title: Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease.
abstract: Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-β were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE ε4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-β was more strongly related to APOE ε4 whereas positron emission tomography amyloid-β was more strongly related to tau levels (P < 0.05). Discordance (mainly isolated cerebrospinal fluid amyloid-β positivity) differed by diagnostic group (P < 0.001) and was seen in 21% of cognitively healthy people but only 6% in dementia patients. The finding that cerebrospinal fluid and positron emission tomography amyloid-β provide partially independent information about a wide range of Alzheimer's measures supports the theory that these modalities represent partly different aspects of Alzheimer's pathology. The fact that mismatch, with positive cerebrospinal fluid amyloid-β but normal positron emission tomography amyloid-β, is relatively common in cognitively healthy people may be considered when using these biomarkers to identify early stage Alzheimer's disease. Reduced cerebrospinal fluid amyloid-β may be more strongly related to early stage Alzheimer's disease, whereas increased positron emission tomography amyloid-β may be more strongly related to disease progression.
authors.affiliation: 1 Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden 2 Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA 3 Department of Veterans Affairs Medical Centre, Centre for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA niklas.mattsson@neuro.gu.se.
authors.forename: Niklas
authors.initials: N
authors.lastname: Mattsson
authors.affiliation: 2 Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA 3 Department of Veterans Affairs Medical Centre, Centre for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Insel
authors.affiliation: 4 Division of Biostatistics and Bioinformatics, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Donohue
authors.affiliation: 5 Helen Wills Neuroscience Institute and School of Public Health, University of California, Berkeley, CA, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Landau
authors.affiliation: 5 Helen Wills Neuroscience Institute and School of Public Health, University of California, Berkeley, CA, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jagust
authors.affiliation: 6 Department of Pathology and Laboratory Medicine, Institute on Aging, Centre for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.affiliation: 6 Department of Pathology and Laboratory Medicine, Institute on Aging, Centre for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: 1 Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden 7 UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: 1 Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: 2 Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA 3 Department of Veterans Affairs Medical Centre, Centre for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000150:complications / Q000000981:diagnostic imaging* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000814:Aniline Compounds; D053327:Apolipoprotein E4 / Q000235:genetics; D003072:Cognition Disorders / Q000209:etiology; D015331:Cohort Studies; D005026:Ethylene Glycols; D005260:Female; D005462:Fluorine Radioisotopes; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D049268:Positron-Emission Tomography
chemical_list: D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D053327:Apolipoprotein E4; D005026:Ethylene Glycols; D005462:Fluorine Radioisotopes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D019788:Fluorodeoxyglucose F18; C545186:florbetapir
keywords: Alzheimer's disease; amyloid; biomarker; cerebrospinal fluid; positron emission tomography