Cerebrospinal Fluid Data Research Articles

Impaired default mode network along with increased functional connectivity of the medial temporal lobe as a function of CSF p‐Tau/Ab42 ratio in cognitively unimpaired individuals

AbstractBackgroundAmyloid‐b (Ab) and tau exert a synergistic action on brain structure and function in cognitively unimpaired (CU) individuals. However, these two biomarkers have so far been investigated separately. Recently, it was proposed that the cerebrospinal fluid (CSF) phospho‐tau (pTau)/Ab42 ratio may represent a novel prognostic core biomarker, providing information on both proteinopathies along the preclinical Alzheimer’s disease (AD) continuum. Here, we aim to characterize the association between CSF pTau/Ab42 and resting‐state functional connectivity (FC), an established imaging marker of AD, in CU individuals.MethodWe included 349 CU participants from the ALFA study (mean age=60.21 years) who underwent deep phenotype screening, including CSF data collection and resting‐state functional magnetic resonance imaging (fMRI). CSF Ab42 was assessed with the exploratory Roche NeuroToolKit arobust prototype assays, while pTau181 was measured with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (Roche Diagnostics International Ltd). The CONN toolbox was used to preprocess and analyze the fMRI data. fMRI volumes were parceled into 218 regions and bivariate correlations in the filtered fMRI signal among parcels were computed. A linear regression model was used to assess the impact of continuous pTau/Ab42 ratio on FC, adjusting for age, sex, years of education and APOE‐e4 status. A threshold of uncorrected p<0.005 using non‐parametric pair‐wise clustering was implemented.ResultHigher pTau/Ab42 ratio were associated with decreased FC within the default mode network (DMN) (Fig. 1), but increased FC within the temporo‐hippocampal (THN) and visual networks (VN) (Fig. 2). Also, we observed a reduced FC between the sensorimotor network and both the DMN and THN, as a function of pTau/Ab42 levels (Fig. 2).ConclusionOur results suggest that individuals with more advanced pathology in the preclinical AD continuum, reflected by higher pTau/Ab42 ratio, present altered FC across different distributed neural systems, both within and between networks. The reduced within‐DMN connectivity resembles earlier findings of DMN disruption as a function of cerebral Ab accumulation. However, the increased FC within the THN and VM may be indicative of a compensatory strategy to sustain cognitive functions despite AD pathology. Future studies shall include measures of cognitive performance along with longitudinal assessment to clarify this aspect.

Sharper in the morning: Cognitive time of day effects revealed with high-frequency smartphone testing

ABSTRACT Decades of research has established a shift from an “eveningness” preference to a “morningness” preference with increasing age. Accordingly, older adults typically have better cognition in morning hours compared to evening hours. We present the first known attempt to capture circadian fluctuations in cognition in individuals at risk for Alzheimer disease (AD) using a remotely administered smartphone assessment that samples cognition rapidly and repeatedly over several days. Older adults (N = 169, aged 61–94 years; 93% cognitively normal) completed four brief smartphone-based testing sessions per day for 7 consecutive days at quasi-random time intervals, assessing associate memory, processing speed, and visual working memory. Scores completed during early hours were averaged for comparison with averaged scores completed during later hours. Mixed effects models evaluated time of day effects on cognition. Additional models included clinical status and cerebrospinal fluid (CSF) biomarkers for beta amyloid (Aβ42) and phosphorylated tau181 (pTau). Models with terms for age, gender, education, APOE ε4 status, and clinical status revealed significantly worse performance on associate memory in evening hours compared to morning hours. Contemporaneously reported mood and fatigue levels did not moderate relationships. Using CSF data to classify individuals with and without significant AD pathology, there were no group differences in performance in morning hours, but subtle impairment emerged in associate memory in evening hours in those with CSF-confirmed AD pathology. These findings indicate that memory is worse in evening hours in older adults, that this pattern is consistent across several days, and is independent of measures of mood and fatigue. Further, they provide preliminary evidence of a “cognitive sundowning” in the very earliest stages of AD. Time of day may be an important consideration for assessments in observational studies and clinical trials in AD populations.

Cerebrospinal Fluid Amyloid-β Oligomer Levels in Patients with Idiopathic Normal Pressure Hydrocephalus.

Background:The amyloid-β oligomers, consisting of 10–20 monomers (AβO10–20), have strong neurotoxicity and are associated with cognitive impairment in Alzheimer’s disease (AD). However, their role in patients with idiopathic normal pressure hydrocephalus (iNPH) is poorly understood.Objective:We hypothesized that cerebrospinal fluid (CSF) AβO10–20 accumulates in patients with iNPH, and its clearance after CSF shunting contributes to neurological improvement. We measured CSF AβO10–20 levels before and after CSF shunting in iNPH patients evaluating their diagnostic and prognostic role.Methods:We evaluated two iNPH cohorts: “evaluation” (cohort-1) with 32 patients and “validation” (cohort-2) with 13 patients. Comparison cohorts included: 27 neurologically healthy controls (HCs), and 16 AD, 15 Parkinson’s disease (PD), and 14 progressive supranuclear palsy (PSP) patients. We assessed for all cohorts CSF AβO10–20 levels and their comprehensive clinical data. iNPH cohort-1 pre-shunting data were compared with those of comparison cohorts, using cohort-2 for validation. Next, we compared cohort-1’s clinical and CSF data: 1) before and after CSF shunting, and 2) increased versus decreased AβO10–20 levels at baseline, 1 and 3 years after shunting.Results:Cohort-1 had higher CSF AβO10–20 levels than the HCs, PD, and PSP cohorts. This result was validated with data from cohort-2. CSF AβO10–20 levels differentiated cohort-1 from the PD and PSP groups, with an area under receiver operating characteristic curve of 0.94. AβO10–20 levels in cohort-1 decreased after CSF shunting. Patients with AβO10–20 decrease showed better cognitive outcome than those without.Conclusion:AβO10–20 accumulates in patients with iNPH and is eliminated by CSF shunting. AβO10–20 can be an applicable diagnostic and prognostic biomarker.

Diagnostic biomarkers from proteomic characterization of cerebrospinal fluid in patients with brain malignancies.

Recent technological advances in molecular diagnostics through liquid biopsies hold the promise to repetitively monitor tumor evolution and treatment response of brain malignancies without the need of invasive surgical tissue accrual. Here, we implemented a mass spectrometry-based protein analysis pipeline which identified hundreds of proteins in 251 cerebrospinal fluid (CSF) samples from patients with four types of brain malignancies (glioblastoma, lymphoma, brain metastasis, and leptomeningeal disease [LMD]) and from healthy individuals with a focus on glioblastoma in a retrospective and confirmatory prospective observational study. CSF proteome deregulation via disruption of the blood brain barrier appeared to be largely conserved across brain tumor entities. CSF analysis of glioblastoma patients identified two proteomic clusters that correlated with tumor size and patient survival. By integrating CSF data with proteomic analyses of matching glioblastoma tumor tissue and primary glioblastoma cells, we identified potential CSF biomarkers for glioblastoma, in particular chitinase-3-like protein 1 (CHI3L1) and glial fibrillary acidic protein (GFAP). Key findings were validated in a prospective cohort consisting of 35 glioma patients. Finally, in LMD patients who frequently undergo repeated CSF work-up, we explored our proteomic pipeline as a mean to profile consecutive CSF samples. Therefore, proteomic analysis of CSF in brain malignancies has the potential to reveal biomarkers for diagnosis and therapy monitoring.

High-Order Laplacian Regularized Low-Rank Representation for Multimodal Dementia Diagnosis.

Multimodal heterogeneous data, such as structural magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF), are effective in improving the performance of automated dementia diagnosis by providing complementary information on degenerated brain disorders, such as Alzheimer's prodromal stage, i.e., mild cognitive impairment. Effectively integrating multimodal data has remained a challenging problem, especially when these heterogeneous data are incomplete due to poor data quality and patient dropout. Besides, multimodal data usually contain noise information caused by different scanners or imaging protocols. The existing methods usually fail to well handle these heterogeneous and noisy multimodal data for automated brain dementia diagnosis. To this end, we propose a high-order Laplacian regularized low-rank representation method for dementia diagnosis using block-wise missing multimodal data. The proposed method was evaluated on 805 subjects (with incomplete MRI, PET, and CSF data) from the real Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Experimental results suggest the effectiveness of our method in three tasks of brain disease classification, compared with the state-of-the-art methods.

Peripheral Blood Biomarkers CXCL12 and TNFRSF13C Associate with Cerebrospinal Fluid Biomarkers and Infiltrating Immune Cells in Alzheimer Disease.

Neuroinflammation-induced neurodegeneration and immune cell infiltration are two features of Alzheimer disease (AD). This study aimed to identify potential peripheral biomarkers that interact with cerebrospinal fluid (CSF) and infiltrating immune cells in AD. Blood and CSF data were downloaded from the Alzheimer's disease Neuroimaging Initiative database. We identified differentially expressed genes (DEGs) in AD and assessed infiltrating immune cells using the Immune Cell Abundance Identifier (ImmuCellAI) algorithm. Blood-brain barrier (BBB) and immune-related genes were identified from medical databases, and common genes were used to construct a protein-protein interactionnetwork (PPI). Potential biomarkers reflecting the clinical features of AD were screened using Pearson correlations and logistic regression analysis. We identified 210 DEGs in the AD group. ImmuCellAI indicated that blood samples from patients with AD had a higher abundance of exhausted T (Tex; 0.196 vs. 0.132) and induced regulatory T (iTreg; 0.180 vs. 0.137) cells than controls. Thirty-two genes overlapped between the BBB and immune-related genes, and 27 genes in the PPI network were associated with eight pathways, including the cytokine-cytokine receptor interaction pathway (hsa04060) and the chemokine signaling pathway (hsa04062). Pearson correlations showed that five genes were associated with the CSF biomarkers, Aβ, total, and phosphorylated tau. Logistics analysis showed that the B cell-associated genes, CXCL12 and TNFRSF13C, were independent risk factors for AD diagnosis. Peripheral CXCL12 and TNFRSF13C genes that correlated with immune cell infiltration in AD might serve as easily accessible biomarkers for the early diagnosis of AD.

Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer\u2019s disease

BackgroundRecognizing clinical manifestations heralding the development of Alzheimer’s disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults.MethodsThis prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n = 2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [18F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1 years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change.ResultsWeight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00–1.61, p = 0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19–1.89, p = 0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25–2.20, p = 0.001) and was greater among participants with an A+T+ profile (p < 0.01) at follow-up. Weight change was positively associated with CSF Aβ42/40 ratio (β = 0.099, p = 0.032) and negatively associated with CSF p-tau (β = − 0.141, p = 0.005), t-tau (β = − 0.147 p = 0.004) and neurogranin levels (β = − 0.158, p = 0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only.ConclusionsWeight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-β accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment.Trial registrationNCT01835717, NCT02485730, NCT02685969.

Biomarker testing in MCI patients\u2014deciding who to test

BackgroundWe aimed to derive an algorithm to define the optimal proportion of patients with mild cognitive impairment (MCI) in whom cerebrospinal fluid (CSF) testing is of added prognostic value.MethodsMCI patients were selected from the Amsterdam Dementia Cohort (n = 402). Three-year progression probabilities to dementia were predicted using previously published models with and without CSF data (amyloid-beta1-42 (Abeta), phosphorylated tau (p-tau)). We incrementally augmented the proportion of patients undergoing CSF, starting with the 10% patients with prognostic probabilities based on clinical data around the median (percentile 45–55), until all patients received CSF. The optimal proportion was defined as the proportion where the stepwise algorithm showed similar prognostic discrimination (Harrell’s C) and accuracy (three-year Brier scores) compared to CSF testing of all patients. We used the BioFINDER study (n = 221) for validation.ResultsThe optimal proportion of MCI patients to receive CSF testing selected by the stepwise approach was 50%. CSF testing in only this proportion improved the performance of the model with clinical data only from Harrell’s C = 0.60, Brier = 0.198 (Harrell’s C = 0.61, Brier = 0.197 if the information on magnetic resonance imaging was available) to Harrell’s C = 0.67 and Brier = 0.190, and performed similarly to a model in which all patients received CSF testing. Applying the stepwise approach in the BioFINDER study would again select half of the MCI patients and yielded robust results with respect to prognostic performance.InterpretationCSF biomarker testing adds prognostic value in half of the MCI patients. As such, we achieve a CSF saving recommendation while simultaneously retaining optimal prognostic accuracy.

Biomarker-based stability in limbic-predominant amnestic mild cognitive impairment.

The amnestic presentation of mild cognitive impairment (aMCI) represents the most common prodromal stage of Alzheimer's disease (AD) dementia. There is, however, some evidence of aMCI with typical amnestic syndrome but showing long-term clinical stability. The ability to predict stability or progression to dementia in the aMCI condition is important, particularly for the selection of candidates in clinical trials. We aimed to establish the role of in vivo biomarkers, as assessed by cerebrospinal fluid (CSF) measures and [18 F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging, in predicting prognosis in a large aMCI cohort. We conducted a retrospective study, including 142 aMCI subjects who had a long follow-up (4-19years), baseline CSF data and [18 F]FDG-PET scans individually assessed by validated voxel-based procedures, classifying subjects into either limbic-predominant or AD-like hypometabolism patterns. The two aMCI cohorts were clinically comparable at baseline. At follow-up, the aMCI group with a limbic-predominant [18 F]FDG-PET pattern showed clinical stability over a very long follow-up (8.20±3.30years), no decline in Mini-Mental State Examination score, and only 7% conversion to dementia. Conversely, the aMCI group with an AD-like [18 F]FDG-PET pattern had a high rate of dementia progression (86%) over a shorter follow-up (6.47±2.07years). Individual [18 F]FDG-PET hypometabolism patterns predicted stability or conversion with high accuracy (area under the curve=0.89), sensitivity (0.90) and specificity (0.89). In the limbic-predominant aMCI cohort, CSF biomarkers showed large variability and no prognostic value. In a large series of clinically comparable subjects with aMCI at baseline, the specific [18 F]FDG-PET limbic-predominant hypometabolism pattern was associated with clinical stability, making progression to AD very unlikely. The identification of a biomarker-based benign course in aMCI subjects has important implications for prognosis and in planning clinical trials.

Biomarker testing in MCI patients: Deciding who to tap

AbstractBackgroundIt is unlikely that biomarker testing contributes to a more accurate prognosis in every patient with Mild Cognitive Impairment (MCI). We therefore aimed to derive a stepwise approach to select MCI patients for cerebrospinal fluid (CSF) testing and determine the optimal proportion of patients to receive CSF testing.MethodsWe selected n=402 MCI patients from the Amsterdam Dementia Cohort (ADC) and n=221 from the BioFinder study, with available demographic information, Magnetic Resonance Imaging (MRI) and CSF data. Three‐year progression probabilities to dementia were predicted for all patients, using previously published model (van Maurik et al. 2019, The Lancet Neurology) based on 1) patient characteristics (age, sex, MMSE; demographic model), or 2) additional MRI (hippocampal volume; MRI model). We incrementally augmented the proportion of patients to receive CSF testing, first the most uncertain 10% of patients (percentile 45‐55 of demographic‐ or MRI model derived probabilities), then 20% (percentile 40‐60), and so on. Prognostic performance of this stepwise model was measured with Harrell’s C. The optimal proportion was selected as the point where the stepwise model performed similar to testing all patients. This proportion provides the range of probabilities where additional CSF testing would be indicated (Table 1). To study generalizability, we replicated this approach in BioFINDER.ResultsOn top of demographic characteristics, the stepwise approach showed that 60% of the patients required CSF testing in both cohorts in order to reach optimal prognostic performance (i.e. similar to CSF model; Figure 1A). This proportion corresponded with progression probability between 32%‐56%. This range was similar in BioFINDER (34%‐56%; Table 1). If we took the MRI model as a starting point, the optimal proportion was 60% in the ADC and 70% in BioFINDER (i.e. similar to ATN model; Figure 1B). This corresponded with a probability range of 19%‐40% in the ADC and 19%‐48% in BioFINDER (Table 1).ConclusionWe showed that CSF biomarker testing adds prognostic value on clinical and/or imaging information in 60‐70% of the MCI patients that had less certain probability of progression between 32%‐56% or 19%‐48%. As such, we achieve a generalizable CSF saving recommendation with optimal prognostic accuracy.

Cerebrospinal fluid protein in Guillain-Barré syndrome: Need for age-dependent interpretation.

Background and purposeElevated cerebrospinal fluid (CSF) total protein in patients with acute ascending paresis is indicative of Guillain–Barré syndrome (GBS). Recent studies showed that the outdated, but still widely used upper reference limit (URL) for CSF total protein of 0.45 g/L leads to false‐positive results, mainly as a result of lack of age‐adjustment. The objective of this study was to assess the frequency of increased CSF total protein in adult GBS patients according to a new age‐dependent URL.MethodsPatients with GBS treated at the Medical University of Innsbruck between 2000 and 2018 were included in this study. Demographic, clinical, electrophysiological and CSF data were obtained from patients' medical charts. Frequency of increased CSF total protein depending on disease duration was compared using the conventional URL of 0.45 g/L and the age‐dependent URL.ResultsNinety‐seven patients with GBS aged 57 ± 18 years, comprising 38% women, underwent CSF sampling within a median of 6 days after symptom onset. The median CSF total protein concentration was 0.65 g/L and correlated with disease duration. Overall, 74% of patients had elevated CSF total protein levels using the conventional URL, as opposed to 52% applying the age‐dependent URL. At 0–3, 4–7, 8–14 and >14 days after disease onset, elevated CSF total protein was found in 46%, 84%, 78% and 100% of patients using the conventional URL, and in 32%, 53%, 65% and 64% of patients using the age‐dependent URL. In multivariate analysis, significant predictors of elevated CSF total protein were disease duration and the demyelinating GBS variant. Similar results were obtained for CSF/serum albumin quotient (Qalb).ConclusionFewer true‐positives for CSF total protein and Qalb must be considered in suspected GBS, especially in the early disease course.

Association Analysis of Peripheral and CSF Biomarkers in Late Mild Cognitive Impairment.

Research shows that late mild cognitive impairment (LMCI) has a high risk of turning into Alzheimer’s disease (AD). Due to the invasion of detection methods and physical damage to the patients, it is not a convenient way to diagnose and detect early AD and LMCI by cerebrospinal fluid (CSF) data. So there is an urgent need to find the correlation between peripheral biological data and CSF data in the brain, and to find new diagnostic methods through changes in the peripheral biological data. Studies have shown that during the pathogenesis of LMCI and AD, peripheral immune cells specifically infiltrate into the brain through the blood–brain barrier, causing an imbalance in the brain’s immune response and dysregulating the clearance of Aβ in CSF. Therefore, in this paper, canonical correlation analysis (CCA) algorithm is presented to derive the correlation between peripheral and CSF biomarkers based on LMCI peripheral gene expression data and plasma marker information. Firstly, to explore the influence of the infiltration of peripheral blood immune cells on the brain, the abundance of 28 immune cells were calculated by using the gene set enrichment analysis algorithm of LMCI samples. Then, to identify the correlation between biomarkers inside and outside of the brain, we performed CCA to calculate the relationship between CSF and peripheral biomarkers. Results of CCA showed significant correlations between the variable sets of 8 peripheral biomarkers and the variable sets of CSF biomarkers (at 0.794). Finally, according to Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis, it was found that the obtained peripheral biomarkers are involved in many immune-related pathways and functions which can be activated in peripheral blood of LMCI patients. Most related genes enriched in immune-related pathways and functions were up-regulated. Through receiver operating characteristic curve (ROC) analysis, it was also found that FP40/FP42 and type 1 T helper can accurately predict the pathological changes of LMCI (at 0.747).

Evolution of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Early Parkinson's Disease.

ObjectiveWe analyzed the longitudinal profile of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in early Parkinson's disease (PD) compared with healthy controls (HCs) and tested baseline CSF biomarkers for prediction of clinical decline in PD.MethodsAmyloid‐β 1 to 42 (Aβ42), total tau (t‐tau) and phosphorylated tau (p‐tau) at the threonine 181 position were measured using the high‐precision Roche Elecsys electrochemiluminescence immunoassay in all available CSF samples from longitudinally studied patients with PD (n = 416) and HCs (n = 192) followed for up to 3 years in the Parkinson's Progression Markers Initiative (PPMI). Longitudinal CSF and clinical data were analyzed with linear‐mixed effects models.ResultsWe found patients with PD had lower CSF t‐tau (median = 157.7 pg/mL; range = 80.9–467.0); p‐tau (median = 13.4 pg/mL; range = 8.0–40.1), and Aβ42 (median = 846.2 pg/mL; range = 238.8–3,707.0) than HCs at baseline (CSF t‐tau median = 173.5 pg/mL; range = 82.0–580.8; p‐tau median = 15.4 pg/mL; range = 8.1–73.6; and Aβ42 median = 926.5 pg/mL; range = 239.1–3,297.0; p < 0.05–0.001) and a moderate‐to‐strong correlation among these biomarkers in both patients with PD and HCs (Rho = 0.50–0.97; p < 0.001). Of the patients with PD, 31.5% had pathologically low levels of CSF Aβ42 at baseline and these patients with PD had lower p‐tau levels (median = 10.8 pg/mL; range = 8.0–32.8) compared with 27.7% of HCs with pathologically low CSF Aβ42 (CSF p‐tau median = 12.8 pg/mL; range 8.2–73.6; p < 0.03). In longitudinal CSF analysis, we found patients with PD had greater decline in CSF Aβ42 (mean difference = −41.83 pg/mL; p = 0.03) and CSF p‐tau (mean difference = −0.38 pg/mL; p = 0.03) at year 3 compared with HCs. Baseline CSF Aβ42 values predicted small but measurable decline on cognitive, autonomic, and motor function in early PD.InterpretationOur data suggest baseline CSF AD biomarkers may have prognostic value in early PD and that the dynamic change of these markers, although modest over a 3‐year period, suggest biomarker profiles in PD may deviate from healthy aging. ANN NEUROL 2020;88:574–587

Plasma and cerebrospinal fluid pharmacokinetics of ondansetron in humans.

Changes in serotonergic sensory modulation associated with overexpression of 5-HT3 receptors in the central nervous system (CNS) have been implicated in the pathophysiology of neuropathic pain after peripheral nerve damage. 5-HT3 receptor antagonists such as ondansetron can potentially alleviate neuropathic pain, but have limited effectiveness, due potentially to limited CNS access. However, there is currently limited information on CNS disposition of systemically-administered 5-HT3 receptor antagonists. This study evaluated the cerebrospinal fluid (CSF) disposition of ondansetron, as a surrogate of CNS penetration. Fifteen patients were given a single 16 mg intravenous 15 minute infusion of ondansetron, followed by serial blood and a single CSF sampling. Population pharmacokinetic (PK) modelling was implemented to describe the average and individual plasma and CSF profiles of ondansetron. A two-compartmental model was used to capture ondansetron plasma PK with a single CSF compartment to describe distribution to the CNS. The individual model-estimated CSF to plasma partition coefficients of ondansetron were between 0.09 and 0.20. These values were mirrored in the calculated CSF penetration ratios, ranging from 0.08 to 0.26. After intravenous administration, CSF concentrations of ondansetron were approximately 7-fold lower than those observed in the plasma. A model could be developed to describe individual CSF concentration-time profiles of ondansetron based on a single CSF data point. The low CSF penetration of ondansetron may explain its limited analgesic effectiveness, and affords an opportunity to explore enhancing its CNS penetration for targeting conditions such as neuropathic pain.

Sensitivity and specificity of cerebrospinal fluid CXCL13 for diagnosing Lyme neuroborreliosis - a study on 1410 patients and review of the literature

IntroductionThe B-cell chemoattractant CXCL13 has been suggested as a cerebrospinal fluid (CSF) biomarker for Lyme neuroborreliosis (LNB). Our aim was to substantiate the value of CXCL13 in a large unselected cohort and determine a practical cut-off value to diagnose LNB. MethodsWe retrospectively studied clinical and CSF data of consecutive patients who underwent CSF CXCL13 testing over a period of three years (February 2015 to January 2018) at our academic teaching hospital. Patients were classified into 12 groups according to their final diagnosis. To diagnose LNB (definite or probable/possible), definitions of the respective guideline of the German Neurological Society were applied. ResultsOf 1410 patients, 29 were diagnosed with definite LNB and 9 with probable/possible LNB. Median CXCL13 levels were highly elevated in both LNB groups (554 pg/mL and 649 pg/mL, respectively) and the group with bacterial/fungal CNS infections (410 pg/mL; n = 6), while all other groups had markedly lower median CXCL13 levels (p < .001). For definite LNB, the best CXCL13 test cut-off was 55.5 pg/mL with a sensitivity of 96.6% (95% confidence interval, CI, 80.4%–99.8%) and a specificity of 94.9% (95% CI 93.5%–95.9%). All patients with LNB showed clinical improvement after antibiotic treatment. ConclusionIn this large monocentric cohort, CSF CXCL13 was found to be a highly sensitive and useful marker for LNB. In conditions with low index of suspicion for LNB, CXCL13 testing may be unwarranted. A review of the literature on the sensitivity and specificity of CSF CXCL13 in the differential of LNB is provided.

Genome‐wide Quantitative Trait Loci (QTL) Mapping of Metabolites in Human Cerebrospinal Fluid

Genome‐wide association studies (GWAS) are used to identify genetic loci that are associated with a trait of interest in order to decipher underlying biological mechanisms. Metabolite measures in cerebrospinal fluid (CSF), the fluid that surrounds the brain, provides insight into brain function that may be relevant for neurobehavioral traits and neuropsychiatric disorders. We performed a GWAS of 1,000 metabolites in a sample of 600 human subjects, the largest set of CSF data used in a GWAS to date. We applied standard quality control of genetic data including missingness, minor allele frequency cut‐off, and population stratification. Phenotype data were checked for outliers, and non‐normal data were transformed using inverse rank normalization. A linear association, including age and sex as additional covariates, was performed using the PLINK whole genome association analysis toolset. Significant SNP associations were found in 45 metabolites. Analysis via functional mapping and annotation (FUMA) downstream GWAS analysis tool found that many of these SNPs have been associated with other traits by other GWAS. Linked traits include blood metabolite levels and brain related traits such as cognitive performance. Results show that a GWAS can be successfully performed with CSF metabolite data, and indicate a relationship between CSF and blood metabolite levels. Further steps include analysis of other CSF metabolites and the use of dosage genotype data for potentially more detailed results.

Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials.

In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks. We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010-2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days. Mortality through 18 weeks was 37% for EFA > = 0.60 (n = 170), 36% for 0.40-0.59 (n = 182), 39% for 0.30-0.39 (n = 112), 35% for 0.20-0.29 (n = 87), and 50% for those with EFA < 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA < 0.20 to those with EFA > = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P = .002). The lowest EFA group had lower median CD4 T-cell counts (P < .01) and lower proportion of patients with CSF pleocytosis (P < .001). EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of > = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA < 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint.

Pathological cerebrospinal fluid protein concentration and albumin quotient at relapse predicts short-term disability progression in multiple sclerosis: a retrospective single center observational study.

Background:Blood–brain barrier dysfunction in active multiple sclerosis (MS) lesions leads to pathological changes of cerebrospinal fluid (CSF). Theoretically, CSF analyses could help to predict relapse recovery and the course of disability. In this monocentric study, we investigated the impact of CSF findings assessed during the first relapse of MS on the short-term course of disability.Methods:We performed a retrospective observational study including MS patients with available CSF data after onset of first MS relapse. Clinical symptoms had to be accompanied by gadolinium-enhanced lesion on magnetic resonance imaging. Expanded Disability Status Scale (EDSS) assessments at timepoint of relapse and after relapse recovery were studied to analyze disability. A two-step multivariate linear regression analysis adjusted for EDSS at spinal tab, duration of symptoms, sex, time until post relapse EDSS assessment, immunotherapy post relapse, and relapse treatment with glucocorticoids/plasma exchange to predict relapse associated disability was run.Results:In the first step of the regression model, pathological albumin quotient (QAlb) [regression coefficient 0.50, 95% confidence interval (CI) (0.07–0.92), p = 0.02, n = 99] and CSF protein concentration [regression coefficient 0.84, 95% CI (0.33–1.35), p = 0.001, n = 99] predicted EDSS after relapse recovery. In the second step, the sum score of both predictors [range 0–2; n per value: 0 (n = 73), 1 (n = 10), 2 (n = 15)] confirmed the negative impact on course of disability after relapse [regression coefficient 0.38, 95% CI (0.13–0.62), p = 0.003, n = 98]. In this final multivariate linear regression model (p < 0.001; R2 0.34), also EDSS at lumbar puncture [regression coefficient 0.58, 95% CI (0.35–0.81), p < 0.001, n = 98] and time between symptom onset and CSF evaluation [regression coefficient 0.03, 95% CI (0.006–0.048), p = 0.01, n = 98] forecast subsequent disabilityDiscussion:Our study conducted in MS patients during first relapse confirmed that both increased CSF protein concentration and pathological QAlb have a negative impact on EDSS after relapse. As secondary finding, we identified time from symptom onset to lumbar puncture as predictor of disability recovery after relapse.

CSF cutoffs for MCI due to AD depend on APOEε4 carrier status

Amyloid and tau pathological accumulation should be considered for Alzheimer's disease (AD) definition and before subjects' enrollment in disease-modifying trials. Although age, APOEε4, and sex influence cerebrospinal fluid (CSF) biomarker levels, none of these variables are considered by current normality/abnormality cutoffs. Using baseline CSF data from 2 independent cohorts (PharmaCOG/European Alzheimer's Disease Neuroimaging Initiative and Alzheimer's Disease Neuroimaging Initiative), we investigated the effect of age, APOEε4 status, and sex on CSF Aβ42/P-tau distribution and cutoff extraction by applying mixture models with covariates. The Aβ42/P-tau distribution revealed the presence of 3 subgroups (AD-like, intermediate, control-like) and 2 cutoffs. The identification of the intermediate subgroup and of the higher cutoff was APOEε4 dependent in both cohorts. APOE-specific classification (higher cutoff for APOEε4+, lower cutoff for APOEε4-) showed higher diagnostic accuracy in identifying MCI due to AD compared to single Aβ42 and Aβ42/P-tau cutoffs. APOEε4 influences amyloid and tau CSF markers and AD progression in MCI patients supporting i) the use of APOE-specific cutoffs to identify MCI due to AD and ii) the utility of considering APOE genotype for early AD diagnosis.

A juvenile case of idiopathic hypertrophic pachymeningitis involved cavernous sinus and proximal trigeminal nerve

AbstractIdiopathic hypertrophic pachymeningitis (HP) is a rare inflammatory disorder characterized by local or diffuse thickening of the cranial or spinal dura mater, which is primarily reported in adults. Here, we report a juvenile idiopathic HP case presenting diplopia and multiple cranial nerve palsies. Although cranial magnetic resonance imaging (MRI) shows evident lesions in cavernous sinus and preganglionic segment of trigeminal nerve, only cerebrospinal fluid (CSF) showed elevated protein (55 mg/dL) and myelin basic protein (MBP, 355 pg/mL) but negative systemic inflammatory markers. Steroid therapy greatly improved the symptom and the CSF data in 1 month.