Cerebrospinal Fluid Research - Latest articles

Cerebrospinal fluid markers in Creutzfeldt-Jakob disease

Anders Skinningsrud, Vidar Stenset, Astrid S Gundersen and Tormod Fladby — 2008-08-27

Background: The objective was to assess the utility of total tau protein (tTau), the ratio of (tTau)/181 phosphorylated tau protein (P-Tau) and 14-3-3 protein, as diagnostic markers in cerebrospinal fluid (CSF) for Creutzfeldt-Jakob disease (CJD). Methods: CSF samples received from Norwegian hospitals between August 2005 and August 2007 were retrospectively selected from consecutive patients with tTau values > 1200 ng/L (n = 38). The samples from patients clinically diagnosed with CJD (n = 12) were compared to those from patients with other degenerative neurological diseases: Alzheimer's/vascular dementia (AD/VaD, n = 21), other neurological diseases (OND, n = 5). Total Tau, P-Tau, and β-Amyloid (Aβ42) were measured with commercial kits. Additionally, 14-3-3 protein was measured semi-quantitatively by immunoblot. Results: The minimum cut-off limits for diagnosis of CJD were chosen from the test results. For tTau the lower limit was fixed at 3000 ng/L, for the tTau/P-Tau ratio it was 60, and for 14-3-3 protein it was 0.75 arbitrary units. For tTau and tTau/P-Tau ratio, all but three CJD patients had levels above the minimum, whereas almost all of the other patients were below. For the 14-3-3 protein, two CJD patients were below the minimum and five were above. Only one of the other patients was higher than the limit. The sensitivities, specificities and diagnostic efficiencies were: tTau 75%, 92%, and 87%; tTau/P-Tau 75%, 96%, and 89%; and 14-3-3 protein 80%, 96%, and 91%. Conclusion: The results suggest that 14-3-3 protein may be the better marker for CJD, tTau/P-Tau ratio and tTau are also efficient markers, but showed slightly inferior diagnostic properties in this study, with tTau/P-Tau marginally better than tTau.

Report on the second Intracranial Hypertension Research Foundation conference

Emanuel Tanne — 2008-08-13

This report highlights a conference designed for patient education on elevated cerebrospinal fluid (CSF) pressure. The conference centered on chronic intracranial hypertension (IH) including the latest research and clinical information. It was sponsored by the Intracranial Hypertension Research Foundation and held at the University of Texas Medical School, Houston, on June 21–22nd, 2008.

Effect of hydrocephalus on rat brain extracellular compartment

Marc R Del Bigio and Terry L Enno — 2008-07-10

Background: The cerebral cortex may be compressed in hydrocephalus and some experiments suggest that movement of extracellular substances through the cortex is impaired. We hypothesized that the extracellular compartment is reduced in size and that the composition of the extracellular compartment changes in rat brains with kaolin-induced hydrocephalus. Methods: We studied neonatal (newborn) onset hydrocephalus for 1 or 3 weeks, juvenile (3 weeks) onset hydrocephalus for 3–4 weeks or 9 months, and young adult (10 weeks) onset hydrocephalus for 2 weeks, after kaolin injection. Freeze substitution electron microscopy was used to measure the size of the extracellular compartment. Western blotting and immunohistochemistry with quantitative image densitometry was used to study the extracellular matrix constituents, phosphacan, neurocan, NG2, decorin, biglycan, and laminin. Results: The extracellular space in cortical layer 1 was reduced significantly from 16.5 to 9.6% in adult rats with 2 weeks duration hydrocephalus. Western blot and immunohistochemistry showed that neurocan increased only in the periventricular white matter following neonatal induction and 3 weeks duration hydrocephalus. The same rats showed mild decorin increases in white matter and around cortical neurons. Juvenile and adult onset hydrocephalus was associated with no significant changes. Conclusion: We conclude that compositional changes in the extracellular compartment are negligible in cerebral cortex of hydrocephalic rats at various ages. Therefore, the functional change related to extracellular fluid flow should be reversible.

The effect of whole body position on lumbar cerebrospinal fluid opening pressure

2008-07-02

We compared cerebrospinal fluid (CSF) opening pressure measurements in the lumbar subarachnoid space between the flexed position (F-OP) and relaxed position (R-OP) in recumbent patients. We devised an equation for using F-OP to determine the existence of raised intracranial pressure (ICP). Patients (n = 83) underwent lumbar puncture while in the flexed lateral decubitus position and then were moved to the relaxed position. F-OP and R-OP were measured with a water manometer. R-OP > 180 mmH2O plus relevant clinical signs were taken as indicators of raised intracranial pressure. Mean pressures for F-OP and R-OP were 178.54 and 160.52 mmH2O respectively, p <0.001. When F-OP > 180, raised ICP could be significantly over diagnosed. The authors recommend an equation [R-OP(calculated, mmH2O) = 0.885 × F-OP(measured, mmH2O)] or using 200 mmH2O as the threshold for increased ICP with flexed posture.

Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

2008-05-14

This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimer's disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces.Outline1 Overview2 CSF formation2.1 Transcription factors2.2 Ion transporters2.3 Enzymes that modulate transport2.4 Aquaporins or water channels2.5 Receptors for neuropeptides3 CSF pressure3.1 Servomechanism regulatory hypothesis3.2 Ontogeny of CSF pressure generation3.3 Congenital hydrocephalus and periventricular regions3.4 Brain response to elevated CSF pressure3.5 Advances in measuring CSF waveforms4 CSF flow4.1 CSF flow and brain metabolism4.2 Flow effects on fetal germinal matrix4.3 Decreasing CSF flow in aging CNS4.4 Refinement of non-invasive flow measurements5 CSF volume5.1 Hemodynamic factors5.2 Hydrodynamic factors5.3 Neuroendocrine factors6 CSF turnover rate6.1 Adverse effect of ventriculomegaly6.2 Attenuated CSF sink action7 CSF composition7.1 Kidney-like action of CP-CSF system7.2 Altered CSF biochemistry in aging and disease7.3 Importance of clearance transport7.4 Therapeutic manipulation of composition8 CSF recycling in relation to ISF dynamics8.1 CSF exchange with brain interstitium8.2 Components of ISF movement in brain8.3 Compromised ISF/CSF dynamics and amyloid retention9 CSF reabsorption9.1 Arachnoidal outflow resistance9.2 Arachnoid villi vs. olfactory drainage routes9.3 Fluid reabsorption along spinal nerves9.4 Reabsorption across capillary aquaporin channels10 Developing translationally effective models for restoring CSF balance11 Conclusion

Cerebrospinal fluid markers before and after shunting in patients with secondary and idiopathic normal pressure hydrocephalus

2008-04-25

Background: The aim of this study was to explore biochemical changes in the cerebrospinal fluid (CSF) induced by shunt surgery and the relationship between these changes and clinical improvement. Methods: We measured clinical symptoms and analysed lumbar CSF for protein content, neurodegeneration and neurotransmission markers in patients with secondary (SNPH, n = 17) and idiopathic NPH (INPH, n = 18) before and 3 months after shunt surgery. Patients were divided into groups according to whether or not there was improvement in clinical symptoms after surgery. Results: Preoperatively, the only pathological findings were elevated neurofilament protein (NFL), significantly more so in the SNPH patients than in the INPH patients, and elevated albumin content. Higher levels of NFL correlated with worse gait, balance, wakefulness and neuropsychological performance. Preoperatively, no differences were seen in any of the CSF biomarkers between patients that improved after surgery and those that did not improve. Postoperatively, a greater improvement in gait and balance performance correlated with a more pronounced reduction in NFL. Levels of albumin, albumin ratio, neuropeptide Y, vasoactive intestinal peptide and ganglioside GD3 increased significantly after shunting in both groups. In addition, Gamma amino butyric acid increased significantly in SNPH and tau in INPH. Conclusion: We conclude that a number of biochemical changes occur after shunt surgery, but there are no marked differences between the SNPH and INPH patients. The results indicate that NFL may be a marker that can predict a surgically reversible state in NPH.

Investigation of the hydrodynamic properties of a new MRI-resistant programmable hydrocephalus shunt

2008-04-21

Background: The Polaris valve is a newly released hydrocephalus shunt that is designed to drain cerebrospinal fluid (CSF) from the brain ventricles or lumbar CSF space. The aim of this study was to bench test the properties of the Polaris shunt, independently of the manufacturer. Methods: The Polaris Valve is a ball-on-spring valve, which can be adjusted magnetically in vivo. A special mechanism is incorporated to prevent accidental re-adjustment by an external magnetic field. The performance and hydrodynamic properties of the valve were evaluated in the UK Shunt Evaluation Laboratory, Cambridge, UK. Results: The three shunts tested showed good mechanical durability over the 3-month period of testing, and a stable hydrodynamic performance over 45 days. The pressure-flow performance curves, operating, opening and closing pressures were stable. The drainage rate of the shunt increased when a negative outlet pressure (siphoning) was applied. The hydrodynamic parameters fell within the limits specified by the manufacturer and changed according to the five programmed performance levels. Hydrodynamic resistance was dependant on operating pressure, changing from low values of 1.6 mmHg/ml/min at the lowest level to 11.2 mmHg/ml/min at the highest performance level. External programming proved to be easy and reliable. Even very strong magnetic fields (3 Tesla) were not able to change the programming of the valve. However, distortion of magnetic resonance images was present. Conclusion: The Polaris Valve is a reliable, adjustable valve. Unlike other adjustable valves (except the Miethke ProGAV valve), the Polaris cannot be accidentally re-adjusted by an external magnetic field.

A unifying hypothesis for hydrocephalus, Chiari malformation, syringomyelia, anencephaly and spina bifida

Helen Williams — 2008-04-11

This work is a modified version of the Casey Holter Memorial prize essay presented to the Society for Research into Hydrocephalus and Spina Bifida, June 29th 2007, Heidelberg, Germany. It describes the origin and consequences of the Chiari malformation, and proposes that hydrocephalus is caused by inadequate central nervous system (CNS) venous drainage. A new hypothesis regarding the pathogenesis, anencephaly and spina bifida is described.Any volume increase in the central nervous system can increase venous pressure. This occurs because veins are compressible and a CNS volume increase may result in reduced venous blood flow. This has the potential to cause progressive increase in cerebrospinal fluid (CSF) volume. Venous insufficiency may be caused by any disease that reduces space for venous volume. The flow of CSF has a beneficial effect on venous drainage. In health it moderates central nervous system pressure by moving between the head and spine. Conversely, obstruction to CSF flow causes localised pressure increases, which have an adverse effect on venous drainage.The Chiari malformation is associated with hindbrain herniation, which may be caused by low spinal pressure relative to cranial pressure. In these instances, there are hindbrain-related symptoms caused by cerebellar and brainstem compression. When spinal injury occurs as a result of a Chiari malformation, the primary pathology is posterior fossa hypoplasia, resulting in raised spinal pressure. The small posterior fossa prevents the flow of CSF from the spine to the head as blood enters the central nervous system during movement. Consequently, intermittent increases in spinal pressure caused by movement, result in injury to the spinal cord. It is proposed that posterior fossa hypoplasia, which has origins in fetal life, causes syringomyelia after birth and leads to damage to the spinal cord in spina bifida. It is proposed that hydrocephalus may occur as a result of posterior fossa hypoplasia, where raised pressure occurs as a result of obstruction to flow of CSF from the head to the spine, and cerebral injury with raised pressure occurs in anencephaly by this mechanism.The current view of dysraphism is that low central nervous system pressure and exposure to amniotic fluid, damage the central nervous system. The hypothesis proposed in this essay supports the view that spina bifida is a manifestation of progressive hydrocephalus in the fetus. It is proposed that that mesodermal growth insufficiency influences both neural tube closure and central nervous system pressure, leading to dysraphism.

Report on a conference analyzing the role of cerebrospinal fluid prophylaxis for brain tumors

Michael Glantz and Conrad Johanson — 2008-03-26

This is a report of a meeting sponsored by MundiPharma International to identify ways to exploit the cerebrospinal fluid system pharmacologically, for more effective management and prevention of primary and metastatic CNS tumors.

Prostaglandin E2 metabolism in rat brain: Role of the blood-brain interfaces

2008-03-04

Background: Prostaglandin E2 (PGE2) is involved in the regulation of synaptic activity and plasticity, and in brain maturation. It is also an important mediator of the central response to inflammatory challenges. The aim of this study was to evaluate the ability of the tissues forming the blood-brain interfaces to act as signal termination sites for PGE2 by metabolic inactivation. Methods: The specific activity of 15-hydroxyprostaglandin dehydrogenase was measured in homogenates of microvessels, choroid plexuses and cerebral cortex isolated from postnatal and adult rat brain, and compared to the activity measured in peripheral organs which are established signal termination sites for prostaglandins. PGE2 metabolites produced ex vivo by choroid plexuses were identified and quantified by HPLC coupled to radiochemical detection. Results: The data confirmed the absence of metabolic activity in brain parenchyma, and showed that no detectable activity was associated with brain microvessels forming the blood-brain barrier. By contrast, 15-hydroxyprostaglandin dehydrogenase activity was measured in both fourth and lateral ventricle choroid plexuses from 2-day-old rats, albeit at a lower level than in lung or kidney. The activity was barely detectable in adult choroidal tissue. Metabolic profiles indicated that isolated choroid plexus has the ability to metabolize PGE2, mainly into 13,14-dihydro-15-keto-PGE2. In short-term incubations, this metabolite distributed in the tissue rather than in the external medium, suggesting its release in the choroidal stroma. Conclusion: The rat choroidal tissue has a significant ability to metabolize PGE2 during early postnatal life. This metabolic activity may participate in signal termination of centrally released PGE2 in the brain, or function as an enzymatic barrier acting to maintain PGE2 homeostasis in CSF during the critical early postnatal period of brain development.