| 1. |
- Andersson, Kennet, et al.
(författare)
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Effect of resting pressure on the estimate of cerebrospinal fluid outflow conductance
- 2011
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Ingår i: Fluids and barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 8:1, s. 15-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A lumbar infusion test is commonly used as a predictive test for patients with normal pressure hydrocephalus and for evaluation of cerebrospinal fluid (CSF) shunt function. Different infusion protocols can be used to estimate the outflow conductance (Cout) or its reciprocal the outflow resistance, (Rout) with or without using the baseline resting pressure, Pr. Both from a basic physiological research and a clinical perspective, it is important to understand the limitations of the model on which infusion tests are based. By estimating Cout using two different analyses, with or without Pr, the limitations could be explored. The aim of this study was to compare the Cout estimates, and investigate what effect Pr had on the results. METHODS: Sixty-three patients that underwent a constant pressure infusion protocol as part of their preoperative evaluation for normal pressure hydrocephalus, were included (age 70.3+/-10.8 years (mean +/-SD). The analysis was performed without (Cexcl Pr) and with (Cincl Pr) Pr. The estimates were compared using Bland-Altman plots and paired sample t-tests (p<0.05 considered significant). RESULTS: Mean Cout for the 63 patients was: Cexcl Pr = 7.0+/-4.0 (mean +/-SD) ul/(s kPa) and Cincl Pr = 9.1+/-4.3 ul/(s kPa) and Rout was 19.0+/-9.2 and 17.7+/-11.3 mmHg/ml/min, respectively. There was a positive correlation between methods (r=0.79, n=63, p<0.01). The difference, DeltaCout, -2.1+/-2.7 ul/(s kPa) between methods was significant (p<0.01) and DeltaRout was 1.2 +/- 8.8 mmHg/ml/min). The Bland-Altman plot visualized that the variation around the mean difference was similar all through the range of measured values and there was no correlation between DeltaCout and Cout. CONCLUSIONS: The difference between Cout estimates, obtained from analyses with or without Pr, needs to be taken into consideration when comparing results from studies using different infusion test protocols. The study suggests variation in CSF formation rate, variation in venous pressure or a pressure dependent Cout as possible causes for the deviation from the CSF absorption model seen in some patients.
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| 2. |
- Behrens, Anders, et al.
(författare)
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A computerized neuropsychological test battery designed for idiopathic normal pressure hydrocephalus
- 2014
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Ingår i: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A tool for standardized and repeated neuropsychological assessments in patients with idiopathic normal pressure hydrocephalus (INPH) is needed. The objective of this study was to develop a computerized neuropsychological test battery designed for INPH and to evaluate its reliability, validity and patient's ability to complete the tests.METHODS: Based on a structured review of the literature on neuropsychological testing in INPH, the eight tests most sensitive to the INPH cognitive profile were implemented in a computerized format. The Geriatric Depression Scale (GDS) was also included. Tests were presented on a touch-screen monitor, with animated instructions and speaker sound. The battery was evaluated with the following cohorts: A. Test-retest reliability, 44 healthy elderly; B. Validity against standard pen and pencil testing, 28 patients with various cognitive impairments; C. Ability to complete test battery, defined as completion of at least seven of the eight tests, 40 investigated for INPH.RESULTS: A. All except the figure copy test showed good test-retest reliability, r = 0.67-0.90; B. A high correlation was seen between conventional and computerized tests (r = 0.66-0.85) except for delayed recognition and figure copy task; C. Seventy-eight percent completed the computerized battery; Patients diagnosed with INPH (n = 26) performed worse on all tests, including depression score, compared to healthy controls.CONCLUSIONS: A new computerized neuropsychological test battery designed for patients with communicating hydrocephalus and INPH was introduced. Its reliability, validity for general cognitive impairment and completion rate for INPH was promising. After exclusion of the figure copy task, the battery is ready for clinical evaluation and as a next step we suggest validation for INPH and a comparison before and after shunt surgery.TRIAL REGISTRATION: ClinicalTrials.org NCT01265251.
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| 3. |
- Chen, Xiaomei, et al.
(författare)
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Effect of transporter inhibition on the distribution of cefadroxil in rat brain
- 2014
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Ingår i: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCefadroxil, a cephalosporin antibiotic, is a substrate for several membrane transporters including peptide transporter 2 (PEPT2), organic anion transporters (OATs), multidrug resistance-associated proteins (MRPs), and organic anion transporting polypeptides (OATPs). These transporters are expressed at the blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB), and/or brain cells. The effect of these transporters on cefadroxil distribution in brain is unknown, especially in the extracellular and intracellular fluids within brain.MethodsIntracerebral microdialysis was used to measure unbound concentrations of cefadroxil in rat blood, striatum extracellular fluid (ECF) and lateral ventricle cerebrospinal fluid (CSF). The distribution of cefadroxil in brain was compared in the absence and presence of probenecid, an inhibitor of OATs, MRPs and OATPs, where both drugs were administered intravenously. The effect of PEPT2 inhibition by intracerebroventricular (icv) infusion of Ala-Ala, a substrate of PEPT2, on cefadroxil levels in brain was also evaluated. In addition, using an in vitro brain slice method, the distribution of cefadroxil in brain intracellular fluid (ICF) was studied in the absence and presence of transport inhibitors (probenecid for OATs, MRPs and OATPs; Ala-Ala and glycylsarcosine for PEPT2).ResultsThe ratio of unbound cefadroxil AUC in brain ECF to blood (Kp,uu,ECF) was ~2.5-fold greater during probenecid treatment. In contrast, the ratio of cefadroxil AUC in CSF to blood (Kp,uu,CSF) did not change significantly during probenecid infusion. Icv infusion of Ala-Ala did not change cefadroxil levels in brain ECF, CSF or blood. In the brain slice study, Ala-Ala and glycylsarcosine decreased the unbound volume of distribution of cefadroxil in brain (Vu,brain), indicating a reduction in cefadroxil accumulation in brain cells. In contrast, probenecid increased cefadroxil accumulation in brain cells, as indicated by a greater value for Vu,brain.ConclusionsTransporters (OATs, MRPs, and perhaps OATPs) that can be inhibited by probenecid play an important role in mediating the brain-to-blood efflux of cefadroxil at the BBB. The uptake of cefadroxil in brain cells involves both the influx transporter PEPT2 and efflux transporters (probenecid-inhibitable). These findings demonstrate that drug-drug interactions via relevant transporters may affect the distribution of cephalosporins in both brain ECF and ICF.
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| 4. |
- Eklund, Anders, et al.
(författare)
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Hydrodynamics of the CertasTM programmable valve for the treatment of hydrocephalus
- 2012
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Ingår i: Fluids and barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 9:1, s. 12-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The new CertasTM shunt for the treatment of hydrocephalus has seven standard pressure settings that according to the manufacturer range from 36 to 238 mmH2O, and an additional "Virtual Off" setting with an opening pressure >400 mmH2O. Information on actual pressure response and reliability of shunt performance is important in clinical application, especially the "Virtual Off" setting as a non-surgical replacement for shunt ligation. The objective of this study was to evaluate the in-vitro hydrodynamic performance of the CertasTM shunt.METHODS: Six new CertasTM shunts with proximal and distal catheters were tested with an automated, computerized test system that raised the pressure from zero to a maximum pressure and back to zero at each valve setting. Opening pressure and flow resistance were determined.RESULTS: For settings 1-7 the measured opening pressure range was 26 to 247 mmH2O, and the mean change in opening pressure for a one-step adjustment was between 33 and 38 mmH2O. For setting 8 ("Virtual Off") the measured mean opening pressure was 494 +/- 34 mmH2O (range 451 to 556 mmH2O). The mean outflow resistance was 7.0 mmHg/ml/min (outflow conductance 17.9 ul/s/kPa).CONCLUSIONS: The six shunts had similar characteristics and closely matched the manufacturer's specifications for opening pressure at settings 1-7. The opening pressure for the "Virtual Off" setting was nearly 500 mmH2O, which is 100 mmH2O higher than the manufacturer's specification of ">400" and should be functionally off for most patients with communicating hydrocephalus. Clinical studies are needed to evaluate if the CSF dynamic profile persists after implantation in patients.
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| 5. |
- Loryan, Irena, et al.
(författare)
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The brain slice method for studying drug distribution in the CNS
- 2013
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Ingår i: Fluids and Barriers of the CNS. - : BioMed Central. - 2045-8118. ; 10, s. 6-
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Tidskriftsartikel (refereegranskat)abstract
- The high-throughput brain slice method is a precise and robust technique for estimating the overall uptake of drugs into brain tissue through determination of the unbound volume of distribution in the brain (Vu,brain; ml·g brain-1). Vu,brain describes the relationship between the total drug concentration in the brain and the concentration of unbound drug in the brain interstitial fluid, regardless of blood–brain barrier function. The brain slice method is more physiologically based than the brain homogenate method with respect to the assessment of drug distribution in the brain because the cell-cell interactions, pH gradients and active transport systems are all conserved. The method provides information that is directly relevant to issues such as nonspecific binding to brain tissue, lysosomal trapping, and active uptake into the cells. For these reasons, the brain slice method is recommended for estimation of target-site pharmacokinetics in the early drug discovery process and fundamental pharmacological studies. This article provides a detailed protocol for the rat and mouse brain slice methods, with the aim of enabling simple, cost-effective profiling of compounds with diverse physicochemical properties. The procedure for assessing the viability of the brain slices after the 5 h incubation period is also described. The results are interpreted for a set of compounds covering a wide range of physicochemical properties and various pharmacological targets. Application of the method for evaluating the unbound intracellular-to-extracellular concentration ratio (Kp,uu,cell) and the unbound brain-to-plasma concentration ratio (Kp,uu,brain) is discussed.
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| 6. |
- Malm, Jan, Professor, 1957-, et al.
(författare)
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Influence of comorbidities in idiopathic normal pressure hydrocephalus - research and clinical care : A report of the ISHCSF task force on comorbidities in INPH
- 2013
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Ingår i: Fluids and Barriers of the CNS. - : BioMed Central (BMC). - 2045-8118. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Idiopathic normal pressure hydrocephalus (INPH) is a syndrome of ventriculomegaly, gait impairment, cognitive decline and incontinence that occurs in an elderly population prone to many types of comorbidities. Identification of the comorbidities is thus an important part of the clinical management of INPH patients. In 2011, a task force was appointed by the International Society for Hydrocephalus and Cerebrospinal Fluid Disorders (ISHCSF) with the objective to compile an evidence-based expert analysis of what we know and what we need to know regarding comorbidities in INPH. This article is the final report of the task force. The expert panel conducted a comprehensive review of the literature. After weighing the evidence, the various proposals were discussed and the final document was approved by all the task force members and represents a consensus of expert opinions. Recommendations regarding the following topics are given: I. Musculoskeletal conditions; II. Urinary problems; III. Vascular disease including risk factors, Binswanger disease, and white matter hyperintensities; IV. Mild cognitive impairment and Alzheimer disease including biopsies; V. Other dementias (frontotemporal dementia, Lewy body, Parkinson); VI. Psychiatric and behavioral disorders; VII. Brain imaging; VIII. How to investigate and quantify. The task force concluded that comorbidity can be an important predictor of prognosis and post-operative outcome in INPH. Reported differences in outcomes among various INPH cohorts may be partly explained by variation in the rate and types of comorbidities at different hydrocephalus centers. Identification of comorbidities should thus be a central part of the clinical management of INPH where a detailed history, physical examination, and targeted investigations are the basis for diagnosis and grading. Future INPH research should focus on the contribution of comorbidity to overall morbidity, mortality and long-term outcomes.
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| 7. |
- Rabiei, Katrin, 1979, et al.
(författare)
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Diverse arachnoid cyst morphology indicates different pathophysiological origins
- 2014
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Ingår i: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background There are few, limited, and to some extent contradictory, reports on the cellular and subcellular morphology of arachnoid cysts. In the literature cyst membranes are described as similar to, or as vastly different from, normal arachnoid membranes. Methods This paper reports electron microscopic analyses of symptomatic cysts from 24 patients (12 males and 12 females; age 10–79), that underwent fenestration surgery. Fourteen cysts were located in the middle cranial fossa (temporal), one in the interpeduncular cistern, five in the posterior fossa, and four were overlying the frontal cortex. Results Microscopic findings confirmed the diverse nature of this clinical condition. Twelve cyst walls resembled normal arachnoid, four had a conspicuous core of dense fibrous tissue with a simple epithelial lining, and the remaining aberrant cysts exhibited non-arachnoid luminal epithelia with plentiful microvilli and/or cilia, and also nervous tissue components in the wall. The possible identity and origin of various cyst types are discussed. We hypothesize that cysts are formed mostly at an early stage of embryonic development, as a teratological event. Conclusions Cysts with various epithelial linings and extracellular components most likely have different barrier properties and fluid turnover characteristics. Further studies are needed to elucidate relations between cyst morphology, fluid composition, pathogenesis, and clinical behaviour including growth rate and relapse tendency.
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| 8. |
- Adam, A, et al.
(författare)
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Abstracts from Hydrocephalus 2016.
- 2017
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Ingår i: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 14:Suppl 1
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Tidskriftsartikel (refereegranskat)
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| 9. |
- Andersson, E. Axel, et al.
(författare)
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Circulating tight-junction proteins are potential biomarkers for blood-brain barrier function in a model of neonatal hypoxic/ischemic brain injury
- 2021
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Ingår i: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Neonatal encephalopathy often leads to lifelong disabilities with limited treatments currently available. The brain vasculature is an important factor in many neonatal neurological disorders but there is a lack of diagnostic tools to evaluate the brain vascular dysfunction of neonates in the clinical setting. Measurement of blood-brain barrier tight-junction (TJ) proteins have shown promise as biomarkers for brain injury in the adult. Here we tested the biomarker potential of tight-junctions in the context of neonatal brain injury. Methods The levels of TJ-proteins (occluding, claudin-5, and zonula occludens protein 1) in both blood plasma and cerebrospinal fluid (CSF) as well as blood-brain barrier function via C-14-sucrose (342 Da) and Evans blue extravasation were measured in a hypoxia/ischemia brain-injury model in neonatal rats. Results Time-dependent changes of occludin and claudin-5 levels could be measured in blood and CSF after hypoxia/ischemia with males generally having higher levels than females. The levels of claudin-5 in CSF correlated with the severity of the brain injury at 24 h post- hypoxia/ischemia. Simultaneously, we detected early increase in blood-brain barrier-permeability at 6 and 24 h after hypoxia/ischemia. Conclusions Levels of circulating claudin-5 and occludin are increased after hypoxic/ischemic brain injuries and blood-brain barrier-impairment and have promise as early biomarkers for cerebral vascular dysfunction and as a tool for risk assessment of neonatal brain injuries.
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| 10. |
- Bergman, Joakim, et al.
(författare)
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Location matters : highly divergent protein levels in samples from diferent CNS compartments in a clinical trial of rituximab for progressive MS
- 2020
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Ingår i: Fluids and Barriers of the CNS. - : BioMed Central. - 2045-8118. ; :1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The relationship between proteins in different CNS extracellular compartments is unknown. In this study the levels of selected proteins in three compartments in people with progressive multiple sclerosis (PMS) were compared.Methods: During an open label, phase 1b study on intraventricular administration of rituximab for PMS, samples were collected from the interstitial space (ISS) of the brain through microdialysis. Samples were also obtained from ventricular and lumbar cerebrospinal fluid (CSF). These samples were analyzed with a multiplexed proximity extension assay, measuring the levels of 180 proteins split equally between two panels, detecting proteins associated with immunology and neurology, respectively.Results: Considerable differences in concentrations were observed between the three analyzed compartments. Compared to ventricular CSF, ISS fluid contained statistically significant higher levels of 25 proteins (84% immunology panel and 16% neurology panel). Ventricular CSF contained significantly higher levels of 54 proteins (31% immunology panel and 69% neurology panel) compared to ISS fluid, and 17 proteins (76% immunology panel and 24% neurology panel) compared to lumbar CSF. Lumbar CSF showed significantly higher levels of 115 proteins (32% immunology panel and 68% neurology panel) compared to ventricular CSF. The three compartments displayed poor correlation with a median Spearman’s rho of -0.1 (IQR 0.4) between ISS and ventricular CSF and 0.3 (IQR 0.4) between ventricular and lumbar CSF.Conclusion: A substantial heterogeneity in the protein levels of samples obtained from different CNS compartments was seen. Therefore, data obtained from analysis of lumbar CSF should be interpreted with caution when making conclusions about pathophysiological processes in brain tissue.
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