title: Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid β-amyloid 42: a cross-validation study against amyloid positron emission tomography.
abstract: OBJECTIVE
  Before adding cerebrospinal fluid (CSF) biomarkers to the diagnostic workup of Alzheimer disease, it needs to be determined whether CSF biomarkers analyzed in routine clinical practice can reliably predict cortical β-amyloid (Aβ) deposition.
  
  
  OBJECTIVE
  To study whether CSF biomarkers, analyzed consecutively in routine clinical practice during 2 years, can predict cortical Aβ deposition and to establish a threshold for Aβ42 abnormality.
  
  
  METHODS
  This cross-sectional study (The Swedish BioFINDER [Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably] Study) was conducted at 3 memory clinics. It involved consecutively referred, nondemented patients with mild cognitive symptoms (original cohort, n = 118; validation cohort, n = 38).
  
  
  METHODS
  Amyloid positron emission tomography imaging with 18F-flutemetamol.
  
  
  METHODS
  Analyses of CSF Aβ42, total tau, and phosphorylated tau using an enzyme-linked immunosorbent assay (INNOTEST) in clinical samples.
  
  
  RESULTS
  The agreement between Aβ classification with CSF Aβ42 and 18F-flutemetamol positron emission tomography was very high (κ = 0.85). Of all the cases, 92% were classified identically using an Aβ42 cutoff of 647 pg/mL or less. Cerebrospinal fluid Aβ42 predicted abnormal cortical Aβ deposition accurately (odds ratio, 165; 95% CI, 39-693; area under the receiver operating characteristic curve, 0.94; 95% CI, 0.88-0.97). The association was independent of age, sex, APOE (apolipoprotein E) genotype, hippocampal volume, memory, and global cognition (adjusted odds ratio, 169; 95% CI, 25-1143). Using ratios of CSF Aβ42:tau or Aβ42:phosphorylated tau did not improve the prediction of Aβ deposition. Cerebrospinal fluid Aβ42 correlated significantly with Aβ deposition in all cortical regions. The highest correlations were in regions with high 18F-flutemetamol retention (eg, posterior cingulum and precuneus, r = -0.72). 18F-flutemetamol retention, but not CSF Aβ42, correlated significantly with global cognition (r = -0.32), memory function (r = -0.28), and hippocampal volume (r = -0.36) among those with abnormal Aβ deposition. Finally, the CSF Aβ42 cutoff derived from the original cohort (≤647 pg/mL) had an equally high agreement (95%; κ = 0.89) with 18F-flutemetamol positron emission tomography in the validation cohort.
  
  
  CONCLUSIONS
  Cerebrospinal fluid Aβ42 analyzed consecutively in routine clinical practice at an accredited laboratory can be used with high accuracy to determine whether a patient has normal or increased cortical Aβ deposition and so can be valuable for the early diagnosis of Alzheimer disease. Abnormal 18F-flutemetamol retention levels correlate with disease stage in patients with mild cognitive symptoms, but this is not the case for CSF Aβ42 measurements.
authors.affiliation: Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden2Department of Neurology, Skåne University Hospital, Malmö, Sweden.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Palmqvist
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg and Mölndal, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg and Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Geriatric Psychiatry Unit, Department of Clinical Sciences, Lund University, Lund, Sweden5Department of Psychology, Lund University, Lund, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Vestberg
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg and Mölndal, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Andreasson
authors.affiliation: Department of Medicine, Imperial College London, London, England7Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: David J
authors.initials: DJ
authors.lastname: Brooks
authors.affiliation: GE Healthcare, Life Sciences, Uppsala, Sweden.
authors.forename: Rikard
authors.initials: R
authors.lastname: Owenius
authors.affiliation: Department of Clinical Neurophysiology, Skåne University Hospital, Lund, Sweden.
authors.forename: Douglas
authors.initials: D
authors.lastname: Hägerström
authors.affiliation: Clinical Physiology and Nuclear Medicine Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Wollmer
authors.affiliation: Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Minthon
authors.affiliation: Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.
authors.forename: Oskar
authors.initials: O
authors.lastname: Hansson
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 / Q000378:metabolism*; D000814:Aniline Compounds; D052160:Benzothiazoles; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002540:Cerebral Cortex / Q000000981:diagnostic imaging* / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000000981:diagnostic imaging; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D042241:Early Diagnosis; D005260:Female; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D015203:Reproducibility of Results
chemical_list: D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D052160:Benzothiazoles; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; C075222:amyloid beta-protein (1-42); C581552:flutemetamol