Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 1954-1963 |
| Number of pages | 10 |
| Journal | Nature medicine |
| Volume | 29 |
| Issue number | 8 |
| Early online date | 2023 |
| DOIs | |
| Publication status | Published - Aug 2023 |
Access to Document
Other files and links
Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Nature medicine, Vol. 29, No. 8, 08.2023, p. 1954-1963.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease
AU - Horie, Kanta
AU - Salvadó, Gemma
AU - Barthélemy, Nicolas R.
AU - Janelidze, Shorena
AU - Li, Yan
AU - He, Yingxin
AU - Saef, Benjamin
AU - Chen, Charles D.
AU - Jiang, Hong
AU - Strandberg, Olof
AU - Pichet Binette, Alexa
AU - Palmqvist, Sebastian
AU - Sato, Chihiro
AU - Sachdev, Pallavi
AU - Koyama, Akihiko
AU - Gordon, Brian A.
AU - Benzinger, Tammie L. S.
AU - Holtzman, David M.
AU - Morris, John C.
AU - Mattsson-Carlgren, Niklas
AU - Stomrud, Erik
AU - Ossenkoppele, Rik
AU - Schindler, Suzanne E.
AU - Hansson, Oskar
AU - Bateman, Randall J.
N1 - Funding Information: This work was supported by resources and effort provided by the Tracy Family SILQ Center (Principal Investigator (PI) R.J.B.) established by the Tracy Family, Richard Frimel and Gary Werths, GHR Foundation, David Payne and the Willman Family brought together by The Foundation for Barnes-Jewish Hospital. This work was also supported by resources and effort provided by the Hope Center for Neurological Disorders and the Department of Neurology at the Washington University School of Medicine and by the Clinical, Fluid Biomarker and Imaging Cores of the Knight ADRC (P30 AG066444, PI J.C.M., P01 AG03991, PI J.C.M. and P01 AG026276, PI J.C.M.) at the Washington University School of Medicine for participant evaluation, samples and data collection. The mass spectrometry analyses of BioFINDER-2 and Knight ADRC samples were supported by an Eisai industry grant to Washington University (PIs K.H. and R.J.B.) and the Knight ADRC developmental project (PI N.R.B.). Statistical analyses were partially supported by R01AG070941. The Swedish BioFINDER-2 study was by the Swedish Research Council (2016-00906), the Knut and Alice Wallenberg foundation (2017-0383), the Marianne and Marcus Wallenberg foundation (2015.0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer Foundation (AF-939932), the Swedish Brain Foundation (FO2021-0293), The Parkinson foundation of Sweden (1280/20), the Cure Alzheimer’s fund, the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Skåne University Hospital Foundation (2020-O000028), Regionalt Forskningsstöd (2020-0314) and the Swedish federal government under the ALF agreement (2018-Projekt0279). The precursor of [F]-flutemetamol was provided by GE Healthcare and the precursor of [F]-RO948 was provided by Roche. The Knight ADRC PET imaging was supported by P30 NS048056. Florbetapir F18 (AV45) doses were provided by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly. Flortaucipr F18 (FTP, T807 and AV1451) was performed at Washington University through technology and materials transfer agreement with Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly. G.S. received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie action grant agreement no. 101061836, from Greta och Johan Kocks research grants and travel grants from the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s Disease) at Lund University. We thank the participants and families for their contribution to this study. We also thank the Clinical, Biomarker and Imaging Cores at the Washington University School of Medicine for participant evaluation, samples and data collection. We thank H. Liu, R. Koppisetti, B. Androff, M. Li and C. Hodge for assistance with CSF sample processing and coordination. We thank K. Wildsmith for the project discussion and manuscript review. 18 18 Funding Information: This work was supported by resources and effort provided by the Tracy Family SILQ Center (Principal Investigator (PI) R.J.B.) established by the Tracy Family, Richard Frimel and Gary Werths, GHR Foundation, David Payne and the Willman Family brought together by The Foundation for Barnes-Jewish Hospital. This work was also supported by resources and effort provided by the Hope Center for Neurological Disorders and the Department of Neurology at the Washington University School of Medicine and by the Clinical, Fluid Biomarker and Imaging Cores of the Knight ADRC (P30 AG066444, PI J.C.M., P01 AG03991, PI J.C.M. and P01 AG026276, PI J.C.M.) at the Washington University School of Medicine for participant evaluation, samples and data collection. The mass spectrometry analyses of BioFINDER-2 and Knight ADRC samples were supported by an Eisai industry grant to Washington University (PIs K.H. and R.J.B.) and the Knight ADRC developmental project (PI N.R.B.). Statistical analyses were partially supported by R01AG070941. The Swedish BioFINDER-2 study was by the Swedish Research Council (2016-00906), the Knut and Alice Wallenberg foundation (2017-0383), the Marianne and Marcus Wallenberg foundation (2015.0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer Foundation (AF-939932), the Swedish Brain Foundation (FO2021-0293), The Parkinson foundation of Sweden (1280/20), the Cure Alzheimer’s fund, the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Skåne University Hospital Foundation (2020-O000028), Regionalt Forskningsstöd (2020-0314) and the Swedish federal government under the ALF agreement (2018-Projekt0279). The precursor of [18F]-flutemetamol was provided by GE Healthcare and the precursor of [18F]-RO948 was provided by Roche. The Knight ADRC PET imaging was supported by P30 NS048056. Florbetapir F18 (AV45) doses were provided by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly. Flortaucipr F18 (FTP, T807 and AV1451) was performed at Washington University through technology and materials transfer agreement with Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly. G.S. received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie action grant agreement no. 101061836, from Greta och Johan Kocks research grants and travel grants from the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s Disease) at Lund University. We thank the participants and families for their contribution to this study. We also thank the Clinical, Biomarker and Imaging Cores at the Washington University School of Medicine for participant evaluation, samples and data collection. We thank H. Liu, R. Koppisetti, B. Androff, M. Li and C. Hodge for assistance with CSF sample processing and coordination. We thank K. Wildsmith for the project discussion and manuscript review. Publisher Copyright: © 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2023/8
Y1 - 2023/8
N2 - Aggregated insoluble tau is one of two defining features of Alzheimer’s disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available cannot specifically track tau aggregates. We show that the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is a new cerebrospinal fluid (CSF) biomarker specific for insoluble tau aggregates and compared it to multiple other phosphorylated tau measures (p-tau181, p-tau205, p-tau217 and p-tau231) in two independent cohorts (BioFINDER-2, n = 448; and Knight Alzheimer Disease Research Center, n = 219). MTBR-tau243 was most strongly associated with tau-positron emission tomography (PET) and cognition, whereas showing the lowest association with amyloid-PET. In combination with p-tau205, MTBR-tau243 explained most of the total variance in tau-PET burden (0.58 ≤ R 2 ≤ 0.75) and the performance in predicting cognitive measures (0.34 ≤ R 2 ≤ 0.48) approached that of tau-PET (0.44 ≤ R 2 ≤ 0.52). MTBR-tau243 levels longitudinally increased with insoluble tau aggregates, unlike CSF p-tau species. CSF MTBR-tau243 is a specific biomarker of tau aggregate pathology, which may be utilized in interventional trials and in the diagnosis of patients. Based on these findings, we propose to revise the A/T/(N) criteria to include MTBR-tau243 as representing insoluble tau aggregates (‘T’).
AB - Aggregated insoluble tau is one of two defining features of Alzheimer’s disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available cannot specifically track tau aggregates. We show that the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is a new cerebrospinal fluid (CSF) biomarker specific for insoluble tau aggregates and compared it to multiple other phosphorylated tau measures (p-tau181, p-tau205, p-tau217 and p-tau231) in two independent cohorts (BioFINDER-2, n = 448; and Knight Alzheimer Disease Research Center, n = 219). MTBR-tau243 was most strongly associated with tau-positron emission tomography (PET) and cognition, whereas showing the lowest association with amyloid-PET. In combination with p-tau205, MTBR-tau243 explained most of the total variance in tau-PET burden (0.58 ≤ R 2 ≤ 0.75) and the performance in predicting cognitive measures (0.34 ≤ R 2 ≤ 0.48) approached that of tau-PET (0.44 ≤ R 2 ≤ 0.52). MTBR-tau243 levels longitudinally increased with insoluble tau aggregates, unlike CSF p-tau species. CSF MTBR-tau243 is a specific biomarker of tau aggregate pathology, which may be utilized in interventional trials and in the diagnosis of patients. Based on these findings, we propose to revise the A/T/(N) criteria to include MTBR-tau243 as representing insoluble tau aggregates (‘T’).
UR - http://www.scopus.com/inward/record.url?scp=85164793186&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41591-023-02443-z
DO - https://doi.org/10.1038/s41591-023-02443-z
M3 - Article
C2 - 37443334
SN - 1078-8956
VL - 29
SP - 1954
EP - 1963
JO - Nature medicine
JF - Nature medicine
IS - 8
ER -