title: Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.
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.
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
authors.forename: Qiao-Xin
authors.initials: QX
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Villemagne
authors.affiliation: CSIRO Digital Productivity/Australian e-Health Research Centre and Cooperative Research Centre for Mental Health, Brisbane, QLD, Australia.
authors.forename: James D
authors.initials: JD
authors.lastname: Doecke
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
authors.forename: Alan
authors.initials: A
authors.lastname: Rembach
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
authors.forename: Shannon
authors.initials: S
authors.lastname: Sarros
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
authors.forename: Shiji
authors.initials: S
authors.lastname: Varghese
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
authors.forename: Amelia
authors.initials: A
authors.lastname: McGlade
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Laughton
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Pertile
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fowler
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Rumble
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
authors.forename: Brett O
authors.initials: BO
authors.lastname: Trounson
authors.affiliation: 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.
authors.forename: Kevin
authors.initials: K
authors.lastname: Taddei
authors.affiliation: 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.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Rainey-Smith
authors.affiliation: 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.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Laws
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
authors.forename: Joanne S
authors.initials: JS
authors.lastname: Robertson
authors.affiliation: Centre for Anaesthesia and Cognitive Function, Department of Anaesthesia, and Department of Surgery, St. Vincent's Hospital, The University of Melbourne, VIC, Australia.
authors.forename: Lisbeth A
authors.initials: LA
authors.lastname: Evered
authors.affiliation: Centre for Anaesthesia and Cognitive Function, Department of Anaesthesia, and Department of Surgery, St. Vincent's Hospital, The University of Melbourne, VIC, Australia.
authors.forename: Brendan
authors.initials: B
authors.lastname: Silbert
authors.affiliation: 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.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Ellis
authors.affiliation: 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.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Rowe
authors.affiliation: CSIRO Food and Nutrition Flagship, Parkville, VIC, Australia.
authors.forename: S Lance
authors.initials: SL
authors.lastname: Macaulay
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Darby
authors.affiliation: 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.
authors.forename: Ralph N
authors.initials: RN
authors.lastname: Martins
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Ames
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.|Department of Pathology, The University of Melbourne, Parkville, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Collins
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000814:Aniline Compounds / Q000378:metabolism; D001315:Australia; D052160:Benzothiazoles / Q000378:metabolism; D005026:Ethylene Glycols / Q000378:metabolism; D005260:Female; D006801:Humans; D008019:Life Style; D008137:Longitudinal Studies; D008297:Male; D008609:Mental Status Schedule; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D049268:Positron-Emission Tomography; D012372:ROC Curve; D013844:Thiazoles / Q000378:metabolism; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D052160:Benzothiazoles; D005026:Ethylene Glycols; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C581552:flutemetamol; C545186:florbetapir
keywords: Alzheimer’s disease; amyloid-β; cerebrospinal fluid biomarkers; positron emission tomography Aβ imaging; tau