The Connected Steady State Model and the Interdependence of the CSF Proteome and CSF Flow Characteristics

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.

Cortisol promotes breast‐to‐brain metastasis through the blood‐cerebrospinal fluid barrier

“…The BBB is a highly specialized structure connected by the interactions of vascular brain endothelial cells (BECs), an ensheathed basement membrane housing pericytes, and projecting astrocytic foot processes. Unlike peripheral endothelial cells, BECs are nonfenestrated and inhibit the untethered paracellular diffusion of water‐soluble molecules by an interconnected network of tight junctions (TJs) 13,14 . Analogous to the endothelial barrier, the BCSFB correlate are apical TJs expressed within choroid plexus epithelial cells (CPEs) preventing the free flow of water‐soluble molecules.…”

“…Unlike peripheral endothelial cells, BECs are nonfenestrated and inhibit the untethered paracellular diffusion of water‐soluble molecules by an interconnected network of tight junctions (TJs). 13 , 14 Analogous to the endothelial barrier, the BCSFB correlate are apical TJs expressed within choroid plexus epithelial cells (CPEs) preventing the free flow of water‐soluble molecules. These choroid plexus cells have a supplemental secretory function—production of cerebrospinal fluid (CSF) which extravasates into the brain's ventricles and is dispersed throughout the CNS.…”

Blood-cerebrospinal fluid (CSF) barrier dysfunction means reduced CSF flow not barrier leakage - conclusions from CSF protein data

“…3) Analogies to animal models 32,33 reopen the discussion about lymphatics in the human brain and the CSF outflow ways 34 . 4) Mathematical models, which ignore biological contexts 14 or do not apply Fick's 2 nd law of diffusion 13,35 lead to contradictions with the empirical data 25 or miss explaining the dynamics of brain and leptomeningeal proteins presented in this review.…”

“…The facts 1-8 and paragraph 5 disprove a morphological barrier disorder (leakage). It is therefore not necessary to discuss the details of the different errors in those barrier models which are based on a leakage concept in one way or another 3,4,5,9,10,11,12,13,14,16,35 .…”

Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases

“…Such studies provide further in vivo evidence on the role of glymphatic dysfunction in different late-onset dementia types. Mathematical models of the glymphatic system are also being developed to better understand the glymphatic system dynamics and pathways under physiological and pathological conditions, as well as to provide quantitative maps for understanding disease pathophysiology and monitoring disease progression [338][339][340][341][342][343]. The continuous development of noninvasive imaging techniques and computational models will allow for the wider application of future in vivo studies investigating the role of the glymphatic system across the spectrum of age-related neurodegenerative diseases.…”