The cerebrospinal fluid and barriers – anatomic and physiologic considerations

Tumani, Hayrettin; Huss, André; Bachhuber, Franziska

doi:10.1016/b978-0-12-804279-3.00002-2

Cited by 139 publications

(95 citation statements)

References 64 publications

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“…Lipocalin-type prostaglandin D2 Synthase (L-PGDS) is the second most abundant protein in the cerebrospinal fluid (CSF) and a chaperone for Aβ peptides [3] and may disaggregate preformed amyloids [4]. The composition of the CSF in the brain is very dynamic with a constant turnover of proteins throughout the extracellular and interstitial volumes with 3-5 times daily renewal of CSF at the rate of 0.3-0.4 ml/min in human adults [5]. The protein and metabolite composition of CSF may directly affect amyloid formation in AD brain and reduce the aggregation of amyloids [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…The protein and metabolite composition of CSF may directly affect amyloid formation in AD brain and reduce the aggregation of amyloids [6,7]. L-PGDS is intrathecally synthesized in the arachnoid membrane and choroid plexus before getting secreted from astrocytes into the CSF [5,8]. Its CSF concentration lies within the range of 15-30 mg/l and undergoes circadian changes with serum level fluctuations [5].…”

Section: Introductionmentioning

confidence: 99%

“…L-PGDS is intrathecally synthesized in the arachnoid membrane and choroid plexus before getting secreted from astrocytes into the CSF [5,8]. Its CSF concentration lies within the range of 15-30 mg/l and undergoes circadian changes with serum level fluctuations [5].…”

Section: Introductionmentioning

confidence: 99%

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Conjugates of neuroprotective chaperone L-PGDS provide MRI contrast for detection of amyloid β-rich regions in live Alzheimer’s Disease mouse model brain

Sharma¹,

Grandjean²,

Phillips³

et al. 2020

Preprint

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Endogenous brain proteins can recognize the toxic oligomers of amyloid-β (Aβ) peptides implicated in Alzheimer's disease (AD) and interact with them to prevent their aggregation.Lipocalin-type Prostaglandin D Synthase (L-PGDS) is a major Aβ-chaperone protein in the human cerebrospinal fluid. Here we demonstrate that L-PGDS detects amyloids in diseased mouse brain. Conjugation of L-PGDS with magnetic nanoparticles enhanced the contrast for magnetic resonance imaging. We conjugated the L-PGDS protein with ferritin nanocages to detect amyloids in the AD mouse model brain. We show here that the conjugates administered through intraventricular injections co-localize with amyloids in the mouse brain.These conjugates can target the brain regions through non-invasive intranasal administration, as shown in healthy mice. These conjugates can inhibit the aggregation of amyloids in vitro and show potential neuroprotective function by breaking down the mature amyloid fibrils.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Conjugates of neuroprotective chaperone L-PGDS provide MRI contrast for detection of amyloid β-rich regions in live Alzheimer’s Disease mouse model brain

Sharma¹,

Grandjean²,

Phillips³

et al. 2020

Preprint

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“…The blood-CSF barrier is formed by apical tight junctions between the epithelial cells of the choroid plexus, which prevent the passage of solutes from the blood to the CSF [13]. The choroid plexus is also the primary producer of the CSF [17], however around one-third of the CSF is derived from the CNS parenchymal interstitial fluid [18]. In contrast, the BBB and BSCB comprise endothelial cells knitted together by tight junctions, with a basement membrane of structural matrix proteins, pericytes embedded within this matrix, and astrocytes whose endfeet encircle the basement membrane [19].…”

Section: Introductionmentioning

confidence: 99%

Blood-spinal cord barrier leakage is independent of motor neuron pathology in ALS

Waters

Dieriks

Swanson

et al. 2019

Preprint

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BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive degeneration of upper and lower motor neurons. Both lower motor neuron loss and the deposition of phosphorylated TDP-43 inclusions display regional patterning along the spinal cord. The blood-spinal cord barrier (BSCB) ordinarily restricts entry into the spinal cord parenchyma of blood components that are neurotoxic, but in ALS there is evidence for barrier breakdown. Here we sought to examine whether BSCB breakdown, motor neuron loss, and TDP-43 proteinopathy display the same regional patterning across and along the spinal cord.MethodsWe measured cerebrospinal fluid (CSF) hemoglobin in living ALS patients (n=87 controls, n=236 ALS) as a potential biomarker of BSCB and blood-brain barrier leakage. We then immunostained cervical, thoracic, and lumbar post mortem spinal cord tissue (n=5 controls, n=13 ALS) and employed semi-automated imaging and analysis to quantify and map lower motor neuron loss and phosphorylated TDP-43 inclusion load against hemoglobin leakage.ResultsMotor neuron loss and TDP-43 proteinopathy were seen at all three levels of the ALS spinal cord, with most abundant TDP-43 deposition in the ventral grey (lamina IX) of the cervical and lumbar cord. In contrast, hemoglobin leakage was observed along the ALS spinal cord axis but was most severe in the dorsal grey and white matter in the thoracic spinal cord.ConclusionsOur data show that leakage of the blood-spinal cord barrier occurs during life but at end-stage its distribution is independent from the major motor neuron pathology and is unlikely to be a major contributor to pathogenesis in ALS.

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“…Contributions to intraventricular CSF production may also come from the ependyma and parenchyma (McComb, 1983). In addition to provide mechanical protection and maintain the electrolytic environment and acid-base balance (Tumani et al, 2018), the discovery of the paravascular pathway proposed a potentially more important role of the CSF; namely a clearance of metabolic waste throughout the brain (Iliff et al, 2012;Lundgaard et al, 2017;Plog et al, 2015) and to drive lymphatic efflux of waste molecules from the craniospinal compartment (Ma et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal Fluid Volumetric Net Flow Rate and Direction in Idiopathic Normal Pressure Hydrocephalus

et al. 2018

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The aim of the present study was to examine cerebrospinal fluid (CSF) volumetric net flow rate and direction at the cranio-cervical junction (CCJ) and cerebral aqueduct in individuals with idiopathic normal pressure hydrocephalus (iNPH) using cardiac-gated phase-contrast magnetic resonance imaging (PC-MRI). An in-depth, pixel-by-pixel analysis of regions of interest from the CCJ and cerebral aqueduct, respectively, was done in 26 iNPH individuals, and in 4 healthy subjects for validation purposes. Results from patients were compared with overnight measurements of static and pulsatile intracranial pressure (ICP). In iNPH, CSF net flow at CCJ was cranially directed in 17/22 as well as in 4/4 healthy subjects. Estimated daily CSF volumetric net flow rate at CCJ was 6.9 ± 9.9 L/24 h in iNPH patients and 4.5 ± 5.0 L/24 h in healthy individuals. Within the cerebral aqueduct, the CSF net flow was antegrade in 7/21 iNPH patients and in 4/4 healthy subjects, while it was retrograde (i.e. towards ventricles) in 14/21 iNPH patients. Estimated daily CSF volumetric net flow rate in cerebral aqueduct was 1.1 ± 2.2 L/24 h in iNPH while 295 ± 53 mL/24 h in healthy individuals. Magnitude of cranially directed CSF net flow in cerebral aqueduct was highest in iNPH individuals with signs of impaired intracranial compliance. The study results indicate CSF flow volumes and direction that are profoundly different from previously assumed. We hypothesize that spinal CSF formation may serve to buffer increased demand for CSF flow through the glymphatic system during sleep and during deep inspiration to compensate for venous outflow. 2014; Tisell et al., 2000), as well as chronic obstructive hydrocephalus

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The cerebrospinal fluid and barriers – anatomic and physiologic considerations

Cited by 139 publications

References 64 publications

Conjugates of neuroprotective chaperone L-PGDS provide MRI contrast for detection of amyloid β-rich regions in live Alzheimer’s Disease mouse model brain

Conjugates of neuroprotective chaperone L-PGDS provide MRI contrast for detection of amyloid β-rich regions in live Alzheimer’s Disease mouse model brain

Blood-spinal cord barrier leakage is independent of motor neuron pathology in ALS

Cerebrospinal Fluid Volumetric Net Flow Rate and Direction in Idiopathic Normal Pressure Hydrocephalus

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