Ratio Of Cerebrospinal Fluid Research Articles

Correlation Between Serum and CSF Concentrations of Midazolam and 1-Hydroxy-Midazolam in Critically Ill Neurosurgical Patients.

Midazolam (MZ) is commonly used in critically ill neurosurgical patients. Neuro-penetration of MZ and its metabolite, 1-hydroxy-midazolam (1-OH-MZ), is not well characterized. This study evaluated correlations between serum and cerebrospinal fluid (CSF) concentrations of MZ and 1-OH-MZ and assessed implications on patient sedation. Adults in the neurosurgical intensive care unit (ICU) with external ventricular drains receiving MZ via continuous infusion were prospectively studied. Serum and CSF samples were obtained 12-24 h and 72-96 h after initiation, and concentrations were determined in duplicate by high-performance liquid chromatography with tandem mass spectrometry. Bivariate correlation analyses used Pearson coefficient. A total of 31 serum and CSF samples were obtained from 18 subjects. At sampling, mean MZ infusion rate was 3.9 ± 4.4 mg/h, and previous 12-h cumulative dose was 51.4 ± 78.2 mg. Mean concentrations of MZ and 1-OH-MZ in serum and CSF were similar between timepoints. Similarly, ratios of 1-OH-MZ to MZ in serum and CSF remained stable over time. Serum MZ (126.2 ± 89.3 ng/mL) showed moderate correlation (r2 = 0.68, P < 0.001) with serum 1-OH-MZ (17.7 ± 17.6 ng/mL) but not CSF MZ (3.9 ± 2.5 ng/mL; r2 = 0.24, P = 0.005) or CSF 1-OH-MZ (2.5 ± 0.6 ng/mL; r2 = 0.47, P = 0.30). CSF MZ did not correlate with CSF 1-OH-MZ (r2 = 0.003, P < 0.001). Mean serum ratio of 1-OH-MZ to MZ (0.14 ± 0.2 ng/mL) did not correlate with CSF ratio (1.06 ± 0.83 ng/mL; r2 = 0.06, P = 0.19). Concentrations and ratios were unrelated to MZ infusion rate or 12-h cumulative dose. Sedation was weakly correlated with CSF 1-OH-MZ, but not with serum MZ, serum 1-OH-MZ, or CSF MZ. Continuous infusions of MZ result in measurable concentrations of MZ and 1-OH-MZ in CSF; however, CSF concentrations of MZ and 1-OH-MZ poorly represent serum concentrations or dosages. Accumulation of MZ and 1-OH-MZ in serum or CSF over time was not evident. Concentrations of MZ and 1-OH-MZ do not predict sedation levels, reinforcing that pharmacodynamic assessments are warranted.

Association of impulsive behavior and cerebrospinal fluid/plasma oxidation and antioxidation ratio in Chinese men

ObjectivesImpulsive behavior is the precursor of many psychiatric and neurological conditions. High levels of impulsive behavior will increase health risk behavior and related injuries. Impulsive behavior is produced and regulated by central and peripheral biological factors, and oxidative stress (OS) can aggravate it. However, previous studies only showed that impulsive behavior was related to the level of the peripheral OS. Therefore, this study aims to clarify the relationship between OS and impulsive behavior in the brain and peripheral blood. MethodsWe recruited 64 Chinese men. We measured superoxide dismutase (SOD) (including copper, zinc and manganese) and nitric oxide synthase (NOS) (including total, inducible and constitutive) in cerebrospinal fluid (CSF) and plasma. The Barratt Impulsiveness Scale version 11 (BIS-11) was used to evaluate impulsive behavior. The relationship between OS and impulsive behavior was evaluated by partial correlation analysis and stepwise multiple regression analysis. ResultsPartial correlation analysis showed that the ratio of total NOS-to-MnSOD and iNOS-to-MnSOD in CSF were negatively correlated with the BIS-11 motor scores (r = −0.431, p = −0.001; r = −0.434, p = −0.001). Stepwise multiple regression analysis showed that the ratio of CSF iNOS-to-MnSOD was the most influential variable on the BIS-11 motor scores(β = −0.434, t = −3.433, 95 %CI(−0.374, −0.098), p = 0.001). Conclusions and RelevanceThe imbalance of central oxidation and antioxidation is related to impulsive behavior, which broadens our understanding of the correlation between impulsive behavior and OS.

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.

Abstract 54: Investigating the Relationship Between Reperfusion and Cerebral Edema Using Novel Cerebrospinal Fluid and Net Water Uptake Biomarkers

Introduction: Studies show that successful reperfusion after large-vessel occlusion (LVO) stroke can lead to reduced mass effect and midline shift (MLS). However, MLS typically occurs late in the edema cascade and only develops in approximately half of patients treated with endovascular thrombectomy (EVT). This study aimed to explore the connection between reperfusion and cerebral edema in more detail, utilizing CSF volumetrics and tissue water concentration. Methods: Using a deep-learning algorithm, we measured cerebrospinal fluid (CSF) volumes and their interhemispheric ratio on CT images at baseline, 24 hours, and 72 hours following a stroke. Automated segmentation of infarct regions on follow-up scans was used to measure net water uptake (NWU), the ratio of density within infarcted tissue relative to the mirrored contralateral region. The change in edema markers from baseline to 24 hours, as well as 72-hour NWU, were dichotomized at the median into significant edema growth and low/moderate edema growth. Reperfusion status was assessed by the modified thrombolysis in cerebral infarction score. Results: This study included 137 patients (mean age 69 ± 15, mean NIHSS 14) with LVO stroke who underwent EVT. There was a gradual decrease in the CSF ratio change at 24 and 72 hours with lower (worse) TICI scores (p=0.023 and p&lt;0.001, respectively, Figure 1A). After adjusting for age, admission NIHSS, and ASPECT score, successful reperfusion was associated with lower odds of significant edema by CSF ratio change at 24 hours (aOR 0.25, 95% CI 0.1-0.6, p=0.002) and NWU at 72 hours (aOR 0.26, 95% CI 0.1-0.7, p=0.01) when compared with unsuccessful reperfusion. Lower CSF ratio growth and NWU at 24 hours were significantly associated with lower global disability measured by the modified Rankin Scale at 90 days (p&lt;0.001 and p=.008, respectively, Figure 1B). Conclusions: Successful reperfusion is associated with reduced edema and better functional outcomes following thrombectomy.

Diagnosing Alzheimer's disease: Which dementia screening test to use in elderly Puerto Ricans with mild cognitive impairment and early Alzheimer's disease?

Typically, Alzheimer's disease (AD) diagnosis is not made at its earliest period, for instance, at mild cognitive impairment (MCI) and early AD (E-AD). Our study aims to demonstrate a correlation between the screening tools, including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating (CDR), and the biological biomarkers in the cerebrospinal fluid (CSF) amyloid beta 1-42 (Aβ42), phosphorylated tau (p-tau) proteins and total tau (t-tau)/Aβ42 ratio in Puerto Ricans>55 years old with MCI and E-AD. We evaluated 30 participants, including demographics, memory scales, and CSF biomarkers. Twenty-eight CSF biomarkers (Aβ42, p-tau protein, and t-tau/Aβ42 ratio) were analyzed using the Meso Scale Discovery Platform (MSD). Associations between memory scales (MoCA, MMSE, CDR) and CSF markers were performed using Spearman rho correlation. Our study revealed a statistical association favoring a direct relationship between MMSE and MoCA with t-tau/Aβ42 ratio in CSF (P=0.022, P=0.035, respectively). We found a trend toward significance with an inverse relationship with MMSE and Aβ42 (P=0.069) and a direct relationship with MMSE and p-tau (P=0.098). MMSE and MoCA screening tests were identified with a statistically significant association with the CSF biomarkers, specifically t-tau/Aβ42 ratio, in elderly Puerto Ricans with MCI and E-AD. Puerto Ricans>55 years old with MCI and E-AD could be screened confidently with MMSE and MoCA for a higher likelihood of earlier detection and, thus, initiation of disease-modifying treatment and prompt non-pharmacological interventions.

Utility of cerebrospinal fluid protein biomarkers in predicting the outcome of Guillain-Barre syndrome

Objectives The study aimed to investigate the potential of peripheral myelin protein 2 (P2) and Alpha B-crystallin (αBC) as predictive biomarkers in Guillain-Barré syndrome (GBS). Given the unpredictability of GBS prognosis, the need for specific and reliable biomarkers for disease development and intensity assessment is crucial. Material and Methods A prospective observational study was conducted on a cohort of 220 individuals diagnosed with GBS at a tertiary general hospital in South India. P2 and αBC levels in cerebrospinal fluid (CSF) were quantified using ELISA assay kits. The study spanned from March 2021 to April 2023, with participants aged 18–60 years. The study protocol adhered to ethical standards, and the Brighton criteria were employed for GBS diagnosis. CSF samples were collected at admission and two weeks post-onset. Data analysis utilised SPSS, and statistical significance was set at p &lt; 0.05. Results Upon admission, mean P2 levels were 2.2 ± 0.5 ng/mL, and αBC levels were 9.8 ± 2.3 ng/mL. After two weeks, P2 increased to 4.8 ± 0.8 ng/mL, and αBC increased to 15.1 ± 2.3 ng/mL. A positive correlation was observed between the rise in P2 and αBC levels and enhanced muscle strength at 4 weeks and 6 months. Conclusion The study suggests a significant increase in P2 and αBC levels in GBS patients, correlating with improved muscle strength. P2 and αBC ratios in CSF between the second and first weeks may serve as prognostic markers for GBS. Limitations include a small sample size and the absence of a control group, necessitating caution in generalizability.

Assessing bone density on MRI: comparison between routine MRI sequences and DEXA scans.

Magnetic Resonance Imaging (MRI) is frequently utilised to aid in the comprehensive assessment of back pain, while dual-energy x-ray absorptiometry (DEXA) is the gold standard test for the assessment of bone density. Assessing bone density on MRI could reduce costs and avoid exposing patients to ionising radiation. The aim of this paper is to investigate whether the relative signal intensity of vertebral bodies compared to other structures can detect osteoporosis on MRI. 100 patients that had undergone both a lumbar spine MRI and a DEXA scan were identified. The T1 and T2 signal intensity of L1-L4 vertebral bodies (VB), cerebro-spinal fluid (CSF), and psoas muscle were measured within a 1-cm2 region of interest (ROI), and the signal intensity ratios were calculated. The ratios were stratified as normal, osteopenic, or osteoporotic based on DEXA T-scores. The T1 VB /T1 CSF ratio was significantly higher in the osteoporotic group than the normal and osteopenic groups (p < 0.001). The T1 VB /T1 CSF ratio had excellent discrimination (AUC = 0.841) for the presence of osteoporosis. The Pearson correlation coefficient between the DEXA T-score and the T1VB/T1CSF ratio was -0.474 (p < 0.001). The intra-observer (ICC = 0.910, 95% CI = 0.757-0.966) and inter-observer reliability (ICC = 0.927, 95% CI = 0.824-0.970) were excellent. In our cohort, a T1 VB / T1 CSF ratio of greater than 4 is 66.7% sensitive but 90.0% specific for the presence of osteoporosis. A high T1VB/T1CSF ratio suggests osteoporosis on MRI. Prospective validation is needed to confirm these findings.

Comparison of cerebrospinal fluid space between probable normal pressure hydrocephalus and Alzheimer's disease.

Idiopathic normal pressure hydrocephalus (INPH) is a potentially reversible syndrome characterized by complex symptoms, difficulty in diagnosis and a lack of detailed clinical description, and it is difficult to distinguish from Alzheimer's disease (AD). The objective of this study was to design a method for measuring the actual amount of hydrocephalus in patients with INPH and to evaluate INPH. All subjects underwent a 3D T1-weighted MRI. Statistical parametric mapping 12 was used for preprocessing images, statistical analysis, and voxel-based morphometric gray matter (GM) volume, white matter (WM) volume, and cerebrospinal fluid (CSF) volume analysis. The demographic and clinical characteristics of the groups were compared using a t-test for continuous variables and a chi-square test for categorical variables. Pearson's correlation analysis and Bonferroni's statistic-corrected one-way ANOVA were used to determine the relationship among demographic variables. Receiver operating characteristic (ROC) curves were used to assess the accuracy of the callosal angle (CA), WM ratio, and CSF ratio in distinguishing probable INPH from AD. The study included 42 patients with INPH, 32 patients with AD, and 24 healthy control subjects (HCs). There were no differences among the three groups in basic characteristics except for Mini-Mental State Examination (MMSE). There was a correlation between the intracranial CSF ratio and CA. The WM ratio and CSF ratio in patients with INPH and AD were statistically different. Furthermore, the combination of CA, WM ratio, and CSF ratio had a greater differential diagnostic value between INPH and AD patients than CA alone. INPH can be accurately assessed by measuring intracranial CSF ratio, and the addition of WM ratio and CSF ratio significantly improved the differential diagnostic value of probable INPH from AD compared to CA alone.

Reliable Cerebrospinal Fluid Cytology and Immunocytochemistry Reporting over an Extended Period by the Addition of Aldehyde and Osmolyte-Based Preservative Solution

Introduction: The cytological examination of cerebrospinal fluid (CSF) is an important investigation in the workup of various inflammatory, malignant, or traumatic disorders of the central nervous system. The cells in the CSF lyse and degenerate at a very fast rate owing to its low tonicity, buffering capacity, redox potential, and pH, making it crucial to examine it within 2 h of sampling. We have hereby designed an aliphatic aldehyde, osmolyte, metal halide, and a buffer-based solution which will preserve the cellular components of CSF for 48 h. Methods: Thirty-nine CSF specimens were examined within 2 h of collection, and this reading was recorded as time zero reading. The CSF specimens were then divided into two tubes with (i) pre‐servative:CSF ratio of 1:5; and (ii) no preservative. Total and differential leukocyte counts and immunocytochemistry were performed on the paired specimens at 24 h and 48 h and were compared with the readings at zero hours. Results: The preservative-containing CSF showed significantly higher cellularity than the undiluted samples at 24 h and 48 h (p < 0.001). Median cell counts observed in the preservative-containing CSF were 5 times and 12 times higher than in the undiluted CSF. Neutrophils, lymphocytes, and RBCs showed immunopositivity for MPO, CD45, and GLUT-1 at both time intervals. Conclusion: Adding the prepared preservative solution to CSF in the ratio of 1:5 can optimally preserve the CSF cells for absolute and differential quantitation, morphological assessment, and immunological testing at a later date.

Measuring blood glucose before or after lumbar puncture.

The ratio of cerebrospinal fluid (CSF) to peripheral blood glucose at the same period is an important index for diagnosing and monitoring the efficacy of central nervous system infection, especially bacterial meningitis. Some guidelines refer that blood glucose measurement should be carried out before lumbar puncture. The main reason is to avoid possible effect of stress response induced by lumbar puncture on the level of blood glucose. However, there is no consensus on whether it should be followed in actual clinical work, since up to now no research work having been published on whether lumbar puncture will induce the changes on blood glucose. Our study aimed to investigate the changes of peripheral blood glucose before and after lumbar puncture. In order to clarify the influence of timing of peripheral blood glucose measurement at the same period of lumbar puncture, a prospective study was conducted including children with an age range from 2 months to 12 years old in the neurology department of a medical center. For those children who need lumbar puncture due to their illness, their blood glucose was measured within 5 min before and after lumbar puncture, respectively. The blood glucose level and the ratio of CSF to blood glucose before and after lumbar puncture were compared. Meanwhile, the patients were divided into different groups according to the factors of sex, age and sedation or not for further comparison. All statistical analyses of the data were performed using SPSS version 26.0 for Windows. In total, 101 children who needed lumbar puncture during hospitalization from January 1, 2021, to October 1, 2021, were recruited with 65 male and 36 female respectively. There was no significant difference on the level of blood glucose, CSF to blood glucose ratio before and after lumbar puncture among the children (p>0.05). No differences were observed within different groups (sex, age, sedation or not) either. It is unnecessary to emphasize blood glucose measurement should be carried out before lumbar puncture, especially for pediatric patients. From the perspective of facilitating smoother cerebrospinal fluid puncture in children, blood glucose measurement after lumbar puncture might be a better choice.

ABTEST‐IA: A new reliable tool for the quantification of Aβ40 and Aβ42 in CSF

AbstractBackgroundThe ratio Aβ42/Aβ40 in cerebrospinal fluid (CSF) is considered one of the most reliable biomarkers of Alzheimer’s Disease. ABtest40‐IA and ABtest42‐IA have been widely used for amyloid‐β (Aβ) quantification in plasma samples. The aim of this study was to validate these tests for the quantification of Aβ40 and Aβ42 in CSF.MethodAnalytical validation of ABtest40‐IA and ABtest42‐IA was accomplished following FDA and EMA reference guidelines. Calibration curves, sensitivity, specificity, accuracy, precision, recovery and dilution linearity were evaluated.Correlations between ABtest‐IA and an independent fully automated IVD test, (Lumipulse ® G β‐amyloid 1‐40 and 1‐42, Fujirebio), were estimated using 93 CSF samples of PET‐Aβ positive (75%) and PET‐Aβ negative (25%) individuals. Differences in CSF Aβ42/Aβ40 levels between both PET‐Aβ groups were analyzed (Mann Whitney test).The ability of CSF Aβ42/Aβ40 ratio to discriminate between PET‐Aβ positive and PET‐Aβ negative subjects was evaluated by means of Receiver Operating Characteristic (ROC) curve analysis, considering PET‐Aβ the gold standard.ResultCalibration curves ranges were set at 43.9 to 500 pg/mL for ABtest40‐IA and 5 to 100 pg/mL for ABtest42‐IA. Intra‐assay, inter‐assay and inter‐lot coefficients of variation were below 5.2% and 7.4% for ABtest40‐IA and ABtest42‐IA respectively. Accuracy evaluation provided mean relative errors of 4.6% and 7.5%.Spearman correlation coefficients between ABtest‐IA and Lumipulse® were 0.96, 0.95 and 0.93 for Aβ40, Aβ42 and Aβ42/Aβ40 respectively (p values &lt; 0.0001). As expected, Aβ42/Aβ40 ratio levels were significantly lower in the PET‐Aβ positive group (p &lt; 0.0001).ROC analysis of CSF Aβ42/Aβ40 gave an AUC of 0.85 (95% CI 0.74 to 0.97), very similar to that obtained with Lumipulse®: 0.84 (95% CI 0.72 to 0.98). The overall agreement of PET‐Aβ and ABtest‐IA Aβ42/Aβ40 was 90%, being false positives the majority (78%) of the misclassified subjects. Results are supporting that CSF Aβ42/Aβ40 is an early biomarker of cerebral amyloid deposition.ConclusionABtest40‐IA and ABtest42‐IA were successfully validated as new precise and accurate tools for the quantification of Aβ40 and Aβ42 in CSF samples. ABtest‐IA measures of Aβ42/Aβ40 ratio in CSF identified individuals with brain amyloid deposition with equivalent ability to other test commercially available.

Loss of hepatic manganese transporter ZIP8 disrupts serum transferrin glycosylation and the glutamate-glutamine cycle

BackgroundZIP8, encoded by SLC39A8, is a membrane transporter that facilitates the cellular uptake of divalent biometals including zinc (Zn), manganese (Mn), and iron (Fe). The hepatic system has long been accepted as the central modulator for whole-body biometal distribution. Earlier investigations suggest the propensity of ZIP8 to prioritize Mn influx, as opposed to Fe or Zn, in hepatocytes. Hepatic ZIP8 Mn transport is crucial for maintaining homeostasis of various Mn-dependent metalloenzymes and their associated pathways. Herein, we hypothesize that a drastic decrease in systemic Mn, via the loss of hepatic ZIP8, disrupts two unique cellular pathways, post-translational glycosylation and the glutamate-glutamine cycle. MethodsZIP8 liver-specific knockout (LSKO) mice were chosen in an attempt to substantially decrease whole-body Mn levels. To further elucidate the role of Mn in serum glycosylation, a Mn-deficient diet was adopted in conjunction with the LSKO mice to model a near-complete loss of systemic Mn. After the treatment course, transferrin sialylation profiles were determined using imaged capillary isoelectric focusing (icIEF). We also investigated the role of Mn in the glutamate-glutamine cycle; the conversion of glutamate to glutamine in F/F and LSKO mice was assessed by the glutamine/glutamate ratio in cerebrospinal fluid (CSF) via HPLC-MS. An open-field study was ultimately conducted to check if these mice displayed atypical behavior. ResultsTwo major biological pathways were found to be significantly altered due to the loss of hepatic ZIP8. We identified a disparity between F/F and LSKO transferrin sialylation profiles that were exacerbated under a Mn-deficient diet. Additionally, we discovered a neurotransmitter imbalance between the levels of glutamine and glutamate, exclusive to LSKO mice. This was characterized by the decreased glutamine/glutamate ratio in CSF. Secondary to the neurotransmitter alteration, LSKO mice exhibited an increase in locomotor activity in an open-field. ConclusionOur model successfully established a connection between the loss of hepatic ZIP8 and two Mn-dependent cellular pathways, namely, protein glycosylation and the glutamate-glutamine cycle.

Imaging biomarkers of cerebral edema automatically extracted from routine CT scans of large vessel occlusion strokes.

Volumetric and densitometric biomarkers have been proposed to better quantify cerebral edema after stroke, but their relative performance has not been rigorously evaluated. Patients with large vessel occlusion stroke from three institutions were analyzed. An automated pipeline extracted brain, cerebrospinal fluid (CSF), and infarct volumes from serial CTs. Several biomarkers were measured: change in global CSF volume from baseline (ΔCSF); ratio of CSF volumes between hemispheres (CSF ratio); and relative density of infarct region compared with mirrored contralateral region (net water uptake [NWU]). These were compared to radiographic standards, midline shift and relative hemispheric volume (RHV) and malignant edema, defined as deterioration resulting in need for osmotic therapy, decompressive surgery, or death. We analyzed 255 patients with 210 baseline CTs, 255 24-hour CTs, and 81 72-hour CTs. Of these, 35 (14%) developed malignant edema and 63 (27%) midline shift. CSF metrics could be calculated for 310 (92%), while NWU could only be obtained from 193 (57%). Peak midline shift was correlated with baseline CSF ratio (ρ=-.22) and with CSF ratio and ΔCSF at 24 hours (ρ=-.55/.63) and 72 hours (ρ=-.66/.69), but not with NWU (ρ=.15/.25). Similarly, CSF ratio was correlated with RHV (ρ=-.69/-.78), while NWU was not. Adjusting for age, National Institutes of Health Stroke Scale, tissue plasminogen activator treatment, and Alberta Stroke Program Early CT Score, CSF ratio (odds ratio [OR]:1.95 per 0.1, 95% confidence interval [CI]: 1.52-2.59) and ΔCSF at 24 hours (OR:1.87 per 10%, 95% CI: 1.47-2.49) were associated with malignant edema. CSF volumetric biomarkers can be automatically measured from almost all routine CTs and correlate better with standard edema endpoints than net water uptake.

Serum but not cerebrospinal fluid levels of allantoin are increased in de novo Parkinson’s disease

Oxidative stress supposedly plays a role in the pathogenesis of Parkinson’s disease (PD). Uric acid (UA), a powerful antioxidant, is lowered in PD while allantoin, the oxidation product of UA and known biomarker of oxidative stress, was not systematically studied in PD. We aim to compare serum and cerebrospinal fluid (CSF) levels of UA, allantoin, and allantoin/UA ratio in de novo PD patients and controls, and evaluate their associations with clinical severity and the degree of substantia nigra degeneration in PD. We measured serum and CSF levels of UA, allantoin, and allantoin/UA ratio in 86 PD patients (33 females, mean age 57.9 (SD 12.6) years; CSF levels were assessed in 51 patients) and in 40 controls (19 females, 56.7 (14.1) years). PD patients were examined using Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment (MoCA), Scales for Outcomes in Parkinson Disease-Autonomic (SCOPA-AUT), the University of Pennsylvania Smell Identification Test (UPSIT), one-night video-polysomnography, and dopamine transporter single-photon emission computed tomography (DAT-SPECT). Serum allantoin and allantoin/UA ratio were significantly increased in the PD group compared to controls (p < 0.001 and p = 0.002, respectively). Allantoin/UA ratios in serum and CSF were positively associated with the SCOPA-AUT score (p = 0.005 and 0.031, respectively) and RBD presence (p = 0.044 and 0.028, respectively). In conclusion, serum allantoin and allantoin/UA ratio are elevated in patients with de novo PD. Allantoin/UA ratio in serum and CSF is associated with autonomic dysfunction and RBD presence, indicating that higher systemic oxidative stress occurs in PD patients with more diffuse neurodegenerative changes.

Evidence of intrathecally-derived antibodies against Toxoplasma gondii in horses suspected of neurological disease consistent with equine protozoal myeloencephalitis

Among the recognized neurologic diseases in horses, equine protozoal myeloencephalitis (EPM) has been reported around the world and still presents challenges in diagnosis and treatment. Horses can present with clinical neurologic signs consistent with EPM while testing negative for the two main causative agents, Sarcocystis neurona or Neospora hughesi, and may still be clinically responsive to anti-parasitic drug therapy. This context led to our hypothesis that another protozoal parasite, Toxoplasma gondii, which is known to cause toxoplasmosis in other mammalian species, is a potential pathogen to cause neurologic disease in horses. To evaluate this hypothesis, serum and cerebrospinal fluid (CSF) were collected from 210 horses presenting with clinical signs compatible with EPM, and the indirect immunofluorescent antibody test (IFAT) was used to detect antibody titers for T. gondii, S. neurona, and N. hughesi. Additionally, the serum to CSF titer ratio was calculated for T. gondii, S. neurona, and N. hughesi infections, suggesting intrathecally-derived antibodies for each of the three agents if the serum:CSF ratio was ≤ 64. There were 133 (63.3%) horses positive for serum T. gondii antibodies using a cutoff titer of 160, and 31 (14.8%) positive for CSF T. gondii antibodies using a cutoff titer of 5. Overall, 21 (10.0%) of EPM-suspect horses had a serum:CSF ratio ≤ 64 for antibodies for T. gondii, while 43 (20.5%) and 8 (3.8%) horses had a serum to CSF ratio ≤ 64 for antibodies for S. neurona and N. hughesi, respectively. A total of 6 (2.9%) animals presented evidence of concurrent intrathecally-derived antibodies for T. gondii and at least one other apicomplexan parasite in this study. Signalment and clinical signs were not different across the groups aforementioned. These data provide evidence of intrathecal production of anti-T. gondii antibodies, indicative of T. gondii infection in the brain and/or spinal cord of horses with EPM-like disease.

Metal ratios as possible biomarkers for amyotrophic lateral sclerosis

Background and ObjectivesAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown aetiology. Metals have been suspected to contribute to ALS pathogenesis since mid-19th century, yet studies on measured metal concentrations in ALS patients have often yielded conflicting results, with large individual variation in measured values. Calculating metal concentration ratios can unveil possible synergistic effects of neurotoxic metals in ALS pathogenesis. The aim of this study was to investigate if ratios of different metal concentrations in cerebrospinal fluid (CSF) and blood plasma, respectively, differ between ALS patients and healthy controls. MethodsCerebrospinal fluid and blood plasma were collected from 17 ALS patients and 10 controls. Samples were analysed for 22 metals by high-resolution inductively coupled plasma mass spectrometry (HR-ICP-MS), and all possible 231 metal ratios calculated in each body fluid. ResultsFifty-three metal ratios were significantly elevated in ALS cases as compared to controls (p < 0.05); five in blood plasma, and 48 in CSF. The finding of fewer elevated ratios in blood plasma may indicate specific transport of metals into the central nervous system. The elevated metal ratios in CSF include Cd/Se (p = 0.031), and 16 ratios with magnesium, such as Mn/Mg (p = 0.005) and Al/Mg (p = 0.014). ConclusionMetal ratios may be used as biomarkers in ALS diagnosis and as guidelines for preventive measures.

Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the AppNL−F/NL−F knock-in mouse model of Alzheimer’s disease

BackgroundAβ42/Aβ40 ratios in cerebrospinal fluid (CSF) and blood are reduced in preclinical Alzheimer’s disease (AD), but their temporal and correlative relationship with cerebral Aβ pathology at this early disease stage is not well understood. In the present study, we aim to investigate such relationships using App knock-in mouse models of preclinical AD.MethodsCSF, serum, and brain tissue were collected from 3- to 18-month-old AppNL−F/NL−F knock-in mice (n = 48) and 2–18-month-old AppNL/NL knock-in mice (n = 35). The concentrations of Aβ42 and Aβ40 in CSF and serum were measured using Single molecule array (Simoa) immunoassays. Cerebral Aβ plaque burden was assessed in brain tissue sections by immunohistochemistry and thioflavin S staining. Furthermore, the concentrations of Aβ42 in soluble and insoluble fractions prepared from cortical tissue homogenates were measured using an electrochemiluminescence immunoassay.ResultsIn AppNL−F/NL−F knock-in mice, Aβ42/Aβ40 ratios in CSF and serum were significantly reduced from 12 and 16 months of age, respectively. The initial reduction of these biomarkers coincided with cerebral Aβ pathology, in which a more widespread Aβ plaque burden and increased levels of Aβ42 in the brain were observed from approximately 12 months of age. Accordingly, in the whole study population, Aβ42/Aβ40 ratios in CSF and serum showed a negative hyperbolic association with cerebral Aβ plaque burden as well as the levels of both soluble and insoluble Aβ42 in the brain. These associations tended to be stronger for the measures in CSF compared with serum. In contrast, no alterations in the investigated fluid biomarkers or apparent cerebral Aβ plaque pathology were found in AppNL/NL knock-in mice during the observation time.ConclusionsOur findings suggest a temporal sequence of events in AppNL−F/NL−F knock-in mice, in which initial deposition of Aβ aggregates in the brain is followed by a decline of the Aβ42/Aβ40 ratio in CSF and serum once the cerebral Aβ pathology becomes significant. Our results also indicate that the investigated biomarkers were somewhat more strongly associated with measures of cerebral Aβ pathology when assessed in CSF compared with serum.

Abstract 12: Higher Blood Pressure Trajectories After Endovascular Thrombectomy Are Associated With Cerebral Edema Development

Introduction: High blood pressure after endovascular thrombectomy (EVT) can cause cerebral hyperemia and disrupt the blood-brain barrier. However, its role in cerebral edema development is incompletely understood. In this study, we examined the relationship between post-EVT systolic blood pressure (SBP) trajectories and cerebral edema. Methods: We prospectively enrolled patients with large-vessel occlusion stroke who underwent EVT. Cerebrospinal fluid (CSF) volume was measured using a deep-learning algorithm on CT images at baseline, 24 hours, and 72 hours after stroke. The ratio of CSF volumes between hemispheres was calculated. Automated segmentation of infarct regions on follow-up scans was used to measure net water uptake (NWU), the ratio of density within infarcted tissue relative to the mirrored contralateral region. Latent variable mixture modeling (LVMM) divided patients into SBP trajectory groups during the first 72 hours post-EVT (Fig. 1A). Measures of edema (change in CSF ratio, NWU) were compared between groups. Results: One hundred patients (mean age 70 ± 16, mean NIHSS 15) were analyzed. Edema was assessed by a gradual increase in NWU (20.5, 27.0) at 24 and 72 hours, respectively, and by a reduction in CSF ratio (0.95, 0.78, 0.68) in the affected hemisphere at baseline, 24 hours, and 72 hours, respectively. LVMM identified five SBP trajectories. Higher SBP trajectories were associated with higher NWU (Fig. 1B) but not lower CSF ratio at 24 hours (p&lt;0.001 and p=0.343, respectively). After adjusting for age, admission NIHSS, and TICI score, the moderate-to-high and high-to-moderate trajectory groups were independently associated with higher NWU (aOR 11.40, 95% CI 2.14-20.66) and (aOR 10.97, 95% CI 0.12-21.82), relative to the low and moderate groups. Conclusions: Higher SBP trajectories are associated with an increase in NWU post-EVT. NWU is a promising radiographic biomarker for measuring cerebral edema during the early phase after stroke.

Elevated neurofilament light chain CSF/serum ratio indicates impaired CSF outflow in idiopathic intracranial hypertension

BackgroundImpaired cerebrospinal fluid (CSF) homeostasis is central to the pathogenesis of idiopathic intracranial hypertension (IIH), although the precise mechanisms involved are still not completely understood. The aim of the current study was to assess the CSF/serum ratio of neurofilament light chain levels (QNfL) as a potential indicator of functional CSF outflow obstruction in IIH patients.MethodsNfL levels were measured by single molecule array in CSF and serum samples of 87 IIH patients and in three control groups, consisting of 52 multiple sclerosis (MS) patients with an acute relapse, 21 patients with an axonal polyneuropathy (PNP), and 41 neurologically healthy controls (HC). QNfL was calculated as the ratio of CSF and serum NfL levels. Similarly, we also assessed the CSF/serum ratio of glial fibrillary acidic protein (QGFAP) levels to validate the QNfL data. Routine CSF parameters including the CSF/serum albumin ratio (QAlb) were determined in all groups. Lumbar puncture opening pressure of IIH patients was measured by manometry.ResultsCSF-NfL levels (r = 0.29, p = 0.008) and QNfL (0.40, p = 0.0009), but not serum NfL (S-NfL) levels, were associated with lumbar puncture opening pressure in IIH patients. CSF-NfL levels were increased in IIH patients, MS patients, and PNP patients, whereas sNfL levels were normal in IIH, but elevated in MS and PNP. Remarkably, QNfL (p < 0.0001) as well as QGFAP (p < 0.01) were only increased in IIH patients. QNfL was positively correlated with CSF-NfL levels (r = 0.51, p = 0.0012) and negatively correlated with S-NfL levels (r = − 0.51, p = 0.0012) in HC, while it was only positively associated with CSF-NfL levels in IIH patients (r = 0.71, p < 0.0001). An increase in blood-CSF barrier permeability assessed by QAlb did not lead to a decrease in QNfL in any cohort.ConclusionsThe observed elevation of QNfL in IIH patients, which was associated with lumbar puncture opening pressure, indicates a reduced NfL transition from the CSF to serum compartment. This supports the hypothesis of a pressure-dependent CSF outflow obstruction to be critically involved in IIH pathogenesis.

Venetoclax Penetrates the Blood Brain Barrier: A Pharmacokinetic Analysis in Pediatric Leukemia Patients.

Infiltration of malignant cells into the central nervous system in hematological malignancies correlates with poor clinical outcomes. Investigations into the penetration of venetoclax into the central nervous system have been limited. We report venetoclax pharmacokinetics in plasma and cerebrospinal fluid samples from a Phase 1 study in pediatric patients with relapsed or refractory malignancies that demonstrate venetoclax ability to cross into the central nervous system. Venetoclax was detected in cerebrospinal fluid (CSF) samples, with concentrations ranging from < 0.1 to 26 ng/mL (mean, 3.6 ng/mL) and a plasma:CSF ratio ranging from 44 to 1559 (mean, 385). Plasma:CSF ratios were comparable among patients with AML and ALL and no clear trend was observed in the ratios over the course of treatment. Moreover, improvement in central nervous system (CNS) involvement status was observed in patients who had measurable concentrations of venetoclax in the CSF. CNS resolution was observed for up to six months while on treatment. These findings highlight the potential role of venetoclax and provide the opportunity to further investigate its utility in improving clinical outcomes for patients with CNS complications.