Elecsys® Total-Tau and Phospho-Tau (181P) CSF assays: Analytical performance of the novel, fully automated immunoassays for quantification of tau proteins in human cerebrospinal fluid

Background: Tau proteins are established biomarkers of neuroaxonal damage in a wide range of neurodegenerative conditions. Although measurement of total-Tau in the cerebrospinal fluid is widely used in research and clinical settings, the relationship between age and total-Tau in the cerebrospinal fluid is yet to be fully understood. While past studies reported a correlation between age and total-Tau in the cerebrospinal fluid of healthy adults, in clinical practice the same cut-off value is used independently of patient’s age. Objective: To further explore the relationship between age and total-Tau and to disentangle neurodegenerative from drainage-dependent effects. Methods: We analyzed cerebrospinal fluid samples of 76 carefully selected cognitively healthy adults and included amyloid-β 1–40 as a potential marker of drainage from the brain’s interstitial system. Results: We found a significant correlation of total-Tau and age, which was no longer present when correcting total-Tau for amyloid-β 1–40 concentrations. These findings were replicated under varied inclusion criteria. Conclusion: Results call into question the association of age and total-Tau in the cerebrospinal fluid. Furthermore, they suggest diagnostic utility of amyloid-β 1–40 as a possible proxy for drainage-mechanisms into the cerebrospinal fluid when interpreting biomarker concentrations for neurodegenerative diseases.

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The Head Turning Sign in Dementia and Mild Cognitive Impairment: Its Relationship to Cognition, Behavior, and Cerebrospinal Fluid Biomarkers

Dementia and Geriatric Cognitive Disorders ◽

10.1159/000486531 ◽

2018 ◽

Vol 46 (1-2) ◽

pp. 42-49 ◽

Cited By ~ 3

Author(s):

João Durães ◽

Miguel Tábuas-Pereira ◽

Rui Araújo ◽

Diana Duro ◽

Inês Baldeiras ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Geriatric Depression Scale ◽

Depression Scale ◽

Tau Proteins ◽

Cognitive Measures ◽

Head Turning ◽

Total Tau ◽

Scale Scores

Background/Aims: The head turning sign (HTS) is frequently noticed in clinical practice, but few studies have investigated its etiological and neuropsychological correlates. Methods: The presence and frequency of the HTS was operationalized and prospectively evaluated in patients with Alzheimer’s disease (AD), amnestic mild cognitive impairment (MCI), and behavioral-variant frontotemporal dementia (bvFTD). Cerebrospinal fluid (CSF) samples for AD biomarkers were collected. Mini-Mental State Examination, Montreal Cognitive Assessment, Geriatric Depression Scale (GDS), and insight scale scores were ascertained. Results: A total of 84 patients were included. The HTS was more prevalent in AD than in MCI or bvFTD. It correlated negatively with cognitive measures and depression. It also had a positive correlation with CSF total tau and hyperphosphorylated tau proteins. Total tau protein and GDS score were the only variables independently associated with the HTS. Conclusions: The presence of the HTS in a cognitively impaired individual suggests a diagnosis of AD. A higher HTS frequency correlates with higher CSF total tau levels, a smaller GDS score, and worse cognitive measures. In the MCI subgroup, the HTS may suggest a higher risk of progression.

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Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: an elusive quest

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-319266 ◽

2019 ◽

Vol 90 (7) ◽

pp. 740-746 ◽

Cited By ~ 7

Author(s):

Martha S Foiani ◽

Claudia Cicognola ◽

Natalia Ermann ◽

Ione O C Woollacott ◽

Carolin Heller ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Frontotemporal Dementia ◽

Neurodegenerative Disorder ◽

The Novel ◽

Tau Pathology ◽

Total Tau ◽

Significant Difference ◽

T Tau

BackgroundFrontotemporal dementia (FTD) is a pathologically heterogeneous neurodegenerative disorder associated usually with tau or TDP-43 pathology, although some phenotypes such as logopenic variant primary progressive aphasia are more commonly associated with Alzheimer’s disease pathology. Currently, there are no biomarkers able to diagnose the underlying pathology during life. In this study, we aimed to investigate the potential of novel tau species within cerebrospinal fluid (CSF) as biomarkers for tau pathology in FTD.Methods86 participants were included: 66 with a clinical diagnosis within the FTD spectrum and 20 healthy controls. Immunoassays targeting tau fragments N-123, N-mid-region, N-224 and X-368, as well as a non-phosphorylated form of tau were measured in CSF, along with total-tau (T-tau) and phospho-tau (P-tau(181)). Patients with FTD were grouped based on their Aβ42 level into those likely to have underlying Alzheimer’s disease (AD) pathology (n=21) and those with likely frontotemporal lobar degeneration (FTLD) pathology (n=45). The FTLD group was then subgrouped based on their underlying clinical and genetic diagnoses into those with likely tau (n=7) or TDP-43 (n=18) pathology.ResultsSignificantly higher concentrations of tau N-mid-region, tau N-224 and non-phosphorylated tau were seen in both the AD group and FTLD group compared with controls. However, none of the novel tau species showed a significant difference between the AD and FTLD groups, nor between the TDP-43 and tau pathology groups. In a subanalysis, normalising for total-tau, none of the novel tau species provided a higher sensitivity and specificity to distinguish between tau and TDP-43 pathology than P-tau(181)/T-tau, which itself only had a sensitivity of 61.1% and specificity of 85.7% with a cut-off of <0.109.ConclusionsDespite investigating multiple novel CSF tau fragments, none show promise as an FTD biomarker and so the quest for in vivo markers of FTLD-tau pathology continues.

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Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke

Neuroscience Letters ◽

10.1016/s0304-3940(00)01697-9 ◽

2001 ◽

Vol 297 (3) ◽

pp. 187-190 ◽

Cited By ~ 251

Author(s):

Camilla Hesse ◽

Lars Rosengren ◽

Niels Andreasen ◽

Pia Davidsson ◽

Hugo Vanderstichele ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Acute Stroke ◽

Transient Increase ◽

Total Tau ◽

Human Cerebrospinal Fluid

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[P2-238]: ANALYTICAL PERFORMANCE CHARACTERISTICS OF A PROTOTYPE IMMUNOASSAY FOR QUANTIFICATION OF ALPHA-SYNUCLEIN IN HUMAN CEREBROSPINAL FLUID

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.890 ◽

2017 ◽

Vol 13 (7S_Part_14) ◽

pp. P702-P702

Author(s):

Emeric Chassaing ◽

Philippe Vergnaud ◽

Tanja Schubert ◽

Hugo Marcel Vanderstichele ◽

Erik Stoops ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Alpha Synuclein ◽

Performance Characteristics ◽

Analytical Performance ◽

Human Cerebrospinal Fluid

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

10.1101/2021.05.10.21252513 ◽

2021 ◽

Author(s):

Wade Self ◽

John P. Savaryn ◽

Khader Awwad ◽

Michael Schulz

Keyword(s):

Cerebrospinal Fluid ◽

Neurodegenerative Diseases ◽

Tau Protein ◽

Therapeutic Antibodies ◽

Alzheimers Disease ◽

Total Tau ◽

Human Cerebrospinal Fluid ◽

Fit For Purpose

Aims: 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 human cerebrospinal fluid (CSF) without antibody-based enrichment strategies. Results: We demonstrate that the fit-for-purpose validated method in Alzheimers 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. Conclusion: Our Tau LC-MS/MS method is a translational bioanalytical tool for assaying target

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[P1-280]: ANALYTICAL PERFORMANCE CHARACTERISTICS OF A NOVEL IMMUNOASSAY FOR THE QUANTIFICATION OF BACE-1 IN HUMAN CEREBROSPINAL FLUID

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.296 ◽

2017 ◽

Vol 13 (7S_Part_7) ◽

pp. P357-P357

Author(s):

Emeric Chassaing ◽

Mélanie Bodnar-Wachtel ◽

Tanja Schubert ◽

Hugo Marcel Vanderstichele ◽

Erik Stoops ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Performance Characteristics ◽

Analytical Performance ◽

Human Cerebrospinal Fluid ◽

Bace 1

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Effects of Anesthetic Isoflurane and Desflurane on Human Cerebrospinal Fluid Aβ and τ Level

Anesthesiology ◽

10.1097/aln.0b013e31828ce55d ◽

2013 ◽

Vol 119 (1) ◽

pp. 52-60 ◽

Cited By ~ 38

Author(s):

Bin Zhang ◽

Ming Tian ◽

Hui Zheng ◽

Yu Zhen ◽

Yun Yue ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Alzheimer Disease ◽

Spinal Anesthesia ◽

Amyloid Protein ◽

Total Tau ◽

Human Cerebrospinal Fluid ◽

Csf Levels ◽

Β Amyloid ◽

Spinal Catheter

Abstract Background: Accumulation of β-amyloid protein (Aβ) and tau protein is the main feature of Alzheimer disease neuropathogenesis. Anesthetic isoflurane, but not desflurane, may increase Aβ levels in vitro and in animals. Therefore, we set out to determine the effects of isoflurane and desflurane on cerebrospinal fluid (CSF) levels of Aβ and tau in humans. Methods: The participants were assigned into spinal anesthesia (N = 35), spinal plus desflurane anesthesia (N = 33), or spinal plus isoflurane anesthesia (N = 38) group by randomization using computer-generated lists. Pre- and postoperative human CSF samples were obtained through an inserted spinal catheter. The levels of Aβ (Aβ40 and Aβ42) and total tau in the CSF were determined. Results: Here, we show that isoflurane, but not desflurane, was associated with an increase in human CSF Aβ40 levels (from 10.90 to 12.41 ng/ml) 24 h after the surgery under anesthesia compared to spinal anesthesia (from 11.59 to 11.08 ng/ml), P = 0.022. Desflurane, but not isoflurane, was associated with a decrease in Aβ42 levels 2 h after the surgery under anesthesia (from 0.39 to 0.35 ng/ml) compared to spinal anesthesia (from 0.43 to 0.44 ng/ml), P = 0.006. Isoflurane and desflurane did not significantly affect the tau levels in human CSF. Conclusions: These studies have established a system to study the effects of anesthetics on human biomarkers associated with Alzheimer disease and cognitive dysfunction. These findings have suggested that isoflurane and desflurane may have different effects on human CSF Aβ levels.

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