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Original Investigation
July 26, 2021

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

Author Affiliations
  • 1Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
  • 2Department of Neurology, Mayo Clinic, Rochester, Minnesota
  • 3Eli Lilly and Company, Indianapolis, Indiana
  • 4Quanterix Corporation, Lexington, Massachusetts
  • 5Cohen Veterans Bioscience, Cambridge, Massachusetts
  • 6Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
  • 7Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
  • 8Maurice Wohl Institute Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
  • 9NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia, South London and Maudsley NHS Foundation, London, United Kingdom
  • 10Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
  • 11Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  • 12ADx Neurosciences, Ghent, Belgium
  • 13UK Dementia Research Institute, UCL, London, United Kingdom
  • 14Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
  • 15Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
  • 16Department of Radiology, Mayo Clinic, Rochester, Minnesota
  • 17Department of Neuroscience, Mayo Clinic, Jacksonville, Florida
JAMA Neurol. 2021;78(9):1108-1117. doi:10.1001/jamaneurol.2021.2293
Key Points

Question  How do plasma phosphorylated tau (p-tau) 181 and p-tau231 as measured on the single-molecule array (Simoa) platform and p-tau181 and p-tau217 as measured on the Meso Scale Discovery (MSD) platform compare with regards to amyloid and tau positron emission tomography and magnetic resonance imaging measures as well as cognition?

Findings  In this cross-sectional study including 200 participants, MSD p-tau181 and p-tau217 predicted entorhinal cortex tau positron emission tomography measures significantly better than Simoa p-tau181 among cognitively unimpaired participants. MSD p-tau181 and p-tau217 and Simoa p-tau181, but not p-tau231, were associated with magnetic resonance imaging measures of cerebrovascular pathology, and MSD p-tau181 and p-tau217 were most strongly associated with magnetic resonance imaging measures of Alzheimer disease pathology.

Meaning  Results from this study suggest subtle differences across plasma p-tau species and platforms.

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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