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Title: High performance plasma amyloid-β biomarkers for Alzheimer's disease.
Austin Authors: Nakamura, Akinori;Kaneko, Naoki;Villemagne, Victor L ;Kato, Takashi;Doecke, James;Doré, Vincent ;Fowler, Chris;Li, Qiao-Xin;Martins, Ralph N;Rowe, Christopher C ;Tomita, Taisuke;Matsuzaki, Katsumi;Ishii, Kenji;Ishii, Kazunari;Arahata, Yutaka;Iwamoto, Shinichi;Ito, Kengo;Tanaka, Koichi;Masters, Colin L ;Yanagisawa, Katsuhiko
Affiliation: Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
Koichi Tanaka Mass Spectrometry Research Laboratory, Shimadzu Corporation, Kyoto, Japan
Department of Nuclear Medicine & Centre for PET, Austin Health, Heidelberg, Victoria, Australia
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
National Hospital for Geriatric Medicine, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
Health and Biosecurity, CSIRO, Brisbane, Australia
Edith Cowan University, Joondalup, Western Australia, Australia
Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
Team for Neuroimaging Research, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
Department of Radiology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
Issue Date: 8-Feb-2018 2018-01-31
Publication information: Nature 2018; 554(7691): 249-254
Abstract: To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-β deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-β in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-β markers. Here we demonstrate the measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-β precursor protein (APP)669-711/amyloid-β (Aβ)1-42 and Aβ1-40/Aβ1-42 ratios, and their composites, to predict individual brain amyloid-β-positive or -negative status was determined by amyloid-β-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-β burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-β-PET burden and levels of Aβ1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.
DOI: 10.1038/nature25456
ORCID: 0000-0003-3910-2453
PubMed URL: 29420472
Type: Journal Article
Appears in Collections:Journal articles

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