Barrier dysfunction or drainage reduction: differentiating causes of CSF protein increase

Abstract

BackgroundCerebrospinal 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 cranio-spinal 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.MethodsWe 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.ResultsOur 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.ConclusionsHigh 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.

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

“…Convective mixing is perhaps better called dispersion [ 78 ]. Papisov [ 133 ] and Asgari et al [ 134 ] discuss a similar effect in the spinal cord allowing transport of solutes down their concentration gradients against the direction of net flow of CSF and at rates much greater than allowed by diffusion. In this proposal diffusion is taken to be adequate to explain movements within the interstitial spaces in the parenchyma because the distances involved are sufficiently short (see Sect.…”

Clearance of cerebrospinal fluid from the sacral spine through lymphatic vessels

“…These include flow through arachnoid villi to spinal veins (Elman, 1923; Welch and Pollay, 1963; Kido et al, 1976), routes along spinal nerve roots to epidural lymphatics (Iwanow, 1928; Brierley and Field, 1948), and routes through the arachnoid layer of the spinal meninges to dural lymphatics (Zenker et al, 1994; Antila et al, 2017). Previous groups have estimated that 16–25% of total CSF outflow may occur from the spine (Marmarou et al, 1975; Bozanovic-Sosic et al, 2001; Asgari et al, 2017). Others have suggested that spinal outflow pathways to lymphatic vessels are not active under normal conditions and that pathways through the cranial outflow routes must be blocked and/or that CSF pressures need to be elevated to produce outflow (Miura et al, 1998; Voelz et al, 2007).…”

Inflammation may be correlated with Symptomatic Neurosyphilis

“…Hence, if the CSF protein concentration increases, it may indicate the progress of the disease, and timely treatment is necessary. As we know, reduction of CSF drainage from the cranio-spinal space, inflammation induced-protein production as well as BBB damage have been suggested as possible causes of increased concentration of CSF proteins [18].Our study showed that the QAlb in the symptomatic NS group was significantly higher than in the ANS group, suggesting that the BBB damage was more severe in the symptomatic NS group. This may explain why the symptomatic NS group had higher CSF protein.…”