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Association of Plasma p-tau181 and p-tau231 Concentrations with Cognitive Decline in Patients with Probable Dementia with Lewy Bodies

Research output: Contribution to journalArticlepeer-review

Maria C. Gonzalez, Nicholas J. Ashton, Bárbara Fernandes Gomes, Diego Alejandro Tovar-Rios, Frédéric Blanc, Thomas K. Karikari, Brit Mollenhauer, Andrea Pilotto, Afina Lemstra, Claire Paquet, Carla Abdelnour, Milica G. Kramberger, Laura Bonanni, Rik Vandenberghe, Abdul Hye, Kaj Blennow, Henrik Zetterberg, Dag Aarsland

Original languageEnglish
Pages (from-to)32-37
Number of pages6
JournalJAMA Neurology
Volume79
Issue number1
Early online date22 Nov 2021
DOIs
Accepted/In press2021
E-pub ahead of print22 Nov 2021
Published2022

Bibliographical note

Funding Information: independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. Dr Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF) (201809-2016862), the AD Strategic Fund and the Alzheimer's Association (ADSF-21-831376-C, ADSF-21-831381-C, and ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (FO2019-0228), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. Dr Blennow is supported by the Swedish Research Council (2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), (RDAPB-201809-2016615), the Swedish Alzheimer Foundation (AF-742881), Hjärnfonden, Sweden (FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institutes of Health (grant 1R01AG068398-01), and the Alzheimer’s Association 2021 Zenith Award. The University of Stavanger supported Dr Gonzalez. Funding Information: coordinator for France for EISAI Delphia study, Axovant E2027 study, and Roche Graduate study outside the submitted work. Dr Mollenhauer reported serving as a consultant for and receiving honoraria from Roche, Biogen, Servier, AbbVie, and Amprion; receiving grants from Michael J. Fox Foundation for Parkinson’s Research, Deutsche Forschungsgemeinschaft, EU (Horizon2020), Parkinson Fonds Deutschland, Deutsche Parkinsonvereinigung, Parkinson’s Foundation, Hilde Ulrichs Stiftung für Parkinsonforschung outside the submitted work; and serving as a member of the executive steering committee of the Parkinson Progression Marker Initiative and principal investigator of the Systemic Synuclein Sampling Study of the Michael J. Fox Foundation for Parkinson’s Research. Dr Pilotto reported receiving personal fees from AbbVie, Bial, BIomarine, UCB, and Zambon Pharma and grants from Zambon Italy, H2020 IMI initiative, and Italian Ministry of Health outside the submitted work. Dr Paquet reported serving as a member of the international advisory boards for Lilly; serving as a consultant for Fujiribio, Alzohis, Neuroimmune, Ads Neuroscience, Roche, AgenT, and Gilead; being involved as an investigator in several clinical trials for Roche, Eisai, Lilly, Biogen, AstraZeneca, Lundbeck, and Neuroimmune; and being a current member of the national boards of Roche, Lilly, and Biogen. Dr Abdelnour reported receiving personal fees from KRKA, Hoffmann-La Roche, and Nutricia outside the submitted work. Dr Bonanni reported receiving grants from the European Commission and the Italian Ministry of Health outside the submitted work. Dr Blennow reported having served as a consultant on advisory boards or on data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers and being a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Dr Zetterberg reported being a cofounder of and stockholder in Brain Biomarker Solutions in Gothenburg AB and receiving personal fees from Denali, Roche Diagnostics, Wave, Samumed, Siemens Funding Information: This study represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King?s College London. Dr Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF) (201809-2016862), the AD Strategic Fund and the Alzheimer's Association (ADSF-21-831376-C, ADSF-21-831381-C, and ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen f?r Gamla Tj?narinnor, Hj?rnfonden, Sweden (FO2019-0228), the European Union?s Horizon 2020 research and innovation program under the Marie Sk?odowska-Curie grant agreement 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. Dr Blennow is supported by the Swedish Research Council (2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), (RDAPB-201809-2016615), the Swedish Alzheimer Foundation (AF-742881), Hj?rnfonden, Sweden (FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institutes of Health (grant 1R01AG068398-01), and the Alzheimer?s Association 2021 Zenith Award. The University of Stavanger supported Dr Gonzalez. Publisher Copyright: © 2022 American Medical Association. All rights reserved.

King's Authors

Abstract

Importance: Plasma phosphorylated tau (p-tau) has proven to be an accurate biomarker for Alzheimer disease (AD) pathologic characteristics, offering a less expensive and less invasive alternative to cerebrospinal fluid (CSF) and positron emission tomography biomarkers for amyloid-β and tau. Alzheimer disease comorbid pathologic characteristics are common and are associated with more rapid cognitive decline in patients with dementia with Lewy bodies (DLB); therefore, it is anticipated that plasma p-tau concentrations may have utility in assessing cognitive impairment in individuals with this disorder. Objective: To measure the concentrations of plasma p-tau (p-tau181 and p-tau231) and evaluate their associations with cognitive decline in individuals with probable DLB. Design, Setting, and Participants: This multicenter longitudinal cohort study included participants from the European-DLB (E-DLB) Consortium cohort enrolled at 10 centers with harmonized diagnostic procedures from January 1, 2002, to December 31, 2020, with up to 5 years of follow-up. A total of 1122 participants with plasma samples were available. Participants with acute delirium or terminal illness and patients with other previous major psychiatric or neurologic disorders were excluded, leaving a cohort of 987 clinically diagnosed participants with probable DLB (n = 371), Parkinson disease (n = 204), AD (n = 207), as well as healthy controls (HCs) (n = 205). Main Outcomes and Measures: The main outcome was plasma p-tau181 and p-tau231 levels measured with in-house single molecule array assays. The Mini-Mental State Examination (MMSE) was used to measure cognition. Results: Among this cohort of 987 patients (512 men [51.9%]; mean [SD] age, 70.0 [8.8] years), patients with DLB did not differ significantly regarding age, sex, or years of education from those in the AD group, but the DLB group was older than the HC group and included more men than the AD and HC groups. Baseline concentrations of plasma p-tau181 and p-tau231 in patients with DLB were significantly higher than those in the HC group but lower than in the AD group and similar to the Parkinson disease group. Higher plasma concentrations of both p-tau markers were found in a subgroup of patients with DLB with abnormal CSF amyloid-β42 levels compared with those with normal levels (difference in the groups in p-tau181, -3.61 pg/mL; 95% CI, -5.43 to -1.79 pg/mL; P =.049; difference in the groups in p-tau231, -2.51 pg/mL; 95% CI, -3.63 to -1.39 pg/mL; P =.02). There was no difference between p-tau181 level and p-tau231 level across confirmed AD pathologic characteristcs based on reduced Aβ42 level in CSF in individuals with DLB. In DLB, a significant association was found between higher plasma p-tau181 and p-tau231 levels and lower MMSE scores at baseline (for p-tau181, -0.092 MMSE points; 95% CI, -0.12 to -0.06 MMSE points; P =.001; for p-tau231, -0.16 MMSE points; 95% CI, -0.21 to -0.12 MMSE points; P <.001), as well as more rapid MMSE decline over time. Plasma p-tau181 level was associated with a decrease of -0.094 MMSE points per year (95% CI, -0.144 to -0.052 MMSE points; P =.02), whereas plasma p-tau231 level was associated with an annual decrease of -0.130 MMSE points (95% CI, -0.201 to -0.071 MMSE points; P =.02), after adjusting for sex and age. Conclusions and Relevance: This study suggests that plasma p-tau181 and p-tau231 levels may be used as cost-effective and accessible biomarkers to assess cognitive decline in individuals with DLB..

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