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. 2023 Nov;19(11):4967-4977.
doi: 10.1002/alz.13026. Epub 2023 Apr 20.

Equivalence of plasma p-tau217 with cerebrospinal fluid in the diagnosis of Alzheimer's disease

Joseph Therriault  1   2 , Stijn Servaes  1   2 , Cécile Tissot  1 , Nesrine Rahmouni  1 , Nicholas J Ashton  3   4   5   6 , Andréa Lessa Benedet  3 , Thomas K Karikari  4   7 , Arthur C Macedo  1   2 , Firoza Z Lussier  1   7 , Jenna Stevenson  1 , Yi-Ting Wang  1   2 , Jaime Fernandez-Arias  1   2 , Alyssa Stevenson  1 , Kely Quispialaya Socualaya  1   2 , Arlette Haeger  1   2 , Tahnia Nazneen  1   2 , Étienne Aumont  1   2 , Ali Hosseini  1   2 , Soham Rej  8 , Paolo Vitali  2 , Gallen Triana-Baltzer  9 , Hartmuth C Kolb  9 , Jean-Paul Soucy  2 , Tharick A Pascoal  7 , Serge Gauthier  1   2 , Henrik Zetterberg  3   10   11   12   13 , Kaj Blennow  3   10 , Pedro Rosa-Neto  1   2
Affiliations

Equivalence of plasma p-tau217 with cerebrospinal fluid in the diagnosis of Alzheimer's disease

Joseph Therriault et al. Alzheimers Dement. 2023 Nov.

Abstract

Introduction: Plasma biomarkers are promising tools for Alzheimer's disease (AD) diagnosis, but comparisons with more established biomarkers are needed.

Methods: We assessed the diagnostic performance of p-tau181 , p-tau217 , and p-tau231 in plasma and CSF in 174 individuals evaluated by dementia specialists and assessed with amyloid-PET and tau-PET. Receiver operating characteristic (ROC) analyses assessed the performance of plasma and CSF biomarkers to identify amyloid-PET and tau-PET positivity.

Results: Plasma p-tau biomarkers had lower dynamic ranges and effect sizes compared to CSF p-tau. Plasma p-tau181 (AUC = 76%) and p-tau231 (AUC = 82%) assessments performed inferior to CSF p-tau181 (AUC = 87%) and p-tau231 (AUC = 95%) for amyloid-PET positivity. However, plasma p-tau217 (AUC = 91%) had diagnostic performance indistinguishable from CSF (AUC = 94%) for amyloid-PET positivity.

Discussion: Plasma and CSF p-tau217 had equivalent diagnostic performance for biomarker-defined AD. Our results suggest that plasma p-tau217 may help reduce the need for invasive lumbar punctures without compromising accuracy in the identification of AD.

Highlights: p-tau217 in plasma performed equivalent to p-tau217 in CSF for the diagnosis of AD, suggesting the increased accessibility of plasma p-tau217 is not offset by lower accuracy. p-tau biomarkers in plasma had lower mean fold-changes between amyloid-PET negative and positive groups than p-tau biomarkers in CSF. CSF p-tau biomarkers had greater effect sizes than plasma p-tau biomarkers when differentiating between amyloid-PET positive and negative groups. Plasma p-tau181 and plasma p-tau231 performed worse than p-tau181 and p-tau231 in CSF for AD diagnosis.

Keywords: Alzheimer's disease; CSF; PET; amyloid-β; p-tau; plasma; tau.

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Conflict of interest statement

CONFLICT OF INTEREST and DISCLOSURE STATEMENT

PRN has served at scientific advisory boards and/or as a consultant for Roche, Novo Nordisk, Eisai and Cerveau radiopharmaceuticals. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. All other authors report no disclosures.

Figures

Figure 1:
Figure 1:. Distributions of CSF and plasma p-tau181, 217 and 231 by amyloid-PET status
Density plots represent the continuous distribution of CSF (top) and plasma (bottom) biomarkers of p-tau181 (left), p-tau217 (middle) and p-tau231 (right). Beige indicates amyloid-PET negative participants and blue indicates amyloid-PET positive participants. Boxplots are also presented for each biomarker, where lines indicate 95% confidence intervals and individual circles are data points that lie outside 95% confidence intervals. Plasma p-tau181 and p-tau231 had considerably greater overlap between amyloid-PET positive and amyloid-PET negative participants compared to evaluations in CSF. CSF p-tau181 and CSF p-tau231 had significantly greater effect sizes when differentiating between amyloid-PET positive and amyloid-PET negative participants compared to plasma (Table 2). CSF and plasma p-tau217 had similar degrees of overlap and similar effect sizes to distinguish amyloid-PET positive and amyloid-PET negative participants. All comparisons were significant at p<0.0001.
Figure 2:
Figure 2:. Relationship between CSF and plasma p-tau concentrations
A: Black lines of origin along the horizontal depict a theoretical linear relationship between variables without over- or under-estimation. The true line below the origin indicates that plasma p-tau measurements underestimate p-tau concentrations from CSF, a finding observed for p-tau181, p-tau217 and p-tau231. B: Bland-Altman analysis assessing bias between CSF and plasma measurements. Dashed lines indicate limits of agreement. Z-scores for each biomarker are represented to facilitate comparisons between measurements. C: Within-subject agreement between classification from CSF and plasma p-tau biomarkers. Cut-off values for plasma biomarkers were determined from independent cohorts and cut-offs for CSF biomarkers were determined using a support vector classification model (see methods). Of all three p-tau biomarkers investigated, plasma p-tau217 had the highest rates of agreement (88.5%), followed by p-tau231 (75.0%) and p-tau181 (66.7%). Abnormal plasma p-tau in individuals without abnormal CSF p-tau (plasma+/CSF-) was more common than the reverse for all p-tau biomarkers, but was most pronounced for p-tau181 and p-tau217.
Figure 3:
Figure 3:. Discriminative accuracy of CSF and plasma p-tau for amyloid-PET positivity and for biological AD defined by PET
A: ROC curves displaying discriminative accuracy of CSF (purple lines) and plasma (blue lines) for amyloid-PET positivity. DeLong’s test revealed that plasma p-tau181 and plasma p-tau231 performed significantly worse than CSF, whereas no difference was observed for p-tau217. Plasma p-tau217 also outperformed plasma p-tau181 and plasma p-tau231 for the identification of amyloid-PET positivity. B: ROC curves displaying discriminative accuracy of CSF (purple lines) and plasma (blue lines) for concurrent amyloid-PET positivity and tau-PET positivity. DeLong’s test revealed that plasma p-tau231 performed significantly worse than CSF, whereas no difference was observed for p-tau217 and p-tau181. Plasma p-tau217 also had higher discriminative accuracy than plasma p-tau181 and plasma p-tau231 for the identification of biological AD (A+T+). The summary of all statistical comparisons is reported in Table 3 and Supplementary Table 1.
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References

    1. Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010. J Neuropathol Exp Neurol 2012;71:266–73. doi:10.1097/NEN.0b013e31824b211b. - DOI - PMC - PubMed
    1. Therriault J, Pascoal TA, Benedet AL, Savard M, Chamoun M, Lussier F, et al. Frequency of biologically-defined AD in relation to age, sex, APOEε4 and cognitive impairment. Neurology 2021. - PMC - PubMed
    1. Kostopoulou O, Delaney BC, Munro CW. Diagnostic difficulty and error in primary care - A systematic review. Fam Pract 2008;25:400–13. doi:10.1093/fampra/cmn071. - DOI - PubMed
    1. Rabinovici GD, Gatsonis C, Apgar C, Chaudhary K, Gareen I, Hanna L, et al. Association of Amyloid Positron Emission Tomography with Subsequent Change in Clinical Management among Medicare Beneficiaries with Mild Cognitive Impairment or Dementia. JAMA 2019;321:1286–94. doi:10.1001/jama.2019.2000. - DOI - PMC - PubMed
    1. Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, et al. Donanemab in Early Alzheimer’s Disease. N Engl J Med 2021;384:1691–704. doi:10.1056/nejmoa2100708. - DOI - PubMed

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