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The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.
The cerebrospinal fluid (CSF) offers a window into the workings of the brain and blood-brain barrier (BBB). Molecules that enter into the central nervous system (CNS) by passive diffusion or receptor-mediated transport through the choroid plexus often appear in the CSF prior to acting within the brain. Other molecules enter the CNS by passing through the BBB into the brain's interstitial fluid prior to appearing in the CSF. This pattern is also often observed for molecules synthesized by neurons or glia within the CNS. The CSF is therefore an important conduit for the entry and clearance of molecules into/from the CNS and thereby constitutes an important window onto brain activity and barrier function. Assessing the CSF basally, under experimental conditions, or in the context of challenges or metabolic diseases can provide powerful insights about brain function. Here, we review important findings made by our labs, as influenced by the late Randall Sakai, by interrogating the CSF.
Copyright © 2016. Published by Elsevier Inc.
PURPOSE - To empirically characterize and quantify the impact of gradient weighting schemes on the appearance and fidelity of diffusion tensor imaging of the human spinal cord in vivo in clinically relevant scan time equivalents (STE).
MATERIALS AND METHODS - In five healthy controls at 3T, we evaluated test-retest reproducibility and performed voxelwise analysis of diffusion tensor imaging (DTI)-derived indices (fractional anisotropy [FA], mean [MD], axial [AD], and radial [RD] diffusivity) in the cervical spinal cord to assess spatial dependencies of measurement error and differences across three different sampling schemes (6, 15, and 32 directions) at STE of 4.5, 9, and 18 minutes. A subjective assessment was also performed.
RESULTS - With six directions, column-specific errors are highest (effect size = 2.9%, 4.4%, 7.2% for FA in dorsal column, lateral column, and gray matter) and different than the 15-direction scheme (P < 0.05). STE sequences with 15 and 32 directions exhibited small differences in error (P > 0.05). For FA and AD, measurement errors are prevalent in gray matter, while partial volume effects with cerebrospinal fluid heavily influence RD. Measurement errors decreased with increasing scan time (P < 0.01), albeit with diminishing returns at scan times longer than 9 minutes (P < 0.05).
CONCLUSION - A 15-direction scheme of 9 minutes yields measurements of the cervical spinal cord with low error. J. Magn. Reson. Imaging 2016;44:1608-1618.
© 2016 International Society for Magnetic Resonance in Medicine.
BACKGROUND - Amyloid-beta (Aβ) imaging with positron emission tomography (PET) holds promise for detecting the presence of Aβ plaques in the cortical gray matter. Many image analyses focus on regional average measurements of tracer activity distribution; however, considerable additional information is available in the images. Metrics that describe the statistical properties of images, such as the two-point correlation function (S2), have found wide applications in astronomy and materials science. S2 provides a detailed characterization of spatial patterns in images typically referred to as clustering or flocculence. The objective of this study was to translate the two-point correlation method into Aβ-PET of the human brain using 11C-Pittsburgh compound B (11C-PiB) to characterize longitudinal changes in the tracer distribution that may reflect changes in Aβ plaque accumulation.
METHODS - We modified the conventional S2 metric, which is primarily used for binary images and formulated a weighted two-point correlation function (wS2) to describe nonbinary, real-valued PET images with a single statistical function. Using serial 11C-PiB scans, we calculated wS2 functions from two-dimensional PET images of different cortical regions as well as three-dimensional data from the whole brain. The area under the wS2 functions was calculated and compared with the mean/median of the standardized uptake value ratio (SUVR). For three-dimensional data, we compared the area under the wS2 curves with the subjects' cerebrospinal fluid measures.
RESULTS - Overall, the longitudinal changes in wS2 correlated with the increase in mean SUVR but showed lower variance. The whole brain results showed a higher inverse correlation between the cerebrospinal Aβ and wS2 than between the cerebrospinal Aβ and SUVR mean/median. We did not observe any confounding of wS2 by region size or injected dose.
CONCLUSION - The wS2 detects subtle changes and provides additional information about the binding characteristics of radiotracers and Aβ accumulation that are difficult to verify with mean SUVR alone.
PURPOSE - Our goal is to develop an accurate, automated tool to characterize the optic nerve (ON) and cerebrospinal fluid (CSF) to better understand ON changes in disease.
METHODS - Multi-atlas segmentation is used to localize the ON and sheath on T2-weighted MRI (0.6 mm(3) resolution). A sum of Gaussian distributions is fit to coronal slice-wise intensities to extract six descriptive parameters, and a regression forest is used to map the model space to radii. The model is validated for consistency using tenfold cross-validation and for accuracy using a high resolution (0.4 mm(2) reconstructed to 0.15 mm(2)) in vivo sequence. We evaluated this model on 6 controls and 6 patients with multiple sclerosis (MS) and a history of optic neuritis.
RESULTS - In simulation, the model was found to have an explanatory R-squared for both ON and sheath radii greater than 0.95. The accuracy of the method was within the measurement error on the highest possible in vivo resolution. Comparing healthy controls and patients with MS, significant structural differences were found near the ON head and the chiasm, and structural trends agreed with the literature.
CONCLUSION - This is a first demonstration that the ON can be exclusively, quantitatively measured and separated from the surrounding CSF using MRI.
© 2015 Wiley Periodicals, Inc.
Invasive electrocorticography (ECoG) is used in patients when it is difficult to localize epileptogenic foci for potential surgical resection. As MR neuroimaging has improved over the past decade, we hypothesized the utilization of ECoG diminishing over time. Using the USA Nationwide Inpatient Sample, we collected demographic and complication data on patients receiving ECoG over the years 1988-2008 and compared this to patients with medically refractory epilepsy during the same time period. A total of 695 cases using extraoperative ECoG were identified, corresponding to 3528 cases nationwide and accounting for 1.1% of patients with refractory epilepsy from 1988-2008. African Americans were less likely to receive ECoG than whites, as were patients with government insurance in comparison to those with private insurance. Large, urban, and academic hospitals were significantly more likely to perform ECoG than smaller, rural, and private practice institutions. The most frequent complication was cerebrospinal fluid leak (11.7%) and only one death was reported from the entire cohort, corresponding to an estimated six patients nationally. Invasive ECoG is a relatively safe procedure offered to a growing number of patients with refractory epilepsy each year. However, these data suggest the presence of demographic disparities in those patients receiving ECoG, possibly reflecting barriers due to race and socioeconomic status. Among patients with nonlocalized seizures, ECoG often represents their only hope for surgical treatment. We therefore must further examine the indications and efficacy of ECoG, and more work must be done to understand if and why ECoG is preferentially performed in select socioeconomic groups.
Copyright © 2014 Elsevier Ltd. All rights reserved.
The blood-brain barrier (BBB) dynamically controls exchange between the brain and the body, but this interaction cannot be studied directly in the intact human brain or sufficiently represented by animal models. Most existing in vitro BBB models do not include neurons and glia with other BBB elements and do not adequately predict drug efficacy and toxicity. Under the National Institutes of Health Microtissue Initiative, we are developing a three-dimensional, multicompartment, organotypic microphysiological system representative of a neurovascular unit of the brain. The neurovascular unit system will serve as a model to study interactions between the central nervous system neurons and the cerebral spinal fluid (CSF) compartment, all coupled to a realistic blood-surrogate supply and venous return system that also incorporates circulating immune cells and the choroid plexus. Hence all three critical brain barriers will be recapitulated: blood-brain, brain-CSF, and blood-CSF. Primary and stem cell-derived human cells will interact with a variety of agents to produce critical chemical communications across the BBB and between brain regions. Cytomegalovirus, a common herpesvirus, will be used as an initial model of infections regulated by the BBB. This novel technological platform, which combines innovative microfluidics, cell culture, analytical instruments, bioinformatics, control theory, neuroscience, and drug discovery, will replicate chemical communication, molecular trafficking, and inflammation in the brain. The platform will enable targeted and clinically relevant nutritional and pharmacologic interventions for or prevention of such chronic diseases as obesity and acute injury such as stroke, and will uncover potential adverse effects of drugs. If successful, this project will produce clinically useful technologies and reveal new insights into how the brain receives, modifies, and is affected by drugs, other neurotropic agents, and diseases.
OBJECT - The Hydrocephalus Clinical Research Network (HCRN), which comprises 7 pediatric neurosurgical centers in North America, provides a unique multicenter assessment of the current outcomes of CSF shunting in nonselected patients. The authors present the initial results for this cohort and compare them with results from prospective multicenter trials performed in the 1990s.
METHODS - Analysis was restricted to patients with newly diagnosed hydrocephalus undergoing shunting for the first time. Detailed perioperative data from 2008 through 2012 for all HCRN centers were prospectively collected and centrally stored by trained research coordinators. Historical control data were obtained from the Shunt Design Trial (1993-1995) and the Endoscopic Shunt Insertion Trial (1996-1999). The primary outcome was time to first shunt failure, which was determined by using Cox regression survival analysis.
RESULTS - Mean age of the 1184 patients in the HCRN cohort was older than mean age of the 720 patients in the historical cohort (2.51 years vs 1.60 years, p < 0.0001). The distribution of etiologies differed (p < 0.0001, chi-square test); more tumors and fewer myelomeningoceles caused the hydrocephalus in the HCRN cohort patients. The hazard ratio for first shunt failure significantly favored the HCRN cohort, even after the model was adjusted for the prognostic effects of age and etiology (adjusted HR 0.82, 95% CI 0.69-0.96).
CONCLUSIONS - Current outcomes of shunting in general pediatric neurosurgery practice have improved over those from the 1990s, although the reasons remain unclear.
OBJECT - Postresection hydrocephalus is observed in approximately 30% of pediatric patients with posterior fossa tumors. However, which patients will develop postresection hydrocephalus is not known. The Canadian Preoperative Prediction Rule for Hydrocephalus (CPPRH) was developed in an attempt to identify this subset of patients, allowing for the optimization of their care. The authors sought to validate and critically appraise the CPPRH.
METHODS - The authors conducted a retrospective chart review of 99 consecutive pediatric patients who presented between 2002 and 2010 with posterior fossa tumors and who subsequently underwent resection. The data were then analyzed using bivariate and multivariate analyses, and a modified CPPRH (mCPPRH) was applied.
RESULTS - Seventy-six patients were evaluated. Four variables were found to be significant in predicting postresection hydrocephalus: age younger than 2 years, moderate/severe hydrocephalus, preoperative tumor diagnosis, and transependymal edema. The mCPPRH produced observed likelihood ratios of 0.737 (95% CI 0.526-1.032) and 4.688 (95% CI 1.421-15.463) for low- and high-risk groups, respectively.
CONCLUSIONS - The mCPPRH utilizes readily obtainable and reliable preoperative variables that together stratify children with posterior fossa tumors into high- and low-risk categories for the development of postresection hydrocephalus. This new predictive model will aid patient counseling and tailor the intensity of postoperative clinical and radiographic monitoring for hydrocephalus, as well as provide evidence-based guidance for the use of prophylactic CSF diversion.
Persistent neutrophilic meningitis presents a diagnostic challenge, because the differential diagnosis is broad and includes atypical infectious causes. We describe a case of persistent neutrophilic meningitis due to Aspergillus fumigatus in an immunocompetent man who had no evidence of sinopulmonary or cutaneous disease. An epidural glucocorticoid injection was identified as a potential route of entry for this organism into the central nervous system, and the case was reported to the state health department.