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Cited by 108Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCerebrospinal fluid and hydrocephalus

Longitudinal CSF proteomics identifies NPTX2 as a prognostic biomarker of Alzheimer's disease

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Libiger, Ondrej, Shaw, Leslie M., Watson, Mark H., Nairn, Angus C., Umaña, Kelly L., Biarnes, Michael C., Canet‐Avilés, Rosa M., Jack, Clifford R. +9 more·2021·Alzheimer's & Dementia
DOI 10.1002/alz.12353PMC PMC9222372
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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.

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  1. [1]Goedert M, Spillantini MG. A century of Alzheimer's disease. Science. 2006; 314: 777‐ 781. 17082447
  2. [2]Beeri MS, Haroutunian V, Schmeidler J, et al. Synaptic protein deficits are associated with dementia irrespective of extreme old age. Neurobiol Aging. 2012; 33: 1125.e1‐ 8. PMC3318958 22206847
  3. [3]Robinson JL, Molina‐Porcel L, Corrada MM, et al. Perforant path synaptic loss correlates with cognitive impairment and Alzheimer's disease in the oldest‐old. Brain J Neurol. 2014; 137: 2578‐ 2587. PMC4132652 25012223
  4. [4]Shah H, Albanese E, Duggan C, et al. Research priorities to reduce the global burden of dementia by 2025. Lancet Neurol. 2016; 15: 1285‐ 1294. 27751558
  5. [6]Veitch DP, Weiner MW, Aisen PS, et al. Understanding disease progression and improving Alzheimer's disease clinical trials: recent highlights from the Alzheimer's Disease Neuroimaging Initiative. Alzheimers Dement J Alzheimers Assoc. 2019; 15: 106‐ 152. 30321505
  6. [7]Jack CR, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010; 9: 119‐ 128. 20083042 PMC2819840
  7. [8]Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, Hansson O. Cerebrospinal fluid levels of β‐amyloid 1‐42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry. 2012; 69: 98‐ 106. 22213792
  8. [11]Molinuevo JL, Ayton S, Batrla R, et al. Current state of Alzheimer's fluid biomarkers. Acta Neuropathol (Berl). 2018; 136: 821‐ 853. 30488277 PMC6280827
  9. [12]Jack CR, Wiste HJ, Weigand SD, et al. Amyloid‐first and neurodegeneration‐first profiles characterize incident amyloid PET positivity. Neurology. 2013; 81: 1732‐ 1740. 24132377 PMC3821718
  10. [13]Spellman DS, Wildsmith KR, Honigberg LA, et al. Development and evaluation of a multiplexed mass spectrometry based assay for measuring candidate peptide biomarkers in Alzheimer's Disease Neuroimaging Initiative (ADNI) CSF. Proteomics Clin Appl. 2015; 9: 715‐ 731. 25676562 PMC4739636
  11. [14]Tarawneh R, D'Angelo G, Crimmins D, et al. Diagnostic and prognostic utility of the synaptic marker neurogranin in Alzheimer disease. JAMA Neurol. 2016; 73: 561‐ 571. 27018940 PMC4861689
  12. [15]Olsson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta‐analysis. Lancet Neurol. 2016; 15: 673‐ 684. 27068280
  13. [16]Hendrickson RC, Lee AYH, Song Q, et al. High resolution discovery proteomics reveals candidate disease progression markers of Alzheimer's disease in human cerebrospinal fluid. PloS One. 2015; 10: e0135365. 26270474 PMC4535975
  14. [17]Wildsmith KR, Schauer SP, Smith AM, et al. Identification of longitudinally dynamic biomarkers in Alzheimer's disease cerebrospinal fluid by targeted proteomics. Mol Neurodegener. 2014; 9: 22. 24902845 PMC4061120
  15. [18]Craig‐Schapiro R, Kuhn M, Xiong C, et al. Multiplexed immunoassay panel identifies novel CSF biomarkers for Alzheimer's disease diagnosis and prognosis. PloS One. 2011; 6: e18850. 21526197 PMC3079734
  16. [19]Desikan RS, Thompson WK, Holland D, et al. Heart fatty acid binding protein and Aβ‐associated Alzheimer's neurodegeneration. Mol Neurodegener. 2013; 8: 39. 24088526 PMC3850652
  17. [20]Chiasserini D, Biscetti L, Eusebi P, et al. Differential role of CSF fatty acid binding protein 3, α‐synuclein, and Alzheimer's disease core biomarkers in Lewy body disorders and Alzheimer's dementia. Alzheimers Res Ther. 2017; 9: 52. 28750675 PMC5532764
  18. [22]Galasko D, Xiao M, Xu D, et al. Synaptic biomarkers in CSF aid in diagnosis, correlate with cognition and predict progression in MCI and Alzheimer's disease. Alzheimers Dement N Y N. 2019; 5: 871‐ 882. PMC6911971 31853477
  19. [23]Soares HD, Potter WZ, Pickering E, et al. Plasma biomarkers associated with the apolipoprotein E genotype and Alzheimer disease. Arch Neurol. 2012; 69: 1310‐ 1317. 22801723 PMC3683865
  20. [24]Weiner MW, Veitch DP, Aisen PS, et al. The Alzheimer's Disease Neuroimaging Initiative: a review of papers published since its inception. Alzheimers Dement J Alzheimers Assoc. 2013; 9: e111‐ 194. PMC4108198 23932184
  21. [25]Blennow K, Shaw LM, Stomrud E, et al. Predicting clinical decline and conversion to Alzheimer's disease or dementia using novel Elecsys Aβ(1‐42), pTau and tTau CSF immunoassays. Sci Rep. 2019; 9: 19024. 31836810 PMC6911086
  22. [26]Portelius E, Zetterberg H, Skillbäck T, et al. Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer's disease. Brain J Neurol. 2015; 138: 3373‐ 3385. PMC4643642 26373605
  23. [28]Kvartsberg H, Portelius E, Andreasson U, et al. Characterization of the postsynaptic protein neurogranin in paired cerebrospinal fluid and plasma samples from Alzheimer's disease patients and healthy controls. Alzheimers Res Ther. 2015; 7: 40. 26136856 PMC4487851
  24. [30]Toledo JB, Xie SX, Trojanowski JQ, Shaw LM. Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI. Acta Neuropathol (Berl). 2013; 126: 659‐ 670. 23812320 PMC3875373
  25. [33]Chang MC, Park JM, Pelkey KA, et al. Narp regulates homeostatic scaling of excitatory synapses on parvalbumin‐expressing interneurons. Nat Neurosci. 2010; 13: 1090‐ 1097. 20729843 PMC2949072
  26. [34]Cho RW, Park JM, Wolff SBE, et al. mGluR1/5‐dependent long‐term depression requires the regulated ectodomain cleavage of neuronal pentraxin NPR by TACE. Neuron. 2008; 57: 858‐ 871. 18367087 PMC2701195
  27. [35]Gu Y, Huang S, Chang MC, Worley P, Kirkwood A, Quinlan EM. Obligatory role for the immediate early gene NARP in critical period plasticity. Neuron. 2013; 79: 335‐ 346. 23889936 PMC3804028
  28. [37]O'Brien RJ, Xu D, Petralia RS, Steward O, Huganir RL, Worley P. Synaptic clustering of AMPA receptors by the extracellular immediate‐early gene product Narp. Neuron. 1999; 23: 309‐ 323. 10399937
  29. [38]O'Brien R, Xu D, Mi R, Tang X, Hopf C, Worley P. Synaptically targeted narp plays an essential role in the aggregation of AMPA receptors at excitatory synapses in cultured spinal neurons. J Neurosci Off J Soc Neurosci. 2002; 22: 4487‐ 4498. PMC6758786 12040056
  30. [39]Pelkey KA, Barksdale E, Craig MT, et al. Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons. Neuron. 2015; 85: 1257‐ 1272. 25754824 PMC4368480
  31. [41]Borchelt DR, Ratovitski T, van Lare J, et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron. 1997; 19: 939‐ 945. 9354339
  32. [43]van der Ende EL, Xiao M, Xu D, et al. Neuronal pentraxin 2: a synapse‐derived CSF biomarker in genetic frontotemporal dementia. J Neurol Neurosurg Psychiatry. 2020; 91: 612‐ 621. 32273328 PMC7279197

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Authors
Libiger, O., Shaw, L. M., Watson, M. H., Nairn, A. C., Umaña, K. L., Biarnes, M. C., Canet‐Avilés, R. M., Jack, C. R., Breton, Y., Cortes, L., Chelsky, D., Spellman, D. S., Baker, S. A., Raghavan, N., Potter, W. Z., (ADNI), A. D. N. I., & Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium, L. C. P. P. T.
Affiliations
  • Janssen Research and Development San Diego California USA
  • University of Pennsylvania (US)
  • Caprion (Canada) (CA)
  • Yale University (US)
  • Foundation for the National Institutes of Health (US)
  • Foundation for the National Institutes of Health North Bethesda Maryland USA
  • Mayo Clinic (US)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • Janssen Research and Development Titusville New Jersey USA
  • National Institute of Mental Health (US)
Corresponding author
Libiger, Ondrej
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2021-05-13
Volume
17
Issue
12
Pages
1976-1987
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.12353
PMC
PMC9222372
OpenAlex
W3162851360
Cited by
108
References
10
Citations by year
2026: 15 · 2025: 30 · 2024: 38 · 2023: 12 · 2022: 9 · 2021: 4
FWCI
11.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • Foundation for the National Institutes of Health
  • Alzheimer's Disease Neuroimaging Initiative
  • National Institutes of Health
  • Canadian Institutes of Health Research
  • National Institute on Aging (U19AG024904, P30AG072979)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
Keywords
NPTX2
MeSH terms
Pentraxins, Aged, Alzheimer Disease, C-Reactive Protein, Humans, Longitudinal Studies, Nerve Tissue Proteins, Phosphorylation, Mass Spectrometry, Biomarkers, Amyloid beta-Peptides, tau Proteins, Proteomics, Cognitive Dysfunction

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