Dan Greitz Dept. of Neuroradiology Karolinska University Hospital Stockholm, Sweden
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Transcript of Dan Greitz Dept. of Neuroradiology Karolinska University Hospital Stockholm, Sweden
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Dan GreitzDept. of Neuroradiology
Karolinska University HospitalStockholm, Sweden
New view on the CSF circulation:New view on the CSF circulation: CSF production and CSF absorption CSF production and CSF absorption
by brain capillariesby brain capillaries
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Major differences between Major differences between the new and old concept of the new and old concept of CSF circulation
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Normal CSF circulationNormal CSF circulationold CSF bulk flow modelold CSF bulk flow model
• There is bulk flow of CSF from the intraventricular plexus to the arachnoid granulations
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Normal CSF circulationNormal CSF circulation New model New model
The CSF is producedand absorbed by thebrain capillaries
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CSF pCSF production and CSF absorptionBulk flow model New model
The CSF is produced and absorbed by the brain capillaries
The CSF is produced by the choroid plexus and absorbed by the arachnoid granulations
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Bulk flow model New modelBulk flow model New model
Major routes of water flow into and out of the brainMajor routes of water flow into and out of the brain
choroid plexus
arachnoid granulation blood-brain barrier
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Bulk flow model New modelBulk flow model New model
choroid plexus
arachnoid granulation blood-brain barrier
Major routes of water flow into and out of the brainMajor routes of water flow into and out of the brain
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New Concept of CSF CirculationNew Concept of CSF Circulation
1. The CSF is absorbed by the brain capillaries
2. The major part of the CSF is produced by the brain capillaries
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New Concept of CSF CirculationNew Concept of CSF Circulation
1. CSF absorption by brain capillaries
2. CSF production by brain capillaries
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The CSF bulk flow modelThe CSF bulk flow model
is based on the assumption that the arachnoid granulations absorb all proteins and macromolecules in the CNS and that –
brain capillaries are impermeable to macromolecules !
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Blood-brain barrierBlood-brain barrier
Due to the tight junctions, the BBB is almost impermeable to water-soluble molecules
Can they pass in the other direction from brain-to-blood?
Tight junctions
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Reed & Woodbury: J Physiol 1963
Rapid elimination of albumin from the CSF
Rapid transport of albumin from CSF to plasma – half-time max in plasma occurs at 90 min
Rapid transport of albuminfrom the CSF into the brain
Albumin transport Albumin transport from from CSF to bloodCSF to blood
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Inulin transport from CSF to bloodInulin transport from CSF to blood
Reed & Woodbury: J Physiol 1963
Rapid elimination of inulin from the CSF
Rapid transport of inulin from CSF to plasma – half-time max in plasma 60 min
Rapid transport of inulinfrom the CSF into the brain
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Albumin transport from blood to CSFAlbumin transport from blood to CSF
Reed & Woodbury: J Physiol 1963
After i.v. injection, there is a small but significant transport of albumin from the blood to the CSF and to the brain
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Absorption of contrast medium from CSF to bloodAbsorption of contrast medium from CSF to blood
Golman K: Neuroradiology 1979
At myelography in rabbits, there is a rapid transport of contrast from CSF to blood
Peak concentration in blood occurs within 1 hour
Golman K: Neuroradiology 1979
Blood concentration curve
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Absorption of contrast medium from CSF to bloodAbsorption of contrast medium from CSF to blood
Enzmann D: Radiology 1979
At myelography in humans, there is a rapid transport of contrast from CSF to blood
Peak concentration in bloodoccurs within 2 hours
CT-cisternography (yellow): convexity-maximum occurs at 24h
Blood concentration curve
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Rapid transport of contrast mediuminto the brain cortex
1 hour after i.c. injection in rabbit Sage M: AJR 1983
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3 hours
24 hours
T. Hindmarsh
CT-cisternography
At 3 hours,there is penetration of the contrast medium into the brain cortex
At 24 hours, almost all contrast is located in brain tissue
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Blood brain barrier?Blood brain barrier?
BloodBrain
CSF
BloodBrain
CSF
BloodBrain
CSF
Conclusion:Non diffusible colour tracer
Ehrlich 1885 and Goldmann 1913
Impermeable to dye Permeable to dye
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Blood brain barrierBlood brain barrier
BloodBrain
CSF
BloodBrain
CSF
BloodBrain
CSF
BloodBrain
CSF
Conclusion:
Inulin, albumin, Iodine, contrast media
Reed & Woodbury 1963
1-2 days
CSF
Brain
2-8 hours
Rapid transport from CNS to blood
D Greitz 1993
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What is the biological substrate for the What is the biological substrate for the active transport at the BBB ?active transport at the BBB ?
Tight junctions
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• Betz discovered the first efflux transporter of amino acids (1978) – since then 40 different efflux transporters have been identified
Several brain to blood efflux transporters have been discovered at the BBB
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transport numerous of endogenous and exogenous molecules
from the brain to the blood
Brain to blood efflux transporters
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Brain-to-blood efflux transporters
Löscher 2005
Immuno-fluorescence study of P-glycoprotein
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Multidrug transporter P-glycoprotein (fluorescence green)
Capillary wall
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The efflux transporters act as a detoxifying system for the brain
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p-Aminohippuric acid (PAH)
Half-time disappearancerate from brain:
12 min for PAH
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= capillary endothelium
Brain Blood
The BBB is the only membrane that separates The BBB is the only membrane that separates the brain from the bloodthe brain from the blood
Brain water and protein concentrationBrain water and protein concentration
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= capillary endothelium
Brain Blood ISF CSF Plasma
Protein concentration in plasma is 200 times higher than in CSF
Brain water and protein concentrationBrain water and protein concentration
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= capillary endothelium
Protein concentration in plasma is 200 times higher than in CSF
Active transportof proteins
Brain Blood ISF CSF Plasma
Brain water and protein concentrationBrain water and protein concentration
The low protein concentration in the CSF and ISF The low protein concentration in the CSF and ISF is maintained by active transport is maintained by active transport
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Further evidence of Further evidence of rapid transport and rapid absorption rapid transport and rapid absorption
in brain tissuein brain tissue
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Intracerebral transport of HRPIntracerebral transport of HRP
Wagner: Acta Neuropathol 1974
10 min post intracisternal injection !!
Frontal section of rat brain Artery W-R space
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Capillary absorption ofCapillary absorption of HRP HRP
Wagner: Acta Neuropathol 1974Capillary after intracisternal injection
1h 24h triple dose
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Banks & Broadwell: J Neurochem 1994
Intracerebral transportIntracerebral transport of HRP of HRP afterafter intraintraventricular injectionventricular injection in mice in mice
5 min postinjection
4 h postinjection
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Banks & Broadwell: J Neurochem 1994
BrainBrain to blood efflux of HRP and albumin to blood efflux of HRP and albuminafter intraventricular injectionafter intraventricular injection
Half-time disappearance
from brain:
44 min for HRP
42 min for albumin
Brain concentration curve
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Thus: macromolecules are actively absorbed by the capillaries
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To sum up:
• The CSF is absorbed by the brain capillaries
• Water-soluble molecules in the CSF are actively absorbed by the brain capillaries
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New Concept of CSF CirculationNew Concept of CSF Circulation
1. CSF absorption by brain capillaries
2. CSF production by brain capillaries
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The CSF bulk flow modelThe CSF bulk flow model
is based on the assumption thatthe major part of the intracranial fluid is formed by the choroid plexus and that –
there is no fluid production in the brain capillaries !
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Ekstedt 1975
CSFprod
ICP
CSF infusion tests in healthy volunteersCSF infusion tests in healthy volunteers
Linear relation between CSF production and intracranial pressure (ICP) Linear relation between CSF production and intracranial pressure (ICP)
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Intracranial pressure (ICP)
ICP = CSFprod x R
R
The ICP is directly dependent on
the CSF production in choroid plexus
plexus arachnoid granulation
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Intracranial pressure (ICP)
ICP = CSFprod x R
R
plexus
Capillaryfluid prod
The bulk flow theory is based on assumption that - there is no fluid production in the capillaries!
= 0
arachnoid granulation
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Intracranial pressure (ICP)
ICP = Capfluid prod x R
R
plexus
Capillaryfluid prod
outflow resistance
If the fluid production in the capillary is significant – the ICP instead must be dependent on this production!
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How much of the CSF formation How much of the CSF formation is produced by the choroid plexus?is produced by the choroid plexus?
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Milhorat Science 1969
Experimental hydrocephalus in monkeyswith and without plexectomy
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Measurement of CSF formation
• Infusion with a CSF tracer of known concentration and inflow rate
• With no CSF formation the outflow concentration equals inflow concentration
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Measurement of CSF formation
• With CSF formation, there is dilution in the outflow concentration
• CSF prod = inflow rate x dilution in %
dilution = (inflow conc – outflow conc) / outflow conc
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Subarachnoid CSF production:
(red arrows)60 % of total CSF production isproduced in the subarachnoid space
Inflow
Outflow
Sato Bering 1965
CSF production
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Subarachnoid CSF production:
(red arrows)60 % of total CSF production isproduced in the subarachnoid space
Ventricular CSF production:
(via 2 ventricular needles)Only 40 % of total CSF production isproduced in the ventricular system
Sato Bering 1965
CSF production
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Ventricular CSF production:
Only 40 % of total CSF is producedin the ventricular system
Milhorat Science 1969
CSF production after plexectomy
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Ventricular CSF production:
Only 40 % of total CSF is produced inthe ventricular system
Ventricular CSF prod. after plexectomy:
Only 30% of the ventricular CSF is produced in the choroid plexus
Milhorat Science 1969
CSF production after plexectomy
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Ventricular CSF production:
Only 40 % of total CSF is produced inthe ventricular system
Ventricular CSF prod. after plexectomy:
Of the ventricular CSF production, only30% is produced in the choroid plexus
This indicates that:12% of the total CSF is produced by the choroid plexus
Milhorat Science 1969
CSF production after plexectomy
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Ventricular infusion without plexectomy:
Only 40 % of total CSF is produced inthe ventricular system
Ventricular infusion after plexectomy:
Of the ventricular CSF production, only30% is produced in the choroid plexus
Thus:12% of the total CSF is produced by the choroid plexus88% of the total CSF is produced by the brain capillaries
Milhorat Science 1969
CSF production after plexectomy
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CSF production
Only a minor part of the CSF is produced by the choroid plexus
New model
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Bulk flow model New modelBulk flow model New model
Major route of water flow into and out of the brainMajor route of water flow into and out of the brain
choroid plexus
arachnoid granulation blood-brain barrier
XX
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1. The major part of the CSF is produced
and absorbed by the brain capillaries
2. Brain capillaries actively transport water-
soluble molecules from the brain
3. Active transport from brain to blood is
a prerequisite for brain homeostasis
ConclusionsConclusions