1 Overview
CSF Formation Rate
| Produced mainly by choroid plexuses, CSF is formed at 0.4 ml/min/g in several mammals. Human production rates vary from 0.3 to 0.6 ml/min depending upon measurement method. CSF formation, an active secretion by epithelial cells, involves pumps, cotransporters & antiporters, ion channels and aquaporins [1, 77]. It is under neuroendocrine & hormonal modulation [6, 246]. Daily volume of CSF produced in adult humans is 500–600 ml. |
CSF Pressure
| In adult humans the normal CSFP is about 100 mm H2O. Ventricular pressure is normally about 35 mm H20 in rats. CSFP is typically slightly higher than venous pressure in the dural sinuses. CSFP is stable when CSF formation and reabsorption are balanced. Elevated CSFP is reduced by acetazolamide, which inhibits formation of fluid by the choroid plexus [36, 43, 44]. |
CSF Flow
| Flow of CSF is pulsatile [185, 192]. CSF pulsations depend upon the arterial hemodynamics in the plexus. CSF flow is from the lateral to 3rd and 4th ventricles. CSF flows out of 4th ventricular foramina into basal cisterns [1]. It is then convected into the spinal and cortical subarachnoid spaces. |
CSF Volume
| In healthy humans, the ventricular and subarachnoid CSF spaces, respectively, are about 25% and 75% of total CSF volume [1]. Total CSF space in young adults is about 160 ml, i.e., more than half that of brain interstitial fluid volume. The ratio of CSF volume to brain volume increases in aging and neurodegeneration [9, 19]. |
CSF Turnover Rate
| CSF turnover rate is directly proportional to CSF formation rate and inversely related to CSF volume [3]. It is an index of CSF sink action on brain interstitial solutes [33]. Clearance of brain metabolites depends on a CSF renewal of 0.3–0.4% per min. Mammalian CSF is totally replaced about 4 times each day. |
CSF Composition
| CSF is an active secretion, not simply a plasma ultrafiltrate [1]. Carrier transport of ions and molecules, along with molecular sieving at blood-CSF barrier, generates a CSF concentration lower than plasma in protein, K [221] & urea [33]; and higher in Cl & Mg. Disease distorts CSF chemistry, enabling CSF biomarking [227]. CSF is 99% water, compared to the 92% water of plasma. |
CSF Recycling
| In addition to CSF macrocirculation through ventriculo-subarachnoid spaces, there is limited microcirculation of CSF recirculated by bulk flow from the cortical subarachnoid space into Virchow-Robin perivascular spaces and then out of brain via CSF drainage routes [253–255]. |
CSF Reabsorption
| CSF is cleared from CNS by bulk flow along sleeves of the subarachnoid space surrounding cranial nerves that enter the nose and eyes [263, 264]. Substantial drainage occurs through the cribriform plate, the CSF eventually reaching the nasal submucosa and downstream cervical lymphatics [267, 268]. CSF is also cleared along spinal nerves [279]. Lymphatic drainage of CSF needs substantiation in humans. Arachnoid villi in dural venous sinuses may serve as ancillary drainage sites when CSFP is elevated. |
2 CSF formation
- Modulation of transcription factors or nuclear receptors that control expression of enzymes involved in CSF formation |
Molecular targets: p73, foxJ1, and E2F5 [30, 31] |
- Interference with the basolateral and apical membrane-associated ion translocaters (cotransporters, exchangers and pumps) |
Molecular targets: Na-K-Cl cotransporter [45–48]; Na-H exchanger [36–38]; Cl-HCO3 exchanger [40, 55]; Na pump [49, 106, 107, 110] Na-HCO3 cotransporter [41]; Na-dependent Cl-HCO3 exchanger [42] K and anion channels in apical membrane [68] |
- Inhibition of the enzymatic generation of labile ions in cytoplasm and in microdomains of the plasma membrane |
Molecular targets: carbonic anhydrase isoforms [43, 44, 52, 53, 56–58] |
- Regulation of the expression and activity of aquaporin water-conducting channels in the apical (CSF-facing) plasma membrane |
Molecular target: Aquaporin 1 channel [65–68, 70–78, 292] |
- Stimulation of plasma membrane receptors for fluid-regulating neuropeptides |
Molecular targets: V1 receptor [83, 84, 90, 207, 210, 217]; NPR receptors [85, 97, 101, 103]; AT1 receptor [217] |
2.1 Transcription factors
2.2 Ion transporters
2.3 Enzymes that modulate transport
2.4 Aquaporins or water channels
2.5 Receptors for neuropeptides
ANP | AVP | ANG II | FGF2 | |
---|---|---|---|---|
Effect on CSF formation after i.c.v. administration of neuropeptide [84, 87, 178, 217] | ↓ | ↓ | ↓ | ↓ |
Peptidergic effect on choroidal blood flow [84, 139] | ↑ | ↓ | ↓ | N/A* |
Inducer of neuro-endocrine-like dark epithelial cells in choroid plexus? [82, 83, 178] | Yes | Yes | N/A | Yes |
Choroid epithelial receptors for peptides [83, 85, 103, 211, 217] | NPR-A | V1 | AT1 | FGFR2 |
Concentration of peptide in CSF in hydrocephalus or increased ICP [98–100, 104] | ↑ | ↑ | N/A | N/A |
3 CSF pressure
3.1 Servomechanism regulatory hypothesis
3.2 Ontogeny of CSF pressure generation
3.3 Congenital hydrocephalus and periventricular regions
3.4 Brain response to elevated CSF pressure
3.5 Advances in measuring CSF waveforms
4 CSF flow
4.1 CSF flow and brain metabolism
4.2 Flow effects on fetal germinal matrix
4.3 Decreasing CSF flow in aging CNS
4.4 Refinement of non-invasive flow measurements
5 CSF volume
5.1 Hemodynamic factors
5.2 Hydrodynamic factors
5.3 Neuroendocrine factors
6 CSF turnover rate
Rat Aging* | Human Disease† | |||||
---|---|---|---|---|---|---|
3 mo | 19 mo | 30 mo | Normal | NPH | AD | |
CSF Formation Rate (ml/min)
| 0.00121 | 0.00148 | 0.00065 | 0.40 | 0.25 | 0.20 |
CSF Volume (space) (ml)
| 0.156 | 0.196 | 0.308 | 150 | 300 | 250 |
CSF Turnover Rate (volumes/day)
| 11 | 10.8 | 3.0 | 4 | 1.2 | 1.2 |
6.1 Adverse effects of ventriculomegaly
6.2 Attenuated CSF sink action
7 CSF composition
7.1 Kidney-like action of CP-CSF system
7.2 Altered CSF biochemistry in aging and disease
7.3 Importance of clearance transport
7.4 Therapeutic manipulation of composition
8 CSF recycling in relation to ISF dynamics
8.1 CSF exchange with brain interstitium
8.2 Components of ISF movement in brain
8.3 Compromised ISF/CSF dynamics and amyloid retention
9 CSF reabsorption
9.1 Arachnoidal outflow resistance
9.2 Arachnoid villi vs. olfactory drainage routes
9.3 Fluid reabsorption along spinal nerves
9.4 Reabsorption across capillary aquaporin channels
10 Developing translationally effective models for restoring CSF balance
A | |
---|---|
Aquaporin 1 (Blood-CSF Interface) | Aquaporin 4 (Blood-Brain Interface) |
AQP1 is present at the CSF-facing pole of choroid plexus epithelium [70 – 73, 77, 78], and in the CSF-brain ependymal lining [281]. | AQP4 is located in astrocytic foot processes at the BBB. It is associated with fluid transfer across cerebral microvessels. |
Reduced expression in choroid plexus is associated with slower rates of CSF secretion and thus decreases ICP [77, 78]. | Elevated expression of AQP4 in the BBB occurs in chronic hydrocephalus [281 – 283]; may be associated with fluid reabsorption. |
Attenuated expression in aging [57] and in Alzheimer's disease is accompanied by slower fluid turnover rate [79]. | Diminished expression at BBB leads to a reduction in brain edema formation in some animal models. |
B
| |
LRP-1 (Low density lipophilic receptor associated protein) | RAGE (Receptor for advanced glycation end products) |
Expressed in choroidal epithelium and capillary endothelium [229, 257]. | Expressed in choroidal epithelium and brain capillary endothelium [257]. |
Removes Aβ peptide from CSF and brain ISF [229, 243] for excretion via blood. | Transports Aβ from blood into brain ISF where the retained peptide may predispose to Aβ plaque formation in the interstitium. |
Sustained or increased expression in choroid plexus during aging, NPH and AD. | Enhanced expression of RAGE at BBB in aging, NPH [219] and AD [225] may destabilize BBB and precipitate plaque. |
Decreased expression of LRP-1 at the BBB in aging, NPH and AD likely interferes with Aβ removal [219, 225, 229]. | Expression of RAGE is generally opposite to that of LRP-1 at the barriers and in neurons [225]. |