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. 2024 Dec;31(12):e16255.
doi: 10.1111/ene.16255. Epub 2024 Oct 24.

Plasma phosphorylated tau181 outperforms [18F] fluorodeoxyglucose positron emission tomography in the identification of early Alzheimer disease

Kely Monica Quispialaya  1   2   3 , Joseph Therriault  1   2   4 , Antonio Aliaga  1   3   5 , Cécile Tissot  1   2   4 , Stijn Servaes  1   2   4 , Nesrine Rahmouni  1   2   4 , Thomas K Karikari  6   7 , Andrea L Benedet  1   6 , Nicholas J Ashton  6   8 , Arthur C Macedo  1   2   4 , Firoza Z Lussier  1   7 , Jenna Stevenson  1 , Yi-Ting Wang  1   2   4 , Jaime Fernandez Arias  1   2   4 , Ali Hosseini  1   2   4 , Takashi Matsudaira  9   10 , Bertrand Jean-Claude  3 , Brian M Gilfix  11 , Eduardo R Zimmer  1   5   12   13 , Jean-Paul Soucy  2 , Tharick A Pascoal  7 , Serge Gauthier  1   4   14 , Henrik Zetterberg  6   15   16   17   18   19 , Kaj Blennow  6   15 , Pedro Rosa-Neto  1   2   3   4   14 ; Alzheimer's Disease Neuroimaging Initiative
Affiliations

Plasma phosphorylated tau181 outperforms [18F] fluorodeoxyglucose positron emission tomography in the identification of early Alzheimer disease

Kely Monica Quispialaya et al. Eur J Neurol. 2024 Dec.

Abstract

Background and purpose: This study was undertaken to compare the performance of plasma p-tau181 with that of [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in the identification of early biological Alzheimer disease (AD).

Methods: We included 533 cognitively impaired participants from the Alzheimer's Disease Neuroimaging Initiative. Participants underwent PET scans, biofluid collection, and cognitive tests. Receiver operating characteristic analyses were used to determine the diagnostic accuracy of plasma p-tau181 and [18F]FDG-PET using clinical diagnosis and core AD biomarkers ([18F]florbetapir-PET and cerebrospinal fluid [CSF] p-tau181) as reference standards. Differences in the diagnostic accuracy between plasma p-tau181 and [18F]FDG-PET were determined by bootstrap-based tests. Correlations of [18F]FDG-PET and plasma p-tau181 with CSF p-tau181, amyloid β (Aβ) PET, and cognitive performance were evaluated to compare associations between measurements.

Results: We observed that both plasma p-tau181 and [18F]FDG-PET identified individuals with positive AD biomarkers in CSF or on Aβ-PET. In the MCI group, plasma p-tau181 outperformed [18F]FDG-PET in identifying AD measured by CSF (p = 0.0007) and by Aβ-PET (p = 0.001). We also observed that both plasma p-tau181 and [18F]FDG-PET metabolism were associated with core AD biomarkers. However, [18F]FDG-PET uptake was more closely associated with cognitive outcomes (Montreal Cognitive Assessment, Mini-Mental State Examination, Clinical Dementia Rating Sum of Boxes, and logical memory delayed recall, p < 0.001) than plasma p-tau181.

Conclusions: Overall, although both plasma p-tau181 and [18F]FDG-PET were associated with core AD biomarkers, plasma p-tau181 outperformed [18F]FDG-PET in identifying individuals with early AD pathophysiology. Taken together, our study suggests that plasma p-tau181 may aid in detecting individuals with underlying early AD.

Keywords: Alzheimer disease; [18F]FDG‐PET; [18F]florbetapir‐PET; cerebrospinal fluid; plasma p‐tau181.

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Conflict of interest statement

P.R.‐N. is a member of the CIHR‐CCNA Canadian Consortium of Neurodegeneration in Aging and Colin J. Adair Charitable Foundation. S.G. serves as a scientific advisor for Cerveau and Enigma US. E.R.Z. serves on the scientific advisory board of Next Innovative Therapeutics. H.Z. has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures at symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a cofounder of Brain Biomarker Solutions in Gothenburg, which is a part of the GU Ventures Incubator Program. The other authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Fluid biomarkers and neuroimaging across clinically defined diagnostics groups. Distribution of cerebrospinal fluid (CSF) p‐tau181 (pg/mL), CSF amyloid β (Aβ) 42 (pg/mL), plasma p‐tau181 (pg/mL), [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET) standardized uptake value ratio (SUVR), and [18F]florbetapir‐PET SUVR between the clinically defined diagnostics groups mild cognitive impairment (MCI) and probable Alzheimer disease (pAD), using Mann–Whitney U‐test, is shown. Statistically significant differences in fluid biomarkers (CSF p‐tau181, CSF Aβ42, and plasma p‐tau181) were found between the MCI and pAD groups (****p < 0.0001). Similarly, significant differences in neuroimaging ([18F]FDG‐PET SUVR and [18F]florbetapir‐PET SUVR) were found between the MCI and pAD groups (****p < 0.0001).
FIGURE 2
FIGURE 2
Receiver operating characteristic (ROC) curves for discrimination of patients with cerebrospinal fluid (CSF) and amyloid β positron emission tomography (PET) positivity. ROC curve analysis for the detection of Alzheimer disease pathophysiology is shown. (a) ROC curve analyses for detection of CSF positivity according to established thresholds across each diagnostic group individually and all clinical groups. (b) ROC curve analyses for detection of amyloid‐PET positivity according to established threshold across the different diagnostic groups. The p‐value for the difference between the three ROC curves was obtained using a bootstrap‐based method implemented in the pROC package in R (http://www.r‐project.org). AUC, area under the curve; MCI, mild cognitive impairment; pAD, probable Alzheimer disease; FDG, [18F] fluorodeoxyglucose.
FIGURE 3
FIGURE 3
Association of plasma p‐tau181 and [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) standardized uptake value ratio (SUVR) with core Alzheimer disease (AD) biomarkers. Spearman partial correlation coefficient (r 12.34) of (a) cerebrospinal fluid (CSF) p‐tau181 with plasma p‐tau181, CSF p‐tau181, and [18F]FDG SUVR and (b) Spearman partial correlation of amyloid β 42‐PET with plasma p‐tau181 and [18F]FDG‐PET SUVR adjusted by age and gender were computed in individuals in the cross‐sectional dataset stratified by clinical diagnosis. These measures showed significant correlation between CSF p‐tau181 and plasma p‐tau181, and between CSF p‐tau181 and [18F]FDG‐PET SUV. Similarly, [18F]florbetapir‐PET SUVR showed significant correlation with plasma p‐tau181 and with [18F]FDG‐PET SUVR. Association of plasma p‐tau181 and [18F]FDG‐PET SUVR with cognitive tests is shown. MCI, mild cognitive impairment; pAD, probable Alzheimer disease.
FIGURE 4
FIGURE 4
Associations of plasma p‐tau181 and [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) standardized uptake value ratio (SUVR) with cognitive function. Spearman partial correlation coefficient (r 12.34) adjusted by sex, age, and education was determined between plasma p‐tau181 as well as [18F]FDG‐PET SUVR and each cognitive test. (a) Correlations of plasma p‐tau181 with Montreal Cognitive Assessment (MoCA) score, Mini‐Mental State Examination (MMSE) score, Clinical Dementia Rating Sum of Boxes (CDR‐SB) score, and logical memory delayed recall (LDEL) score. (b) Correlations of [18F]FDG‐PET SUVR with MoCA score, MMSE score, CDR‐SB score, and LDEL score. Both plasma p‐tau181 and [18F]FDG‐PET SUVR correlated with MoCA, MMSE, CDR‐SB, and LDEL scores. However, [18F]FDG‐PET SUVR is more closely associated with cognitive outcomes than plasma p‐tau181. MCI, mild cognitive impairment; pAD, probable Alzheimer disease.
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