Cerebrospinal fluid production by the choroid plexus: a century of barrier research revisited

MacAulay, Nanna; Keep, Richard F.; Zeuthen, Thomas

doi:10.1186/s12987-022-00323-1

Cited by 71 publications

(68 citation statements)

References 202 publications

(413 reference statements)

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“…The osmolality of bulk CSF is similar to that of the plasma [11], and CSF secretion thus appears to be able to occur in the absence of conventional osmotic forces and, curiously, can readily proceed even in the face of an experimentally-inflicted, oppositely-directed osmotic gradient [11][12][13]. Such fluid secretion is proposed to take place by a mechanism relying on transporter-mediated water transport [11,36,37]. However, the CSF secretion rate increases with elevated ventricular osmolality [11][12][13][14]38], in the order of 0.4% elevation of the secretion rate with each milliosmole in the rat [11].…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid osmolality cannot predict development or surgical outcome of idiopathic normal pressure hydrocephalus

Oernbo

Steffensen

Gredal

et al. 2022

Fluids Barriers CNS

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Background The etiology of idiopathic normal pressure hydrocephalus (iNPH) is currently unknown. With no visible obstructions, altered cerebrospinal fluid (CSF) dynamics may explain the accumulation of ventricular fluid. We hypothesized that elevated osmolality in the CSF of iNPH patients could potentiate formation of ventricular fluid and thereby cause the disease progression and/or predict the surgical outcome. To address this hypothesis, we determined the lumbar and ventricular CSF osmolality of iNPH patients at different disease stages and compared with lumbar CSF samples obtained from control subjects. Methods The osmolality of CSF was determined on a total of 35 iNPH patients at diagnosis and at the subsequent treatment with shunt surgery (n = 20) and compared with the CSF osmolality from 20 control subjects. Simultaneously collected lumbar and ventricular CSF samples from experimental pigs were used to evaluate the compatibility between CSF from different compartments. Results We found no evidence of increased osmolality in the CSF of iNPH patients upon diagnosis or at the time of shunt treatment months after the diagnosis, compared with control individuals. CSF tapped from the lumbar space could be used as a read-out for ventricular CSF osmolality, as these were similar in both the patient group and in experimental pigs. We further observed no correlation between the CSF osmolality in iNPH patients and their responsiveness to shunt surgeries. Conclusions The osmolality of lumbar CSF is a reliable reflection of the ventricular CSF osmolality, and is not elevated in iNPH patients. iNPH therefore does not appear to arise as a function of osmotic imbalances in the CSF system and CSF osmolality cannot serve as a biomarker for iNPH or as a predictive tool for shunt responsiveness.

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Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid osmolality cannot predict development or surgical outcome of idiopathic normal pressure hydrocephalus

Oernbo

Steffensen

Gredal

et al. 2022

Fluids Barriers CNS

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“…The area of the choroid plexus region was A choroid = 9.33 × 10 2 mm 2 . Given that the daily CSF production from the choroid plexus is Q ∼ 500 ml d −1 [36], the CSF production rate of the choroid plexus was defined as vchoroid=QAchoroid∼6.2 μnormalm normals−1.Note that while the CSF production rate may be varied among choroid plexus [37], we assumed the same production rate for simplicity. The CSF production from the choroid plexus was modelled as a velocity boundary condition.…”

Section: Methodsmentioning

confidence: 99%

“…Note that while the CSF production rate may be varied among choroid plexus [37], we assumed the same production rate for simplicity. The CSF production from the choroid plexus was modelled as a velocity boundary condition.…”

Section: Choroid Plexusmentioning

confidence: 99%

Effect of cilia-induced surface velocity on cerebrospinal fluid exchange in the lateral ventricles

Yoshida

Ishida

Yamamoto

et al. 2022

J. R. Soc. Interface.

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Ciliary motility disorders are known to cause hydrocephalus. The instantaneous velocity of cerebrospinal fluid (CSF) flow is dominated by artery pulsation, and it remains unclear why ciliary dysfunction results in hydrocephalus. In this study, we investigated the effects of cilia-induced surface velocity on CSF flow using computational fluid dynamics. A geometric model of the human ventricles was constructed using medical imaging data. The CSF produced by the choroid plexus and cilia-induced surface velocity were given as the velocity boundary conditions at the ventricular walls. We developed healthy and reduced cilia motility models based on experimental data of cilia-induced velocity in healthy wild-type and Dpcd-knockout mice. The results indicate that there is almost no difference in intraventricular pressure between healthy and reduced cilia motility models. Additionally, it was found that newly produced CSF from the choroid plexus did not spread to the anterior and inferior horns of the lateral ventricles in the reduced cilia motility model. These findings suggest that a ciliary motility disorder could delay CSF exchange in the anterior and inferior horns of the lateral ventricles.

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“…In clinical studies, the PK is sampled from the cerebrospinal fluid (CSF) as a surrogate of brain exposure ( Pestalozzi and Brignoli, 2000 ; Rubenstein et al, 2007 ; Stemmler et al, 2007 ), however this is not appropriately reflecting the drug concentration in the ISF of the brain ( Pardridge, 2016 ). This discrepancy may be caused by the high perfusion of the choroid plexus ( Kouhi et al, 2021 )as well as the comparative leakiness of their capillary ( Damkier et al, 2013 ; MacAulay et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Investigating brain uptake of a non-targeting monoclonal antibody after intravenous and intracerebroventricular administration

et al. 2022

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Monoclonal antibodies play an important role in the treatment of various diseases. However, the development of these drugs against neurological disorders where the drug target is located in the brain is challenging and requires a good understanding of the local drug concentration in the brain. In this original research, we investigated the systemic and local pharmacokinetics in the brain of healthy rats after either intravenous (IV) or intracerebroventricular (ICV) administration of EGFRvIII-T-Cell bispecific (TCB), a bispecific monoclonal antibody. We established an experimental protocol that allows serial sampling in serum, cerebrospinal fluid (CSF) and interstitial fluid (ISF) of the prefrontal cortex in freely moving rats. For detection of drug concentration in ISF, a push-pull microdialysis technique with large pore membranes was applied. Brain uptake into CSF and ISF was characterized and quantified with a reduced brain physiologically-based pharmacokinetic model. The model allowed us to interpret the pharmacokinetic processes of brain uptake after different routes of administration. The proposed model capturing the pharmacokinetics in serum, CSF and ISF of the prefrontal cortex suggests a barrier function between the CSF and ISF that impedes free antibody transfer. This finding suggests that ICV administration may not be better suited to reach higher local drug exposure as compared to IV administration. The model enabled us to quantify the relative contribution of the blood-brain barrier (BBB) and Blood-CSF-Barrier to the uptake into the interstitial fluid of the brain. In addition, we compared the brain uptake of three monoclonal antibodies after IV dosing. In summary, the presented approach can be applied to profile compounds based on their relative uptake in the brain and provides quantitative insights into which pathways are contributing to the net exposure in the brain.

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Cerebrospinal fluid production by the choroid plexus: a century of barrier research revisited

Cited by 71 publications

References 202 publications

Cerebrospinal fluid osmolality cannot predict development or surgical outcome of idiopathic normal pressure hydrocephalus

Cerebrospinal fluid osmolality cannot predict development or surgical outcome of idiopathic normal pressure hydrocephalus

Effect of cilia-induced surface velocity on cerebrospinal fluid exchange in the lateral ventricles

Investigating brain uptake of a non-targeting monoclonal antibody after intravenous and intracerebroventricular administration

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