low-resistance pathway for the distribution of solutes through and efflux of solutes from the wider brain interstitium.

Bulk Flow in the Extracellular Space

While tracer efflux studies in rodents demonstrate that the clearance of interstitial macromolecules is dependent on bulk flow, it is unclear whether bulk flow is present throughout the brain interstitium or it is restricted to permissive pathways such as perivascular spaces or white matter tracks. Recent modeling studies suggest that the hydraulic resistance of the extracellular space and capillary basal lamina may be too high to support rapid distributed bulk flow. ^, However, for large molecules such as peptides and proteins, even very slow rates of bulk flow would play an important role in clearance from the extracellular space. Thus the relative contributions of diffusion and bulk flow along permissive anatomic routes versus the wider interstitium remain to be conclusively defined.

Bulk flow differs from diffusion in that it requires a hydrostatic or osmotic force to drive the movement of extracellular fluid and associated solutes down the respective pressure gradients. In the periphery, extremely small hydrostatic pressure gradients between the interstitial space and the primary lymphatics are sufficient to maintain bulk flow of interstitial fluid and solute clearance. Within the brain, the sources of hydrostatic or osmotic forces that drive interstitial bulk flow are unclear. A small amount of water is produced by cellular metabolism in the brain, whereas water filtration across the relatively impermeable but vast capillary surface area may account for a substantial fraction of brain ISF production and may provide one of the driving forces for interstitial bulk flow. ^,

With each cardiac cycle, pressure waves propagate along the cerebrovascular tree and drive bulk flow along perivascular spaces surrounding large intraparenchymal vessels within the brain. ^{, ,} This may be a result of the action of the cerebral arterial wall on the surrounding fluid as the pulse wave passes. The movement of the systolic and diastolic elements of the pulse waves through the complex cerebral vasculature and system of sinuses may generate hydrostatic pressure gradients between the different CSF compartments that could drive interstitial bulk flow. Phase-contrast MRI shows that with each cardiac cycle, a prominent pressure gradient originates within the cisterna magna and then propagates to the prepontine, interpeduncular, and suprasellar cisterns. Propagation diminishes within the sylvian cistern and along the cerebral convexity but is maintained along the middle cerebral artery. In contrast with pressure gradients associated with each cardiac cycle, standing posterior CSF flows were observed in the ambient and quadrigeminal cisterns as well as crural cisterns, whereas standing superior-posterior CSF flow was observed in the pericallosal cistern. In principle, the interactions between transient and standing hydrostatic pressures within these CSF compartments may determine the magnitude and direction of interstitial bulk flow throughout the brain. However, the important subject of the interrelationship between pressure dynamics and fluid flow in different brain regions remains to be explored.

Role of Astrocytes in Fluid Movement Through the Extracellular Space

In addition to the dimensions and characteristics of the extracellular space, the presence of intracellular and intercellular pathways for fluid and solute movement are important determinants of fluid movement through the brain. Astrocytes extend processes that surround millions of synapses within a 100- to 200-μm span and are coupled by gap junctions, potentially permitting the free movement of water and solutes throughout the entire network. Astrocytes surround the entire cerebral microcirculation with perivascular end-foot processes and form the glia limitans that bounds the subpial space and the Virchow-Robin spaces associated with penetrating cerebral blood vessels ( Fig. 71.3 ). Thus astrocytes form the interface between the subarachnoid CSF compartments, perivascular spaces, blood vessels, and the wider brain interstitium. At end-feet that surround cerebral blood vessels and at the glia limitans, astrocytes express massive amounts of the water channel aquaporin 4 (AQP4) (see Fig. 71.3A–B ). AQP4 is also expressed by ependymyal cells lining the cerebral ventricles. The presence of this water channel at the BBB and the brain-CSF barrier provides a low-resistance pathway to facilitate fluid movement between the CSF, perivascular spaces, and the wider brain interstitium.

Blood−Cerebrospinal Fluid Interactions

Although this chapter will briefly discuss aspects of CSF physiology relevant to ISF flow and solute clearance, the physiologic basis for CSF secretion is presented in detail in Chapter 62 . In the classical model, CSF secreted at the choroid plexus moves by bulk flow through the ventricular system, eventually spilling into the cisternal compartments and subarachnoid space through the foramina of Magendie and Luschka. From the subarachnoid space, CSF is believed to be reabsorbed into the blood through arachnoid granulations that protrude into the dural sinuses by traveling along cranial nerve sheaths or through the dural lymphatics. The bulk reabsorption of CSF along these pathways is the reason that CSF can function as a sink for interstitial solutes as they are cleared from the brain interstitium to the periphery.