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Cerebrospinal fluid biomarkers distinguish postmortem-confirmed Alzheimer's disease from other dementias and healthy controls in the OPTIMA cohort.
J Alzheimers Dis. 2015; 44(2):525-39.JA

Abstract

Cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau have been studied as markers of Alzheimer's disease (AD). Combined Aβ42 and t-tau distinguishes AD from healthy controls with a sensitivity and specificity (sens/spec) near 89% across studies. This study examined these markers in the homogeneous OPTIMA cohort, using extensive longitudinal follow up and postmortem evaluation to confirm clinicopathological status. Baseline CSF was analyzed from 227 participants with AD (97% autopsy-confirmed), mild cognitive impairment (MCI; 73% confirmed), other dementia syndrome (ODS; 100% confirmed), and controls (CTL; 27% confirmed, follow up approximately 9-13 years). Biomarker concentrations were analyzed using validated ELISAs. AD patients had lower CSF Aβ42 and higher t-tau, p-tau, t-tau/Aβ42, and t-tau/Aβ40 compared to CTLs, with MCI intermediate. CTL and MCI participants who progressed to AD demonstrated more AD-like profiles. Aβ40, sAβPPα, and sAβPPβ were lower in AD compared to CTL. High-level discriminators of AD from CTL were t-tau/Aβ40 (AUROC 0.986, sens/spec of 92%/94%), p-tau/Aβ42 (AUROC 0.972, sens/spec of 94%/90%), and Aβ42 (AUROC 0.941, sens/spec of 88%). For discriminating AD from ODS, p-tau/Aβ42 demonstrated sens/spec of 88%/100% (95%/86% at the AD versus CTL cutoff) and Aβ42 demonstrated sens/spec of 84%/100% (88%/100% at the AD versus CTL cutoff). In a well-characterized, homogeneous population, a single cutoff for baseline CSF Aβ and tau markers can distinguish AD with a high level of sens/spec compared to other studies. It may be important to characterize sources of demographic and biological variability to support the effective use of CSF diagnostic assays in the broader AD population.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Seeburger JL
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Holder DJ
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Combrinck M
OPTIMA, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK Current address: University of Cape Town, Groote Schuur Hospital, Cape Town, ZA.
Joachim C
OPTIMA, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK.
Laterza O
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Tanen M
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Dallob A
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Chappell D
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Snyder K
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Flynn M
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Simon A
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Modur V
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Potter WZ
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Wilcock G
OPTIMA, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK.
Savage MJ
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Smith AD
OPTIMA, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK OPTIMA, Department of Pharmacology, Mansfield Rd., Oxford, UK.

MeSH

AdultAgedAged, 80 and overAlzheimer DiseaseAmyloid beta-PeptidesAmyloid beta-Protein PrecursorBiomarkersCognitive DysfunctionDementiaFollow-Up StudiesHumansLongitudinal StudiesMaleMiddle AgedPeptide FragmentsPhosphorylationSensitivity and Specificitytau Proteins

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25391385

Citation

Seeburger, Jeffrey L., et al. "Cerebrospinal Fluid Biomarkers Distinguish Postmortem-confirmed Alzheimer's Disease From Other Dementias and Healthy Controls in the OPTIMA Cohort." Journal of Alzheimer's Disease : JAD, vol. 44, no. 2, 2015, pp. 525-39.
Seeburger JL, Holder DJ, Combrinck M, et al. Cerebrospinal fluid biomarkers distinguish postmortem-confirmed Alzheimer's disease from other dementias and healthy controls in the OPTIMA cohort. J Alzheimers Dis. 2015;44(2):525-39.
Seeburger, J. L., Holder, D. J., Combrinck, M., Joachim, C., Laterza, O., Tanen, M., Dallob, A., Chappell, D., Snyder, K., Flynn, M., Simon, A., Modur, V., Potter, W. Z., Wilcock, G., Savage, M. J., & Smith, A. D. (2015). Cerebrospinal fluid biomarkers distinguish postmortem-confirmed Alzheimer's disease from other dementias and healthy controls in the OPTIMA cohort. Journal of Alzheimer's Disease : JAD, 44(2), 525-39. https://doi.org/10.3233/JAD-141725
Seeburger JL, et al. Cerebrospinal Fluid Biomarkers Distinguish Postmortem-confirmed Alzheimer's Disease From Other Dementias and Healthy Controls in the OPTIMA Cohort. J Alzheimers Dis. 2015;44(2):525-39. PubMed PMID: 25391385.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cerebrospinal fluid biomarkers distinguish postmortem-confirmed Alzheimer's disease from other dementias and healthy controls in the OPTIMA cohort. AU - Seeburger,Jeffrey L, AU - Holder,Daniel J, AU - Combrinck,Marc, AU - Joachim,Catharine, AU - Laterza,Omar, AU - Tanen,Michael, AU - Dallob,Aimee, AU - Chappell,Derek, AU - Snyder,Karen, AU - Flynn,Mary, AU - Simon,Adam, AU - Modur,Vijay, AU - Potter,William Z, AU - Wilcock,Gordon, AU - Savage,Mary J, AU - Smith,A David, PY - 2014/11/14/entrez PY - 2014/11/14/pubmed PY - 2015/9/22/medline KW - Alzheimer's disease KW - amyloid-β KW - biomarker KW - cerebrospinal fluid KW - frontotemporal dementia KW - mild cognitive impairment KW - postmortem examination KW - tau SP - 525 EP - 39 JF - Journal of Alzheimer's disease : JAD JO - J Alzheimers Dis VL - 44 IS - 2 N2 - Cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau have been studied as markers of Alzheimer's disease (AD). Combined Aβ42 and t-tau distinguishes AD from healthy controls with a sensitivity and specificity (sens/spec) near 89% across studies. This study examined these markers in the homogeneous OPTIMA cohort, using extensive longitudinal follow up and postmortem evaluation to confirm clinicopathological status. Baseline CSF was analyzed from 227 participants with AD (97% autopsy-confirmed), mild cognitive impairment (MCI; 73% confirmed), other dementia syndrome (ODS; 100% confirmed), and controls (CTL; 27% confirmed, follow up approximately 9-13 years). Biomarker concentrations were analyzed using validated ELISAs. AD patients had lower CSF Aβ42 and higher t-tau, p-tau, t-tau/Aβ42, and t-tau/Aβ40 compared to CTLs, with MCI intermediate. CTL and MCI participants who progressed to AD demonstrated more AD-like profiles. Aβ40, sAβPPα, and sAβPPβ were lower in AD compared to CTL. High-level discriminators of AD from CTL were t-tau/Aβ40 (AUROC 0.986, sens/spec of 92%/94%), p-tau/Aβ42 (AUROC 0.972, sens/spec of 94%/90%), and Aβ42 (AUROC 0.941, sens/spec of 88%). For discriminating AD from ODS, p-tau/Aβ42 demonstrated sens/spec of 88%/100% (95%/86% at the AD versus CTL cutoff) and Aβ42 demonstrated sens/spec of 84%/100% (88%/100% at the AD versus CTL cutoff). In a well-characterized, homogeneous population, a single cutoff for baseline CSF Aβ and tau markers can distinguish AD with a high level of sens/spec compared to other studies. It may be important to characterize sources of demographic and biological variability to support the effective use of CSF diagnostic assays in the broader AD population. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/25391385/Cerebrospinal_fluid_biomarkers_distinguish_postmortem_confirmed_Alzheimer's_disease_from_other_dementias_and_healthy_controls_in_the_OPTIMA_cohort_ DB - PRIME DP - Unbound Medicine ER -