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Comparative Study
. 2021 Sep 1;78(9):1108-1117.
doi: 10.1001/jamaneurol.2021.2293.

Comparison of Plasma Phosphorylated Tau Species With Amyloid and Tau Positron Emission Tomography, Neurodegeneration, Vascular Pathology, and Cognitive Outcomes

Michelle M Mielke  1   2 , Ryan D Frank  1 , Jeffrey L Dage  3 , Andreas Jeromin  4   5 , Nicholas J Ashton  6   7   8   9   10 , Kaj Blennow  6   10   11 , Thomas K Karikari  6   10 , Eugene Vanmechelen  12 , Henrik Zetterberg  6   10   11   13   14 , Alicia Algeciras-Schimnich  15 , David S Knopman  2 , Val Lowe  16 , Guojun Bu  17 , Prashanthi Vemuri  16 , Jonathan Graff-Radford  2 , Clifford R Jack Jr  16 , Ronald C Petersen  1   2
Affiliations
Comparative Study

Comparison of Plasma Phosphorylated Tau Species With Amyloid and Tau Positron Emission Tomography, Neurodegeneration, Vascular Pathology, and Cognitive Outcomes

Michelle M Mielke et al. JAMA Neurol. .

Abstract

Importance: Cerebrospinal fluid phosphorylated tau (p-tau) 181, p-tau217, and p-tau231 are associated with neuropathological outcomes, but a comparison of these p-tau isoforms in blood samples is needed.

Objective: To conduct a head-to-head comparison of plasma p-tau181 and p-tau231 measured on the single-molecule array (Simoa) platform and p-tau181 and p-tau217 measured on the Meso Scale Discovery (MSD) platform on amyloid and tau positron emission tomography (PET) measures, neurodegeneration, vascular pathology, and cognitive outcomes.

Design, setting, and participants: This study included data from the Mayo Clinic Study on Aging collected from March 1, 2015, to September 30, 2017, and analyzed between December 15, 2020, and May 17, 2021. Associations between the 4 plasma p-tau measures and dichotomous amyloid PET, metaregion of interest tau PET, and entorhinal cortex tau PET were analyzed using logistic regression models; the predictive accuracy was summarized using area under the receiver operating characteristic curve (AUROC) statistic. Of 1329 participants without dementia and with p-tau181 and p-tau217 on MSD, 200 participants with plasma p-tau181 and p-tau231 on Simoa and magnetic resonance imaging and amyloid and tau PET data at the same study visit were eligible.

Main outcomes and measures: Primary outcomes included amyloid (greater than 1.48 standardized uptake value ratio) and tau PET, white matter hyperintensities, white matter microstructural integrity (fractional anisotropy genu of corpus callosum and hippocampal cingulum bundle), and cognition.

Results: Of 200 included participants, 101 (50.5%) were male, and the median (interquartile range [IQR]) age was 79.5 (71.1-84.1) years. A total of 177 were cognitively unimpaired (CU) and 23 had mild cognitive impairment. Compared with amyloid-negative CU participants, among amyloid-positive CU participants, the median (IQR) Simoa p-tau181 measure was 49% higher (2.58 [2.00-3.72] vs 1.73 [1.45-2.13] pg/mL), MSD p-tau181 measure was 53% higher (1.22 [0.91-1.56] vs 0.80 [0.66-0.97] pg/mL), MSD p-tau217 measure was 77% higher (0.23 [0.17-0.34] vs 0.13 [0.09-0.18] pg/mL), and Simoa p-tau231 measure was 49% higher (20.21 [15.60-25.41] vs 14.27 [11.27-18.10] pg/mL). There were no differences between the p-tau species for amyloid PET and tau PET metaregions of interest. However, among CU participants, both MSD p-tau181 and MSD p-tau217 more accurately predicted abnormal entorhinal cortex tau PET than Simoa p-tau181 (MSD p-tau181: AUROC, 0.80 vs 0.70; P = .046; MSD p-tau217: AUROC, 0.81 vs 0.70; P = .04). MSD p-tau181 and p-tau217 and Simoa p-tau181, but not p-tau231, were associated with greater white matter hyperintensity volume and lower white matter microstructural integrity.

Conclusions and relevance: In this largely presymptomatic population, these results suggest subtle differences across plasma p-tau species and platforms for the prediction of amyloid and tau PET and magnetic resonance imaging measures of cerebrovascular and Alzheimer-related pathology.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Mielke has received grants from the National Institute on Aging and US Department of Defense and served as a consultant for Biogen and Brain Protection Company. Dr Dage holds stocks in Eli Lilly and Company and has a patent pending for compounds and methods targeting human tau assigned to Eli Lilly and Company. Dr Jeromin holds stocks in Quanterix Corporation. Dr Blennow has served as a consultant, on advisory boards, or on data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Eli Lilly and Company, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers and is a co-founder of Brain Biomarker Solutions. Dr Vanmechelen is a co-founder of ADx NeuroSciences and founder of Key4AD. Dr Zetterberg has served on scientific advisory boards for Eisai, Denali, Roche Diagnostics, Wave Life Sciences, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, and CogRx; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen; and is a co-founder of Brain Biomarker Solutions. Dr Knopman has received grants from Eli Lilly and Company and Biogen; serves on a data safety monitoring board for the Dominantly Inherited Alzheimer Network (DIAN) study and for Biogen; is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California; and serves as a consultant for Roche, Samus Therapeutics, Third Rock, and Alzeca Biosciences. Dr Lowe received consulting fees from Bayer Schering Pharma, Piramal Life Sciences, and Merck Research and grants from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the National Institutes of Health. Dr Bu serves as a consultant for AbbVie, E-Scape, and SciNeuro. Dr Vemuri received speaking fees from Miller Medical Communications. Dr Graff-Radford has received grants from the National Institutes of Health and serves as Assistant Editor for Neurology. Dr Jack has received research support from the National Institutes of Health and Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic; serves on an independent data monitoring board for Roche; has served as a speaker for Eisai; and has consulted for Biogen. Dr Petersen has received grants from the National Institutes of Health and consulting fees from Hoffman-La Roche, Merck, Genentech, Biogen, GE Healthcare, and Eisai. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Scatterplots and Spearman Correlations Between Plasma P-tau Measures and Amyloid and Tau Positron Emission Tomography (PET) Measures
Solid lines indicate the correlation, and dashed lines indicate cut points for determining abnormal neuroimaging results. ERC indicates entorhinal cortex; MSD, Meso Scale Discovery; ROI, region of interest; Simoa, single-molecule array.
Figure 2.
Figure 2.. Comparison of the Accuracy of the 4 Plasma P-tau Measures for Elevated Brain Amyloid Measured via Amyloid Pittsburgh Compound B on Positron Emission Tomography
AUROC indicates area under the receiver operating characteristic curve; CU, cognitively unimpaired; MCI, mild cognitive impairment; MSD, Meso Scale Discovery; Simoa, single-molecule array.
Figure 3.
Figure 3.. Comparison of the Accuracy of the 4 Plasma P-tau Measures for Tau Positron Emission Tomography Entorhinal Cortex Region of Interest
AUROC indicates area under the receiver operating characteristic curve; CU, cognitively unimpaired; MCI, mild cognitive impairment; MSD, Meso Scale Discovery; Simoa, single-molecule array.
See this image and copyright information in PMC

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