Barrier dysfunction or drainage reduction: differentiating causes of CSF protein increase
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Fluids and Barriers of the CNS Open Access
RESEARCH
Barrier dysfunction or drainage reduction: differentiating causes of CSF protein increase Mahdi Asgari1,2, Diane A. de Zélicourt1 and Vartan Kurtcuoglu1,2,3*
Abstract Background: Cerebrospinal fluid (CSF) protein analysis is an important element in the diagnostic chain for various central nervous system (CNS) pathologies. Among multiple existing approaches to interpreting measured protein levels, the Reiber diagram is particularly robust with respect to physiologic inter-individual variability, as it uses multiple subject-specific anchoring values. Beyond reliable identification of abnormal protein levels, the Reiber diagram has the potential to elucidate their pathophysiologic origin. In particular, both reduction of CSF drainage from the craniospinal space as well as blood–CNS barrier dysfunction have been suggested ρas possible causes of increased concentration of blood-derived proteins. However, there is disagreement on which of the two is the true cause. Methods: We designed two computational models to investigate the mechanisms governing protein distribution in the spinal CSF. With a one-dimensional model, we evaluated the distribution of albumin and immunoglobulin G (IgG), accounting for protein transport rates across blood–CNS barriers, CSF dynamics (including both dispersion induced by CSF pulsations and advection by mean CSF flow) and CSF drainage. Dispersion coefficients were determined a priori by computing the axisymmetric three-dimensional CSF dynamics and solute transport in a representative segment of the spinal canal. Results: Our models reproduce the empirically determined hyperbolic relation between albumin and IgG quotients. They indicate that variation in CSF drainage would yield a linear rather than the expected hyperbolic profile. In contrast, modelled barrier dysfunction reproduces the experimentally observed relation. Conclusions: High levels of albumin identified in the Reiber diagram are more likely to originate from a barrier dysfunction than from a reduction in CSF drainage. Our in silico experiments further support the hypothesis of decreasing spinal CSF drainage in rostro-caudal direction and emphasize the physiological importance of pulsation-driven dispersion for the transport of large molecules in the CSF. Background Despite continued advances in non-invasive medical imaging, cerebrospinal fluid (CSF) analysis in general and CSF protein analysis in particular have remained important tools for the diagnosis of various disorders of the central nervous system (CNS) [1]. Yet while it is accepted that abnormal changes in CSF protein content are indicative of pathological conditions, the reasons leading to the *Correspondence: [email protected] 1 The Interface Group, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland Full list of author information is available at the end of the article
measured protein concentrations are often a matter of debate [2]. While some proteins fou
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