Abstract
Original language | English |
---|---|
Article number | e12456 |
Journal | Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring |
Volume | 15 |
Issue number | 3 |
DOIs | |
Publication status | Published - 1 Jul 2023 |
Keywords
- Alzheimer's disease
- CSF
- THOP1
- biomarkers
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In: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring, Vol. 15, No. 3, e12456, 01.07.2023.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Thimet oligopeptidase as a potential CSF biomarker for Alzheimer's disease
T2 - A cross-platform validation study
AU - Hok-A-Hin, Yanaika S.
AU - Bolsewig, Katharina
AU - Ruiters, Daimy N.
AU - Lleó, Alberto
AU - Alcolea, Daniel
AU - Lemstra, Afina W.
AU - van der Flier, Wiesje M.
AU - Teunissen, Charlotte E.
AU - del Campo, Marta
N1 - Funding Information: Research of Neurochemistry lab and Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam. The chair of Wiesje van der Flier is supported by the Pasman Stichting. The clinical database structure was developed with funding from Stichting Dioraphte. This project was supported by Alzheimer Nederland (PRIDE project; WE.03-2018-05). M.C. is supported by the attraction talent fellowship of Comunidad de Madrid (2018-T2/BMD-11885) and “PROYECTOS I+D+I – 2020”- Retos de investigación from the Ministerio Español de Ciencia e innovación (PID2020-115613RA-I00). K.B. is supported by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE). The SPIN cohort was supported by the Fondo de Investigaciones Sanitario (FIS), Instituto de Salud Carlos III, the CIBERNED program (Program 1, Alzheimer Disease to AL), jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, “Una manera de hacer Europa”, National Institutes of Health, Generalitat de Catalunya and “Marató TV3” foundation. Funding Information: Y.S.H., K.B., D.R., A.W.L., and M.C. report no conflicts of interest. D.A. participated in advisory boards from Fujirebio‐Europe and Roche Diagnostics and received speaker honoraria from Fujirebio‐Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U., and Esteve Pharmaceuticals S.A., D.A. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). A.L. participated in advisory boards from Fujirebio‐Europe, Grifols, Eisai, Novartis, Roche Diagnostics, Otsuka Pharmaceutical, Nutricia, Zambón S.A.U., and Biogen, and received speaker honoraria from Eli Lilly, Biogen, KRKA, and Zambon. A.L. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). Research programs of W.F. have been funded by ZonMW, NWO, EU‐FP7, EU‐JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes‐Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis‐NL, Life‐MI, AVID, Roche BV, Fujifilm, Eisai, and Combinostics. W.F. holds the Pasman chair. W.F. is recipient of ABOARD, which is a public‐private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). W.F. has been an invited speaker at Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, NovoNordisk, and European Brain Council. W.F. is a consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. W.F. participated in advisory boards of Biogen MA Inc, Roche, and Eli Lilly. All funding is paid to her institution. W.F. is member of the steering committee of PAVE and Think Brain Health. W.F. was associate editor of in 2020/2021. W.F. is associate editor at . C.T. has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly, and performed contract research or received grants from AC‐Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama, and Vivoryon. C.T. serves on editorial boards of /Springer, and is editor of a Neuromethods book (Springer). She had speaker contracts for Roche, Grifols, and Novo Nordisk. Author disclosures are available in the supporting information . Alzheimer's Research & Therapy Brain Medidact Neurologie , Alzheimer's Research & Therapy and Neurology: Neuroimmunology & Neuroinflammation Funding Information: Research of Neurochemistry lab and Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam. The chair of Wiesje van der Flier is supported by the Pasman Stichting. The clinical database structure was developed with funding from Stichting Dioraphte. This project was supported by Alzheimer Nederland (PRIDE project; WE.03‐2018‐05). M.C. is supported by the attraction talent fellowship of Comunidad de Madrid (2018‐T2/BMD‐11885) and “PROYECTOS I+D+I – 2020”‐ Retos de investigación from the Ministerio Español de Ciencia e innovación (PID2020‐115613RA‐I00). K.B. is supported by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 860197 (MIRIADE). The SPIN cohort was supported by the Fondo de Investigaciones Sanitario (FIS), Instituto de Salud Carlos III, the CIBERNED program (Program 1, Alzheimer Disease to AL), jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, “Una manera de hacer Europa”, National Institutes of Health, Generalitat de Catalunya and “Marató TV3” foundation. Publisher Copyright: © 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.
PY - 2023/7/1
Y1 - 2023/7/1
N2 - INTRODUCTION: Our previous antibody-based cerebrospinal fluid (CSF) proteomics study showed that Thimet oligopeptidase (THOP1), an amyloid beta (Aβ) neuropeptidase, was increased in mild cognitive impairment with amyloid pathology (MCI-Aβ+) and Alzheimer's disease (AD) dementia compared with controls and dementia with Lewy bodies (DLB), highlighting the potential of CSF THOP1 as an early specific biomarker for AD. We aimed to develop THOP1 immunoassays for large-scale analysis and validate our proteomics findings in two independent cohorts. METHODS: We developed in-house CSF THOP1 immunoassays on automated Ella and Simoa platforms. The performance of the different assays were compared using Passing–Bablok regression analysis in a subset of CSF samples from the discovery cohort (n = 72). Clinical validation was performed in two independent cohorts (cohort 1: n = 200; cohort 2: n = 165) using the Ella platform. RESULTS: THOP1 concentrations moderately correlated between proteomics analysis and our novel assays (Rho > 0.580). In both validation cohorts, CSF THOP1 was increased in MCI-Aβ+ (>1.3-fold) and AD (>1.2-fold) compared with controls; and between MCI-Aβ+ and DLB (>1.2-fold). Higher THOP1 concentrations were detected in AD compared with DLB only when both cohorts were analyzed together. In both cohorts, THOP1 correlated with CSF total tau (t-tau), phosphorylated tau (p-tau), and Aβ40 (Rho > 0.540) but not Aβ42. DISCUSSION: Validation of our proteomics findings underpins the potential of CSF THOP1 as an early specific biomarker associated with AD pathology. The use of antibody-based platforms in both the discovery and validation phases facilitated the translation of proteomics findings, providing an additional workflow that may accelerate the development of biofluid-based biomarkers.
AB - INTRODUCTION: Our previous antibody-based cerebrospinal fluid (CSF) proteomics study showed that Thimet oligopeptidase (THOP1), an amyloid beta (Aβ) neuropeptidase, was increased in mild cognitive impairment with amyloid pathology (MCI-Aβ+) and Alzheimer's disease (AD) dementia compared with controls and dementia with Lewy bodies (DLB), highlighting the potential of CSF THOP1 as an early specific biomarker for AD. We aimed to develop THOP1 immunoassays for large-scale analysis and validate our proteomics findings in two independent cohorts. METHODS: We developed in-house CSF THOP1 immunoassays on automated Ella and Simoa platforms. The performance of the different assays were compared using Passing–Bablok regression analysis in a subset of CSF samples from the discovery cohort (n = 72). Clinical validation was performed in two independent cohorts (cohort 1: n = 200; cohort 2: n = 165) using the Ella platform. RESULTS: THOP1 concentrations moderately correlated between proteomics analysis and our novel assays (Rho > 0.580). In both validation cohorts, CSF THOP1 was increased in MCI-Aβ+ (>1.3-fold) and AD (>1.2-fold) compared with controls; and between MCI-Aβ+ and DLB (>1.2-fold). Higher THOP1 concentrations were detected in AD compared with DLB only when both cohorts were analyzed together. In both cohorts, THOP1 correlated with CSF total tau (t-tau), phosphorylated tau (p-tau), and Aβ40 (Rho > 0.540) but not Aβ42. DISCUSSION: Validation of our proteomics findings underpins the potential of CSF THOP1 as an early specific biomarker associated with AD pathology. The use of antibody-based platforms in both the discovery and validation phases facilitated the translation of proteomics findings, providing an additional workflow that may accelerate the development of biofluid-based biomarkers.
KW - Alzheimer's disease
KW - CSF
KW - THOP1
KW - biomarkers
UR - http://www.scopus.com/inward/record.url?scp=85166007931&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/dad2.12456
DO - https://doi.org/10.1002/dad2.12456
M3 - Article
C2 - 37502019
SN - 2352-8729
VL - 15
JO - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
JF - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
IS - 3
M1 - e12456
ER -