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

Abstract

Background: Increased concentrations of serum proteins in cerebrospinal fluid (CSF) are interpreted as blood-CSF barrier dysfunction. Frequently used interpretations such as barrier leakage, disruption or breakdown contradict CSF protein data, which suggest a reduced CSF flow rate as the cause. Results: Even the severest barrier dysfunctions do not change the molecular size-dependent selectivity or the interindividual variation of the protein transfer across barriers. Serum protein concentrations in lumbar CSF increase with hyperbolic functions, but the levels of proteins that do not pass the barrier remain constant (brain proteins) or increase linearly (leptomeningal proteins). All CSF protein dynamics above and below a lumbar blockade can also be explained, independent of their barrier passage, by a reduced caudally directed flow. Local accumulation of gadolinium in multiple sclerosis (MS) is now understood as due to reduced bulk flow elimination by interstitial fluid (ISF). Nonlinear change of the steady state in barrier dysfunction and along normal rostro-caudal gradients supports the diffusion/flow model and contradicts obstructions of diffusion pathways. Regardless of the cause of the disease, pathophysiological flow blockages are found in bacterial meningitis, leukemia, meningeal carcinomatosis, Guillain-Barré syndrome, MS and experimental allergic encephalomyelitis. In humans, the fortyfold higher albumin concentrations in early fetal development decrease later with maturation of the arachnoid villi, i.e., with beginning CSF outflow, which contradicts a relevant outflow to the lymphatic system. Respiration- and heartbeat-dependent oscillations do not disturb net direction of CSF flow. Conclusion: Blood-CSF and blood-brain barrier dysfunctions are an expression of reduced CSF or ISF flow rate.

Importance of CSF-based Aβ clearance with age in humans increases with declining efficacy of blood-brain barrier/proteolytic pathways

“…The increase in Q osc with age may be similar to the increase in pulse wave velocity with age due to stiffening of the arteries 64 . Although ISF-to-lumbar gradients can be inferred from experiments, there is scant evidence of a ventriculo-lumbar gradient for Aβ 21 , 65 , in contrast to the negative gradient for brain proteins such as tau and the positive gradient for blood proteins such as albumin 66 .…”

CSF, Blood, and MRI Biomarkers in Skogholt’s Disease—A Rare Neurodegenerative Disease in a Norwegian Kindred

“…High CSF protein concentrations have previously been reported in conditions with slow CSF turnover [26,27]. It is possible that many of the observed protein changes in Skogholt CSF may be explained by perturbed CSF dynamics, reflecting impaired CSF production.…”

Intrathecal immunoglobin synthesis and its role in patients with neurosyphilis

“…In the N-NS group, the three intrathecal Ig syntheses were not so dissimilar among the three formulas. The molecular diffusion/CSF flow theory provides the sensitive identification of the intrathecal fraction of pathological protein ( 22 , 24 ). When using the hyperbolic function, 79% of NS patients with brain-derived IgG and almost 50% of NS patients with brain-synthesized IgA and IgM.…”