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

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)409
JournalFrontiers in Aging Neuroscience
Volume10
DOIs
Publication statusPublished - 2018

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Amyloid
Positron-Emission Tomography
Cerebrospinal Fluid
Blood Proteins
Biomarkers
Alzheimer Disease
Pathology
Immunoassay
Proteomics
Dementia
Apolipoprotein C-II
Clusterin
Apoprotein(a)
flutemetamol
Complement C3
Ceruloplasmin
Apolipoprotein A-I
Tandem Mass Spectrometry
Cognitive Dysfunction
Liquid Chromatography

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Westwood, S., Baird, A. L., Hye, A., Ashton, N. J., Nevado-Holgado, A. J., Anand, S. N., ... 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

Plasma Protein Biomarkers for the Prediction of CSF Amyloid and Tau and [18F]-Flutemetamol PET Scan Result. / Westwood, Sarah; Baird, Alison L; Hye, Abdul; Ashton, Nicholas J; Nevado-Holgado, Alejo J; Anand, Sneha N; Liu, Benjamine; Newby, Danielle; Bazenet, Chantal; Kiddle, Steven J; Ward, Malcolm; Newton, Ben; Desai, Keyur; Tan Hehir, Cristina; Zanette, Michelle; Galimberti, Daniela; Parnetti, Lucilla; Lleó, Alberto; Baker, Susan; Narayan, Vaibhav A; van der Flier, Wiesje M; Scheltens, Philip; Teunissen, Charlotte E; Visser, Pieter Jelle; Lovestone, Simon.

In: Frontiers in Aging Neuroscience, Vol. 10, 2018, p. 409.

Research output: Contribution to journalArticle

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
Westwood, Sarah ; Baird, Alison L ; Hye, Abdul ; Ashton, Nicholas J ; Nevado-Holgado, Alejo J ; Anand, Sneha N ; Liu, Benjamine ; Newby, Danielle ; Bazenet, Chantal ; Kiddle, Steven J ; Ward, Malcolm ; Newton, Ben ; Desai, Keyur ; Tan Hehir, Cristina ; Zanette, Michelle ; Galimberti, Daniela ; Parnetti, Lucilla ; Lleó, Alberto ; Baker, Susan ; Narayan, Vaibhav A ; van der Flier, Wiesje M ; Scheltens, Philip ; Teunissen, Charlotte E ; Visser, Pieter Jelle ; Lovestone, Simon. / Plasma Protein Biomarkers for the Prediction of CSF Amyloid and Tau and [18F]-Flutemetamol PET Scan Result. In: Frontiers in Aging Neuroscience. 2018 ; Vol. 10. pp. 409.
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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",
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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

C2 - 30618716

VL - 10

SP - 409

JO - Frontiers in Aging Neuroscience

JF - Frontiers in Aging Neuroscience

SN - 1663-4365

ER -