Cerebrospinal Fluid Distribution Research Articles

Anesthesia Blunts Carbon Dioxide Effects on Glymphatic Cerebrospinal Fluid Dynamics in Mechanically Ventilated Rats.

Impaired glymphatic clearance of cerebral metabolic products and fluids contribute to traumatic and ischemic brain edema and neurodegeneration in preclinical models. Glymphatic perivascular cerebrospinal fluid flow varies between anesthetics possibly due to changes in vasomotor tone and thereby in the dynamics of the periarterial cerebrospinal fluid (CSF)-containing space. To better understand the influence of anesthetics and carbon dioxide levels on CSF dynamics, this study examined the effect of periarterial size modulation on CSF distribution by changing blood carbon dioxide levels and anesthetic regimens with opposing vasomotor influences: vasoconstrictive ketamine-dexmedetomidine (K/DEX) and vasodilatory isoflurane. End-tidal carbon dioxide (ETco2) was modulated with either supplemental inhaled carbon dioxide to reach hypercapnia (Etco2, 80 mmHg) or hyperventilation (Etco2, 20 mmHg) in tracheostomized and anesthetized female rats. Distribution of intracisternally infused radiolabeled CSF tracer 111In-diethylamine pentaacetate was assessed for 86 min in (1) normoventilated (Etco2, 40 mmHg) K/DEX; (2) normoventilated isoflurane; (3) hypercapnic K/DEX; and (4) hyperventilated isoflurane groups using dynamic whole-body single-photon emission tomography. CSF volume changes were assessed with magnetic resonance imaging. Under normoventilation, cortical CSF tracer perfusion, perivascular space size around middle cerebral arteries, and intracranial CSF volume were higher under K/DEX compared with isoflurane (cortical maximum percentage of injected dose ratio, 2.33 [95% CI, 1.35 to 4.04]; perivascular size ratio 2.20 [95% CI, 1.09 to 4.45]; and intracranial CSF volume ratio, 1.90 [95% CI, 1.33 to 2.71]). Under isoflurane, tracer was directed to systemic circulation. Under K/DEX, the intracranial tracer distribution and CSF volume were uninfluenced by hypercapnia compared with normoventilation. Intracranial CSF tracer distribution was unaffected by hyperventilation under isoflurane despite a 28% increase in CSF volume around middle cerebral arteries. K/DEX and isoflurane overrode carbon dioxide as a regulator of CSF flow. K/DEX could be used to preserve CSF space and dynamics in hypercapnia, whereas hyperventilation was insufficient to increase cerebral CSF perfusion under isoflurane.

Automated volumetric evaluation of intracranial compartments and cerebrospinal fluid distribution on emergency trauma head CT scans to quantify mass effect.

Intracranial space is divided into three compartments by the falx cerebri and tentorium cerebelli. We assessed whether cerebrospinal fluid (CSF) distribution evaluated by a specifically developed deep-learning neural network (DLNN) could assist in quantifying mass effect. Head trauma CT scans from a high-volume emergency department between 2018 and 2020 were retrospectively analyzed. Manual segmentations of intracranial compartments and CSF served as the ground truth to develop a DLNN model to automate the segmentation process. Dice Similarity Coefficient (DSC) was used to evaluate the segmentation performance. Supratentorial CSF Ratio was calculated by dividing the volume of CSF on the side with reduced CSF reserve by the volume of CSF on the opposite side. Two hundred and seventy-four patients (mean age, 61 years ± 18.6) after traumatic brain injury (TBI) who had an emergency head CT scan were included. The average DSC for training and validation datasets were respectively: 0.782 and 0.765. Lower DSC were observed in the segmentation of CSF, respectively 0.589, 0.615, and 0.572 for the right supratentorial, left supratentorial, and infratentorial CSF regions in the training dataset, and slightly lower values in the validation dataset, respectively 0.567, 0.574, and 0.556. Twenty-two patients (8%) had midline shift exceeding 5 mm, and 24 (8.8%) presented with high/mixed density lesion exceeding >25 ml. Fifty-five patients (20.1%) exhibited mass effect requiring neurosurgical treatment. They had lower supratentorial CSF volume and lower Supratentorial CSF Ratio (both p < 0.001). A Supratentorial CSF Ratio below 60% had a sensitivity of 74.5% and specificity of 87.7% (AUC 0.88, 95%CI 0.82-0.94) in identifying patients that require neurosurgical treatment for mass effect. On the other hand, patients with CSF constituting 10-20% of the intracranial space, with 80-90% of CSF specifically in the supratentorial compartment, and whose Supratentorial CSF Ratio exceeded 80% had minimal risk. CSF distribution may be presented as quantifiable ratios that help to predict surgery in patients after TBI. Automated segmentation of intracranial compartments using the DLNN model demonstrates a potential of artificial intelligence in quantifying mass effect. Further validation of the described method is necessary to confirm its efficacy in triaging patients and identifying those who require neurosurgical treatment.

Gold nanoparticle-enhanced X-ray microtomography of the rodent reveals region-specific cerebrospinal fluid circulation in the brain

Cerebrospinal fluid (CSF) is essential for the development and function of the central nervous system (CNS). However, the brain and its interstitium have largely been thought of as a single entity through which CSF circulates, and it is not known whether specific cell populations within the CNS preferentially interact with the CSF. Here, we develop a technique for CSF tracking, gold nanoparticle-enhanced X-ray microtomography, to achieve micrometer-scale resolution visualization of CSF circulation patterns during development. Using this method and subsequent histological analysis in rodents, we identify previously uncharacterized CSF pathways from the subarachnoid space (particularly the basal cisterns) that mediate CSF-parenchymal interactions involving 24 functional-anatomic cell groupings in the brain and spinal cord. CSF distribution to these areas is largely restricted to early development and is altered in posthemorrhagic hydrocephalus. Our study also presents particle size-dependent CSF circulation patterns through the CNS including interaction between neurons and small CSF tracers, but not large CSF tracers. These findings have implications for understanding the biological basis of normal brain development and the pathogenesis of a broad range of disease states, including hydrocephalus.

605. Efficacy and pharmacokinetics-pharmacodynamics of ATI-2307 in a rabbit model of cryptococcal meningoencephalitis

Abstract Background Cryptococcal meningitis (CM) is a fungal disease with significant global morbidity and mortality. There are multiple new therapies being developed to improve the current regimens involving amphotericin B, flucytosine, and fluconazole. ATI-2307 is a novel arylamidine which inhibits mitochondrial function in yeasts. We tested ATI-2307 in a rabbit model of CM and evaluated its efficacy, pharmacokinetics, and pharmacodynamics (PK-PD). Methods Immune suppressed rabbits were infected with Cryptococcus neoformans. Starting two days after the infection, they were treated with ATI-2307 (1, 2, or 3 mg/kg), amphotericin B (1 mg/kg), fluconazole (80 mg/kg), a combination of ATI-2307 (1 mg/kg) and fluconazole (80 mg/kg), or they were untreated. ATI-2307 was given daily subcutaneously. Fungal burden and drug levels were quantified in the CSF during the infection and in the brain tissue at study termination, day 4, 10, or 14 post infection. Drug pharmacokinetics in the blood were examined on day 8 post infection. Drug pharmacokinetics in the CSF and brain tissue were examined at day 4 post infection. Results Daily dosing with ATI-2307 reduced the yeast burden in both the cerebrospinal fluid (CSF) and brain tissue compared to controls. Furthermore, when combined with fluconazole, ATI-2307 reduced the CSF fungal burden below the limit of detection. In fact, we observed a large reduction in fungal burden relative to untreated controls with only three doses, which was sustained for 1 week after the cessation of dosing. The kinetics of ATI-2307 indicated that the drug has a long gamma phase in both blood and CSF. In addition, our analysis of the drug levels in the brain tissue indicated that it dramatically accumulated in the meninges, which may then serve as a site of sustained release. Efficacy of ATI-2307 on CSF Fungal Burden and Distribution of ATI-2307 in Brain Tissue ATI-2307 was dosed daily starting at day 2 post infection through the study endpoint, day 10 or 14 post infection, with the exception of the 2 mg/kg, 3 dose group, which only received doses on days 2, 3, and 4 post infection. Conclusion Taken together, these data provide evidence for ATI-2307 as a promising therapy for CM and it may require fewer doses than existing treatments and provide additive anticryptococcal activity with azole treatment. Disclosures Charles D. Giamberardino, Jr., MR, Affimed NV: Stocks/Bonds|Appili Therapeutics: Grant/Research Support|Interventional Analgesix Inc: Grant/Research Support|Minnetronix: Grant/Research Support|Pfizer: Grant/Research Support|Quoin Pharmaceuticals: Stocks/Bonds|Sfunga: Grant/Research Support Jennifer L. Tenor, PhD, Appili: Grant/Research Support|Pfizer: Grant/Research Support Dena Toffaletti, PhD, Appili Therapeutics: Grant/Research Support|Pfizzer: Grant/Research Support Don Cilla, Pharm.D., M.B.A., Appili Therapeutics: Employee|Appili Therapeutics: Stocks/Bonds William Hope, OBE (FRACP, FRCPA, PhD), Antabio: Grant/Research Support|Appili Therapeutics: Advisor/Consultant|BioVersys: Grant/Research Support|Bugworks: Grant/Research Support|Centauri: Advisor/Consultant|F2G: Advisor/Consultant|F2G: Grant/Research Support|NAEJA-RGM Pharmaceuticals Inc: Advisor/Consultant|NAEJA-RGM Pharmaceuticals Inc: Grant/Research Support|National Institute of Health Research (NIHR).: Co-lead for Infectious Diseases|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Phico Therapeutics: Grant/Research Support|Specialist Advisory Committee for GARDP: Advisor/Consultant|Spero Therapeutics: Advisor/Consultant|Spero Therapeutics: Grant/Research Support|The Global Antibiotic Research and Development Partnership (GARDP): Grant/Research Support|VenatoRx: Advisor/Consultant John R. Perfect, MD, Appili Therapeutics: Advisor/Consultant|Appili Therapeutics: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Matinas: Advisor/Consultant|Merck: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Scynexis: Advisor/Consultant.

Response to Pralsetinib Observed in Meningeal-Metastatic EGFR-Mutant NSCLC With Acquired RET Fusion: A Brief Report

IntroductionRET is well known as an important driver gene in NSCLC. Moreover, RET is a rare acquired resistance mechanism to EGFR-mutant NSCLC. Only 36 NSCLC cases of coexistence of EGFR and RET were reported previously worldwide. So far, there have been no reports on the following: (1) whether combination of EGFR tyrosine kinase inhibitor (TKI) and RET TKI works for meningeal metastasis; (2) the concentrations of EGFR TKI and RET TKI in the cerebrospinal fluid (CSF) and plasma; and (3) whether RET fusions and EGFR mutation happened in the same clone or not. MethodsWe reported a patient with an EGFR-mutant NSCLC with acquired RET fusions and meningeal metastasis treated with pralsetinib and osimertinib; the specimen was analyzed by next-generation sequencing (Illumina NovaSeq 6000 platform). Symptom improvement and magnetic resonance imaging scan were used for effect evaluation. Furthermore, we determined the concentrations of pralsetinib and osimertinib in CSF and plasma by means of liquid chromatography tandem mass spectrometry. We also detected RET fusion and EGFR L858R mutation by methods of fluorescence in situ hybridization and immunohistochemistry with continuous sections to analyze whether RET fusions coexist with EGFR mutation in the same clone or not. ResultsThe allele frequency of the RET fusion was detected to be 12.88%. This patient achieved a partial response, indicating pralsetinib combined with osimertinib may be clinically beneficial for meningeal metastasis in patients harboring acquired coexistent RET fusions. The concentrations of pralsetinib in the CSF and plasma were 704.76 nM and 91.31 μM, whereas those of osimertinib in the CSF and plasma were 23.70 nM and 2148.94 nM, respectively. RET fusion was found in the same clone of EGFR L858R mutation. ConclusionsOur finding of this case indicated that RET fusion and EGFR mutation occur in the same population of cell clones, rather than in different cell clones. Combined pralsetinib may be an effective way to overcome the resistance, even for meningeal metastasis, owing to high CSF distribution of pralsetinib.

197 Gold Nanoparticle Enhanced X-ray Nanotomography Reveals Region-Specific CSF Pathways Through the Brain and Spinal Cord that are Altered in Post-hemorrhagic Hydrocephalus

INTRODUCTION: Cerebrospinal fluid (CSF) is essential for the healthy development and function of the brain, but understanding the mechanisms of its distribution in and around the central nervous system (CNS) remains a major challenge. To address this need, we developed a new technique, gold nanoparticle-enhanced x-ray nanotomography (AuNp-XRM), to achieve micrometer-scale resolution visualization of CSF pathways across the entire brain and spinal cord of rodents with further applications to a model of interventricular hemorrhage/post-hemorrhagic hydrocephalus (IVH/PHH). METHODS: P4 rodents were injected with aCSF or hemoglobin to create the control and IVH conditions. 72 hours later, animals underwent MRIs to determine onset of PHH. Animals were then injected with 1.9 nm and 15 nm gold nanoparticles and imaged using XRM. Following XRM, the brains, spines and meninges were harvested for histology. RESULTS: Using AuNp-XRM, we demonstrate visualization of previously characterized glymphatic, cranial nerve, and choroid plexus-mediated CSF circulation patterns, and present evidence to further identify CSF interactions with the leptomeninges, choroid plexus, and parenchyma of the brain and spinal cord. We also identified an intraparenchymal CSF circulation that targets stem-cell rich and cholinergic neuronal populations. CSF distribution to these areas was mediated by flow of CSF through the paravascular spaces of perforators originating from the large blood vessels of the basal cisterns and was significantly decreased in an animal model of PHH. CONCLUSION: Our findings using AuNp-XRM show that cholinergic cell populations in the brain and spinal cord differentially handle CSF, and that PHH alters CSF distribution to these areas of the brain. These region-specific patterns of CSF distribution may have critical relevance to normal brain development, brain development following PHH, and other neuropathological conditions.

513 Surveilling Cerebrospinal Fluid Protein Biomarkers in Brain Metastasis

INTRODUCTION: Cerebrospinal fluid (CSF) is in constant and direct contact with the brain parenchyma, vessels and meninges. The distribution and relative isolation of CSF makes it valuable in the evaluation of central nervous system pathologies. CSF protein profiling has been widely studied in neuro-degenerative and inflammatory diseases. This analysis may also be relevant in patients with brain metastases. METHODS: Patients were enrolled between May 2017 and March 2020 under an IRB protocol. CSF and plasma were processed and stored at -80°C. Concentrations of 142 soluble proteins were quantified by Luminex (Eve Technologies). RESULTS: Seventy-four patients were included in this study. Of the 60 patients with brain metastases, most had lung cancer (N=29), melanoma (N=10) and breast cancer (N=7). Non-malignant samples included normal pressure hydrocephalus (NPH, N=5), CSF leak (N=9) and radiation necrosis (N=9). Of the 142 soluble proteins profiled, 44 were significantly elevated in patients with LMD compared to intraparenchymal disease. None were more elevated in intraparenchymal disease. This finding was not replicated in the plasma. The CSF profile of patients with LMD and NPH were highly similar. CONCLUSION: Soluble CSF proteins are detectable in patients with brain metastases and concentrations differ based on extent of intracranial disease. This difference was not seen in plasma. These findings suggest that patients with LMD have a protein signature, different from those with intraparenchymal brain metastases only, which can help augment current diagnostic standards and reflect the tumor microenvironment. The similarity of LMD and NPH CSF proposes a similar pathogenesis and warrants further exploration. Further analysis of clinical data including survival and treatment response may assist in the management of patients with brain metastases.

Investigation of the role and quantitative impact of breast cancer resistance protein on drug distribution into brain and CSF in rats

Breast cancer resistance protein (BCRP) expressed in the blood-brain barrier plays a major role in limiting drug distribution into the central nervous system (CNS). However, functional involvement of BCRP in drug distribution into the brain and cerebrospinal fluid (CSF) remains unclear. The aim of present study was to reveal the role and quantitative impact of BCRP on CNS distribution. The brain-to-plasma unbound concentration ratio (Kp,uu,brain) and CSF-to-plasma unbound concentration ratio (Kp,uu,CSF) values of BCRP-specific substrates were determined in rats. The Kp,uu,brain values decreased, as the in vitro BCRP corrected flux ratio (CFR) increased. The Kp,uu,CSF values of BCRP-specific substrates were greater than the Kp,uu,brain values. Increase in the Kp,uu,brain values induced by co-administration of BCRP inhibitor correlated with the in vitro BCRP CFR and were greater than the increase in Kp,uu,CSF values induced by BCRP inhibitor except nebicapone. The contribution of BCRP to the brain and CSF distribution of the dual P-glycoprotein/BCRP substrates, imatinib and prazosin, was similar to that of BCRP-specific substrates. Thus, we revealed that the impact of in vivo BCRP on CNS distribution is correlated with in vitro BCRP CFR, and that BCRP limits drug distribution into the brain more strongly than into the CSF.

Cerebrospinal fluid and plasma distribution of anti-α-synuclein IgMs and IgGs in multiple system atrophy and Parkinson's disease

IntroductionUbiquitous naturally occurring autoantibodies (nAbs) against alpha-synuclein (α-syn) may play important roles in the pathogenesis of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Recently, we reported reduced high-affinity/avidity anti-α-syn nAbs levels in plasma from MSA and PD patients, along with distinct inter-group immunoglobulin (Ig)G subclass distributions. The extent to which these observations in plasma may reflect corresponding levels in the cerebrospinal fluid (CSF) is unknown. MethodsUsing competitive and indirect ELISAs, we investigated the affinity/avidity of CSF anti-α-syn nAbs as well as the CSF and plasma distribution of IgG subclasses and IgM nAbs in a cross-sectional cohort of MSA and PD patients. ResultsRepertoires of high-affinity/avidity anti-α-syn IgG nAbs were reduced in CSF samples from MSA and PD patients compared to controls. Furthermore, anti-α-syn IgM nAb levels were relatively lower in CSF and plasma from MSA patients but were reduced only in plasma from PD patients. Interestingly, anti-α-syn IgG subclasses presented disease-specific profiles both in CSF and plasma. Anti-α-syn IgG1, IgG2 and IgG3 levels were relatively increased in CSF of MSA patients, whereas PD patients showed increased anti-α-syn IgG2 and reduced anti-α-syn IgG4 levels. ConclusionsDifferences in the plasma/CSF distribution of anti-α-syn nAbs seem to be a common feature of synucleinopathies. Our data add further support to the notion that MSA and PD patients may have compromised immune reactivity towards α-syn. The differing α-syn-specific systemic immunological responses may reflect their specific disease pathophysiologies. These results are encouraging for further investigation of these immunological mechanisms in neurodegenerative diseases.

Letter: Cranioplasty Reverses Dysfunction of the Solutes Distribution in the Brain Parenchyma After Decompressive Craniectomy

Letter: Cranioplasty Reverses Dysfunction of the Solutes Distribution in the Brain Parenchyma After Decompressive Craniectomy

Hydrocephalus

Hydrocephalus is caused by excessive accumulation of cerebrospinal fluid(CSF)in the ventricles or the skull. Unlike acute hydrocephalus presenting with elevated intracranial pressure, chronic hydrocephalus is called normal-pressure hydrocephalus(NPH). Because the CSF volume increases slowly, the brain compressively deforms without increasing intracranial pressure. NPH should be diagnosed and treated according to the following three categories: idiopathic NPH(iNPH), secondary NPH(sNPH), and congenital NPH(cNPH). The intracranial CSF distribution in iNPH differed from that in sNPH or cNPH. In iNPH, the Sylvian fissure and basal cistern were conspicuously enlarged, whereas the convexity subarachnoid space was severely decreased. CSF distribution in the subarachnoid space specific to iNPH is known as "disproportionately enlarged subarachnoid space hydrocephalus(DESH)," which might be due to direct CSF communication between the lateral ventricles and the basal cistern at the inferior choroidal point of the choroidal fissure. After shunt surgery in a patient with NPH, the lateral ventricles and Sylvian fissure shrank from top to bottom, while the convexity subarachnoid space expanded. In NPH, except for obstructive hydrocephalus, the flow void sign on spin-echo T2-weighted images is usually observed around the aqueduct, which reflects the increased CSF movement.

Circadian control of brain glymphatic and lymphatic fluid flow

The glymphatic system is a network of perivascular spaces that promotes movement of cerebrospinal fluid (CSF) into the brain and clearance of metabolic waste. This fluid transport system is supported by the water channel aquaporin-4 (AQP4) localized to vascular endfeet of astrocytes. The glymphatic system is more effective during sleep, but whether sleep timing promotes glymphatic function remains unknown. We here show glymphatic influx and clearance exhibit endogenous, circadian rhythms peaking during the mid-rest phase of mice. Drainage of CSF from the cisterna magna to the lymph nodes exhibits daily variation opposite to glymphatic influx, suggesting distribution of CSF throughout the animal depends on time-of-day. The perivascular polarization of AQP4 is highest during the rest phase and loss of AQP4 eliminates the day-night difference in both glymphatic influx and drainage to the lymph nodes. We conclude that CSF distribution is under circadian control and that AQP4 supports this rhythm.

Phenol-Soluble Modulin-Mediated Aggregation of Community-Associated Methicillin-Resistant Staphylococcus Aureus in Human Cerebrospinal Fluid.

Phenol-soluble modulins (PSMs) are major determinants of Staphylococcus aureus virulence and their increased production in community-associated methicillin-resistant S. aureus (CA-MRSA) likely contributes to the enhanced virulence of MRSA strains. Here, we analyzed the differences in bacterial cell aggregation according to PSM presence in the specific human cerebrospinal fluid (CSF) environment. CSF samples from the intraventricular or lumbar intrathecal area of each patient and tryptic soy broth media were mixed at a 1:1 ratio, inoculated with WT and PSM-deleted mutants (Δpsm) of the CA-MRSA strain, USA300 LAC, and incubated overnight. Cell aggregation images were acquired after culture and image analysis was performed. The cell aggregation ratio in WT samples differed significantly between the two sampling sites (intraventricular: 0.2% vs. lumbar intrathecal: 6.7%, p < 0.001). The cell aggregation ratio in Δpsm samples also differed significantly between the two sampling sites (intraventricular: 0.0% vs. lumbar intrathecal: 1.2%, p < 0.001). Division of the study cases into two groups according to the aggregated area ratio (WT/Δpsm; group A: ratio of ≥ 2, group B: ratio of < 2) showed that the median aggregation ratio value differed significantly between groups A and B (5.5 and 0, respectively, p < 0.001). The differences in CSF distribution and PSM presence within the specific CSF environment are significant factors affecting bacterial cell aggregation.

Ciliary Beating Compartmentalizes Cerebrospinal Fluid Flow in the Brain and Regulates Ventricular Development

SummaryMotile cilia are miniature, propeller-like extensions, emanating from many cell types across the body. Their coordinated beating generates a directional fluid flow, which is essential for various biological processes, from respiration to reproduction. In the nervous system, ependymal cells extend their motile cilia into the brain ventricles and contribute to cerebrospinal fluid (CSF) flow. Although motile cilia are not the only contributors to CSF flow, their functioning is crucial, as patients with motile cilia defects develop clinical features, like hydrocephalus and scoliosis. CSF flow was suggested to primarily deliver nutrients and remove waste, but recent studies emphasized its role in brain development and function. Nevertheless, it remains poorly understood how ciliary beating generates and organizes CSF flow to fulfill these roles. Here, we study motile cilia and CSF flow in the brain ventricles of larval zebrafish. We identified that different populations of motile ciliated cells are spatially organized and generate a directional CSF flow powered by ciliary beating. Our investigations revealed that CSF flow is confined within individual ventricular cavities, with little exchange of fluid between ventricles, despite a pulsatile CSF displacement caused by the heartbeat. Interestingly, our results showed that the ventricular boundaries supporting this compartmentalized CSF flow are abolished during bodily movement, highlighting that multiple physiological processes regulate the hydrodynamics of CSF flow. Finally, we showed that perturbing cilia reduces hydrodynamic coupling between the brain ventricles and disrupts ventricular development. We propose that motile-cilia-generated flow is crucial in regulating the distribution of CSF within and across brain ventricles.

Diffusion Tensor Imaging of the Superior Thalamic Radiation and Cerebrospinal Fluid Distribution in Idiopathic Normal Pressure Hydrocephalus.

Ventricular enlargement in elderly raises a challenging differential diagnosis to physicians. While Alzheimer's disease is the most common form of dementia, idiopathic normal pressure hydrocephalus (iNPH) constitutes a potentially reversible syndrome. iNPH has a unique pathophysiology pertaining to cerebrospinal fluid (CSF) dynamics and periventricular white matter. We aimed to determine the effects of iNPH on periventricular white matter bundles and to further characterize its ventricular and sulcal CSF distribution by using diffusion tensor tractography (DTT) and CSF volumetrics on high resolution T1-weighted magnetic resonance imaging data. Deterministic DTT and validated volumetric parcellation were performed on 20 healthy elderly, 13 Alzheimer's disease (AD), and 9 iNPH patients. The superior thalamic radiation, corticospinal tract, and dentatorubrothalamic tract were traced and quantified using DTI studio software. Cloud-based volumetric parcellation was also performed on 138 healthy subjects across the lifespan, 13 AD, and 9 iNPH-patients. Ventricular and sulcal CSF volumes in the three groups were compared. Combining increased mean diffusivity of the superior thalamic radiation with ventricular volume resulted in clear separation of iNPH from the AD and age-matched healthy subject groups. Additionally, ventricular to sulcal CSF ratio, utilizing fully automated methods, was significantly greater in the iNPH patients compared to AD and healthy age-matched controls. Combined microstructural (DTT) and macrostructural (ventricular volume) changes is a promising radiological approach in studying ventriculomegaly. Automated estimation of the disproportionate ventricular and sulcal CSF ratio in patients presenting with ventriculomegaly may be important as radiologic markers in differentiating iNPH from other causes of ventriculomegaly.

Analysis of the Variables Influencing Valproic Acid Concentration in the Serum and Cerebrospinal Fluid of Chinese Patients After Craniotomy.

Valproic acid (VPA) has been widely used in Chinese patients after craniotomy. Many studies have focused on the influencing factors of VPA serum concentration, but conclusions are sometimes paradoxical. Furthermore, the concentration of VPA in the cerebrospinal fluid (CSF) has been rarely reported. In the present study, VPA CSF concentrations were measured, and the potential factors influencing serum concentration and CSF distribution of VPA were investigated. In addition, the functional relationship between serum and CSF concentration was explored. Subjects were patients who underwent craniotomy and were administrated with VPA and had a lumbar puncture. Serum and CSF VPA concentrations were measured by use of the Abbott i1000 system. CYP2C9 (430 C>T, 1075 A>C, 1076 T>C, 1080 C>G), UGT1A6 (541 A>G, 552 A>C), UGT2B7 (211 G>T, 802 C>T), and ABCB1 (1236 C>T, 2677 G>T/A, 3435 C>T) genotypes were determined by direct sequencing. Information, such as age, gender, and height, was collected, and their effect on serum and CSF VPA concentrations was investigated by univariate analysis and multiple linear regression analysis. First, the concomitant use of carbapenems (β' = -0.422) and UGT1A6 (552 AA → AC) (β' = -0.249) had a significant negative correlation with the weight-adjusted VPA serum concentration (C:W ratio), whereas CYP2C9 (1075 AA → AC) (β' = 0.186) and gender (female compared with male) (β' = 0.322) showed a positive correlation with VPA serum C:W ratio. The coefficient of determination (R) was only 0.348. Second, the relationship between the serum concentration and the CSF square root of the concentration (R = 0.705) had a better linear fit. Third, serum VPA concentration (β' = 0.810), concomitant use of glycerol fructose (β' = 0.160), and age (≥65 compared with <65) (β' = 0.118) showed a positive correlation (R = 0.748) with the variability of square root of the concentration of the CSF. In Chinese patients, after craniotomy, female patients with 1 or more of CYP2C9 (1075 AC) and UGT1A6 (552 AA) genotypes required a lower VPA dosage compared with male patient. There was a better-fitted linear relationship between VPA serum and the square root of CSF concentrations. CSF VPA concentrations were relatively stable, with only age and the use of glycerol fructose having a small influence.

An observational study examining the effects of a surgically induced inflammatory response on the distribution of morphine and its metabolites into cerebrospinal fluid

Morphine is administered intravenously for pain management in the perioperative period. The effect of the inflammatory response to surgery on morphine distribution across the blood-brain barrier (BBB) in humans was investigated. We hypothesized that a graded surgically induced, systemic inflammatory response alters cerebrospinal fluid (CSF) levels of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a temporary reduction in BBB drug efflux transporter function. We conducted a prospective pharmacokinetic study of the plasma and CSF distribution of the P-glycoprotein (PGP) substrate morphine in 33 patients undergoing open thoracic (n=18) or endovascular (n=15) aortic aneurysm repair. Morphine was administered with induction of anesthesia and in the intensive care unit. Plasma and CSF concentrations of interleukin (IL)-6, morphine, M3G, M6G, and albumin were measured prior to surgery (baseline), during surgery, and postoperatively every six hours until removal of the CSF drain. The area under the curve (AUC) was determined for plasma and CSF IL-6, morphine, M3G, and M6G concentrations vs time. The primary endpoint measures were the correlations between the morphine, M6G, and M3G AUC CSF/plasma ratios and systemic inflammation as quantified by the time-normalized IL-6 exposure, which was calculated for each individual by dividing the total exposure (AUC) by time (t). A Bonferroni corrected P<0.017 indicated a significant correlation. Plasma and CSF IL-6 concentrations increased postoperatively. The median [interquartile range] IL-6 exposures were significantly higher in the open vs endovascular surgical group for plasma (105 [40-256] pg·mL-1 vs 29 [16-70] pg·mL-1, respectively; P=0.013) and CSF (79 [26-133] pg·mL-1 vs 16 [9-80] pg·mL-1, respectively; P=0.013). For the primary endpoint, the plasma IL-6 AUC/t did not correlate with the CSF accumulation of morphine (r=-0.009; P=0.96) or M3G (r=0.37; P=0.04) when corrected for surgical procedure, age, and sex. There were insufficient data on CSF concentration to complete the primary analysis for M6G. Morphine distribution into the CSF was not significantly altered in patients undergoing thoracic aortic aneurysm repair. This suggests that BBB PGP function may not be affected by the perioperative inflammatory response. www.clinicaltrials.gov , NCT 00878371. Registered 7 April 2009.

The spectrum of aseptic central nervous system infections in southern Germany - demographic, clinical and laboratory findings.

Aseptic infections of the central nervous system (CNS) are frequently observed in Germany. However, no study has systematically addressed the spectrum of aseptic CNS infections in Germany. Data on 191 adult patients diagnosed from January 2007 to December 2014 with aseptic meningitis or encephalitis/meningoencephalitis at our hospital were collected by chart review and analyzed for demographic, clinical and laboratory findings. Patients were stratified according to the causative virus and findings were compared between groups. In our cohort, meningitis was caused in 36% by enterovirus (EV), 15% by herpes simplex virus (HSV), 12% by varicella zoster virus (VZV) and 5% by tick borne encephalitis (TBE). Encephalitis/meningoencephalitis was caused in 13% by HSV, 13% by VZV, and three out of 11 tested patients were positive for TBE. The highest incidence of EV infections was between 25 and 35 years and of HSV infections between 30 and 60 years. VZV infections had a bimodal distribution peaking below 30 and above 70 years. VZV and EV infections were more frequently observed during summer, whereas HSV infections showed no seasonal preference. Inflammatory changes in cerebrospinal fluid (CSF) were highest in HSV and lowest in EV infections. Polymerase chain reaction tests for HSV, VZV and EV in CSF and TBE serology determined the causative virus in over 60% of tested patients. The age of affected patients, seasonal distribution, disease course and inflammatory changes in CSF differ between groups of patients affected by the most common viral infections.

Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue

ObjectiveSignal hyperintensity on unenhanced MRI in certain brain regions has been reported after multiple administrations of some, but not all, gadolinium-based contrast agents (GBCAs). One potential initial pathway of GBCA entry into the brain, infiltration from blood into the cerebrospinal fluid (CSF), was systematically evaluated in this preclinical study.MethodsGBCA infiltration and distribution in the CSF were investigated in healthy rats using repeated fluid-attenuated MRI up to 4 h after high-dose (1.8 mmol/kg) administration of six marketed and one experimental GBCA. Additionally, gadolinium measurements in CSF, blood and brain tissue samples (after 24 h) were performed using inductively coupled plasma mass spectrometry.ResultsEnhanced MRI signals in the CSF spaces with similar distribution kinetics were observed for all GBCAs. No substantial differences in the gadolinium concentrations among the marketed GBCAs were found in the CSF, blood or brain tissue. After 4.5 h, the concentration in the CSF was clearly higher than in blood but was almost completely cleared and lower than the brain tissue concentration after 24 h.ConclusionsIn contrast to the brain signal hyperintensities, no differences in penetration and distribution into the CSF of healthy rats exist among the marketed GBCAs.Key Points• Gadolinium-based contrast agents can cross the blood-CSF barrier.• Fluid-attenuated MRI shows GBCA distribution with CSF flow.• GBCA structure and physicochemical properties do not impact CSF penetration and distribution.• GBCA clearance from CSF was almost complete within 24 h in rats.• CSF is a potential pathway of GBCA entry into the brain.

Patterns of cerebrospinal fluid (CSF) distribution in patients with spontaneous intracranial hypotension: Assessed with magnetic resonance myelography

BackgroundDiagnosis of spontaneous intracranial hypotension (SIH) relies on the ability of medical staff to recognize cerebrospinal fluid (CSF) leakage at the spine. However, difficulties with interobserver discrepancy sometimes occurred while reading magnetic resonance myelography (MRM) because clear image definition was lacking. In this study, we tried to determine which pattern of CSF distribution is more reliable for diagnosis of CSF leakage by using MRM. MethodsFrom January 2012 to August 2014, 19 SIH patients and 27 healthy controls (HC) were recruited into our study; 10 of the 19 patients were recovered (SIH-R) after treatment. Whole spine MRM was performed using the 3D-SPACE (three-dimensional sampling perfection with application-optimized contrasts using different flip-angle evolutions) sequence, and interpreted by two experienced neuroradiologists. Two 4-point classification systems of CSF distribution were used to evaluate the three-dimensional maximum intensity projection (3D MIP) and the thin-slice axial multiplanar reconstruction (MPR) images, respectively. ResultsThe interobserver agreement between the two readers interpreting the 3D MIP and thin-slice axial MPR MRM were moderate to good (κ=0.60–0.78). Grade 3 of 3D MIP and Type D of axial MPR MRM were only noticed in the SIH. Overall, Grade 3 of MIP and Type D of MPR showed significant difference (p<0.008) between the SIH and the HC in the whole spine. Type C at the T-spine was more frequently noted in the SIH than in the HC (p<0.038). By using “Grade 3”, “Type D”, “Type D and Type C at T-spine” as the diagnostic criteria of CSF leakage, the sensitivity, specificity, positive predict value (PPV), and negative predict value (NPV) were all > 70%. ConclusionGrade 3 on 3D MIP and Type D on axial MPR MRM were definite criteria of MRM for localizing CSF leakage, and Type C in the T-spine was a probable leakage sign with high sensitivity and NPV.