Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 β-Amyloid Measures Across the Spectrum of Alzheimer Disease

Jon B Toledo; Maria Bjerke; Xiao Da; Susan M Landau; Norman L Foster; William Jagust; Clifford  Jack Jr; Michael Weiner; Christos Davatzikos; Leslie M Shaw; John Q Trojanowski; Alzheimer’s Disease Neuroimaging Initiative Investigators

doi:10.1001/jamaneurol.2014.4829

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Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 β-Amyloid Measures Across the Spectrum of Alzheimer Disease

Journal article

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Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 β-Amyloid Measures Across the Spectrum of Alzheimer Disease

Jon B Toledo, Maria Bjerke, Xiao Da, Susan M Landau, Norman L Foster, William Jagust, Clifford Jack Jr, Michael Weiner, Christos Davatzikos, Leslie M Shaw, …

JAMA neurology, Vol.72(5), pp.571-581

05/2015

DOI: 10.1001/jamaneurol.2014.4829

PMCID: PMC5642905

PMID: 25822737

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Abstract

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. To determine the association between CSF and PET amyloid biomarkers (cross-sectional and longitudinal measures) and compare the cutoffs for these measures. 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. 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. 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. 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.

Biomarkers

Peptide Fragments - cerebrospinal fluid

Cross-Sectional Studies

Aniline Compounds

Humans

Male

Positron-Emission Tomography

Alzheimer Disease - cerebrospinal fluid

Ethylene Glycols

Alzheimer Disease - metabolism

Amyloid beta-Peptides - metabolism

Aged, 80 and over

Amyloid beta-Peptides - cerebrospinal fluid

Female

Aged

Alzheimer Disease - diagnostic imaging

Longitudinal Studies

Details

Title: Subtitle: Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 β-Amyloid Measures Across the Spectrum of Alzheimer Disease
Creators: Jon B Toledo - Institute on Aging, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
Maria Bjerke - Institute on Aging, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
Xiao Da - Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia
Susan M Landau - Helen Wills Neuroscience Institute, University of California, Berkeley
Norman L Foster - Center for Alzheimer's Care, Imaging and Research, Department of Neurology, University of Utah, Salt Lake City
William Jagust - Helen Wills Neuroscience Institute, University of California, Berkeley
Clifford Jack Jr - Mayo Clinic College of Medicine, Rochester, Minnesota
Michael Weiner - Center for Imaging of Neurodegenerative Diseases, Department of Radiology, San Francisco VA Medical Center/University of California, San Francisco
Christos Davatzikos - Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia
Leslie M Shaw - Institute on Aging, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
John Q Trojanowski - Institute on Aging, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
Alzheimer’s Disease Neuroimaging Initiative Investigators
Contributors: Laura L Boles-Ponto (Contributor) - University of Iowa, Radiology
Resource Type: Journal article
Publication Details: JAMA neurology, Vol.72(5), pp.571-581
DOI: 10.1001/jamaneurol.2014.4829
PMID: 25822737
PMCID: PMC5642905
NLM abbreviation: JAMA Neurol
ISSN: 2168-6149
eISSN: 2168-6157
Publisher: United States
Grant note: U01 AG006786 / NIA NIH HHS U01 HL096917 / NHLBI NIH HHS P01 AG032953 / NIA NIH HHS R01AG043392 / NIA NIH HHS R01 AG043392 / NIA NIH HHS U01-AG06786 / NIA NIH HHS P30 AG010124 / NIA NIH HHS P30 AG013846 / NIA NIH HHS R01 AG011378 / NIA NIH HHS P01 AG017586 / NIA NIH HHS U01 AG024904 / NIA NIH HHS R01 AG37551 / NIA NIH HHS P50 NS053488 / NINDS NIH HHS R01 AG041851 / NIA NIH HHS U01-AG024904 / NIA NIH HHS R01 AG037551 / NIA NIH HHS R01-AG011378 / NIA NIH HHS U01-HL096917 / NHLBI NIH HHS
Language: English
Date published: 05/2015
Academic Unit: Radiology; Pharmaceutical Sciences and Experimental Therapeutics
Record Identifier: 9984051796402771

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