YKL-40: A novel prognostic fluid biomarker for preclinical Alzheimer's disease

Rebecca Craig-Schapiro, Richard J. Perrin, Catherine M. Roe, Chengjie Xiong, Deborah Carter, Nigel J. Cairns, Mark A. Mintun, Elaine R. Peskind, Ge Li, Douglas R. Galasko, Christopher M. Clark, Joseph Quinn, Gina D'Angelo, James P. Malone, R. Reid Townsend, John C. Morris, Anne M. Fagan, David M. Holtzman

Research output: Contribution to journalArticle

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Abstract

Background Disease-modifying therapies for Alzheimer's disease (AD) would be most effective during the preclinical stage (pathology present, cognition intact) before significant neuronal loss occurs. Therefore, biomarkers that detect AD pathology in its early stages and predict dementia onset and progression will be invaluable for patient care and efficient clinical trial design. Methods AD-associated changes in cerebrospinal fluid (CSF) were measured using two-dimensional difference gel electrophoresis and liquid chromatography tandem mass spectrometry. Subsequently, CSF YKL-40 was measured by enzyme-linked immunosorbent assay in the discovery cohort (n = 47), validation cohort (n = 292) with paired plasma samples (n = 237), frontotemporal lobar degeneration (PSP; n = 9), and progressive supranuclear palsy (PSP; n = 6). Immunohistochemistry was performed to identify source(s) of YKL-40 in human AD brain. Results Discovery and validation cohorts, showed higher mean CSF YKL-40 in very mild and mild AD-type dementia (Clinical Dementia Rating [CDR] 0.5 and 1) versus control subjects (CDR 0) and PSP subjects. Importantly, CSF YKL-40/Aβ42 ratio predicted risk of developing cognitive impairment (CDR 0 to CDR > 0 conversion), as well as the best CSF biomarkers identified to date, tau/Aβ42 and p-tau 181/Aβ42. Mean plasma YKL-40 was higher in CDR 0.5 and 1 versus CDR 0, and correlated with CSF levels. YKL-40 immunoreactivity labeled astrocytes near a subset of amyloid plaques, implicating YKL-40 in the neuroinflammatory response to Aβ deposition. Conclusions These data demonstrate that YKL-40, a putative indicator of neuroinflammation, is elevated in AD and, together with Aβ42, has potential prognostic utility as a biomarker for preclinical AD.

Original languageEnglish (US)
Pages (from-to)903-912
Number of pages10
JournalBiological Psychiatry
Volume68
Issue number10
DOIs
StatePublished - Nov 15 2010

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Alzheimer Disease
Dementia
Biomarkers
Cerebrospinal Fluid
Two-Dimensional Difference Gel Electrophoresis
Frontotemporal Lobar Degeneration
Pathology
Progressive Supranuclear Palsy
Amyloid Plaques
Tandem Mass Spectrometry
Liquid Chromatography
Astrocytes
Cognition
Gel Chromatography
Patient Care
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Odds Ratio
Clinical Trials
Brain

Keywords

  • Alzheimer's disease
  • biomarkers
  • cerebrospinal fluid
  • chitinase-3 like-1
  • inflammation
  • YKL-40

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Craig-Schapiro, R., Perrin, R. J., Roe, C. M., Xiong, C., Carter, D., Cairns, N. J., ... Holtzman, D. M. (2010). YKL-40: A novel prognostic fluid biomarker for preclinical Alzheimer's disease. Biological Psychiatry, 68(10), 903-912. https://doi.org/10.1016/j.biopsych.2010.08.025

YKL-40 : A novel prognostic fluid biomarker for preclinical Alzheimer's disease. / Craig-Schapiro, Rebecca; Perrin, Richard J.; Roe, Catherine M.; Xiong, Chengjie; Carter, Deborah; Cairns, Nigel J.; Mintun, Mark A.; Peskind, Elaine R.; Li, Ge; Galasko, Douglas R.; Clark, Christopher M.; Quinn, Joseph; D'Angelo, Gina; Malone, James P.; Townsend, R. Reid; Morris, John C.; Fagan, Anne M.; Holtzman, David M.

In: Biological Psychiatry, Vol. 68, No. 10, 15.11.2010, p. 903-912.

Research output: Contribution to journalArticle

Craig-Schapiro, R, Perrin, RJ, Roe, CM, Xiong, C, Carter, D, Cairns, NJ, Mintun, MA, Peskind, ER, Li, G, Galasko, DR, Clark, CM, Quinn, J, D'Angelo, G, Malone, JP, Townsend, RR, Morris, JC, Fagan, AM & Holtzman, DM 2010, 'YKL-40: A novel prognostic fluid biomarker for preclinical Alzheimer's disease', Biological Psychiatry, vol. 68, no. 10, pp. 903-912. https://doi.org/10.1016/j.biopsych.2010.08.025
Craig-Schapiro R, Perrin RJ, Roe CM, Xiong C, Carter D, Cairns NJ et al. YKL-40: A novel prognostic fluid biomarker for preclinical Alzheimer's disease. Biological Psychiatry. 2010 Nov 15;68(10):903-912. https://doi.org/10.1016/j.biopsych.2010.08.025
Craig-Schapiro, Rebecca ; Perrin, Richard J. ; Roe, Catherine M. ; Xiong, Chengjie ; Carter, Deborah ; Cairns, Nigel J. ; Mintun, Mark A. ; Peskind, Elaine R. ; Li, Ge ; Galasko, Douglas R. ; Clark, Christopher M. ; Quinn, Joseph ; D'Angelo, Gina ; Malone, James P. ; Townsend, R. Reid ; Morris, John C. ; Fagan, Anne M. ; Holtzman, David M. / YKL-40 : A novel prognostic fluid biomarker for preclinical Alzheimer's disease. In: Biological Psychiatry. 2010 ; Vol. 68, No. 10. pp. 903-912.
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T2 - A novel prognostic fluid biomarker for preclinical Alzheimer's disease

AU - Craig-Schapiro, Rebecca

AU - Perrin, Richard J.

AU - Roe, Catherine M.

AU - Xiong, Chengjie

AU - Carter, Deborah

AU - Cairns, Nigel J.

AU - Mintun, Mark A.

AU - Peskind, Elaine R.

AU - Li, Ge

AU - Galasko, Douglas R.

AU - Clark, Christopher M.

AU - Quinn, Joseph

AU - D'Angelo, Gina

AU - Malone, James P.

AU - Townsend, R. Reid

AU - Morris, John C.

AU - Fagan, Anne M.

AU - Holtzman, David M.

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N2 - Background Disease-modifying therapies for Alzheimer's disease (AD) would be most effective during the preclinical stage (pathology present, cognition intact) before significant neuronal loss occurs. Therefore, biomarkers that detect AD pathology in its early stages and predict dementia onset and progression will be invaluable for patient care and efficient clinical trial design. Methods AD-associated changes in cerebrospinal fluid (CSF) were measured using two-dimensional difference gel electrophoresis and liquid chromatography tandem mass spectrometry. Subsequently, CSF YKL-40 was measured by enzyme-linked immunosorbent assay in the discovery cohort (n = 47), validation cohort (n = 292) with paired plasma samples (n = 237), frontotemporal lobar degeneration (PSP; n = 9), and progressive supranuclear palsy (PSP; n = 6). Immunohistochemistry was performed to identify source(s) of YKL-40 in human AD brain. Results Discovery and validation cohorts, showed higher mean CSF YKL-40 in very mild and mild AD-type dementia (Clinical Dementia Rating [CDR] 0.5 and 1) versus control subjects (CDR 0) and PSP subjects. Importantly, CSF YKL-40/Aβ42 ratio predicted risk of developing cognitive impairment (CDR 0 to CDR > 0 conversion), as well as the best CSF biomarkers identified to date, tau/Aβ42 and p-tau 181/Aβ42. Mean plasma YKL-40 was higher in CDR 0.5 and 1 versus CDR 0, and correlated with CSF levels. YKL-40 immunoreactivity labeled astrocytes near a subset of amyloid plaques, implicating YKL-40 in the neuroinflammatory response to Aβ deposition. Conclusions These data demonstrate that YKL-40, a putative indicator of neuroinflammation, is elevated in AD and, together with Aβ42, has potential prognostic utility as a biomarker for preclinical AD.

AB - Background Disease-modifying therapies for Alzheimer's disease (AD) would be most effective during the preclinical stage (pathology present, cognition intact) before significant neuronal loss occurs. Therefore, biomarkers that detect AD pathology in its early stages and predict dementia onset and progression will be invaluable for patient care and efficient clinical trial design. Methods AD-associated changes in cerebrospinal fluid (CSF) were measured using two-dimensional difference gel electrophoresis and liquid chromatography tandem mass spectrometry. Subsequently, CSF YKL-40 was measured by enzyme-linked immunosorbent assay in the discovery cohort (n = 47), validation cohort (n = 292) with paired plasma samples (n = 237), frontotemporal lobar degeneration (PSP; n = 9), and progressive supranuclear palsy (PSP; n = 6). Immunohistochemistry was performed to identify source(s) of YKL-40 in human AD brain. Results Discovery and validation cohorts, showed higher mean CSF YKL-40 in very mild and mild AD-type dementia (Clinical Dementia Rating [CDR] 0.5 and 1) versus control subjects (CDR 0) and PSP subjects. Importantly, CSF YKL-40/Aβ42 ratio predicted risk of developing cognitive impairment (CDR 0 to CDR > 0 conversion), as well as the best CSF biomarkers identified to date, tau/Aβ42 and p-tau 181/Aβ42. Mean plasma YKL-40 was higher in CDR 0.5 and 1 versus CDR 0, and correlated with CSF levels. YKL-40 immunoreactivity labeled astrocytes near a subset of amyloid plaques, implicating YKL-40 in the neuroinflammatory response to Aβ deposition. Conclusions These data demonstrate that YKL-40, a putative indicator of neuroinflammation, is elevated in AD and, together with Aβ42, has potential prognostic utility as a biomarker for preclinical AD.

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