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Original research
Use of plasma biomarkers for AT(N) classification of neurodegenerative dementias
  1. Daniel Alcolea1,2,
  2. Constance Delaby1,3,
  3. Laia Muñoz1,2,
  4. Soraya Torres1,2,
  5. Teresa Estellés1,2,
  6. Nuole Zhu1,2,
  7. Isabel Barroeta1,2,
  8. María Carmona-Iragui1,2,
  9. Ignacio Illán-Gala1,2,
  10. Miguel Ángel Santos-Santos1,2,
  11. Miren Altuna1,2,
  12. Isabel Sala1,2,
  13. Mª Belén Sánchez-Saudinós1,2,
  14. Laura Videla1,2,4,
  15. Sílvia Valldeneu1,2,
  16. Andrea Subirana1,2,
  17. Jordi Pegueroles1,2,
  18. Christophe Hirtz3,
  19. Jérôme Vialaret3,
  20. Sylvain Lehmann3,
  21. Thomas K Karikari5,6,
  22. Nicholas J Ashton5,7,8,9,
  23. Kaj Blennow5,6,
  24. Henrik Zetterberg5,8,10,11,
  25. Olivia Belbin1,2,
  26. Rafael Blesa1,2,
  27. Jordi Clarimón1,2,
  28. Juan Fortea1,2,
  29. Alberto Lleó1,2
  1. 1 Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Catalunya, Spain
  2. 2 Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain
  3. 3 IRMB, INM, Université de Montpellier, INSERM, CHU de Montpellier, Laboratoire de Biochimie-Protéomique clinique, Montpellier, France
  4. 4 Fundación Catalana Síndrome Down, Barcelona, Catalunya, Spain
  5. 5 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg Sahlgrenska Academy, Mölndal, Sweden
  6. 6 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  7. 7 Department of Old Age Psychiatry, King's College London Institute of Psychiatry Psychology and Neuroscience, London, UK
  8. 8 Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
  9. 9 NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia, South London and Maudsley NHS Foundation, London, UK
  10. 10 Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
  11. 11 UK Dementia Research Institute, UCL, London, UK
  1. Correspondence to Dr Daniel Alcolea, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Catalunya, Spain; dalcolea{at}santpau.cat

Abstract

Objectives All categories included in the AT(N) classification can now be measured in plasma. However, their agreement with cerebrospinal fluid (CSF) markers is not fully established. A blood signature to generate the AT(N) classification would facilitate early diagnosis of patients with Alzheimer’s disease (AD) through an easy and minimally invasive approach.

Methods We measured Aβ, pTau181 and neurofilament light (NfL) in 150 plasma samples of the Sant Pau Initiative on Neurodegeneration cohort including patients with mild cognitive impairment, AD dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal participants. We classified participants in the AT(N) categories according to CSF biomarkers and studied the diagnostic value of plasma biomarkers within each category individually and in combination.

Results The plasma Aβ composite, pTau181 and NfL yielded areas under the curve (AUC) of 0.75, 0.78 and 0.88 to discriminate positive and negative participants in their respective A, T and N categories. The combination of all three markers did not outperform pTau181 alone (AUC=0.81) to discriminate A+T+ from A–T– participants. There was a moderate correlation between plasma Aβ composite and CSF Aβ1–42/Aβ1–40 (Rho=−0.5, p<0.001) and between plasma pTau181 and CSF pTau181 in the entire cohort (Rho=0.51, p<0.001). NfL levels in plasma showed high correlation with those in CSF (Rho=0.78, p<0.001).

Conclusions Plasma biomarkers are useful to detect the AT(N) categories, and their use can differentiate patients with pathophysiological evidence of AD. A blood AT(N) signature may facilitate early diagnosis and follow-up of patients with AD through an easy and minimally invasive approach.

  • csf
  • amyloid

Data availability statement

Raw anonymised data and code for statistical analysis are available upon reasonable request. All requests should be sent to the corresponding author detailing the study hypothesis and statistical analysis plan. The steering committee of this study will decide whether data/code sharing is appropriate based on the novelty and scientific rigor of the proposal. All applicants will be asked to sign a data access agreement.

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Data availability statement

Raw anonymised data and code for statistical analysis are available upon reasonable request. All requests should be sent to the corresponding author detailing the study hypothesis and statistical analysis plan. The steering committee of this study will decide whether data/code sharing is appropriate based on the novelty and scientific rigor of the proposal. All applicants will be asked to sign a data access agreement.

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Footnotes

  • Twitter @SantPauMemory

  • Contributors DA and AL designed the study. DA, CD, LM, ST, TE, NZ, IB, MC-I, II-G, MAS-S, MA, IS, MBS-S, LV, SV, JP, AS, CH, JV, KB, HZ, JF and AL acquired data relevant for the study. DA, SL, TKK, NA, KB, HZ, JC, JF and AL contributed vital reagents/tools/patents. DA, MC-I, MAS-S, SL, KB, HZ, OB, RB, JC, JF and AL obtained funding for the study. DA and CD performed statistical analysis. DA, CD and AL contributed in analysis and interpretation of data. DA and AL participated in study supervision or coordination. CD, DA and AL drafted the first version of the manuscript. All authors revised the manuscript for content and provided critical feedback.

  • Funding This study was supported by the Fondo de Investigaciones Sanitario (FIS), Instituto de Salud Carlos III (PI14/01126 and PI17/01019 to JF, PI13/01532 and PI16/01825 to RB, PI18/00335 to MC-I, PI18/00435 and INT19/00016 to DA, PI14/1561 and PI17/01896 to AL) and the CIBERNED programme (Programme 1, Alzheimer Disease to AL), jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, “Una manera de hacer Europa”. This work was also supported by Generalitat de Catalunya (2017-SGR-547, SLT006/17/125 to DA, SLT006/17/119 to JF, SLT002/16/408 to AL) and “Marató TV3” foundation grants 20141210 to JF, 044412 to RB and 20142610 to AL. TKK is supported by the BrightFocus Foundation (#A2020812F), the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-930627), the Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), the Swedish Dementia Foundation (Demensförbundet), the Swedish Parkinson’s Foundation, the Gamla Tjänarinnor Foundation, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Agneta Prytz-Folkes & Gösta Folkes Foundation (#2020-00124), the Gun and Bertil Stohnes Foundation and the Anna Lisa and Brother Björnsson’s Foundation. KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#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) and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). HZ 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), USA (#201809-2016862), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE) and the UK Dementia Research Institute at UCL.

  • Competing interests DA is employed by Hospital de la Santa Creu i Sant Pau and received research grants from Pla Estratègic de Recerca i Innovació en Salut (PERIS SLT006/17/125), and from Instituto de Salud Carlos III (PI18/00435 and INT19/00016). He participated in advisory boards from Fujirebio-Europe and Roche Diagnostics and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Esteve and from Krka Farmacéutica S.L. CD is employed by Université de Montpellier and CHU de Montpellier. LM is employed by Biomedical Research Institute Sant Pau. ST is employed by Biomedical Research Institute Sant Pau. TE is employed by Biomedical Research Institute Sant Pau. Declarations of interest: Dr Estellés is funded by a 'Río Hortega' research grant from the Institute of Health Carlos III. NZ is employed by Hospital de la Santa Creu i Sant Pau. IB is employed by Hospital de la Santa Creu i Sant Pau. MC-I is employed by Hospital de la Santa Creu i Sant Pau. II-G is supported by the Global Brain Health Institute (Atlantic Fellow for Equity in Brain Health and pilot award for global brain health leaders GBHI ALZ UK-21-720973) and the 'Juan Rodés' grant from the Institute of Health Carlos III (JR20/00018). MAS-S is employed by Hospital de la Santa Creu i Sant Pau. He is funded by a 'Juan Rodés' research grant from the Institute of Health Carlos III. MA is employed by Biomedical Research Institute Sant Pau. Dr Altuna is funded by a 'Río Hortega' research grant from the Institute of Health Carlos III. IS is employed by Hospital de la Santa Creu i Sant Pau. MBS-S is employed by Biomedical Research Institute Sant Pau. LV is employed by Fundació Catalana Síndrome de Down. SV is employed by Biomedical Research Institute Sant Pau. AS is employed by Biomedical Research Institute Sant Pau. JP is employed by Biomedical Research Institute Sant Pau. CH is employed by Université de Montpellier et CHU de Montpellier. JV is employed by CHU de Montpellier. SL is employed by the University and the Hospital of Montpellier. He participated in advisory boards from Fujirebio-Europe and Roche. TKK is employed by the University of Gothenburg. NA is employed by the University of Gothenburg. KB is employed by Gothenburg University and Sahlgrenska University Hospital. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. HZ is employed by the University of Gothenburg, Sahlgrenska University Hospital and University College London. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. OB is employed by Biomedical Research Institute Sant Pau. Dr Belbin is funded by a 'Miguel Servet' research grant from the Institute of Health Carlos III. RB is employed by Hospital de la Santa Creu i Sant Pau and received research grants from Institute of Health Carlos III, Fundació Bancària Obra Social La Caixa and Fundació La Marató de TV3. He participated in advisory boards from Lilly and Nutricia, and he received speaker honoraria and travel funding from Novartis and Nutricia. JC is employed by Biomedical Research Institute Sant Pau and received research grants from Generalitat de Catalunya and from Institute of Health Carlos III. JF is employed by Hospital de la Santa Creu i Sant Pau and received research grants from Institute of Health Carlos III, Fundació La Marató de TV3, and Pla Estratègic de Recerca i Innovació en Salut (PERIS). AL is employed by Hospital de la Santa Creu i Sant Pau and received research grants from CIBERNED, Institute of Health Carlos III and Fundación BBVA. He participated in advisory boards from Fujirebio-Europe, Nutricia, Biogen, and received speaker honoraria from Lilly.

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