title: Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 β-Amyloid Measures Across the Spectrum of Alzheimer Disease.
abstract: OBJECTIVE
  Cerebrospinal fluid (CSF) and positron emission tomographic (PET) amyloid biomarkers have been proposed for the detection of Alzheimer disease (AD) pathology in living patients and for the tracking of longitudinal changes, but the relation between biomarkers needs further study.
  
  
  OBJECTIVE
  To determine the association between CSF and PET amyloid biomarkers (cross-sectional and longitudinal measures) and compare the cutoffs for these measures.
  
  
  METHODS
  Longitudinal clinical cohort study from 2005 to 2014 including 820 participants with at least 1 florbetapir F-18 (hereafter referred to as simply florbetapir)-PET scan and at least 1 CSF β-amyloid 1-42 (Aβ1-42) sample obtained within 30 days of each other (501 participants had a second PET scan after 2 years, including 150 participants with CSF Aβ1-42 measurements). Data were obtained from the Alzheimer's Disease Neuroimaging Initiative database.
  
  
  METHODS
  Four different PET scans processing pipelines from 2 different laboratories were compared. The PET cutoff values were established using a mixture-modeling approach, and different mathematical models were applied to define the association between CSF and PET amyloid measures.
  
  
  RESULTS
  The values of the CSF Aβ1-42 samples and florbetapir-PET scans showed a nonlinear association (R2 = 0.48-0.66), with the strongest association for values in the middle range. The presence of a larger dynamic range of florbetapir-PET scan values in the higher range compared with the CSF Aβ1-42 plateau explained the differences in correlation with cognition (R2 = 0.36 and R2 = 0.25, respectively). The APOE genotype significantly modified the association between both biomarkers. The PET cutoff values derived from an unsupervised classifier converged with previous PET cutoff values and the established CSF Aβ1-42 cutoff levels. There was no association between longitudinal Aβ1-42 levels and standardized uptake value ratios during follow-up.
  
  
  CONCLUSIONS
  The association between both biomarkers is limited to a middle range of values, is modified by the APOE genotype, and is absent for longitudinal changes; 4 different approaches in 2 different platforms converge on similar pathological Aβ cutoff levels; and different pipelines to process PET scans showed correlated but not identical results. Our findings suggest that both biomarkers measure different aspects of AD Aβ pathology.
authors.affiliation: Institute on Aging, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.affiliation: Institute on Aging, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Maria
authors.initials: M
authors.lastname: Bjerke
authors.affiliation: Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia.
authors.forename: Xiao
authors.initials: X
authors.lastname: Da
authors.affiliation: Helen Wills Neuroscience Institute, University of California, Berkeley.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Landau
authors.affiliation: Center for Alzheimer's Care, Imaging and Research, Department of Neurology, University of Utah, Salt Lake City.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Foster
authors.affiliation: Helen Wills Neuroscience Institute, University of California, Berkeley.
authors.forename: William
authors.initials: W
authors.lastname: Jagust
authors.affiliation: Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Clifford
authors.initials: C
authors.lastname: Jack
authors.affiliation: Center for Imaging of Neurodegenerative Diseases, Department of Radiology, San Francisco VA Medical Center/University of California, San Francisco.
authors.forename: Michael
authors.initials: M
authors.lastname: Weiner
authors.affiliation: Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia.
authors.forename: Christos
authors.initials: C
authors.lastname: Davatzikos
authors.affiliation: Institute on Aging, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.affiliation: Institute on Aging, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000814:Aniline Compounds; D015415:Biomarkers; D003430:Cross-Sectional Studies; D005026:Ethylene Glycols; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D049268:Positron-Emission Tomography
chemical_list: D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D015415:Biomarkers; D005026:Ethylene Glycols; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C545186:florbetapir
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