Cited by 246Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCerebrospinal fluid and hydrocephalus

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

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Mielke, Michelle M., Frank, Ryan D., Dage, Jeffrey L., Jeromin, Andreas, Ashton, Nicholas J., Blennow, Kaj, Karikari, Thomas K., Vanmechelen, Eugene, Zetterberg, Henrik, Algeciras-Schimnich, Alicia, Knopman, David S., Lowe, Val, Bu, Guojun, Vemuri, Prashanthi, Graff-Radford, Jonathan, Jack, Clifford R., Petersen, Ronald C.·2021·JAMA Neurology

DOI 10.1001/jamaneurol.2021.2293PMC PMC8314178

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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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Authors: Mielke, M. M., Frank, R. D., Dage, J. L., Jeromin, A., Ashton, N. J., Blennow, K., Karikari, T. K., Vanmechelen, E., Zetterberg, H., Algeciras-Schimnich, A., Knopman, D. S., Lowe, V., Bu, G., Vemuri, P., Graff-Radford, J., Jack, C. R., & Petersen, R. C.
Affiliations: Mayo Clinic (US)
Eli Lilly (United States) (US)
Cohen Veterans Bioscience (US)
King's College London (GB)
Sahlgrenska University Hospital (SE)
University of Gothenburg (SE)
ADx Neurosciences, Ghent, Belgium
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
Mayo Clinic in Florida (US)
Department of Neurology, Mayo Clinic, Rochester, Minnesota
Corresponding author: Mielke, Michelle M.
ORCID: Mielke, Michelle M.
Frank, Ryan D.
Dage, Jeffrey L.
Ashton, Nicholas J.
Blennow, Kaj
Karikari, Thomas K.
Zetterberg, Henrik
Knopman, David S.
Lowe, Val
Bu, Guojun
Vemuri, Prashanthi
Jack, Clifford R.
Petersen, Ronald C.
Venue: JAMA Neurology
Publisher: American Medical Association (AMA)
Published: 2021-09-01
Volume: 78
Issue: 9
Pages: 1108
ISSN: 2168-6149 (ISSN-L)
DOI: 10.1001/jamaneurol.2021.2293
PMC: PMC8314178
OpenAlex: W3183927686
Cited by: 244
References: 44
Citations by year: 2026: 33 · 2025: 58 · 2024: 50 · 2023: 48 · 2022: 48 · 2021: 6
FWCI: 27.44
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: JAMA Neurology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
IUScholarWorks (Indiana University) (submittedVersion)
UCL Discovery (University College London) (submittedVersion)
Funders: European Commission (860197)
Vetenskapsrådet (2017-00915)
National Institutes of Health
National Institute on Aging (U01AG006786, R01AG011378, R01AG041851, R37AG011378, P30AG062677)
National Institute of Neurological Disorders and Stroke (R01NS097495)
H2020 European Research Council (681712)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
Keywords: phosphorylated tau, plasma biomarkers, p-tau181, p-tau217, p-tau231, amyloid PET, tau PET, amyloid-beta, neurodegeneration, white matter hyperintensities, fractional anisotropy, cognitive impairment, Simoa, MSD, Alzheimer's disease, vascular pathology
MeSH terms: Aged, Aged, 80 and over, Alzheimer Disease, Cross-Sectional Studies, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Nerve Degeneration, Phosphorylation, Biomarkers, Neurofibrillary Tangles, tau Proteins, Positron-Emission Tomography, Plaque, Amyloid, Cognitive Dysfunction

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

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