title: Diagnostic value of cerebrospinal fluid Aβ ratios in preclinical Alzheimer's disease.
abstract: BACKGROUND
  In this study of preclinical Alzheimer's disease (AD) we assessed the added diagnostic value of using cerebrospinal fluid (CSF) Aβ ratios rather than Aβ42 in isolation for detecting individuals who are positive on amyloid positron emission tomography (PET).
  
  
  METHODS
  Thirty-eight community-recruited cognitively intact older adults (mean age 73, range 65-80 years) underwent (18)F-flutemetamol PET and CSF measurement of Aβ1-42, Aβ1-40, Aβ1-38, and total tau (ttau). (18)F-flutemetamol retention was quantified using standardized uptake value ratios in a composite cortical region (SUVRcomp) with reference to cerebellar grey matter. Based on a prior autopsy validation study, the SUVRcomp cut-off was 1.57. Sensitivities, specificities and cut-offs were defined based on receiver operating characteristic analysis with CSF analytes as variables of interest and (18)F-flutemetamol positivity as the classifier. We also determined sensitivities and CSF cut-off values at fixed specificities of 90 % and 95 %.
  
  
  RESULTS
  Seven out of 38 subjects (18 %) were positive on amyloid PET. Aβ42/ttau, Aβ42/Aβ40, Aβ42/Aβ38, and Aβ42 had the highest accuracy to identify amyloid-positive subjects (area under the curve (AUC) ≥ 0.908). Aβ40 and Aβ38 had significantly lower discriminative power (AUC = 0.571). When specificity was fixed at 90 % and 95 %, Aβ42/ttau had the highest sensitivity among the different CSF markers (85.71 % and 71.43 %, respectively). Sensitivity of Aβ42 alone was significantly lower under these conditions (57.14 % and 42.86 %, respectively).
  
  
  CONCLUSIONS
  For the CSF-based definition of preclinical AD, if a high specificity is required, our data support the use of Aβ42/ttau rather than using Aβ42 in isolation.
authors.affiliation: Laboratory for Cognitive Neurology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. kate.adamczuk@med.kuleuven.be.|Alzheimer Research Centre KU Leuven, Leuven Institute of Neuroscience and Disease, Herestraat 49, 3000, Leuven, Belgium. kate.adamczuk@med.kuleuven.be.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Adamczuk
authors.affiliation: Laboratory for Cognitive Neurology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. jolien.schaeverbeke@med.kuleuven.be.|Alzheimer Research Centre KU Leuven, Leuven Institute of Neuroscience and Disease, Herestraat 49, 3000, Leuven, Belgium. jolien.schaeverbeke@med.kuleuven.be.
authors.forename: Jolien
authors.initials: J
authors.lastname: Schaeverbeke
authors.affiliation: ADx NeuroSciences, Technologiepark 4, 9052, Gent, Belgium. hugo.vanderstichele@adxneurosciences.com.
authors.forename: Hugo M J
authors.initials: HM
authors.lastname: Vanderstichele
authors.affiliation: GE Healthcare, Björkgatan 30, 751 25, Uppsala, Sweden. johan.lilja@radiol.uu.se.|Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, 751 85, Uppsala, Sweden. johan.lilja@radiol.uu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Lilja
authors.affiliation: Laboratory for Cognitive Neurology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. natalie.nelissen@psych.ox.ac.uk.|Department of Psychiatry, Oxford University, Oxford, OX3 7JX, UK. natalie.nelissen@psych.ox.ac.uk.
authors.forename: Natalie
authors.initials: N
authors.lastname: Nelissen
authors.affiliation: Alzheimer Research Centre KU Leuven, Leuven Institute of Neuroscience and Disease, Herestraat 49, 3000, Leuven, Belgium. koen.vanlaere@uzleuven.be.|Nuclear Medicine and Molecular Imaging Department, KU Leuven and University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. koen.vanlaere@uzleuven.be.
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.affiliation: Laboratory for Cognitive Neurology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. patrick.dupont@med.kuleuven.be.|Alzheimer Research Centre KU Leuven, Leuven Institute of Neuroscience and Disease, Herestraat 49, 3000, Leuven, Belgium. patrick.dupont@med.kuleuven.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Dupont
authors.affiliation: Laboratory for Neuroimmunology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. kelly.hilven@med.kuleuven.be.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hilven
authors.affiliation: Laboratory for Molecular Neurobiomarker Research, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. koen.poesen@uzleuven.be.|Laboratory Medicine, UZ Leuven, Herestraat 49, 3000, Leuven, Belgium. koen.poesen@uzleuven.be.
authors.forename: Koen
authors.initials: K
authors.lastname: Poesen
authors.affiliation: Laboratory for Cognitive Neurology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. rik.vandenberghe@uz.kuleuven.ac.be.|Alzheimer Research Centre KU Leuven, Leuven Institute of Neuroscience and Disease, Herestraat 49, 3000, Leuven, Belgium. rik.vandenberghe@uz.kuleuven.ac.be.|Neurology Department, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. rik.vandenberghe@uz.kuleuven.ac.be.
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000000981:diagnostic imaging; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000814:Aniline Compounds; D019540:Area Under Curve; D052160:Benzothiazoles; D015415:Biomarkers / Q000134:cerebrospinal fluid; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010766:Phosphorylation; D049268:Positron-Emission Tomography; D012372:ROC Curve; D019275:Radiopharmaceuticals; D012680:Sensitivity and Specificity; D013129:Spinal Puncture; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D052160:Benzothiazoles; D015415:Biomarkers; C054369:MAPT protein, human; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; C078639:amyloid beta-protein (1-38); C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C581552:flutemetamol