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.
Highlights
Cerebrospinal fluid (CSF) protein analysis is an important element in the diagnostic chain for various central nervous system (CNS) pathologies
While some proteins found in the CSF are synthesized within the CNS or the meninges, most of them originate in the blood serum under normal conditions [2,3,4]
Since albumin is not synthesized in the mature CNS [2], a higher than expected immunoglobulin G (IgG) quotient for the given albumin quotient is seen as evidence for intrathecal synthesis of IgG and for an inflammatory process in the CNS
Summary
Cerebrospinal fluid (CSF) protein analysis is an important element in the diagnostic chain for various central nervous system (CNS) pathologies. Beyond reliable identification of abnormal protein levels, the Reiber diagram has the potential to elucidate their pathophysiologic origin 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. While some proteins found in the CSF are synthesized within the CNS (choroid plexus, brain and spine) or the meninges, most of them originate in the blood serum under normal conditions [2,3,4]. Since protein levels in the CSF show normal fluctuations as serum protein concentrations change, and since there are inter-individual variations, it is helpful to use relative values for diagnostic purposes. He further defined upper and lower bounds for the relationship between the two quotients, both of which follow a hyperbolic function, and noted that the relative spread of these bounds, as quantified by a population variation coefficient, remains constant over the entire range of investigated albumin levels (Fig. 1b)
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