P4-039: Fit-for-purpose validation of the cerebrospinal fluid markers Aβ1-40, Aβ1-42 and total tau

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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P1-316: ‘Fit-for-purpose’ method validation of cerebrospinal fluid Alzheimer's biomarkers (Aβ38, Aβ40, Aβ42, ptau181 and total tau)

Alzheimer s & Dementia ◽

10.1016/j.jalz.2012.05.2002 ◽

2012 ◽

Vol 8 (4S_Part_6) ◽

pp. P214-P215

Author(s):

Lorella Di Donato

Keyword(s):

Cerebrospinal Fluid ◽

Method Validation ◽

Total Tau ◽

Fit For Purpose

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Increased levels of total tau protein in the cerebrospinal fluid in Huntington’s disease

Parkinsonism & Related Disorders ◽

10.1016/j.parkreldis.2011.06.010 ◽

2011 ◽

Vol 17 (9) ◽

pp. 714-715 ◽

Cited By ~ 22

Author(s):

Radu Constantinescu ◽

Megan Romer ◽

Henrik Zetterberg ◽

Lars Rosengren ◽

Karl Kieburtz

Keyword(s):

Cerebrospinal Fluid ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Tau Protein ◽

Total Tau

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On the design of early-phase Alzheimer’s disease clinical trials with cerebrospinal fluid tau outcomes

Clinical Trials ◽

10.1177/17407745211034497 ◽

2021 ◽

pp. 174077452110344

Author(s):

Michelle M Nuño ◽

Joshua D Grill ◽

Daniel L Gillen ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Cerebrospinal Fluid ◽

Phosphorylated Tau ◽

Inclusion Criteria ◽

Eligibility Criteria ◽

Total Tau ◽

Prodromal Alzheimer’S Disease ◽

Study Power

Background/Aims: The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power. Methods: We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes. Results: Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau. Conclusion: Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.

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Age-Dependency of Total Tau in the Cerebrospinal Fluid Is Corrected by Amyloid-β 1–40: A Correlational Study in Healthy Adults

Journal of Alzheimer s Disease ◽

10.3233/jad-210286 ◽

2021 ◽

pp. 1-8

Author(s):

Paul Theo Zebhauser ◽

Achim Berthele ◽

Marie-Sophie Franz ◽

Oliver Goldhardt ◽

Janine Diehl-Schmid ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Amyloid Β ◽

Healthy Adults ◽

Tau Proteins ◽

Clinical Settings ◽

Inclusion Criteria ◽

Total Tau ◽

Potential Marker ◽

Wide Range ◽

The Relationship

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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Cerebrospinal Fluid Biomarkers for Kii Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex

Journal of Neurodegenerative Diseases ◽

10.1155/2013/679089 ◽

2013 ◽

Vol 2013 ◽

pp. 1-4

Author(s):

Yui Nakayama ◽

Satoru Morimoto ◽

Misao Yoneda ◽

Shigeki Kuzuhara ◽

Yasumasa Kokubo

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Amyotrophic Lateral Sclerosis ◽

Cerebrospinal Fluid ◽

Enzyme Linked Immunosorbent Assay ◽

Phosphorylated Tau ◽

Total Tau ◽

Lateral Sclerosis

Objective. Amyotrophic lateral sclerosis/parkinsonism-dementia complex is classified as one of the tauopathies. Methods. The total tau, phosphorylated tau, and amyloid β42 levels were assayed in cerebrospinal fluid from patients with Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (), Alzheimer’s disease (), Parkinson’s disease (), amyotrophic lateral sclerosis (), and controls () using specific enzyme-linked immunosorbent assay methods. Results. Total tau and phosphorylated tau did not increase and amyloid β42 was relatively reduced in Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex. Relatively reduced amyloid β42 might discriminate Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex from amyotrophic lateral sclerosis and Parkinson’s disease, and the ratios of phosphorylated-tau to amyloid β42 could discriminate Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex from Alzheimer’s disease. Conclusions. Cerebrospinal fluid analysis may be useful to differentiate amyotrophic lateral sclerosis/parkinsonism-dementia complex from Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease.

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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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Comparison of variables associated with cerebrospinal fluid neurofilament, total-tau, and neurogranin

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.07.009 ◽

2019 ◽

Vol 15 (11) ◽

pp. 1437-1447 ◽

Cited By ~ 4

Author(s):

Michelle M. Mielke ◽

Jeremy A. Syrjanen ◽

Kaj Blennow ◽

Henrik Zetterberg ◽

Ingmar Skoog ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Total Tau

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Quantification of Tau in Cerebrospinal Fluid by Immunoaffinity Enrichment and Tandem Mass Spectrometry

Clinical Chemistry ◽

10.1373/clinchem.2013.216515 ◽

2014 ◽

Vol 60 (4) ◽

pp. 683-689 ◽

Cited By ~ 47

Author(s):

Thomas McAvoy ◽

Michael E Lassman ◽

Daniel S Spellman ◽

Zhenlian Ke ◽

Bonnie J Howell ◽

...

Keyword(s):

Mass Spectrometry ◽

Cerebrospinal Fluid ◽

Tandem Mass Spectrometry ◽

Magnetic Beads ◽

Internal Standard ◽

Tandem Mass ◽

Limit Of Quantification ◽

Total Tau ◽

Liquid Chromatography Tandem Mass ◽

Full Scan

Abstract BACKGROUND Cerebrospinal fluid (CSF) tau is a common biomarker for Alzheimer disease (AD). Measurements of tau have historically been performed using immunoassays. Given the molecular diversity of tau in CSF, the selectivity of these immunoassays has often been questioned. Therefore, we aimed to develop an analytically sensitive and selective immunoaffinity liquid chromatography–tandem mass spectrometry (LC-MS/MS) (IA-MS) assay. METHODS IA-MS sample analysis involved the addition of an internal standard, immunoaffinity purification of tau using a tau monoclonal antibody coupled to magnetic beads, trypsin digestion, and quantification of a surrogate tau peptide by LC-MS/MS using a Waters Trizaic nanoTile ultraperformance LC microfluidic device. Further characterization of tau peptides was performed by full-scan MS using a Thermo Orbitrap LC-MS. CSF samples from a cohort of age-matched controls and patients with AD were analyzed by the IA-MS method as well as a commercially available immunoassay. RESULTS The IA-MS assay had intra- and interassay imprecision values of 3.2% to 8.1% CV and 7.8% to 18.9% C, respectively, a mean recovery of 106%, and a limit of quantification of 0.25 pmol/L and was able to quantify tau concentrations in all human specimens tested. The IA-MS assay showed a correlation of R2 = 0.950 against a total-tau immunoassay. In patients with AD, tau was increased approximately 2-fold. CONCLUSIONS Combining immunoaffinity enrichment with microflow LC-MS/MS analysis is an effective approach for the development of a highly selective assay to measure total tau and, potentially, other posttranslationally modified forms of tau in CSF.

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