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Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.
J Alzheimers Dis. 2015; 48(1):175-87.JA

Abstract

BACKGROUND

The cerebrospinal fluid (CSF) amyloid-β (Aβ)(1-42), total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD).

OBJECTIVE

The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands.

METHODS

Aβ pathology was determined by PET imaging, utilizing ¹¹C-Pittsburgh Compound B, ¹⁸F-flutemetamol, or ¹⁸F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ(1-42) >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology.

RESULTS

CSF Aβ(1-42) was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ(1-42) provided greater accuracy, predicting MCI/AD with Aβ pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ(1-42) to predict MCI/AD, reached ≥92% sensitivity and specificity.

CONCLUSIONS

CSF Aβ(1-42) levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.

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    • Authors+Show Affiliations

    Li QX
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
    Villemagne VL
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia. Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, Australia.
    Doecke JD
    CSIRO Digital Productivity/Australian e-Health Research Centre and Cooperative Research Centre for Mental Health, Brisbane, QLD, Australia.
    Rembach A
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
    Sarros S
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
    Varghese S
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
    McGlade A
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
    Laughton KM
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
    Pertile KK
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
    Fowler CJ
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
    Rumble RL
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
    Trounson BO
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
    Taddei K
    Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical Sciences, Edith Cowan University, Joondalup, Western Australia, Australia. Sir James McCusker Alzheimer's Disease Research Unit (Hollywood Private Hospital), Perth, WA, Australia.
    Rainey-Smith SR
    Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical Sciences, Edith Cowan University, Joondalup, Western Australia, Australia. Sir James McCusker Alzheimer's Disease Research Unit (Hollywood Private Hospital), Perth, WA, Australia.
    Laws SM
    Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical Sciences, Edith Cowan University, Joondalup, Western Australia, Australia. Sir James McCusker Alzheimer's Disease Research Unit (Hollywood Private Hospital), Perth, WA, Australia.
    Robertson JS
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
    Evered LA
    Centre for Anaesthesia and Cognitive Function, Department of Anaesthesia, and Department of Surgery, St. Vincent's Hospital, The University of Melbourne, VIC, Australia.
    Silbert B
    Centre for Anaesthesia and Cognitive Function, Department of Anaesthesia, and Department of Surgery, St. Vincent's Hospital, The University of Melbourne, VIC, Australia.
    Ellis KA
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia. The University of Melbourne Academic Unit for Psychiatry of Old Age, St George's Hospital, Kew, VIC, Australia.
    Rowe CC
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia. Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, Australia.
    Macaulay SL
    CSIRO Food and Nutrition Flagship, Parkville, VIC, Australia.
    Darby D
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
    Martins RN
    Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical Sciences, Edith Cowan University, Joondalup, Western Australia, Australia. Sir James McCusker Alzheimer's Disease Research Unit (Hollywood Private Hospital), Perth, WA, Australia. School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Western Australia, Australia.
    Ames D
    The University of Melbourne Academic Unit for Psychiatry of Old Age, St George's Hospital, Kew, VIC, Australia. National Ageing Research Institute, Parkville, VIC, Australia.
    Masters CL
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
    Collins S
    Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia. Department of Pathology, The University of Melbourne, Parkville, Australia.
    AIBL Research Group
    No affiliation info available

    MeSH

    AgedAged, 80 and overAlzheimer DiseaseAmyloid beta-PeptidesAniline CompoundsAustraliaBenzothiazolesEthylene GlycolsFemaleHumansLife StyleLongitudinal StudiesMaleMental Status SchedulePeptide FragmentsPositron-Emission TomographyROC CurveThiazolestau Proteins

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    26401938

    Citation

    Li, Qiao-Xin, et al. "Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects From the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study." Journal of Alzheimer's Disease : JAD, vol. 48, no. 1, 2015, pp. 175-87.
    Li QX, Villemagne VL, Doecke JD, et al. Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. J Alzheimers Dis. 2015;48(1):175-87.
    Li, Q. X., Villemagne, V. L., Doecke, J. D., Rembach, A., Sarros, S., Varghese, S., McGlade, A., Laughton, K. M., Pertile, K. K., Fowler, C. J., Rumble, R. L., Trounson, B. O., Taddei, K., Rainey-Smith, S. R., Laws, S. M., Robertson, J. S., Evered, L. A., Silbert, B., Ellis, K. A., ... Collins, S. (2015). Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Journal of Alzheimer's Disease : JAD, 48(1), 175-87. https://doi.org/10.3233/JAD-150247
    Li QX, et al. Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects From the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study. J Alzheimers Dis. 2015;48(1):175-87. PubMed PMID: 26401938.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. AU - Li,Qiao-Xin, AU - Villemagne,Victor L, AU - Doecke,James D, AU - Rembach,Alan, AU - Sarros,Shannon, AU - Varghese,Shiji, AU - McGlade,Amelia, AU - Laughton,Katrina M, AU - Pertile,Kelly K, AU - Fowler,Christopher J, AU - Rumble,Rebecca L, AU - Trounson,Brett O, AU - Taddei,Kevin, AU - Rainey-Smith,Stephanie R, AU - Laws,Simon M, AU - Robertson,Joanne S, AU - Evered,Lisbeth A, AU - Silbert,Brendan, AU - Ellis,Kathryn A, AU - Rowe,Christopher C, AU - Macaulay,S Lance, AU - Darby,David, AU - Martins,Ralph N, AU - Ames,David, AU - Masters,Colin L, AU - Collins,Steven, AU - ,, PY - 2015/9/25/entrez PY - 2015/9/25/pubmed PY - 2016/7/7/medline KW - Alzheimer’s disease KW - amyloid-β KW - cerebrospinal fluid biomarkers KW - positron emission tomography Aβ imaging KW - tau SP - 175 EP - 87 JF - Journal of Alzheimer's disease : JAD JO - J. Alzheimers Dis. VL - 48 IS - 1 N2 - BACKGROUND: The cerebrospinal fluid (CSF) amyloid-β (Aβ)(1-42), total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD). OBJECTIVE: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands. METHODS: Aβ pathology was determined by PET imaging, utilizing ¹¹C-Pittsburgh Compound B, ¹⁸F-flutemetamol, or ¹⁸F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ(1-42) >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology. RESULTS: CSF Aβ(1-42) was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ(1-42) provided greater accuracy, predicting MCI/AD with Aβ pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ(1-42) to predict MCI/AD, reached ≥92% sensitivity and specificity. CONCLUSIONS: CSF Aβ(1-42) levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/26401938/Alzheimer's_Disease_Normative_Cerebrospinal_Fluid_Biomarkers_Validated_in_PET_Amyloid_β_Characterized_Subjects_from_the_Australian_Imaging_Biomarkers_and_Lifestyle__AIBL__study_ L2 - https://content.iospress.com/openurl?genre=article&amp;id=doi:10.3233/JAD-150247 DB - PRIME DP - Unbound Medicine ER -