Plasma and CSF biomarkers in a memory clinic: Head‐to‐head comparison of phosphorylated tau immunoassays

Ashton, Nicholas J.; Puig‐Pijoan, Albert; Milà‐Alomà, Marta; Fernández‐Lebrero, Aida; García-Escobar, G.; González‐Ortiz, Fernándo; Kac, Przemysław R; Brum, Wagner S.; Benedet, Andréa Lessa; Lantero‐Rodriguez, Juan; Day, Theresa A.; Vanbrabant, Jeroen; Stoops, Erik; Vanmechelen, Eugeen; Triana‐Baltzer, Gallen; Moughadam, Setareh; Kolb, Hartmuth C.; Ortiz‐Romero, Paula; Karikari, Thomas K.; Minguillón, Carolina; Sánchez, Juan José Hernández; Navalpotro‐Gómez, Irene; Grau‐Rivera, Oriol; Manero, R.M.; Puente‐Periz, Víctor; Torre, Rafael de la; Roquer, Jaume; Dage, Jeff L; Zetterberg, Henrik; Blennow, Kaj; Suárez‐Calvet, Marc

doi:10.1002/alz.12841

Cited by 88 publications

(82 citation statements)

References 41 publications

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“…In Down syndrome, plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions [54]. When more than one p-tau form was included in a study, plasma p-tau217 generally showed stronger associations with brain Aβ deposition than p-tau181 and p-tau231 [49,62,68,69,71]. Moreover, the IP-MS plasma p-tau217 method performed better than immunoassaybased ones in a recent comparative study [68].…”

Section: Plasma P-tau Associations With Clinical and Biological Evide...mentioning

confidence: 99%

Plasma phospho-tau in Alzheimer’s disease: towards diagnostic and therapeutic trial applications

González‐Ortiz

Kac

Brum

et al. 2023

Mol Neurodegeneration

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As the leading cause of dementia, Alzheimer's disease (AD) is a major burden on affected individuals, their families and caregivers, and healthcare systems. Although AD can be identified and diagnosed by cerebrospinal fluid or neuroimaging biomarkers that concord with neuropathological evidence and clinical symptoms, challenges regarding practicality and accessibility hinder their widespread availability and implementation. Consequently, many people with suspected cognitive impairment due to AD do not receive a biomarker-supported diagnosis. Blood biomarkers have the capacity to help expand access to AD diagnostics worldwide. One such promising biomarker is plasma phosphorylated tau (p-tau), which has demonstrated specificity to AD versus non-AD neurodegenerative diseases, and will be extremely important to inform on clinical diagnosis and eligibility for therapies that have recently been approved. This review provides an update on the diagnostic and prognostic performances of plasma p-tau181, p-tau217 and p-tau231, and their associations with in vivo and autopsy-verified diagnosis and pathological hallmarks. Additionally, we discuss potential applications and unanswered questions of plasma p-tau for therapeutic trials, given their recent addition to the biomarker toolbox for participant screening, recruitment and during-trial monitoring. Outstanding questions include assay standardization, threshold generation and biomarker verification in diverse cohorts reflective of the wider community attending memory clinics and included in clinical trials.

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Section: Plasma P-tau Associations With Clinical and Biological Evide...mentioning

confidence: 99%

Plasma phospho-tau in Alzheimer’s disease: towards diagnostic and therapeutic trial applications

González‐Ortiz

Kac

Brum

et al. 2023

Mol Neurodegeneration

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“…Several publications have highlighted that a mass spectrometry measurement of Aβ peptides is more reflective of cerebral Aβ than immunoassay methods . We also acknowledge that there is a range of diagnostic performance in different p-tau measurements in determining AD …”

Section: Discussionmentioning

confidence: 99%

“…3,34 We also acknowledge that there is a range of diagnostic performance in different p-tau measurements in determining AD. 2,35…”

Section: Limitationsmentioning

confidence: 99%

“…xtracellular amyloid-β (Aβ) plaques and neurofibrillary tangles composed of phosphorylated tau (p-tau) are the key protein signatures of a brain with Alzheimer disease (AD). Aβ peptides (Aβ42 and Aβ40) and p-tau can be quantified in cerebrospinal fluid (CSF) and, more recently, in blood, where both biomarkers show high accuracy in determining underlying AD brain pathology 1 in both symptomatic 2,3 and asymptomatic disease. 4,5 When using these biomarkers in studies focusing on disease mechanisms or treatment effects, it is important to understand the differences between biomarker changes observed in CSF and blood relating to the proposed underlying pathophysiology.…”

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Alzheimer Disease Blood Biomarkers in Patients With Out-of-Hospital Cardiac Arrest

et al. 2023

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ImportanceBlood phosphorylated tau (p-tau) and amyloid-β peptides (Aβ) are promising peripheral biomarkers of Alzheimer disease (AD) pathology. However, their potential alterations due to alternative mechanisms, such as hypoxia in patients resuscitated from cardiac arrest, are not known.ObjectiveTo evaluate whether the levels and trajectories of blood p-tau, Aβ42, and Aβ40 following cardiac arrest, in comparison with neural injury markers neurofilament light (NfL) and total tau (t-tau), can be used for neurological prognostication following cardiac arrest.Design, Setting, and ParticipantsThis prospective clinical biobank study used data from the randomized Target Temperature Management After Out-of-Hospital Cardiac Arrest (TTM) trial. Unconscious patients with cardiac arrest of presumed cardiac origin were included between November 11, 2010, and January 10, 2013, from 29 international sites. Serum analysis for serum NfL and t-tau were performed between August 1 and August 23, 2017. Serum p-tau, Aβ42, and Aβ40 were analyzed between July 1 and July 15, 2021, and between May 13 and May 25, 2022. A total of 717 participants from the TTM cohort were examined: an initial discovery subset (n = 80) and a validation subset. Both subsets were evenly distributed for good and poor neurological outcome after cardiac arrest.ExposuresSerum p-tau, Aβ42, and Aβ40 concentrations using single molecule array technology. Serum levels of NfL and t-tau were included as comparators.Main Outcomes and MeasuresBlood biomarker levels at 24 hours, 48 hours, and 72 hours after cardiac arrest. Poor neurologic outcome at 6-month follow-up, defined according to the cerebral performance category scale as category 3 (severe cerebral disability), 4 (coma), or 5 (brain death).ResultsThis study included 717 participants (137 [19.1%] female and 580 male [80.9%]; mean [SD] age, 63.9 [13.5] years) who experienced out-of-hospital cardiac arrest. Significantly elevated serum p-tau levels were observed at 24 hours, 48 hours, and 72 hours in cardiac arrest patients with poor neurological outcome. The magnitude and prognostication of the change was greater at 24 hours (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI, 0.95-0.97), which was similar to NfL (AUC, 0.94; 95% CI, 0.92-0.96). However, at later time points, p-tau levels decreased and were weakly associated with neurological outcome. In contrast, NfL and t-tau maintained high diagnostic accuracies, even 72 hours after cardiac arrest. Serum Aβ42 and Aβ40 concentrations increased over time in most patients but were only weakly associated with neurological outcome.Conclusions and RelevanceIn this case-control study, blood biomarkers indicative of AD pathology demonstrated different dynamics of change after cardiac arrest. The increase of p-tau at 24 hours after cardiac arrest suggests a rapid secretion from the interstitial fluid following hypoxic-ischemic brain injury rather than ongoing neuronal injury like NfL or t-tau. In contrast, delayed increases of Aβ peptides after cardiac arrest indicate activation of amyloidogenic processing in response to ischemia.

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“…These performances have been independently authenticated in dozens of research cohorts, with some studies further showing that plasma p-tau measures correlate well with CSF p-tau in paired samples [1,4,44]. Moreover, plasma p-tau often performs equivalently to CSF p-tau to differentiate Aβ-positive AD dementia individuals from Aβ-negative non-AD dementia and control participants [16 ▪▪ ,47 ▪▪ ]. The specificity of plasma p-tau to AD pathophysiology (compared with other biomarkers like NfL and GFAP) makes it a potential first line of action in the diagnostic workup [1,2].…”

Section: Diagnostic and Prognostic Performances Suggesting That Blood...mentioning

confidence: 96%

Plasma biomarkers for neurodegenerative disorders: ready for prime time?

Balogun

Zetterberg

Blennow

et al. 2023

Current Opinion in Psychiatry

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Purpose of reviewSeveral plasma biomarkers for Alzheimer's disease and related disorders (ADRD) have demonstrated clinical and technical robustness. However, are they ready for clinical implementation? This review critically appraises current evidence for and against the immediate use of plasma biomarkers in clinical care. Recent findingsPlasma biomarkers have significantly improved our understanding of ADRD time-course, risk factors, diagnosis and prognosis. These advances are accelerating the development and in-human testing of therapeutic candidates, and the selection of individuals with subtle biological evidence of disease who fit the criteria for early therapeutic targeting. However, standardized tests and well validated cut-off values are lacking. Moreover, some assays (e.g., plasma Ab methods) have poor robustness to withstand inevitable day-to-day technical variations. Additionally, recent reports suggest that common comorbidities of aging (e.g., kidney disease, diabetes, hypertension) can erroneously affect plasma biomarker levels, clinical utility and generalizability. Furthermore, it is unclear if health disparities can explain reported racial/ethnic differences in biomarker levels and functions. Finally, current clinically approved plasma methods are more expensive than CSF assays, questioning their cost effectiveness.

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Plasma and CSF biomarkers in a memory clinic: Head‐to‐head comparison of phosphorylated tau immunoassays

Cited by 88 publications

References 41 publications

Plasma phospho-tau in Alzheimer’s disease: towards diagnostic and therapeutic trial applications

Plasma phospho-tau in Alzheimer’s disease: towards diagnostic and therapeutic trial applications

Alzheimer Disease Blood Biomarkers in Patients With Out-of-Hospital Cardiac Arrest

Plasma biomarkers for neurodegenerative disorders: ready for prime time?

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