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Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 β-Amyloid Measures Across the Spectrum of Alzheimer Disease.
JAMA Neurol. 2015 May; 72(5):571-81.JN

Abstract

IMPORTANCE

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.

DESIGN, SETTING, AND PARTICIPANTS

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.

MAIN OUTCOMES AND MEASURES

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 AND RELEVANCE

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+Show Affiliations

Institute on Aging, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.Institute on Aging, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia.Helen Wills Neuroscience Institute, University of California, Berkeley.Center for Alzheimer's Care, Imaging and Research, Department of Neurology, University of Utah, Salt Lake City.Helen Wills Neuroscience Institute, University of California, Berkeley.Mayo Clinic College of Medicine, Rochester, Minnesota.Center for Imaging of Neurodegenerative Diseases, Department of Radiology, San Francisco VA Medical Center/University of California, San Francisco.Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia.Institute on Aging, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.Institute on Aging, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.No affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

25822737

Citation

Toledo, Jon B., et al. "Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 β-Amyloid Measures Across the Spectrum of Alzheimer Disease." JAMA Neurology, vol. 72, no. 5, 2015, pp. 571-81.
Toledo JB, Bjerke M, Da X, et al. Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 β-Amyloid Measures Across the Spectrum of Alzheimer Disease. JAMA Neurol. 2015;72(5):571-81.
Toledo, J. B., Bjerke, M., Da, X., Landau, S. M., Foster, N. L., Jagust, W., Jack, C., Weiner, M., Davatzikos, C., Shaw, L. M., & Trojanowski, J. Q. (2015). Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 β-Amyloid Measures Across the Spectrum of Alzheimer Disease. JAMA Neurology, 72(5), 571-81. https://doi.org/10.1001/jamaneurol.2014.4829
Toledo JB, et al. Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 β-Amyloid Measures Across the Spectrum of Alzheimer Disease. JAMA Neurol. 2015;72(5):571-81. PubMed PMID: 25822737.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 β-Amyloid Measures Across the Spectrum of Alzheimer Disease. AU - Toledo,Jon B, AU - Bjerke,Maria, AU - Da,Xiao, AU - Landau,Susan M, AU - Foster,Norman L, AU - Jagust,William, AU - Jack,Clifford,Jr AU - Weiner,Michael, AU - Davatzikos,Christos, AU - Shaw,Leslie M, AU - Trojanowski,John Q, AU - ,, PY - 2015/3/31/entrez PY - 2015/3/31/pubmed PY - 2015/8/4/medline SP - 571 EP - 81 JF - JAMA neurology JO - JAMA Neurol VL - 72 IS - 5 N2 - IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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. SN - 2168-6157 UR - https://www.unboundmedicine.com/medline/citation/25822737/Nonlinear_Association_Between_Cerebrospinal_Fluid_and_Florbetapir_F_18_β_Amyloid_Measures_Across_the_Spectrum_of_Alzheimer_Disease_ L2 - https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/jamaneurol.2014.4829 DB - PRIME DP - Unbound Medicine ER -