Plasma Protein Biomarkers for the Prediction of CSF Amyloid and Tau and [18F]-Flutemetamol PET Scan Result

Sarah Westwood; Alison L Baird; Abdul Hye; Nicholas J Ashton; Alejo J Nevado-Holgado; Sneha N Anand; Benjamine Liu; Danielle Newby; Chantal Bazenet; Steven J Kiddle; Malcolm Ward; Ben Newton; Keyur Desai; Cristina Tan Hehir; Michelle Zanette; Daniela Galimberti; Lucilla Parnetti; Alberto Lleó; Susan Baker; Vaibhav A Narayan; Wiesje M van der Flier; Philip Scheltens; Charlotte E Teunissen; Pieter Jelle Visser; Simon Lovestone

doi:10.3389/fnagi.2018.00409

Plasma Protein Biomarkers for the Prediction of CSF Amyloid and Tau and [18F]-Flutemetamol PET Scan Result

Sarah Westwood
, Alison L Baird
, Abdul Hye
, Nicholas J Ashton
, Alejo J Nevado-Holgado
, Sneha N Anand
, Benjamine Liu
, Danielle Newby
, Chantal Bazenet
, Steven J Kiddle
, Malcolm Ward
, Ben Newton
, Keyur Desai
, Cristina Tan Hehir
, Michelle Zanette
, Daniela Galimberti
, Lucilla Parnetti
, Alberto Lleó
, Susan Baker
, Vaibhav A Narayan

Wiesje M van der Flier, Philip Scheltens, Charlotte E Teunissen, Pieter Jelle Visser, Simon Lovestone

Department of Psychiatry, Division of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
Biomedical Research Unit for Dementia, NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust, London, United Kingdom.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kigndom.
MRC Biostatistics Unit, Cambridge Biomedical Campus, Cambridge Institute of Public Health, University of Cambridge, Cambridge, United Kingdom.
Proteomics Facility, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
GE Healthcare Life Sciences Core Imaging, London, United Kingdom.
Biosciences, GE Global Research, Niskayuna, NY, United States.
GE Healthcare Life Sciences Core Imaging, Marlborough, MA, United States.
Hematology Unit, Anemia Physiopathology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Center for Memory Disorders and Laboratory of Clinical Neurochemistry, Neurology Clinic, University of Perugia, Perugia, Italy.
Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
Janssen Neuroscience Research & Development, Titusville, NJ, United States.

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background: Blood biomarkers may aid in recruitment to clinical trials of Alzheimer's disease (AD) modifying therapeutics by triaging potential trials participants for amyloid positron emission tomography (PET) or cerebrospinal fluid (CSF) Aβ and tau tests. Objective: To discover a plasma proteomic signature associated with CSF and PET measures of AD pathology. Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based proteomics were performed in plasma from participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD, recruited to the Amsterdam Dementia Cohort, stratified by CSF Tau/Aβ42 (n = 50). Technical replication and independent validation were performed by immunoassay in plasma from SCD, MCI, and AD participants recruited to the Amsterdam Dementia Cohort with CSF measures (n = 100), MCI participants enrolled in the GE067-005 study with [18F]-Flutemetamol PET amyloid measures (n = 173), and AD, MCI and cognitively healthy participants from the EMIF 500 study with CSF Aβ42 measurements (n = 494). Results: 25 discovery proteins were nominally associated with CSF Tau/Aβ42 (P < 0.05) with associations of ficolin-2 (FCN2), apolipoprotein C-IV and fibrinogen β chain confirmed by immunoassay (P < 0.05). In the GE067-005 cohort, FCN2 was nominally associated with PET amyloid (P < 0.05) replicating the association with CSF Tau/Aβ42. There were nominally significant associations of complement component 3 with PET amyloid, and apolipoprotein(a), apolipoprotein A-I, ceruloplasmin, and PPY with MCI conversion to AD (all P < 0.05). In the EMIF 500 cohort FCN2 was trending toward a significant relationship with CSF Aβ42 (P ≈ 0.05), while both A1AT and clusterin were nominally significantly associated with CSF Aβ42 (both P < 0.05). Conclusion: Associations of plasma proteins with multiple measures of AD pathology and progression are demonstrated. To our knowledge this is the first study to report an association of FCN2 with AD pathology. Further testing of the proteins in larger independent cohorts will be important.

Original language	English
Pages (from-to)	409
Journal	Frontiers in aging neuroscience
Volume	10
DOIs	https://doi.org/10.3389/fnagi.2018.00409
Publication status	Published - 2018

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Plasma-protein-biomarkers-for-the-prediction-of-csf-amyloid-and-tau-and-18f-flutemetamol-pet-scan-result.pdfFinal published version, 1.2 MBLicence: Taverne

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Westwood, S., Baird, A. L., Hye, A., Ashton, N. J., Nevado-Holgado, A. J., Anand, S. N., Liu, B., Newby, D., Bazenet, C., Kiddle, S. J., Ward, M., Newton, B., Desai, K., Tan Hehir, C., Zanette, M., Galimberti, D., Parnetti, L., Lleó, A., Baker, S., ... Lovestone, S. (2018). Plasma Protein Biomarkers for the Prediction of CSF Amyloid and Tau and [18F]-Flutemetamol PET Scan Result. Frontiers in aging neuroscience, 10, 409. https://doi.org/10.3389/fnagi.2018.00409

@article{796d707a74294289abb8098fe6d836c7,

title = "Plasma Protein Biomarkers for the Prediction of CSF Amyloid and Tau and [18F]-Flutemetamol PET Scan Result",

abstract = "Background: Blood biomarkers may aid in recruitment to clinical trials of Alzheimer's disease (AD) modifying therapeutics by triaging potential trials participants for amyloid positron emission tomography (PET) or cerebrospinal fluid (CSF) Aβ and tau tests. Objective: To discover a plasma proteomic signature associated with CSF and PET measures of AD pathology. Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based proteomics were performed in plasma from participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD, recruited to the Amsterdam Dementia Cohort, stratified by CSF Tau/Aβ42 (n = 50). Technical replication and independent validation were performed by immunoassay in plasma from SCD, MCI, and AD participants recruited to the Amsterdam Dementia Cohort with CSF measures (n = 100), MCI participants enrolled in the GE067-005 study with [18F]-Flutemetamol PET amyloid measures (n = 173), and AD, MCI and cognitively healthy participants from the EMIF 500 study with CSF Aβ42 measurements (n = 494). Results: 25 discovery proteins were nominally associated with CSF Tau/Aβ42 (P < 0.05) with associations of ficolin-2 (FCN2), apolipoprotein C-IV and fibrinogen β chain confirmed by immunoassay (P < 0.05). In the GE067-005 cohort, FCN2 was nominally associated with PET amyloid (P < 0.05) replicating the association with CSF Tau/Aβ42. There were nominally significant associations of complement component 3 with PET amyloid, and apolipoprotein(a), apolipoprotein A-I, ceruloplasmin, and PPY with MCI conversion to AD (all P < 0.05). In the EMIF 500 cohort FCN2 was trending toward a significant relationship with CSF Aβ42 (P ≈ 0.05), while both A1AT and clusterin were nominally significantly associated with CSF Aβ42 (both P < 0.05). Conclusion: Associations of plasma proteins with multiple measures of AD pathology and progression are demonstrated. To our knowledge this is the first study to report an association of FCN2 with AD pathology. Further testing of the proteins in larger independent cohorts will be important.",

author = "Sarah Westwood and Baird, \{Alison L\} and Abdul Hye and Ashton, \{Nicholas J\} and Nevado-Holgado, \{Alejo J\} and Anand, \{Sneha N\} and Benjamine Liu and Danielle Newby and Chantal Bazenet and Kiddle, \{Steven J\} and Malcolm Ward and Ben Newton and Keyur Desai and \{Tan Hehir\}, Cristina and Michelle Zanette and Daniela Galimberti and Lucilla Parnetti and Alberto Lle{\'o} and Susan Baker and Narayan, \{Vaibhav A\} and \{van der Flier\}, \{Wiesje M\} and Philip Scheltens and Teunissen, \{Charlotte E\} and Visser, \{Pieter Jelle\} and Simon Lovestone",

year = "2018",

doi = "10.3389/fnagi.2018.00409",

language = "English",

volume = "10",

pages = "409",

journal = "Frontiers in aging neuroscience",

publisher = "Frontiers Media SA",

}

Westwood, S, Baird, AL, Hye, A, Ashton, NJ, Nevado-Holgado, AJ, Anand, SN, Liu, B, Newby, D, Bazenet, C, Kiddle, SJ, Ward, M, Newton, B, Desai, K, Tan Hehir, C, Zanette, M, Galimberti, D, Parnetti, L, Lleó, A, Baker, S, Narayan, VA, van der Flier, WM , Scheltens, P , Teunissen, CE , Visser, PJ & Lovestone, S 2018, 'Plasma Protein Biomarkers for the Prediction of CSF Amyloid and Tau and [18F]-Flutemetamol PET Scan Result', Frontiers in aging neuroscience, vol. 10, pp. 409. https://doi.org/10.3389/fnagi.2018.00409

TY - JOUR

T1 - Plasma Protein Biomarkers for the Prediction of CSF Amyloid and Tau and [18F]-Flutemetamol PET Scan Result

AU - Westwood, Sarah

AU - Baird, Alison L

AU - Hye, Abdul

AU - Ashton, Nicholas J

AU - Nevado-Holgado, Alejo J

AU - Anand, Sneha N

AU - Liu, Benjamine

AU - Newby, Danielle

AU - Bazenet, Chantal

AU - Kiddle, Steven J

AU - Ward, Malcolm

AU - Newton, Ben

AU - Desai, Keyur

AU - Tan Hehir, Cristina

AU - Zanette, Michelle

AU - Galimberti, Daniela

AU - Parnetti, Lucilla

AU - Lleó, Alberto

AU - Baker, Susan

AU - Narayan, Vaibhav A

AU - van der Flier, Wiesje M

AU - Scheltens, Philip

AU - Teunissen, Charlotte E

AU - Visser, Pieter Jelle

AU - Lovestone, Simon

PY - 2018

Y1 - 2018

N2 - Background: Blood biomarkers may aid in recruitment to clinical trials of Alzheimer's disease (AD) modifying therapeutics by triaging potential trials participants for amyloid positron emission tomography (PET) or cerebrospinal fluid (CSF) Aβ and tau tests. Objective: To discover a plasma proteomic signature associated with CSF and PET measures of AD pathology. Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based proteomics were performed in plasma from participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD, recruited to the Amsterdam Dementia Cohort, stratified by CSF Tau/Aβ42 (n = 50). Technical replication and independent validation were performed by immunoassay in plasma from SCD, MCI, and AD participants recruited to the Amsterdam Dementia Cohort with CSF measures (n = 100), MCI participants enrolled in the GE067-005 study with [18F]-Flutemetamol PET amyloid measures (n = 173), and AD, MCI and cognitively healthy participants from the EMIF 500 study with CSF Aβ42 measurements (n = 494). Results: 25 discovery proteins were nominally associated with CSF Tau/Aβ42 (P < 0.05) with associations of ficolin-2 (FCN2), apolipoprotein C-IV and fibrinogen β chain confirmed by immunoassay (P < 0.05). In the GE067-005 cohort, FCN2 was nominally associated with PET amyloid (P < 0.05) replicating the association with CSF Tau/Aβ42. There were nominally significant associations of complement component 3 with PET amyloid, and apolipoprotein(a), apolipoprotein A-I, ceruloplasmin, and PPY with MCI conversion to AD (all P < 0.05). In the EMIF 500 cohort FCN2 was trending toward a significant relationship with CSF Aβ42 (P ≈ 0.05), while both A1AT and clusterin were nominally significantly associated with CSF Aβ42 (both P < 0.05). Conclusion: Associations of plasma proteins with multiple measures of AD pathology and progression are demonstrated. To our knowledge this is the first study to report an association of FCN2 with AD pathology. Further testing of the proteins in larger independent cohorts will be important.

AB - Background: Blood biomarkers may aid in recruitment to clinical trials of Alzheimer's disease (AD) modifying therapeutics by triaging potential trials participants for amyloid positron emission tomography (PET) or cerebrospinal fluid (CSF) Aβ and tau tests. Objective: To discover a plasma proteomic signature associated with CSF and PET measures of AD pathology. Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based proteomics were performed in plasma from participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD, recruited to the Amsterdam Dementia Cohort, stratified by CSF Tau/Aβ42 (n = 50). Technical replication and independent validation were performed by immunoassay in plasma from SCD, MCI, and AD participants recruited to the Amsterdam Dementia Cohort with CSF measures (n = 100), MCI participants enrolled in the GE067-005 study with [18F]-Flutemetamol PET amyloid measures (n = 173), and AD, MCI and cognitively healthy participants from the EMIF 500 study with CSF Aβ42 measurements (n = 494). Results: 25 discovery proteins were nominally associated with CSF Tau/Aβ42 (P < 0.05) with associations of ficolin-2 (FCN2), apolipoprotein C-IV and fibrinogen β chain confirmed by immunoassay (P < 0.05). In the GE067-005 cohort, FCN2 was nominally associated with PET amyloid (P < 0.05) replicating the association with CSF Tau/Aβ42. There were nominally significant associations of complement component 3 with PET amyloid, and apolipoprotein(a), apolipoprotein A-I, ceruloplasmin, and PPY with MCI conversion to AD (all P < 0.05). In the EMIF 500 cohort FCN2 was trending toward a significant relationship with CSF Aβ42 (P ≈ 0.05), while both A1AT and clusterin were nominally significantly associated with CSF Aβ42 (both P < 0.05). Conclusion: Associations of plasma proteins with multiple measures of AD pathology and progression are demonstrated. To our knowledge this is the first study to report an association of FCN2 with AD pathology. Further testing of the proteins in larger independent cohorts will be important.

U2 - 10.3389/fnagi.2018.00409

DO - 10.3389/fnagi.2018.00409

M3 - Article

VL - 10

SP - 409

JO - Frontiers in aging neuroscience

JF - Frontiers in aging neuroscience

ER -

Plasma Protein Biomarkers for the Prediction of CSF Amyloid and Tau and [18F]-Flutemetamol PET Scan Result

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