Cerebrospinal Fluid: Formation, Absorption, Markers, and Relationship to Blood–Brain Barrier

Introduction

Cerebrospinal fluid (CSF) reflects pathology in the brain, and is essential in diagnosis of many neurological diseases, including those due to inflammation, infection, and immunological processes. CSF indicates pathological processes because of the continuity of the brain interstitial fluid (ISF) with the CSF across the ependymal lining of the ventricles. CSF and ISF are actively secreted by energy-requiring mechanisms: mainly epithelial cells make CSF in the choroid plexus, whereas capillaries and cellular metabolism form ISF. Both processes involve the sodium–potassium ATPase electrolyte pumps. ISF is thought to drain into the CSF spaces by movement along white matter tracts and perivascular spaces. When inflammatory cells cross the capillaries or are activated within brain, the brain edema that results causes brain swelling with raised intracranial pressure. CSF and ISF are continuously produced, resulting in about 500 mL per day, which must be removed or hydrocephalus will result. This dynamic system is routinely sampled for diagnostic and therapeutic reasons, making it essential for the clinician to understand the underlying molecular physiology.

An important concept that was identified by early investigators was the limited capacity of the brain to swell due to the dura and the bones of the skull, which contain the brain tissue, blood, and CSF/ISF; increase in any of these compartments raises intracranial pressure, which if high enough can lead to herniation of the compressed tissue and death. The skull protects the vulnerable brain, composed of 80% water, from minor injury, but severe blows to the head result in movement of the brain tissues against the skull, creating damage to brain cells that can lead acutely to swelling with cell death and over longer periods to neurodegeneration.

Besides the strong external layers protecting vulnerable brain tissues, there are multiple, more delicate internal layers separating brain tissue from the systemic circulation and protecting the internal milieu from being exposed to blood cells and circulating proteins by preventing the blood with toxic electrolyte and protein levels from mixing with the CSF/ISF. These multiple layers prevent cellular dysfunction by maintaining the stable internal milieu needed for normal brain cell function.

The first layer of protection is provided by the endothelial cells, which are joined together by tight junctions . In addition to the physical barrier, there are molecular and enzymatic barriers, including carrier molecules that move substances in and out of the brain, delivering nutrients and removing toxins; enzymes in the endothelial cells degrade unwanted substances and prevent them from entering the brain. Another important interface between the blood and the CSF/ISF occurs at the choroid plexuses. Finally, another site of the blood–brain barrier BBB is the arachnoid villi cells in the subarachnoid space, which transfer CSF/ISF into the blood. All of the interfaces have a common property of being joined with tight junctions. The brain lacks a true lymphatic system to drain metabolic products and deliver nutrients. The CSF and ISF provide the lymphatic function, and have been referred to as the third circulation . Thus this complex series of interfaces, acting as the brain’s lymphatic circulation, moves molecules between cells and along perivascular spaces.

Because of the unique interfaces formed at critical sites in the brain, immunological reactions are limited in brain tissue, creating a site of “immunological privilege” . The tight junctions at each interface prevent the levels of electrolytes in the brain from fluctuating widely with changes in the systemic circulation, which would occur during strenuous exercise. The tight junctions prevent the entrance of large protein molecules into the brain, which results in 40 mg% of albumin in CSF normally with a corresponding level of 4 g in the blood. They also block entry of circulating blood cells.

Sampling of the CSF is a common clinical procedure that is relatively safe and inexpensive compared with other procedures, making it a cost-effective addition to the diagnostic workup. The aim of this chapter is to describe the physiology and biochemistry of the CSF and the blood–brain interfaces, particularly as they relate to stroke .

Blood–Brain Interfaces

Elaborate protective mechanisms are found in the brain mainly to separate the blood from brain cells. Release of blood into the brain as occurs with the rupture of an aneurysm produces a devastating effect. Each of the sites where blood comes into contact with brain fluids has a specialized epithelial-like layer of cells. The major interface is formed by the endothelial cells, which have specialized proteins between the cells that seal them together, forming tight junctions that prevent proteins and cells from passing, and maintains a high electrical resistance. In addition to the endothelial interface, there are similar tight junction proteins found at the choroid plexus and the arachnoid granulations ( Table 4.1 ). Tight junctions are composed of membrane proteins, occludin, claudins, and junctional adhesion molecules. Other proteins that are important in the maintenance of the tight junction cytoplasmic scaffolding proteins include zonula occludens, actin cytoskeleton, and associated proteins, such as protein kinases, small GTPases, and heterotrimeric G-proteins.

Tight junctions restrict passage of all but lipid-soluble molecules. Albumin, for example, which is 4–5 g/dl in the blood, is normally less than 50 mg/dl in the CSF. An important function of the BBB is to maintain differences in the concentrations between the blood and the brain for many electrolytes ( Table 4.2 ), and it prevents the wide fluctuations in blood levels of certain electrolytes related to food intake, exercise, and other factors.