Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease

Ashton, Nicholas J.; Benedet, Andréa Lessa; Pascoal, Tharick A.; Karikari, Thomas K.; Lantero‐Rodriguez, Juan; Brum, Wagner S.; Mathotaarachchi, Sulantha; Therriault, Joseph; Savard, Mélissa; Chamoun, Mira; Stoops, Erik; François, Cindy; Vanmechelen, Eugeen; Gauthier, Serge; Zimmer, Eduardo R.; Zetterberg, Henrik; Blennow, Kaj; Rosa‐Neto, Pedro

doi:10.1016/j.ebiom.2022.103836

Cited by 89 publications

(92 citation statements)

References 67 publications

(98 reference statements)

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“…The slightly lower diagnostic accuracy of serum p-tau231 for AD vs . controls compared with p-tau181 in the present study seems to replicate the preclinical capacity of p-tau231 in brain, CSF, and plasma [ 5 , 10 , 31 , 47 ], since the biomarker-negative control group most likely included those with emerging AD pathology. A significant finding in the present study is that by showing that p-tau231 has good performance in serum that match its demonstrated performance as an early amyloid marker in plasma, we show that the field can expand blood p-tau analyses to include matrices like serum which is preferred in some medical centers and clinical studies.…”

Section: Discussionmentioning

confidence: 75%

“…In the present study, we have demonstrated that the biomarker performances of plasma p-tau231 and p-tau181 are replicable in serum, expanding the repertoire of blood matrix types that are suitable for evaluating these biomarkers. Additionally, p-tau231 and p-tau181 correlated strongly with each other when measured in serum, plasma, and CSF, demonstrating corresponding elevations of both biomarkers in AD that are quantifiable in multiple bodily fluids [ 5 , 10 , 31 ]. Notably, there were similar correlations of p-tau231 and p-tau181 when both were measured in serum (rho = 0.92) vs .…”

Section: Discussionmentioning

confidence: 99%

“…While plasma IPMS Aβ can sometimes detect amyloidosis equally or slightly better than plasma p-tau particularly in preclinical AD [ 7 ], current technical difficulties limit its throughput and widespread adoption [ 17 , 18 ]. Moreover, plasma p-tau217, which has shown substantial potential for brain amyloidosis in blood and CSF [ 2 , 10 , 31 , 43 ], is currently only reliably measurable in plasma; quantification in serum looks less promising given very low concentrations even in plasma, often below the detection limit [ 2 , 44 – 46 ]. Since plasma p-tau biomarker levels in preclinical AD are only marginally increased compared with biomarker-negative controls [ 1 , 2 , 6 – 8 , 10 , 11 , 32 ], robust and reproducible measures are essential.…”

Section: Discussionmentioning

confidence: 99%

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Diagnostic value of serum versus plasma phospho-tau for Alzheimer’s disease

et al. 2022

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Background Blood phosphorylated tau (p-tau) forms are promising Alzheimer’s disease (AD) biomarkers, but validation in matrices other than ethylenediaminetetraacetic acid (EDTA) plasma is limited. Firstly, we assessed the diagnostic potential of p-tau231 and p-tau181 in paired plasma and serum samples. Secondly, we compared serum and cerebrospinal fluid (CSF) samples from biomarker-positive AD and biomarker-negative control participants. Methods We studied three independent cohorts (n=115 total): cohorts 1 and 2 included individuals with paired plasma and serum, while cohort 3 included paired serum and CSF. Blood-based p-tau231 and p-tau181 were measured using in-house or commercial single molecule array (Simoa) methods. Results Serum and plasma p-tau231 and p-tau181 were two- to three-fold increased in biomarker-positive AD versus biomarker-negative controls (P≤0.0008). Serum p-tau231 separated diagnostic groups with area under the curve (AUC) of 82.2% (cohort 3) to 88.2% (cohort 1) compared with 90.2% (cohort 1) for plasma. Similarly, p-tau181 showed AUC of 89.6% (cohort 1) to 89.8% (cohort 3) in serum versus 85.4% in plasma (cohort 1). P-tau231 and p-tau181 correlated slightly better in serum (rho=0.92 for cohort 1, 0.93 for cohort 3) than in plasma (rho=0.88, cohort 1). Within-individual p-tau181 (Quanterix) and p-tau231 concentrations were twice higher in plasma versus serum, but p-tau181 (in-house, Gothenburg) levels were not statistically different. Bland-Altman plots revealed that the relative difference between serum/plasma was larger in the lower range. P-tau levels in paired plasma and serum correlated strongly with each other (rho=0.75–0.93) as well as with CSF Aβ42 (rho= −0.56 to −0.59), p-tau and total-tau (rho=0.53–0.73). Based on the results, it seems possible that serum p-tau reflects the same pool of brain-secreted p-tau as in CSF; we estimated that less than 2% of CSF p-tau is found in serum, being same for both controls and AD. Conclusions Comparable diagnostic performances and strong correlations between serum versus plasma pairs suggest that p-tau analyses can be expanded to research cohorts and hospital systems that prefer serum to other blood matrices. However, absolute biomarker concentrations may not be interchangeable, indicating that plasma and serum samples should be used independently. These results should be validated in independent cohorts.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Diagnostic value of serum versus plasma phospho-tau for Alzheimer’s disease

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“…24 Using plasma pTau, our study extends recent CSF biomarker modeling studies which provide evidence that CSF pTau231 abnormality precedes CSF pTau181 abnormality. 23,26 This follows the framework in which plasma biomarkers are early detectors of AD pathology. 11 Tau-PET has been proven effective in providing information regarding the risk of clinical deterioration in the following months.…”

Section: Discussionmentioning

confidence: 99%

Comparing tau status determined via plasma pTau181, pTau231 and [18F]MK6240 tau-PET

et al. 2022

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Background Tau in Alzheimer's disease (AD) is assessed via cerebrospinal fluid (CSF) and Positron emission tomography (PET). Novel methods to detect phosphorylated tau (pTau) in blood have been recently developed. We aim to investigate agreement of tau status as determined by [ 18 F]MK6240 tau-PET, plasma pTau181 and pTau231. MethodsWe assessed cognitively unimpaired young, cognitively unimpaired, mild cognitive impairment and AD individuals with [ 18 F]MK6240, plasma pTau181, pTau 231, [ 18 F]AZD4694 amyloid-PET and MRI. A subset underwent CSF assessment.We conducted ROC curves to obtain cut-off values for plasma pTau epitopes. Individuals were categorized as positive or negative in all biomarkers. We then compared the distribution among concordant and discordant groups in relation to diagnosis, Ab status, APOEe4 status, [ 18 F]AZD4694 global SUVR, hippocampal volume and CSF pTau181.Findings The threshold for positivity was 15.085 pg/mL for plasma pTau181 and 17.652 pg/mL for plasma pTau231. Most individuals had concordant statuses, however, 18% of plasma181/PET, 26% of plasma231/PET and 25% of the pTau231/pTau181 were discordant. Positivity to at least one biomarker was often accompanied by diagnosis of

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“…investigated CSF p-tau181, p-tau217 and p-tau231 across the Alzheimer's continuum , from the preclinical to the dementia stage, in the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. 8 They demonstrate that all p-tau epitopes are significantly increased in asymptomatic and symptomatic individuals with underlying AD pathology (as defined by Aβ and tau PET), and discriminate them from individuals without AD pathology. Yet, there are remarkable differences between the three p-tau epitopes.…”

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confidence: 94%

CSF p-tau231: A biomarker for early preclinical Alzheimer?

Suárez‐Calvet

2022

eBioMedicine

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Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease

Cited by 89 publications

References 67 publications

Diagnostic value of serum versus plasma phospho-tau for Alzheimer’s disease

Diagnostic value of serum versus plasma phospho-tau for Alzheimer’s disease

Comparing tau status determined via plasma pTau181, pTau231 and [18F]MK6240 tau-PET

CSF p-tau231: A biomarker for early preclinical Alzheimer?

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