Abstract
Introduction: Biomarkers that reflect pathologic processes affecting neuronal function during preclinical and early stages of Alzheimer's disease (AD) are needed to aid drug development. Methods: A targeted, stable isotope, quantitative mass spectrometry-based investigation of longitudinal changes in concentrations of previously identified candidate biomarkers was performed in cerebrospinal fluid (CSF) of Alzheimer's Disease Neuroimaging Initiative participants who were classified as cognitively normal (CN; n = 76) or with mild cognitive impairment (MCI; n = 111) at baseline. Results: Of the candidate biomarkers, the CSF concentration of neuronal pentraxin 2 (NPTX2), a protein involved in synaptic function, exhibited rates of change that were significantly different between three comparison groups (i.e., CN vs. MCI participants; AD pathology positive vs. negative defined by phosphorylated tau181/amyloid beta1-42 ratio; and clinical progressors vs. non-progressors). The rate of change of NPTX2 also significantly correlated with declining cognition. Discussion: CSF NPTX2 concentration is a strong prognostic biomarker candidate of accelerated cognitive decline with potential use as a therapeutic target.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1976-1987 |
| Number of pages | 12 |
| Journal | Alzheimer's and Dementia |
| Volume | 17 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2021 |
Keywords
- Alzheimer's disease
- dementia
- longitudinal cerebrospinal fluid
- mild cognitive impairment
- neuropathology
- prognostic biomarker
- stable isotope-based quantitative mass spectrometry
ASJC Scopus subject areas
- Epidemiology
- Health Policy
- Developmental Neuroscience
- Clinical Neurology
- Geriatrics and Gerontology
- Cellular and Molecular Neuroscience
- Psychiatry and Mental health
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Longitudinal CSF proteomics identifies NPTX2 as a prognostic biomarker of Alzheimer's disease. / Alzheimer’s Disease Neuroimaging Initiative (ADNI); Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium, Longitudinal CSF Proteomics Project Team.
In: Alzheimer's and Dementia, Vol. 17, No. 12, 12.2021, p. 1976-1987.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Longitudinal CSF proteomics identifies NPTX2 as a prognostic biomarker of Alzheimer's disease
AU - Alzheimer’s Disease Neuroimaging Initiative (ADNI)
AU - Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium, Longitudinal CSF Proteomics Project Team
AU - Libiger, Ondrej
AU - Shaw, Leslie M.
AU - Watson, Mark H.
AU - Nairn, Angus C.
AU - Umaña, Kelly L.
AU - Biarnes, Michael C.
AU - Canet-Avilés, Rosa M.
AU - Jack, Clifford R.
AU - Breton, Yannick André
AU - Cortes, Laetitia
AU - Chelsky, Daniel
AU - Spellman, Daniel S.
AU - Baker, Susan A.
AU - Raghavan, Nandini
AU - Potter, William Z.
N1 - Funding Information: We would additionally like to acknowledge ADNI for the cerebrospinal fluid samples and data analyzed in this study. Data used in the preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). The ADNI was launched in 2003 as a public–private partnership, led by Principal Investigator Michael W. Weiner, M.D. The primary goal of the ADNI has been to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of MCI and early Alzheimer's disease. For up‐to‐date information, see www.adni‐info.org . Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U19 AG024904) and DOD ADNI (Department of Defense award number W81XWH‐12‐2‐0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‐Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‐La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company Limited; and Transition Therapeutics. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private‐sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging (LONI) at the University of Southern California. Funding Information: information This study, through multi-institutional collaboration as a project of the Foundation for the National Institute of Health (FNIH) Biomarkers Consortium, Longitudinal Proteomic Changes in Cerebrospinal Fluid from Alzheimer’s Disease Neuroimaging Initiative (ADNI): Towards Better Defining the Trajectory of Prodromal and Early Alzheimer’s Disease, received funding support provided to the FNIH by Genentech, a member of the Roche Group; H. Lundbeck A/S; Janssen Research & Development, LLC; Merck & Co., Inc.; and Takeda Pharmaceutical Company Limited.The results of the study represent the work of the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium “Longitudinal Proteomic Changes in Cerebrospinal Fluid from Alzheimer's Disease Neuroimaging Initiative (ADNI): Towards Better Defining the Trajectory of Prodromal and Early Alzheimer's Disease” project. The study was made possible through the scientific and financial support of government, industry, and academia partners. We are grateful for the contributions of the following Biomarkers Consortium CSF Proteomics Project team members: Justyna Maria Bahl, Ph.D. (Lundbeck); Susan Baker, Ph.D. (Janssen); Michael C. Biarnes, M.S. (FNIH); Rosa M. Canet-Avilés, Ph.D. (FNIH); Daniel Chelsky, Ph.D. (Caprion Biosciences); Pascal Croteau, M.S. (Caprion Biosciences); Mikkel Nors Harndahl, Ph.D. (Lundbeck); Lee Honigberg, Ph.D. (Genentech); Katherine Horn, Ph.D. (Caprion Biosciences); Wesley Horton, M.S. (FNIH); John Hsiao, M.D. (NIA); Hartmuth Kolb, Ph.D. (Janssen); Ondrej Libiger, Ph.D. (Janssen); Yuqun Luo, Ph.D. (FDA); Angus Nairn, Ph.D. (Yale School of Medicine); Jan Torleif Pedersen, Ph.D. (Lundbeck); Niels Plath, Ph.D. (Lundbeck); William Potter, M.D., Ph.D.; Nandini Raghavan, Ph.D. (Janssen); Laura Rosen, M.D., Ph.D. (Takeda); Erin Rosenbaugh, Ph.D. (FNIH); Leslie Shaw, Ph.D. (University of Pennsylvania); Helle Sickmann, Ph.D. (Lundbeck); Daniel Spellman, Ph.D. (Merck & Co., Inc.); Kelly L. Umaña (FNIH); Mark Watson, Ph.D. (Caprion Biosciences); Kristin Wildsmith, Ph.D. (Genentech); Stephen Zicha, Ph.D. (Takeda). Private funding partners of the project include Genentech, a member of the Roche Group; H. Lundbeck A/S; Janssen Research & Development, LLC; Merck & Co., Inc.; and Takeda Pharmaceutical Company Limited. Private-sector funding for the study was managed by the Foundation for the National Institutes of Health. We would additionally like to acknowledge ADNI for the cerebrospinal fluid samples and data analyzed in this study. Data used in the preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). The ADNI was launched in 2003 as a public–private partnership, led by Principal Investigator Michael W. Weiner, M.D. The primary goal of the ADNI has been to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of MCI and early Alzheimer's disease. For up-to-date information, see www.adni-info.org. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U19 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company Limited; and Transition Therapeutics. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private-sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging (LONI) at the University of Southern California. Funding Information: Susan A. Baker, Angus C. Nairn, and Daniel S. Spellman have nothing to declare. Leslie M. Shaw receives research support from NIH/NIA U19 AG024904, ADNI3 grant; NIH/NIA P30 AG010124, UPENN ADCC grant; and the Michael J. Fox Foundation for Parkinson's Research. He is a consultant for Biogen and Roche Diagnostics and is on the speaker's bureaus for Biogen and Fujirebio. Angus C. Nairn receives research support from NIH/NIA P30 AG066508. Clifford R. Jack Jr. serves on an independent data monitoring board for Roche, has consulted for and served as a speaker for Eisai, and consulted for Biogen, but he does not receive personal compensation from any commercial entities. Additionally, Clifford R. Jack Jr. receives research support from the NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. Ondrej Libiger receives salary and company stock as compensation for his employment with Janssen Research & Development. William Z. Potter was previously employed by the National Institute of Mental Health, and he is a stockholder in Merck & Co., Inc.. He is a Co‐Chair Emeritus for the FNIH Biomarkers Consortium Neuroscience Steering Committee. Currently residing in Philadelphia, PA, he serves on DSMBs for AgeneBio and Regenacy and as a consultant for Karuna, Otsuka, Neurocrine, Eliem, and Emerald Lake Safety. Additionally, he receives grant support from the NIA. Nandini Raghavan is employed by Janssen Research & Development and owns stock in Johnson & Johnson. Kelly L. Umaña, Michael C. Biarnes, and Rosa M. Canet‐Avilés were previously employed by the FNIH. Daniel Chelsky and Yannick‐André Breton were previously employed by Caprion Biosciences. Laetitia Cortes and Mark Watson are employed by Caprion Biosciences. The FNIH provided financial support to Caprion Biosciences to perform the submitted work. Funding Information: This study, through multi‐institutional collaboration as a project of the Foundation for the National Institute of Health (FNIH) Biomarkers Consortium, Longitudinal Proteomic Changes in Cerebrospinal Fluid from Alzheimer’s Disease Neuroimaging Initiative (ADNI): Towards Better Defining the Trajectory of Prodromal and Early Alzheimer’s Disease, received funding support provided to the FNIH by Genentech, a member of the Roche Group; H. Lundbeck A/S; Janssen Research & Development, LLC; Merck & Co., Inc.; and Takeda Pharmaceutical Company Limited. Funding information Publisher Copyright: © 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association
PY - 2021/12
Y1 - 2021/12
N2 - Introduction: Biomarkers that reflect pathologic processes affecting neuronal function during preclinical and early stages of Alzheimer's disease (AD) are needed to aid drug development. Methods: A targeted, stable isotope, quantitative mass spectrometry-based investigation of longitudinal changes in concentrations of previously identified candidate biomarkers was performed in cerebrospinal fluid (CSF) of Alzheimer's Disease Neuroimaging Initiative participants who were classified as cognitively normal (CN; n = 76) or with mild cognitive impairment (MCI; n = 111) at baseline. Results: Of the candidate biomarkers, the CSF concentration of neuronal pentraxin 2 (NPTX2), a protein involved in synaptic function, exhibited rates of change that were significantly different between three comparison groups (i.e., CN vs. MCI participants; AD pathology positive vs. negative defined by phosphorylated tau181/amyloid beta1-42 ratio; and clinical progressors vs. non-progressors). The rate of change of NPTX2 also significantly correlated with declining cognition. Discussion: CSF NPTX2 concentration is a strong prognostic biomarker candidate of accelerated cognitive decline with potential use as a therapeutic target.
AB - Introduction: Biomarkers that reflect pathologic processes affecting neuronal function during preclinical and early stages of Alzheimer's disease (AD) are needed to aid drug development. Methods: A targeted, stable isotope, quantitative mass spectrometry-based investigation of longitudinal changes in concentrations of previously identified candidate biomarkers was performed in cerebrospinal fluid (CSF) of Alzheimer's Disease Neuroimaging Initiative participants who were classified as cognitively normal (CN; n = 76) or with mild cognitive impairment (MCI; n = 111) at baseline. Results: Of the candidate biomarkers, the CSF concentration of neuronal pentraxin 2 (NPTX2), a protein involved in synaptic function, exhibited rates of change that were significantly different between three comparison groups (i.e., CN vs. MCI participants; AD pathology positive vs. negative defined by phosphorylated tau181/amyloid beta1-42 ratio; and clinical progressors vs. non-progressors). The rate of change of NPTX2 also significantly correlated with declining cognition. Discussion: CSF NPTX2 concentration is a strong prognostic biomarker candidate of accelerated cognitive decline with potential use as a therapeutic target.
KW - Alzheimer's disease
KW - dementia
KW - longitudinal cerebrospinal fluid
KW - mild cognitive impairment
KW - neuropathology
KW - prognostic biomarker
KW - stable isotope-based quantitative mass spectrometry
UR - http://www.scopus.com/inward/record.url?scp=85105760151&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85105760151&partnerID=8YFLogxK
U2 - 10.1002/alz.12353
DO - 10.1002/alz.12353
M3 - Article
C2 - 33984181
AN - SCOPUS:85105760151
SN - 1552-5260
VL - 17
SP - 1976
EP - 1987
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 12
ER -