Cerebrospinal Fluid Tau Protein Research Articles

1008 Daytime Sleepiness Is Associated with Increased Cerebrospinal Fluid Tau Proteins in Alzheimer’s Disease

1008 Daytime Sleepiness Is Associated with Increased Cerebrospinal Fluid Tau Proteins in Alzheimer’s Disease

331 Validation of a Novel CSF-Based Biomarker of Mitochondrial Function

OBJECTIVES/GOALS: Determine the exosome mitochondrial DNA (mtDNA) copy number in cerebrospinal fluid (CSF) as a measure of neuronal mitochondrial integrity in patients with subarachnoid hemorrhage (SAH). Determine the patterns of beta amyloid and tau protein biology in CSF of SAH patients and correlate those measures with the clinical status of the SAH patients. METHODS/STUDY POPULATION: The CSF is collected from SAH patients undergoing ventriculostomy-based continuous CSF drainage. Adults from all ethnicities and sex are included in this study. The exosomes are isolated from CSF samples using a precipitation method and particle count and size are measured using NanoSight. The DNA is extracted using an exosomal DNA isolation kit (XCF kit). The CSF mtDNA copy number is measured using digital drop PCR with mitochondrial DNA primers. The levels of beta-amyloid (a-beta-40 and -42) and tau protein in CSF are measured using a sensitive ELISA-based assay. A quantitative evaluation of mitochondrial DNA copy number, clinical status of the SAH patients and beta amyloid, and tau protein levels will be conducted and reported. RESULTS/ANTICIPATED RESULTS: Preliminary results of four CSF samples showed similar patterns in CSF exosome particle number, particle size and exosomal mtDNA copy number in relation to samples from the admission day. Particle number decreased with time while particle size increased. More patient samples will be analyzed to confirm the patterns. We anticipate that mtDNA copy number will correlate with brain beta-amyloid and tau protein levels. Moreover, we anticipate that the clinical status of the SAH patients will associate with the mtDNA copy number. We specifically predict that higher mtDNA copy number levels will correlate with better clinical outcomes. DISCUSSION/SIGNIFICANCE: Mitochondrial function is critical to brain health, but we lack effective ways to monitor this parameter. Here we focus on a CSF based biomarker, exosome-derived mtDNA, which is intended to reflect the integrity of brain mitochondria. As bioenergetic metabolism influences beta amyloid and tau biology, predicting those levels are important.

Evaluation of SP3 for antibody-free quantification of tau in CSF mimic and brain by mass spectrometry.

Tubulin-associated unit (tau) has an important role in the pathogenesis and the diagnosis of Alzheimer's disease (AD) and other tauopathies. In view of the diversity of tau proteoforms, antibody-free methods represent a good approach for unbiased quantification. We adapted and evaluated the single-pot, solid-phase-enhanced sample-preparation (SP3) protocol for antibody-free extraction of the tau protein in cerebro-spinal fluid (CSF) mimic and in human brain. A total of 13 non-modified peptides were quantified by high-resolution mass spectrometry (HRMS) after digestion of tau by trypsin. We significantly improved the basic SP3 protocol by carefully optimizing the organic solvents and incubation time for tau binding, as well as the digestion step for the release directly from the SP3 beads of the 13 tau peptides. These optimizations proved to be primarily beneficial for the most hydrophilic tau peptides, increasing the sequence coverage of recombinant tau. Mean recovery in CSF mimic of the 13 non-modified peptides was of 53%, with LODs ranging from 0.75 to 10 ng/mL. Next, we tested the optimized SP3 protocol on pathological tau extracted from the soluble fraction from an AD brain sample (middle frontal gyrus). We could successfully identify and quantify biologically relevant tau peptides including representative peptides of two isoforms and two phospho-peptides (pTau217 and pTau181).

High-dimensional generalized median adaptive lasso with application to omics data.

Recently, there has been a growing interest in variable selection for causal inference within the context of high-dimensional data. However, when the outcome exhibits a skewed distribution, ensuring the accuracy of variable selection and causal effect estimation might be challenging. Here, we introduce the generalized median adaptive lasso (GMAL) for covariate selection to achieve an accurate estimation of causal effect even when the outcome follows skewed distributions. A distinctive feature of our proposed method is that we utilize a linear median regression model for constructing penalty weights, thereby maintaining the accuracy of variable selection and causal effect estimation even when the outcome presents extremely skewed distributions. Simulation results showed that our proposed method performs comparably to existing methods in variable selection when the outcome follows a symmetric distribution. Besides, the proposed method exhibited obvious superiority over the existing methods when the outcome follows a skewed distribution. Meanwhile, our proposed method consistently outperformed the existing methods in causal estimation, as indicated by smaller root-mean-square error. We also utilized the GMAL method on a deoxyribonucleic acid methylation dataset from the Alzheimer's disease (AD) neuroimaging initiative database to investigate the association between cerebrospinal fluid tau protein levels and the severity of AD.

Mixture of regressions with multivariate responses for discovering subtypes in Alzheimer's biomarkers with detection limits.

There is no gold standard for the diagnosis of Alzheimer's disease (AD), except from autopsies, which motivates the use of unsupervised learning. A mixture of regressions is an unsupervised method that can simultaneously identify clusters from multiple biomarkers while learning within-cluster demographic effects. Cerebrospinal fluid (CSF) biomarkers for AD have detection limits, which create additional challenges. We apply a mixture of regressions with a multivariate truncated Gaussian distribution (also called a censored multivariate Gaussian mixture of regressions or a mixture of multivariate tobit regressions) to over 3,000 participants from the Emory Goizueta Alzheimer's Disease Research Center and Emory Healthy Brain Study to examine amyloid-beta peptide 1-42 (Abeta42), total tau protein and phosphorylated tau protein in CSF with known detection limits. We address three gaps in the literature on mixture of regressions with a truncated multivariate Gaussian distribution: software availability; inference; and clustering accuracy. We discovered three clusters that tend to align with an AD group, a normal control profile and non-AD pathology. The CSF profiles differed by race, gender and the genetic marker ApoE4, highlighting the importance of considering demographic factors in unsupervised learning with detection limits. Notably, African American participants in the AD-like group had significantly lower tau burden.

Use of modern classification systems for complex diagnostics of Alzheimer's disease

To compare the content of β-amyloid (Aβ) peptides Aβ40, Aβ42, total and threonine phosphorylated 181 tau-protein in cerebrospinal fluid (CSF) of patients with the clinical diagnosis of Alzheimer's disease (AD). The study was performed on 64 patients with a diagnosis of dementia and MMSE scores of 24 or lower. All patients underwent lumbar puncture. Aβ40, Aβ42, Aβ42/40 ratio, total tau, phosphorylated tau at threonine 181 were determined in the CSF using a multiplex assay according to the manufacturer's protocol, the concentration was determined in pkg/ml. The preliminary diagnosis of AD was made in 3 patients (5%). As a result of the study of protein content in the CSF, signs of AD were detected in 48 (75%) people. The findings suggest that the diagnosis of AD is made 10-14 times less frequently than it should be according to the World Health Organization data. The discrepancy between clinical diagnosis and laboratory findings is confirmed by our study. Differences in the therapy of dementias and the development of new drugs targeting specific links in the pathogenesis of different types of dementias require accurate and complete diagnosis of dementias, especially AD, as the most common type of dementia.

The clinical usefulness of plasma biomarkers of neuronal dysfunction in Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is one of the most common neurodegenerative disorders, and one of the most significant medical and social problems worldwide. Neurodegeneration, which is a pivotal mechanism underlying the disease, begins a few decades before the first symptoms appear. Therefore, establishing biomarkers that allow for the detection of this process as early as possible is vital. Mounting evidence indicates the crucial role of GFAP and NFL in the pathology of neurodegeneration in AD. The aim of the present study was to assess plasma concentrations of GFAP and NFL, and to test their potential utility in AD diagnosis.MethodPlasma concentrations of GFAP and NFL were measured using a Single molecule array (Simoa), while the classical biomarkers (Aβ‐42, Aβ‐42/Aβ‐40, tau, and pTau181) were assessed in the cerebrospinal fluid (CSF) of 20 AD patients and 18 elderly subjects without cognitive deficits using ELISA technique.ResultPlasma concentrations of GFAP and NFL were significantly higher in AD patients as compared to non‐demented controls. The levels of plasma GFAP correlated negatively with MMSE, and CSF Aβ‐42, and positively with plasma concentrations of NFL, and CSF tau proteins in the whole study group. Furthermore, in the AD group, the association between GFAP and NFL was revealed.ConclusionPresented findings indicate that plasma GFAP and NFL could be applied as a non‐invasive and accessible tool for detection of early neuronal dysfunction in patients with AD.

Cerebrospinal Fluid and Serum Biomarker Insights in Aneurysmal Subarachnoid Haemorrhage: Navigating the Brain-Heart Interrelationship for Improved Patient Outcomes.

The pathophysiological mechanisms underlying severe cardiac dysfunction after aneurysmal subarachnoid haemorrhage (aSAH) remain poorly understood. In the present study, we focused on two categories of contributing factors describing the brain-heart relationship. The first group includes brain-specific cerebrospinal fluid (CSF) and serum biomarkers, as well as cardiac-specific biomarkers. The secondary category encompasses parameters associated with cerebral autoregulation and the autonomic nervous system. A group of 15 aSAH patients were included in the analysis. Severe cardiac complications were diagnosed in seven (47%) of patients. In the whole population, a significant correlation was observed between CSF S100 calcium-binding protein B (S100B) and brain natriuretic peptide (BNP) (rS = 0.62; p = 0.040). Additionally, we identified a significant correlation between CSF neuron-specific enolase (NSE) with cardiac troponin I (rS = 0.57; p = 0.025) and BNP (rS = 0.66; p = 0.029), as well as between CSF tau protein and BNP (rS = 0.78; p = 0.039). Patients experiencing severe cardiac complications exhibited notably higher levels of serum tau protein at day 1 (0.21 ± 0.23 [ng/mL]) compared to those without severe cardiac complications (0.03 ± 0.04 [ng/mL]); p = 0.009. Impaired cerebral autoregulation was noted in patients both with and without severe cardiac complications. Elevated serum NSE at day 1 was related to impaired cerebral autoregulation (rS = 0.90; p = 0.037). On the first day, a substantial, reciprocal correlation between heart rate variability low-to-high frequency ratio (HRV LF/HF) and both GFAP (rS = -0.83; p = 0.004) and S100B (rS = -0.83; p = 0.004) was observed. Cardiac and brain-specific biomarkers hold the potential to assist clinicians in providing timely insights into cardiac complications, and therefore they contribute to the prognosis of outcomes.

Relationship between preoperative neutrophil-to-lymphocyte ratio and postoperative delirium: The PNDABLE and the PNDRFAP cohort studies.

In this study, the relationship between preoperative neutrophil-to-lymphocyte ratio (NLR) and Alzheimer-related biomarkers in cerebrospinal fluid (CSF) was investigated to determine whether high NLR is a potential risk factor for postoperative delirium (POD) and to evaluate its predictive efficacy. We selected 1000 patients from the perioperative neurocognitive disorder risk factor and prognosis (PNDRFAP) database and 999 patients from the perioperative neurocognitive disorder and biomarker lifestyle (PNDABLE) database. Patients in the PNDABLE database have been measured for Alzheimer-related biomarkers in CSF (Aβ40 , Aβ42 , P-tau, and tau protein). Mini-mental state examination was used to assess the preoperative mental status of patients. POD was diagnosed using the confusion assessment method and assessed for severity using the memorial delirium assessment scale. Logistic regression analysis was utilized to explore the association of preoperative NLR with POD. What's more, we also performed sensitivity analysis by adding corrected confounders, and the results were almost unchanged. Spearman's rank correlation was used to determine the associations between NLR and Alzheimer-related biomarkers. Mediation analyses with 10,000 bootstrapped iterations were used to explore the mediation effects. Finally, we use decision curves and the nomogram model to evaluate the efficacy of preoperative NLR in predicting POD; we also performed external validation using data from Qilu Hospital. Logistic regression results showed that an elevated preoperative NLR was a risk factor for the development of POD in patients (PNDRFAP: OR=1.067, 95% CI 1.020-1.116; PNDABLE: OR=1.182, 95% CI 1.048-1.335, p<.05). Spearman's rank correlation analysis showed a positive but weak correlation between NLR and P-tau/T-tau (R=.065). The mediating effect results indicate that NLR likely mediates the occurrence of POD through elevated tau protein levels (proportion: 47.47%). The results of the box plots showed statistically significant NLR and CSF biomarkers between the POD and non-POD (NPOD) groups (p<.05), with higher NLR, P-tau, and T-tau in the POD group than in the NPOD group. In contrast, the NPOD group had higher Aβ42 levels compared to the POD group. In addition, we used R package to plot the decision curve and nomogram both suggesting a good predictive effect of preoperative NLR on the occurrence of POD. Elevated preoperative NLR levels may be a risk factor for POD and likely mediate the development of POD through elevated P-tau/T-tau levels.

The predictive value of melanin-concentrating hormone combined with other related biomarkers in cerebrospinal fluid in preoperative cognitive dysfunction of elderly patients

Objective: To explore the predictive value of cerebrospinal fluid melanin-concentrating hormone (MCH) combined with other related biomarkers in preoperative cognitive dysfunction of elderly patients. Methods: A total of 80 patients who underwent elective hip or knee replacement under intravertebral anesthesia in Chifeng Municipal Hospital, Inner Mongolia, from March to November 2022 were prospectively included, with 32 males and 48 females, and aged 65-85 (70.7±5.2) years old. According to the evaluation results of the Montreal Cognitive Assessment (MoCA), patients were divided into the preoperative cognitive dysfunction (n=23) and control (n=57) groups. The levels of MCH, amyloid-β 40 (Aβ40), amyloid-β 42 (Aβ42), and phosphorylated tau protein (p-tau) in cerebrospinal fluid were determined by enzyme-linked immunosorbent assay (ELISA). The receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of each biomarker separately or in combination for preoperative cognitive dysfunction. Spearman's rank correlation analysis was utilized to test the correlation between the level of each biomarker and MoCA scores. Results: The levels of MCH, Aβ40, Aβ42, p-tau, and Aβ42/p-tau in the preoperative cognitive dysfunction group were (35.53±5.94) μg/L, (39.21±9.18) ng/L, (221.83±43.17) ng/L, (42.64±9.74) ng/L, and 5.53±1.92, and the levels of these biomarkers in the control group were (28.74±4.90) μg/L, (36.37±7.87) ng/L, (280.23±45.67) ng/L, (35.00±9.27) ng/L, and 8.62±2.78, respectively. Compared with the control group, the levels of cerebrospinal fluid MCH and p-tau in the preoperative cognitive dysfunction group were significantly increased (all P<0.01), and the levels of Aβ42 and Aβ42/p-tau were significantly decreased (all P<0.001). MCH and Aβ42/p-tau provided higher predictive values. The area under the curve (AUC) of MCH and Aβ42/p-tau were 0.807 (95%CI: 0.703-0.911) and 0.842 (95%CI: 0.741-0.943), the sensitivity were 78.3% and 87.0%, and the specificity were 75.4% and 94.7%. MCH combined with Aβ42/p-tau have the higher AUC of 0.915 (95%CI: 0.837-0.992), the sensitivity (87.0%) and specificity (86.0%) were both high, which had a higher predictive value. The levels of cerebrospinal fluid MCH and p-tau were negatively correlated with MoCA score (r=-0.467, -0.321, all P<0.01), and the levels of Aβ42 and Aβ42/p-tau were positively correlated with MoCA score (r=0.480, 0.520, all P<0.001). Conclusion: The increase in cerebrospinal fluid MCH levels is associated with preoperative cognitive dysfunction in elderly patients. MCH combined with Aβ42/p-tau has the greatest predictive value.

Metabolomic profiling of CSF and blood serum elucidates general and sex-specific patterns for mild cognitive impairment and Alzheimer's disease patients.

Beta-amyloid (Abeta) and tau protein in cerebrospinal fluid (CSF) are established diagnostic biomarkers for Alzheimer's disease (AD). However, these biomarkers may not the only ones existing parameters that reflect Alzheimer's disease neuropathological change. The use of quantitative metabolomics approach could provide novel insights into dementia progression and identify key metabolic alterations in CSF and serum. In the present study, we quantified a set of 45 metabolites in CSF (71 patients) and 27 in serum (76 patients) in patients with mild cognitive impairment (MCI), AD, and controls using nuclear magnetic resonance (NMR)-based metabolomics. We found significantly reduced CSF (1.32-fold, p = 0.0195) and serum (1.47-fold, p = 0.0484) levels of the ketone body acetoacetate in AD and MCI patients. Additionally, we found decreased levels (1.20-fold, p = 0.0438) of the branched-chain amino acid (BCAA) valine in the CSF of AD patients with increased valine degradation pathway metabolites (such as 3-hydroxyisobutyrate and α-ketoisovalerate). Moreover, we discovered that CSF 2-hydroxybutyrate is dramatically reduced in the MCI patient group (1.23-fold, p = 0.039). On the other hand, vitamin C (ascorbate) was significantly raised in CSF of these patients (p = 0.008). We also identified altered CSF protein content, 1,5-anhydrosorbitol and fructose as further metabolic shifts distinguishing AD from MCI. Significantly decreased serum levels of the amino acid ornithine were seen in the AD dementia group when compared to healthy controls (1.36-fold, p = 0.011). When investigating the effect of sex, we found for AD males the sign of decreased 2-hydroxybutyrate and acetoacetate in CSF while for AD females increased serum creatinine was identified. Quantitative NMR metabolomics of CSF and serum was able to efficiently identify metabolic changes associated with dementia groups of MCI and AD patients. Further, we showed strong correlations between these changes and well-established metabolomic and clinical indicators like Abeta.

Cognitive Trajectories and Associated Biomarkers in Patients with Mild Cognitive Impairment.

To diagnose mild cognitive impairment (MCI) patients at risk of progression to dementia is clinically important but challenging. We classified MCI patients based on cognitive trajectories and compared biomarkers among groups. This study analyzed amnestic MCI patients with at least three Clinical Dementia Rating (CDR) scores available over a minimum of 36 months from the Alzheimer's Disease Neuroimaging Initiative database. Patients were classified based on their progression using trajectory modeling with the CDR-sum of box scores. We compared clinical and neuroimaging biomarkers across groups. Of 569 eligible MCI patients (age 72.7±7.4 years, women n = 223), three trajectory groups were identified: stable (58.2%), slow decliners (24.6%), and fast decliners (17.2%). In the fifth year after diagnosis, the CDR-sum of box scores increased by 1.2, 5.4, and 11.8 points for the stable, slow, and fast decliners, respectively. Biomarkers associated with cognitive decline were amyloid-β 42, total tau, and phosphorylated tau protein in cerebrospinal fluid, hippocampal volume, cortical metabolism, and amount of cortical and subcortical amyloid deposits. Cortical metabolism and the amount of amyloid deposits were associated with the rate of cognitive decline. Data-driven trajectory analysis provides new insights into the various cognitive trajectories of MCI. Baseline brain metabolism, and the amount of cortical and subcortical amyloid burden can provide additional information on the rate of cognitive decline.

Взаимосвязь амилоидогенеза и таупатии с клиническими исходами ишемии головного мозга. Экспериментальное исследование

Currently, it has been established that increased formation of β-amyloid and tau protein play a significant role in the pathogenesis of cerebral ischemia. At the same time, these molecules can act as prognostic markers of the severity of cerebral ischemia. The aim of the study. To evaluate the peculiarities of changes in the concentration of β-amyloid and tau protein in blood serum and cerebrospinal fluid in rats with experimental subtotal cerebral ischemia, as well as to establish their relationship with the severity of post-ischemic clinical changes. Materials and methods. Subtotal cerebral ischemia was modeled by simultaneous occlusion of common carotid arteries in Wistar rats. The study assessed changes in neurological, sensorimotor and cognitive deficits. The content of β-amyloid and tau protein was assessed in blood serum and cerebrospinal fluid on the 1st, 3rd, 5th and 7th days of ischemia. During the analysis, species-specific kits for solid-phase enzyme immunoassay were used. Results. It was found that in animals with subtotal cerebral ischemia, as the duration of the ischemic period increases from day 1 to day 7, the concentration of β-amyloid and tau protein in both blood serum and cerebrospinal fluid progressively increases. It is worth noting that these changes strongly correlated with changes in the clinical manifestations of cerebral ischemia — neurological, sensorimotor and cognitive deficits.

Diagnostic Cut-offs for CSF β-amyloid and tau proteins in a Danish dementia clinic

BackgroundAnalysis of beta-amyloid 1–42 (Aβ42), total tau (t-tau) and phosphorylated-tau 181 (p-tau) in the cerebrospinal fluid (CSF) is often performed as a part of the diagnostic work-up in case of suspected Alzheimer's dementia (AD). Unfortunately, studies on optimal CSF biomarker cut-offs in a real-world clinical setting are scarce. MethodsWe retrospectively evaluated the biomarker levels of 264 consecutive patients referred to our dementia clinic. The biomarkers were analysed with the Elecsys(R) assays. Diagnoses were based on all available clinical information, including FDG-PET scans. ResultsIn total, we identified 233 patients diagnosed with dementia. The median MMSE score was 22 (IQR 18–25). AD pathophysiology was suspected in 156 patients, and the corresponding cut-offs based on the Youden index were: Aβ42: 903 ng/L (ROC-AUC 0.78); t-tau: 272 ng/L (ROC-AUC 0.78); p-tau: 24 ng/L (ROC-AUC 0.85); t-tau/Aβ42 ratio: 0.34 (ROC-AUC 0.91); p-tau/Aβ42 ratio: 0.029 (ROC-AUC 0.92). ConclusionsWe found the tau/Aβ42 ratios to possess the best diagnostic performance, but our estimated cut-off values for the ratios were somewhat higher than previously reported. Consequently, if the CSF analyses are used to support a diagnosis of AD in a heterogeneous high-prevalence cohort, adjustment of the cut-offs may be warranted.

Hearing impairment is associated with cognitive decline, brain atrophy and tau pathology.

Hearing impairment was recently identified as the most prominent risk factor for dementia. However, the mechanisms underlying the link between hearing impairment and dementia are still unclear. We investigated the association of hearing performance with cognitive function, brain structure and cerebrospinal fluid (CSF) proteins in cross-sectional, longitudinal, mediation and genetic association analyses across the UK Biobank (N=165,550), the Chinese Alzheimer's Biomarker and Lifestyle (CABLE, N=863) study, and the Alzheimer's Disease Neuroimaging Initiative (ADNI, N=1770) database. Poor hearing performance was associated with worse cognitive function in the UK Biobank and in the CABLE study. Hearing impairment was significantly related to lower volume of temporal cortex, hippocampus, inferior parietal lobe, precuneus, etc., and to lower integrity of white matter (WM) tracts. Furthermore, a higher polygenic risk score (PRS) for hearing impairment was strongly associated with lower cognitive function, lower volume of gray matter, and lower integrity of WM tracts. Moreover, hearing impairment was correlated with a high level of CSF tau protein in the CABLE study and in the ADNI database. Finally, mediation analyses showed that brain atrophy and tau pathology partly mediated the association between hearing impairment and cognitive decline. Hearing impairment is associated with cognitive decline, brain atrophy and tau pathology, and hearing impairment may reflect the risk for cognitive decline and dementia as it is related to bran atrophy and tau accumulation in brain. However, it is necessary to assess the mechanism in future animal studies. A full list of funding bodies that supported this study can be found in the Acknowledgements section.

Associations Between Intrathecal Levels of Vitamin D, Cytokines, and Core Biomarkers of Alzheimer's Disease: A Cross-Sectional Study.

Several studies have examined association between vitamin D levels in serum and cognition, but little is known of vitamin D levels in cerebrospinal fluid (CSF) and association with Alzheimer's disease (AD). In this cross-sectional, explorative study we investigated possible associations of vitamin D in CSF with biomarkers for AD, amyloid-β, tau protein/phosphorylated tau protein in CSF, and with the cytokines IL-6, IL-8, and TNF-α in CSF in patients with cognitive impairment and cognitively healthy controls. We included 100 outpatients ≥65 years referred for assessment of cognitive impairment and 76 age- and sex-matched cognitively healthy controls. Levels of 25-hydroxyvitamin D (25(OH)D), amyloid-β, tau protein and phosphorylated tau protein, as well as IL-6, IL-8, and TNF-α, were analyzed in CSF in both groups. Higher levels of 25(OH)D in CSF in all groups together were associated with lower levels of tau protein (p = 0.01) and phosphorylated tau protein (p = 0.005). We found no association between 25(OH)D levels in CSF and pathological levels of amyloid-β in CSF nor levels of IL-6 or TNF-α in CSF. Higher levels of 25(OH)D in CSF were associated with higher levels of IL-8 in CSF (p = 0.002). However, vitamin D explained only 6% of variance in IL-8. There was no significant difference between the patient groups and the control group regarding the association between 25(OH)D in CSF and any of the three cytokines in CSF. Participants with higher CSF levels of 25(OH)D exhibited reduced CSF levels of tau protein and phosphorylated tau protein.

An immuno-enrichment free, validated quantification of tau protein in human CSF by LC-MS/MS.

Tau protein is a key target of interest in developing therapeutics for neurodegenerative diseases. Here, we sought to develop a method that quantifies extracellular tau protein concentrations in human cerebrospinal fluid (CSF) without antibody-based enrichment strategies. We demonstrate that the fit-for-purpose validated method in Alzheimer’s Disease CSF is limited to quasi quantitative measures of tau surrogate peptides. We also provide evidence that CSF total Tau measures by LC-MS are feasible in the presence of monoclonal therapeutic antibodies in human CSF. Our Tau LC-MS/MS method is a translational bioanalytical tool for assaying target engagement and pharmacodynamics for anti-tau antibody drug development campaigns.

The Early Prognostic Value and Optimal Time of Measuring Serum and Cerebrospinal Fluid Tau Protein for Neurologic Outcomes in Postcardiac Arrest Patients Treated with Targeted Temperature Management.

Neuroprognostication of cardiac arrest patients remains a challenge. We evaluated the early prognostic value and optimal time of measuring serum and cerebrospinal fluid (CSF) tau protein levels to predict neurologic outcome in postcardiac arrest patients treated with targeted temperature management (TTM). We also evaluated the cutoff values in predicting poor outcomes. Patients treated with TTM following cardiac arrest, from May 2018 to June 2019, were included in the study. Serum and CSF tau levels were obtained and compared immediately, at 24, 48, and 72 hours after return of spontaneous circulation (ROSC). The area under the receiver-operating characteristic curve (AUROC) and the Delong method were used to identify the cutoff values of serum and CSF tau protein levels in predicting poor outcomes at each interval. Of 38 patients enrolled, 16 experienced poor outcomes. Both serum and CSF tau levels were consistently higher in the poor outcome group than in the good outcome group. The AUROCs of serum and CSF tau protein were not significantly different at each time point. Immediately after ROSC, sensitivities of both serum and CSF tau protein levels were 31.25% at 100% specificity and increased to 86.6% and 73.3%, respectively, at 72 hours. This study demonstrates that serum and CSF tau protein levels could be used as valuable predictors of neurologic outcomes in postcardiac arrest patients treated with TTM. The early optimal time for measuring the serum and CSF tau protein levels was determined to be 72 hours after ROSC.

Cerebrospinal fluid biomarkers and cognitive functions at multiple sclerosis diagnosis.

Cognitive impairment (CI) is a frequent and disabling symptom in Multiple Sclerosis (MS). Axonal damage may contribute to CI development from early stages. Nevertheless, no biomarkers are at the moment available to track CI in MS patients. We aimed to explore the correlation of cerebrospinal fluid (CSF) axonal biomarkers, in particular: light-chain neurofilaments (NFL), Tau, and Beta-amyloid protein (Abeta) in MS patients with CI at the diagnosis. 62 newly diagnosed MS patients were enrolled, and cognition was evaluated using the Brief International Cognitive Assessment for MS (BICAMS) battery. CSF NFL, Abeta, and Tau levels were determined with commercial ELISA. Patients with CI (45.1%) did not differ for demographic, clinical, and MRI characteristics (except for lower educational level), but they displayed greater neurodegeneration, exhibiting higher mean CSF Tau protein (162.1 ± 52.96pg/ml versus 132.2 ± 63.86pg/ml p:0.03). No differences were observed for Abeta and NFL. The number of impaired tests and Tau were significantly correlated (r:0.32 p:0.01). Tau was higher in particular in patients with slowed information processing speed (IPS) (p:0.006) and a linear regression analysis accounting for EDSS, MRI, and MS subtype confirmed Tau as a weak predictor of IPS and cognitive impairment. In conclusion, CI has an important burden on the quality of life of MS patients and should be looked for even at diagnosis. Axonal damage biomarkers, and in particular Tau, seem to reflect cognition impairment in the early stages.

Comparison of cerebrospinal fluid tau, ptau(181), synuclein, and 14-3-3 for the detection of Creutzfeldt-Jakob disease in clinical practice.

Creutzfeldt-Jakob disease (CJD) is the leading human prion disease and is a major public health concern, with the risk of secondary iatrogenic transmission. Screening for CJD is often based on the detection of 14-3-3 protein in cerebrospinal fluid (CSF) through western blot assay and, in a second step, on a more specific method such as RT-QuIC (Real-Time Quaking-Induced Conversion). Alternatives to the detection of 14-3-3 in CSF have recently been proposed, specifically CSF tau proteins, tau/p-tau(181) ratio, and alpha-synuclein. In the present work, we compare the diagnostic performance of these biomarkers with that of 14-3-3 protein in a cohort of suspected CJD patients. Our results indicate that tau detection is the most effective and suitable approach for routine disease detection in a clinical setting. Combination with other biomarkers does not improve overall performance, while the tau/p-tau(181) ratio remains useful for differentiating Alzheimer's from CJD. In the end, the performance of tau protein detection in CSF reached 78% sensitivity and 80% specificity for the detection of CJD. It is interesting to note that the use of an automated method with a high concentration range allows for rapid and accurate results, which is very useful in clinical practice and allows for confirmatory testing such as RT-QuIC without delay.