Appendix D: The Blood–Brain Barrier, Choroid Plexus, and Cerebrospinal Fluid

• The Blood–Brain Barrier Regulates the Interstitial Fluid in the Brain

  • Distinctive Properties of the Endothelial Cells of Brain Capillaries Account for the Blood–Brain Barrier

  • Tight Junctions Are a Major Feature of the Anatomical Blood–Brain Barrier Composition and Structure

  • The Blood–Brain Barrier Is Permeable in Three Ways

  • Endothelial Enzyme Systems Form a Metabolic Blood–Brain Barrier

  • Some Areas of the Brain Lack a Blood–Brain Barrier

  • Brain-Derived Signals Induce Endothelial Cells to Express a Blood–Brain Barrier

  • Diseases Can Alter the Blood–Brain Barrier

• Cerebrospinal Fluid Is Secreted by the Choroid Plexuses

  • Cerebrospinal Fluid Has Several Functions

  • Epithelial Cells of the Choroid Plexuses Account for the Blood–Cerebral Spinal Fluid Barrier

  • Choroid Plexuses Nurture the Developing Brain

  • Increased Intracranial Pressure May Harm the Brain

• Brain Edema Is an Increase in Brain Volume Because of Increased Water Content

• Hydrocephalus Is an Increase in Volume of Cerebral Ventricles

To function optimally, neurons of the central nervous system and their supporting glia require a highly specialized environment. The fluids that bathe the central nervous system's interstitial and cerebrospinal compartments are regulated by the blood–brain and blood–cerebrospinal fluid (CSF) barriers. Evidence for these barriers was first obtained in the 19th century when it was observed that acidic vital dyes stain the brain if the dye is injected into the cerebrospinal fluid but not if injected into the blood stream.

The interstitial fluid in the brain and the cere- brospinal fluid in the intraventricular and subarachnoid spaces are separately compartmentalized. Homeostasis of these fluid compartments and ultimately the intracellular compartment of brain cells is regulated to a great degree by the blood–brain and blood–CSF barriers (Figure D–1). Endothelial cells of the cerebral microvasculature form the blood–brain barrier that regulates the movement of molecules between the blood and interstitial fluid compartments. Epithelial cells of the choroid plexus produce the cerebrospinal fluid and regulate its composition.

These barriers exclude toxic substances and protect neurons from circulating neurotransmitters such as norepinephrine and glutamate, the blood levels of which can increase greatly after a meal or in response to stress. The selective exclusion by the blood–brain barrier results primarily from specialized anatomical properties of the endothelial cells that limit the passive diffusion of water-soluble substances from the blood into the interstitial and cerebrospinal fluid compartments. As a result, many metabolites required for brain growth and function must be transported selectively across the brain endothelial and choroid epithelial cell surfaces. Specific transporters deliver energy substrates, essential amino acids, and peptides to the brain and remove metabolites.

Distinctive Properties of the Endothelial Cells of Brain Capillaries Account for the Blood–Brain Barrier

The small blood vessels of the brain are composed primarily of endothelial cells that continuously line the vessel luminal surface. On the abluminal side the endothelial cells are associated with pericytes, smooth muscle-like cells imbedded within the basement membrane of microvessels. Perivascular astrocytes extend processes that ensheathe most of the abluminal microvessel surface to form a microvessel-astroglial complex (Figure D–2). The endothelial cells and their extensive intercellular junctions are the principal component of the barrier (Figure D–3).

In capillaries of peripheral organs and in the relatively few brain capillaries that do not contribute to the barrier (eg, those of the circumventricular organs), blood-borne polar molecules diffuse across vessel walls by multiple mechanisms. This diffusion occurs through spaces between endothelial cells, through specialized cytoplasmic fenestrations, or by fluid-phase or receptor-mediated endocytosis.

Fluid-phase endocytosis is a relatively nonspecific process by which endothelial cells (and most other cells) engulf and then internalize molecules encountered in the extracellular space by vesicular endocytosis. Receptor-mediated endocytosis is a specific process in which a ligand binds to a membrane receptor on the external surface of a cell, is internalized by means of clathrin-coated vesicles, and is transported across the cell membrane. Once within the cell the vesicle may traverse the cell, fuse with the cell membrane on the opposite cell surface and release its contents to the extracellular space, or fuse with an intracellular endosome and release its contents.

Endothelial cells of blood–brain barrier vessels are relatively deficient in vesicular transport and they are also nonfenestrated. Instead they are interconnected by complex arrays of tight junctions (Figure D–3B), which block diffusion across vessel walls. All generic endothelial cells are interconnected by a modest number of tight junctional complexes and normally have low transendo- thelial resistance (5–10 ohm-cm²). In the vessels of the blood–brain barrier, however, extensive arrays of tight junctions generate high transendothelial resistance (2,000 ohm-cm²), excluding particles as small as K⁺ ions (Figure D–4).

Tight Junctions Are a Major Feature of the Anatomical Blood–Brain Barrier Composition and Structure

Tight junctions of the blood–brain barrier are composed of three principal transmembranous proteins— claudins, occludins, and junctional adhesion molecules— as well as numerous cytoplasmic accessory proteins (Figure D–5).

Claudin (~22 kDa) has four transmembrane domains and forms the backbone of tight junctional complexes. Of the more than 20 members of the claudin gene family, isoforms 1 and 5 are expressed at the junctions of the blood–brain barrier. Occludin (~65 kDa) is a tight junctional protein, also has four transmembrane domains, and is recruited to junctional complexes by claudins. Claudins and occludins interact intimately at the junctional membrane to influence junctional complexity and tightness. Junctional adhesion molecules (JAMs) are located lateral to the claudins and occludins and mediate cell-cell adhesive interactions required for junctional assembly. JAMs also play an important role in the transmigration of inflammatory cells across barrier endothelial cells.

Numerous accessory proteins positioned on the cytoplasmic side of tight junctions mediate interactions between the transmembrane junctional and cytoskeletal proteins and modulate dynamic junctional properties. The zona occludin proteins link the occludins and claudins to the actin cytoskeleton (Figure D–5). They also form a scaffold for other regulatory proteins such as cingulin, a myosin-like protein, and AF-6, a target of the small G protein Ras. It is currently believed that changes in protein-protein interactions at the cytoplasmic junctional–cytoskeletal interface, resulting from gene transcription and protein phosphorylation events, modulate tight junction structure and function.

The Blood–Brain Barrier Is Permeable in Three Ways

Normal development and brain function require many substances that must cross brain microvessels. Entry into the brain is achieved primarily in three ways: (1) by diffusion of lipid soluble substances, (2) by facilitative and energy-dependent receptor-mediated transport of specific water-soluble substances, and (3) by ion channels.

Diffusion of Lipid-Soluble Substances

The brain is separated from the blood only by the large surface of endothelial cell membrane (approximately 180 cm² /g in gray matter). This membrane permits the efficient exchange of lipid-soluble gases such as oxygen (O₂) and carbon dioxide (CO₂), an exchange limited only by the surface area of the blood vessels and by cerebral blood flow. Barrier vessels are impermeable to molecules with poor lipid-solubility such as mannitol. The permeability coefficient of the blood–brain barrier for many substances is directly proportional to the lipid-solubility of the substance as measured by the oil–water partition coefficient (Figure D–6).

An example of the relationship of permeability and lipid-solubility is the correlation between the relative abuse potential of psychoactive drugs such as nicotine and heroin and their lipid-solubility. Increasing the lipid-solubility of drugs enhances their delivery to the brain. Drugs with great lipid-solubility, however, are poorly soluble in blood and bind to serum albumin protein, properties that reduce delivery to the brain. Lipid-solubility is not an accurate indicator of the permeability of some hydrophilic substances, such as glucose and vinca alkaloids, because of the presence of selective endothelial transport or enzyme systems that increase or inhibit permeability.

Facilitative and Energy-Dependent Transport

Most substances that cross the blood–brain barrier are not lipid-soluble and therefore enter and leave the brain by specific transport systems (Figure D–7). Because the brain uses glucose almost exclusively as its source of energy, the hexose transporter (glucose transporter isotype-1, Glut1) of the barrier endothelial cells is abundant.

Like other transporters Glut1 consists of 12-transmembrane segments. It is a facilitative, saturable, and stereospecific transporter that functions at both the luminal and abluminal endothelial cell membranes. Because it is not energy-dependent, it cannot move glucose against a concentration gradient. In fact, the net flux of glucose is driven by the higher concentration of glucose in the plasma. More than 99% of the glucose that enters barrier endothelial cells is shuttled across for use by neurons and glia.

Monocarboxylic acids such as β-hydroxybutyrate serve as the brain's primary energy source during early development in suckling neonates and in response to starvation in mature animals. These acids are transported across the barrier endothelial cells by the monocarboxylic acid transporter-1 (MCT1).

Amino acids are transported across barrier endothelial cells primarily by three distinct carrier systems. These systems (L, A, and ASC) were initially characterized by their different patterns and mechanisms of transport, and by their preference for different amino acid analogs. The l-system preferentially transports large neutral amino acids with branched or ringed side chains such as leucine and valine. This Na⁺ -independent, facilitative transport system is located at luminal and abluminal endothelial cell membranes. It also transports l-DOPA l-dihydroxyphenylalanine), the dopamine precursor that is the mainstay for treating Parkinson disease.

The A-system preferentially transports glycine and neutral amino acids with short linear or polar side chains, such as alanine or serine. Unlike the L-system this carrier is Na⁺ -dependent, and pumps amino acids down a Na⁺ gradient that is maintained by Na⁺ -K⁺ -adenosine triphosphatase (ATPase), an ionic pump that uses ATP.

The ASC-system is also an energy-dependent and Na⁺ -dependent transporter that preferentially recognizes alanine, serine, and cysteine. A-system and ASC-system expression and function are localized at the abluminal endothelial cell surface. As a consequence of this localization these carriers are the primary means of transport of small neutral amino acids out of brain up a concentration gradient.

Another transport system found to be most abundant in brain barrier microvessels belongs to a family of ATP-binding cassette transporters (ABC transporters), a large family of transmembrane proteins expressed in many cell types. The first member of this family was identified for the ability to impart multiple drug resistance (MDR) to tumor cells. The MDR transporter limits the entry into cells of a wide range of natural and synthetic hydrophobic toxins (eg, vinca alkaloids, actinomycin-D) and therapeutic compounds (eg, cyclosporin). The ability of MDR transporters to pump certain steroid hormones suggests a physiologic role. MDR transporters are expressed by barrier endothelial cells but not by endothelial cells of most other tissues. This explains why MDR substrates do not readily cross the blood–brain barrier. Mice genetically engineered to lack MDR1a gene expression are much more sensitive than wild-type controls to centrally acting toxic compounds, indicating that MDR gene expression at the blood–brain barrier protects the brain from circulating neurotoxins.

Ion Channels and Exchangers

Specific ion channels and ion transporters mediate electrolyte movement across the blood–brain barrier. A nonselective luminal ion channel that is inhibited by both amiloride and atrial natriuretic peptide has been revealed in both in vivo studies of transport across brain microvessels and patch-clamp studies of cultured brain endothelial cells. Na⁺ /H⁺ and Cl^- /bicarbonate (HCO₃ ⁻) exchangers also appear to function at the luminal membrane.

The abluminal membrane of brain endothelial cells has a relatively high concentration of Na⁺ -K⁺ -ATPase that pumps K⁺ from the interstitial fluid into the endothelial cell and pumps Na⁺ out of the cell. This ion exchange uses ATP energy. In conjunction with K⁺ channels in astrocytes, this abluminal endothelial pump may play an important role in removing extracellular K⁺ released during neuronal activity (see Chapter 6).

Endothelial Enzyme Systems Form a Metabolic Blood–Brain Barrier

Transport systems and carriers are not the only mechanisms for regulating the composition of the interstitial fluid. Certain enzyme systems specific to the blood–brain barrier are also important. The first recognized and best characterized is the barrier to l-DOPA.

Plasma l-DOPA enters brain endothelial cells by means of the L-system amino acid transporter. The relatively large amounts of DOPA decarboxylase and monoamine oxidase in barrier endothelial cells rapidly metabolize l-DOPA to 3,4-dihydroxyphenylacetic acid, thereby inhibiting the entry of l-DOPA to brain (Figure D–7). This explains why effective therapy for Parkinson disease requires that l-DOPA be given together with an inhibitor of DOPA decarboxylase.

Other blood-borne amines, including catecholamines, are inactivated by monoamine oxidases of the barrier endothelium. Another barrier enzyme, γ-glutamyl transpeptidase, detoxifies glutathione-bound compounds and vasoactive leukotrienes.

Some Areas of the Brain Lack a Blood–Brain Barrier

Not all cerebral blood vessels are impermeable. Leaky structures include the posterior pituitary and the circumventricular organs: the area postrema, subfornical organ, laminar terminalis, subcommissural organ, and median eminence.

The absence of the blood–brain barrier in these regions is consistent with their physiologic functions. Neurosecretory products of the posterior pituitary have to pass efficiently across endothelial cells into the circulation. The subfornical organ is a chemoreceptor-rich area that monitors the blood level of angiotensin II to regulate water balance and other homeostatic functions.

These regions are isolated from the rest of the brain by specialized ependymal cells called tanycytes located along the ventricular surface close to the midline. The tanycytes are coupled by tight junctions and prevent free exchange between the circumventricular organs and the cerebrospinal fluid.

Brain-Derived Signals Induce Endothelial Cells to Express a Blood–Brain Barrier

The developing brain expresses the cellular and molecular signals that induce endothelial expression of the blood–brain barrier phenotype. The neural anlagen of the brain is vascularized early in development through the invasion of proliferating vessels derived from an extraneural vascular plexus. These perineural vessels are composed of fenestrated endothelial cells that have no blood–brain barrier properties. The fenestrations are lost soon after the endothelial cells penetrate neural tissue. The subsequent expression of different blood–brain barrier properties on the endothelium occurs gradually, consistent with a maturational cascade.

The brain parenchymal signals that induce endothelial barrier formation are not known. Of the principal cell types within the brain, astrocytes are thought to be particularly important for this function because of their intimate association with the abluminal surface of brain blood vessels and from experimental evidence in blood–brain barrier model systems.

Diseases Can Alter the Blood–Brain Barrier

A variety of pathological situations are associated with altered blood–brain barrier function. Many brain tumors, especially highly malignant ones, contain vessels with poorly developed blood–brain barriers. Such vessels are excessively leaky and lack the differentiated transport properties of normal blood–brain barrier vessels. The abnormal permeability accounts for the accumulation of interstitial fluid (ie, vasogenic edema) commonly associated with brain tumors. The abnormal properties of tumor endothelial cells are presumably due to either the absence of normal interactions between astrocytes and capillaries or by the secretion of growth factors and cytokines by tumor cells. Factors secreted by tumors that enhance vessel proliferation and permeability include vascular endothelial growth factor (VEGF), hepatocyte growth factor/scatter factor (HGF/SF), and matrix metalloproteinases.

The blood–brain barrier is also altered in bacterial meningitis. The barrier is normally impermeable to antibiotics such as penicillin. Bacterial meningitis, abscesses, and their associated inflammatory responses cause partial breakdown of the blood–brain barrier. This barrier response appears to be mediated in part by the accumulation of vasoactive eicosanoids; inflammatory cytokines such as tumor necrosis factor, interleukins, and macrophage chemoattractant protein-1; and matrix metalloproteinases that degrade capillary basement membranes. This barrier dysfunction accounts for many adverse neurological effects of meningitis but it also enhances the delivery of antibiotics that inefficiently penetrate across an intact barrier.

Because development and function of the normal brain are closely linked to specific anatomical, biochemical, and transport properties of the blood–brain barrier, specific defects in genes that code for barrier endothelial proteins might account for inherited brain disorders. The first disorder of blood–brain barrier transport to be recognized involves insufficient endothelial transport of glucose because of sporadic mutations in the glut1 gene causing Glut1 haploinsufficiency. Patients with this syndrome are normal at birth but soon develop poorly controlled seizures, diminished brain growth, and mental retardation in association with a substantially diminished concentration of cerebrospinal fluid glucose.

Cerebrospinal fluid is secreted in the cerebral ventricles mainly by the choroid plexuses (Figure D–8A), capillary networks that are surrounded by cuboidal or columnar epithelium. The CSF flows from the lateral ventricles through the interventricular foramina of Monro into the third ventricle. From there it flows into the fourth ventricle through the cerebral aqueduct of Sylvius and then through the foramina of Magendie and Luschka into the subarachnoid space. The subarachnoid space lies between the arachnoid and the pia mater, which, together with the dura mater, form the three meningeal layers that cover the brain (Figure D–8B). Within the subarachnoid space, fluid flows down the spinal canal and also upward back over the convexity of the brain (Figure D–8A).

The CSF flowing over the brain extends into the sulci and the depths of the cerebral cortex in extensions of the subarachnoid space along blood vessels called the Virchow-Robin spaces. Small solutes diffuse freely between the interstitial fluid and the CSF in these perivascular spaces and across the ependymal lining of the ventricular system, facilitating the movement of metabolites from deep within the hemispheres to cortical subarachnoid spaces and the ventricular system. This flow of interstitial fluid across the ependymal surface into the ventricular system (extrachoroidal cerebrospinal fluid production) is believed to account for at most a small percentage of total CSF production.

The total volume of CSF is estimated to be approximately 140 mL. Under normal conditions the lateral and third ventricles contain approximately 12 mL and the spinal subarachnoid space approximately 30 mL as measured by computed tomography. The remaining 100 mL is in the subarachnoid space and the major cisterns of the brain (eg, cisterna magna, mesencephalic cistern).

The CSF is absorbed through the arachnoid granulations and villi. Arachnoid granulations consist of clusters of villi that typically form visible herniations of the arachnoid membrane through the dura and into the lumen of the superior sagittal sinus and other venous structures (Figure D–8). The villi themselves are visible microscopically and positioned between the CSF and venous blood. Cells of the villus membrane contain vacuoles that transport fluid from one side of the cell to the other (Figure D–9).

The granulations appear to function as valves that allow one-way flow of CSF from the subarachnoid spaces into venous blood. This one-way flow of CSF is sometimes called bulk flow because all constituents of CSF leave with the fluid, including small molecules, proteins, microorganisms, and red blood cells. The rate of formation of CSF in adults is 0.35 mL per minute or approximately 500 mL per day, so that the entire volume of CSF is turned over three or four times a day.

Cerebrospinal Fluid Has Several Functions

The CSF communicates with brain interstitial fluid and therefore helps maintain a constant extracellular environment for neurons and glia. The one-way flow of CSF from the ventricular system into the subarachnoid space and into the venous sinuses is a major route for removing potentially harmful brain metabolites.

The CSF also provides a mechanical cushion to protect the brain from impact with the bony calvarium when the head moves. By its buoyant action the CSF allows the brain (average weight 1400 g) to float, thereby reducing its effective weight in situ to less than 50 g.

The CSF may also serve as a lymphatic system for the brain and as a conduit for polypeptides that are secreted by hypothalamic neurons and act at remote sites in the brain. The pH of CSF affects both pulmonary ventilation and cerebral blood flow, another example of the homeostatic role of CSF.

Epithelial Cells of the Choroid Plexuses Account for the Blood–Cerebral Spinal Fluid Barrier

The choroid plexuses are structurally similar to the distal and collecting tubules of the kidney, using capillary filtration and epithelial secretory mechanisms to maintain the chemical stability of the CSF. The capillaries that traverse the choroid plexuses are freely permeable to plasma solutes. A barrier exists, however, at the choroid epithelial cells. The transport and exchange of substances by the choroid plexuses are bidirectional, accounting for both continuous production of CSF and active transport of metabolites out of the central nervous system into the blood (Figure D–10).

The cerebrospinal and extracellular fluids of the brain are in a steady state under normal physiological circumstances. The concentrations of K⁺, Ca²⁺, bicarbonate, and glucose in the CSF are lower than in blood plasma, and CSF is also more acidic (Table D–1). These differences are a result of regulation of the constituents of CSF by active transport at the choroid plexus epithelium. Under normal conditions blood plasma and CSF are in osmotic equilibrium, because water follows the osmotic gradient that is created by active transport of solutes.

Choroid Plexuses Nurture the Developing Brain

The choroid plexuses appear as epithelial invaginations soon after neural tube closure where the lateral, third, and fourth ventricles will eventually form. They become vascularized and begin producing CSF before the brain becomes well vascularized. The ultimate vascularity of the choroid plexuses is high. In the mature rat blood flow per gram of tissue is as much as fivefold higher in the choroid plexus than in cerebral cortex.

Production of CSF during early brain development is believed to have multiple functions. The hydrodynamic and pressure effects of CSF production may specifically influence the developing brain's three-dimensional shape and laminar organization. The CSF may be a source of nutrition for the developing prevascularized brain, as the choroid epithelial cells deliver substances from blood to the CSF for the developing brain. Initially this blood-to-CSF transfer occurs relatively nonspecifically through a transcellular tubular-cisternal endoplasmic reticular system. It becomes more selective as the choroid epithelial cells differentiate to create a mature blood–CSF barrier. The choroid epithelial cells also synthesize and secrete proteins that may have paracrine effects on the development of neighboring neuroepithelial cells.

Increased Intracranial Pressure May Harm the Brain

In considering the factors that regulate intracranial pressure, the cranium and spinal canal should be regarded as a closed system. According to the Monro-Kellie doctrine, an increase in the volume of any one of the contents of the calvarium—brain tissue, blood, CSF, or other brain fluids—will increase intracranial pressure because the bony calvarium rigidly fixes the total cranial volume. Mass lesions and their associated interstitial edema commonly increase intracranial pressure.

Changes in arterial and intracranial venous pressures may also influence intracranial pressure by their actions on intracranial blood volume and CSF dynamics. Acute changes in arterial or venous pressures can change intracranial pressure dramatically. Chronic changes may be compensated by several mechanisms, including venous collateralization and increased absorption or decreased formation of CSF.

Cerebrospinal fluid pressure is ordinarily measured by lumbar puncture. With the patient lying sideways (lateral decubitus position), a needle is inserted between the fourth and fifth lumbar vertebrae and into the lumbar subarachnoid space. Because the spinal cord extends only to the first lumbar vertebra, there is no risk of injuring the spinal cord. When the CSF flows freely through the needle, the hub of the needle is attached to a manometer, and the fluid is allowed to rise. The normal pressure is 65 to 195 mm CSF (or water), or 5 to 15 mm Hg.

In using the lumbar CSF pressure as a guide to intracranial pressure, it is assumed that pressures are equal throughout the neuraxis. Normally this is reasonable; but in many diseases (eg, brain tumor or obstruction of CSF pathways) this may not be true. For this reason, and also because the lumbar needle cannot be left in place for prolonged periods, catheters are sometimes inserted into the lateral ventricles to measure pressure there (Figure D–11).

Equally effective are pressure-sensitive transducers that can be inserted under the skull in the epidural or subarachnoid space for continuous monitoring of intracranial pressure. Continuous monitoring has the advantage of identifying waves of transiently elevated intracranial pressure that can occur in certain disorders, such as normal pressure hydrocephalus.

Brain edema may be local (eg, from a surrounding contusion, infarct, or tumor) or generalized. The brain is divided into compartments by relatively noncompliant membranes. Local brain edema may cause herniation of brain tissue across these membranes. Specific examples include herniation of the cingulate gyrus across the falx cerebri, temporal lobe uncus across the cerebellar tentorium, or cerebral cortex outward through calvarial defects after surgery.

Vasogenic edema is the most common form of brain edema. It is attributed to increased permeability of brain capillary endothelial cells, which increases the volume of the extracellular fluid. White matter is generally affected more than gray because of the tendency of edema fluid to accumulate along tracts of white matter. Vasogenic edema is most easily visualized using magnetic resonance imaging. Pathological increases in permeability of the blood–brain barrier also can be visualized by computerized tomography and magnetic resonance imaging after intravenous administration of contrast agents that selectively enter the brain through the affected vessels

Cytotoxic edema refers to the intracellular swelling of injured neurons, glia, and endothelial cells. It occurs in hypoxia from asphyxia or global cerebral ischemia after cardiac arrest because failure of the ATP-dependent Na⁺ -K⁺ pump allows Na⁺, and therefore water, to accumulate within cells. Another cause of cytotoxic edema is water intoxication, a consequence of the acute systemic hypo-osmolarity caused by drinking excessive amounts of water or administration of hypotonic intravenous fluids. Acute hyponatremia, which can be induced for example by inappropriate secretion of antidiuretic hormone or renal salt-wasting from secretion of atrial natriuretic hormone, can cause cellular swelling and brain edema. Under these circumstances water moves from extracellular to intracellular sites. Cytotoxic edema may also accompany vasogenic edema in encephalitis, trauma, and stroke.

A family of water channels, the aquaporins, regulate fluid homeostasis in the brain and other organs by facilitating the movement of water through cellular membranes. The 11 known aquaporins (AQP0 to AQP10) consist of two tandem repeats of three transmembrane α-helixes and two connecting loops, each containing an asparagine-proline-alanine motif, that form a membrane pore of 3–6 Å diameter (Figure D–12).

Six family members (AQP1, AQP3, AQP4, AQP5, AQP8, AQP9) exist in the rodent brain. The AQP4 protein is produced by ependymal cells and astrocytes but not neurons. It appears in the endothelial cells and perivascular processes of astrocytes concurrent with the development of the blood–brain barrier; expression is altered in disorders producing blood–brain barrier dysfunction and cerebral edema. The AQP4 and AQP9 channels are found in astrocyte processes in periventricular regions and in the glia limitans bordering the subarachnoid space and thus may have a role in facilitating movement of water between CSF and brain parenchyma. The AQP1 channel appears to transport water at the choroid plexus during CSF formation.

Hydrocephalus has three possible causes: oversecretion of cerebrospinal fluid, impaired absorption of CSF, or obstruction of CSF pathways. Oversecretion of CSF is rare but is thought to occur in some functioning tumors of the choroid plexus (papilloma) because removal of the tumor may relieve the hydrocephalus. These tumors are associated with subarachnoid hemorrhage and high CSF protein content, which could also impair the absorption of CSF.

Impaired absorption of CSF may result from any condition that raises intracranial pressure, such as thrombosis of cerebral veins or sinuses. Impaired CSF absorption at the arachnoid villi is a common cause of communicating hydrocephalus (enlargement of the entire ventricular system without obstruction of CSF flow) following subarachnoid hemorrhage, trauma, or bacterial meningitis.

Impaired CSF absorption is also believed to be the cause of normal-pressure hydrocephalus, which is characterized by dementia, urinary incontinence, and a disorder of gait called apraxia. Brain imaging reveals communicating hydrocephalus, and routine lumbar puncture typically shows normal intracranial pressure. However, continuous intracranial pressure monitoring reveals episodic elevations in intracranial pressure, suggesting that intermittent intracranial hypertension causes the condition. The clinical symptoms are believed to result from the effects of the expanded lateral ventricles and abnormal absorption of CSF through the ventricular ependymal lining on the surrounding subcortical white matter tracts.

Obstruction of CSF pathways may result from tumors, congenital malformations, or scarring. A particularly vulnerable site for all three mechanisms is the narrow aqueduct of Sylvius. Aqueductal stenosis may result from congenital malformations or gliosis because of intrauterine infection or hemorrhage. Later in life the aqueduct may be occluded by tumor. The outlets of the fourth ventricle may be obstructed by congenital atresia of the foramina of Luschka and Magendie, which may lead to enlargement of all four ventricles (Dandy-Walker syndrome). Obstruction of flow at the basilar cisterns, resulting from conditions such as intraventricular hemorrhage or meningitis, can also cause enlargement of the entire ventricular system. In early life the cranial vault enlarges with the ventricles; after the sutures fuse, cranial volume is fixed and hydrocephalus develops at the expense of brain volume.