Abstract
Here we show that the hydrodynamic radii-dependent entry of blood proteins into cerebrospinal fluid (CSF) can best be modeled with a diffusional system of consecutive interdependent steady states between barrier-restricted molecular flux and bulk flow of CSF. The connected steady state model fits precisely to experimental results and provides the theoretical backbone to calculate the in-vivo hydrodynamic radii of blood-derived proteins as well as individual barrier characteristics. As the experimental reference set we used a previously published large-scale patient cohort of CSF to serum quotient ratios of immunoglobulins in relation to the respective albumin quotients. We related the inter-individual variances of these quotient relationships to the individual CSF flow time and barrier characteristics. We claim that this new concept allows the diagnosis of inflammatory processes with Reibergrams derived from population-based thresholds to be shifted to individualized judgment, thereby improving diagnostic sensitivity. We further use the source-dependent gradient patterns of proteins in CSF as intrinsic tracers for CSF flow characteristics. We assume that the rostrocaudal gradient of blood-derived proteins is a consequence of CSF bulk flow, whereas the slope of the gradient is a consequence of the unidirectional bulk flow and bidirectional pulsatile flow of CSF. Unlike blood-derived proteins, the influence of CSF flow characteristics on brain-derived proteins in CSF has been insufficiently discussed to date. By critically reviewing existing experimental data and by reassessing their conformity to CSF flow assumptions we conclude that the biomarker potential of brain-derived proteins in CSF can be improved by considering individual subproteomic dynamics of the CSF system.
Highlights
The cerebrospinal fluid is a complex flow system likely involved in many brain-related tasks such as neuronal communication, waste clearance and immune surveillance of the brain (Abbott, 2004; Veening and Barendregt, 2010; Ransohoff and Engelhardt, 2012; Rodan et al, 2015)
We provide evidence that the passage of blood-borne proteins into cerebrospinal fluid (CSF) is at least predominantly based on diffusion (Section Blood-Derived Proteins in CSF), critically review a preceding diffusion-based model, the molecular flux model (Section The Molecular Flux Theory), and show that the diffusion-based protein exchange between blood and CSF can be precisely modeled with a system of steady states connected by bulk flow (Section The Connected Steady State Model)
The CSF system is separated from the blood by the cerebrospinal fluid barrier (BCSFB) at the site of the choroid plexuses (CP), the blood brain barrier (BBB) which makes up 99% of all brain capillaries and the blood-meningeal barrier (BMB, alternatively referred to as outer blood-cerebrospinal fluid barrier (BCSFB)) which separates the subarachnoid space (SAS) from the perfused dura, the outermost meningeal layer
Summary
The cerebrospinal fluid is a complex flow system likely involved in many brain-related tasks such as neuronal communication, waste clearance and immune surveillance of the brain (Abbott, 2004; Veening and Barendregt, 2010; Ransohoff and Engelhardt, 2012; Rodan et al, 2015). The coincidence of Q(RH)−1 and Q( ) (Table 2) supports first the validity of the connected steady state model for the diffusional exchange between CSF and blood and second the assumption that the hydrodynamic radius is the dominant molecule-specific factor in explaining different values for blood proteins. Under the assumption that molecule-specific characteristics other than RH can be ignored a deduction from the model is that in the case of proteins with the same RH no variance between a Qx/Qy value in different individuals exists and that the Qx/Qy ratio is always 1 This allows the calculation of the in vivo RH of blood-derived proteins by the evaluation of their Q values relative to the Q values of a set of reference proteins with known RH according to Equation (16). Relative to the high differences in QAlb (Figure 1) the barrier specificity indicated by the population variation coefficients (Table 1) remains relatively stable, which indicates that barrier permeability and specificity are partly uncoupled
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