Quinckes’ pioneering 19th centuries CSF studies may inform 21th centuries research

Bechter, Karl; Benveniste, Helene

doi:10.1016/j.npbr.2015.02.001

Cited by 6 publications

(7 citation statements)

References 44 publications

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“…Furthermore, although non-statistically significant ( p = 0.07), we did observe a trend toward reduced CLDN-5 protein level in the SCZ CBL as well, suggesting a possibly leaking BBB. Previous clinical and postmortem research in SCZ has suggested that an impaired BBB could be a contributing factor to the pathogenesis of the disease in only a subgroup of SCZ patients [103–105]. It is important to mention that the SCZ and ASD subjects studied were not selected on the basis of specific immune biomarkers and, therefore, may represent a mixed group of patients, which thereby limits the statistical significance of some of our findings.…”

Section: Discussionmentioning

confidence: 89%

Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders

et al. 2016

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BackgroundAutism spectrum disorders (ASD) are complex conditions whose pathogenesis may be attributed to gene–environment interactions. There are no definitive mechanisms explaining how environmental triggers can lead to ASD although the involvement of inflammation and immunity has been suggested. Inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of these antigens or immune-activated complexes through a permissive blood–brain barrier (BBB), can be part of the chain of events leading to these disorders. Our goal was to investigate whether an altered BBB and gut permeability is part of the pathophysiology of ASD.Methods Postmortem cerebral cortex and cerebellum tissues from ASD, schizophrenia (SCZ), and healthy subjects (HC) and duodenal biopsies from ASD and HC were analyzed for gene and protein expression profiles. Tight junctions and other key molecules associated with the neurovascular unit integrity and function and neuroinflammation were investigated.ResultsClaudin (CLDN)-5 and -12 were increased in the ASD cortex and cerebellum. CLDN-3, tricellulin, and MMP-9 were higher in the ASD cortex. IL-8, tPA, and IBA-1 were downregulated in SCZ cortex; IL-1b was increased in the SCZ cerebellum. Differences between SCZ and ASD were observed for most of the genes analyzed in both brain areas. CLDN-5 protein was increased in ASD cortex and cerebellum, while CLDN-12 appeared reduced in both ASD and SCZ cortexes. In the intestine, 75% of the ASD samples analyzed had reduced expression of barrier-forming TJ components (CLDN-1, OCLN, TRIC), whereas 66% had increased pore-forming CLDNs (CLDN-2, -10, -15) compared to controls.ConclusionsIn the ASD brain, there is an altered expression of genes associated with BBB integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity. While these findings seem to be specific for ASD, the possibility of more distinct SCZ subgroups should be explored with additional studies.

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Section: Discussionmentioning

confidence: 89%

Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders

et al. 2016

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“…Heinrich Quincke was among the first to gain direct access to CSF and to study transport of solutes (Bechter and Benveniste 2015; Benveniste and others 2015). He administered an emulsion of cinnabar granules (mercury(II) sulfide, HgS; granule size ~1 μm) into CSF via the lateral ventricles, the subarachnoid space (basal cisterns) and the lumbar intrathecal space of live animals (dog, cats, and rabbits) (Bechter and others 2015). When injecting the cinnabar dye into the lateral ventricles he observed (post mortem) that it had travelled through the central canal of the spine all the way down to the lumbar region (Bechter and others 2015).…”

Section: Csf Transport In the Central Nervous Systemmentioning

confidence: 99%

“…He administered an emulsion of cinnabar granules (mercury(II) sulfide, HgS; granule size ~1 μm) into CSF via the lateral ventricles, the subarachnoid space (basal cisterns) and the lumbar intrathecal space of live animals (dog, cats, and rabbits) (Bechter and others 2015). When injecting the cinnabar dye into the lateral ventricles he observed (post mortem) that it had travelled through the central canal of the spine all the way down to the lumbar region (Bechter and others 2015). Since then numerous investigators have repeated this experiment using state-of-the-art technologies and smaller molecular weight contrast dyes, and we now have a good understanding of CSF circulation in brain and spine.…”

Section: Csf Transport In the Central Nervous Systemmentioning

confidence: 99%

The Glymphatic Pathway: Waste Removal from the CNS via Cerebrospinal Fluid Transport

2017

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The overall premise of this review is that cerebrospinal fluid (CSF) is transported within a dedicated peri-vascular network facilitating metabolic waste clearance from the central nervous system while we sleep. The anatomical profile of the network is complex and has been defined as a peri-arterial CSF influx pathway and peri-venous clearance routes, which are functionally coupled by interstitial bulk flow supported by astrocytic aquaporin 4 water channels. The role of the newly discovered system in the brain is equivalent to the lymphatic system present in other body organs and has been termed the “glymphatic pathway” or “(g)lymphatics” because of its dependence on glial cells. We will discuss and review the general anatomy and physiology of CSF from the perspective of the glymphatic pathway, a discovery which has greatly improved our understanding of key factors that control removal of metabolic waste products from the central nervous system in health and disease and identifies an additional purpose for sleep. A brief historical and factual description of CSF production and transport will precede the ensuing discussion of the glymphatic system along with a discussion of its clinical implications.

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“…Since protein efflux occurs by CSF drainage [ 23 ], the protein efflux pathways are the same as for CSF [ 28 ]. These include the arachnoid granulations mainly expressed in the cranial space but to a minor extent also in the spinal subarachnoid space, and outflow paths along nerves in both cranial and spinal spaces [ 29 ]. Thus, the drainage sink term can be written as where F is the CSF drainage rate.…”

Section: Methodsmentioning

confidence: 99%

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

Asgari

Zélicourt

Kurtcuoglu

2017

Fluids Barriers CNS

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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.

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Quinckes’ pioneering 19th centuries CSF studies may inform 21th centuries research

Cited by 6 publications

References 44 publications

Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders

Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders

The Glymphatic Pathway: Waste Removal from the CNS via Cerebrospinal Fluid Transport

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

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