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Original Investigation |

Comparison of Visual and Quantitative Florbetapir F 18 Positron Emission Tomography Analysis in Predicting Mild Cognitive Impairment Outcomes

Stefanie Schreiber, MD1,2,3; Susan M. Landau, PhD1,4; Allison Fero, BSc1,4; Frank Schreiber, MSc5; William J. Jagust, MD1,4 ; for the Alzheimer’s Disease Neuroimaging Initiative
[+] Author Affiliations
1Helen Wills Neuroscience Institute, University of California, Berkeley
2Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany
3German Center for Neurodegenerative Diseases, Magdeburg
4Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California
5Institute of Control Engineering, Technische Universität Braunschweig, Braunschweig, Germany
JAMA Neurol. 2015;72(10):1183-1190. doi:10.1001/jamaneurol.2015.1633.
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Importance  The applicability of β-amyloid peptide (Aβ) positron emission tomography (PET) as a biomarker in clinical settings to aid in selection of individuals at preclinical and prodromal Alzheimer disease (AD) will depend on the practicality of PET image analysis. In this context, visual-based Aβ PET assessment seems to be the most feasible approach.

Objectives  To determine the agreement between visual and quantitative Aβ PET analysis and to assess the ability of both techniques to predict conversion from mild cognitive impairment (MCI) to AD.

Design, Setting, and Participants  A longitudinal study was conducted among the Alzheimer’s Disease Neuroimaging Initiative (ADNI) sites in the United States and Canada during a 1.6-year mean follow-up period. The study was performed from September 21, 2010, to August 11, 2014; data analysis was conducted from September 21, 2014, to May 26, 2015. Participants included 401 individuals with MCI receiving care at a specialty clinic (219 [54.6%] men; mean [SD] age, 71.6 [7.5] years; 16.2 [2.7] years of education). All participants were studied with florbetapir F 18 [18F] PET. The standardized uptake value ratio (SUVR) positivity threshold was 1.11, and one reader rated all images, with a subset of 125 scans rated by a second reader.

Main Outcomes and Measures  Sensitivity and specificity of positive and negative [18F] florbetapir PET categorization, which was estimated with cerebrospinal fluid Aβ1-42 as the reference standard. Risk for conversion to AD was assessed using Cox proportional hazards regression models.

Results  The frequency of Aβ positivity was 48.9% (196 patients; visual analysis), 55.1% (221 patients; SUVR), and 64.8% (166 patients; cerebrospinal fluid), yielding substantial agreement between visual and SUVR data (κ = 0.74) and between all methods (Fleiss κ = 0.71). For approximately 10% of the 401 participants in whom visual and SUVR data disagreed, interrater reliability was moderate (κ = 0.44), but it was very high if visual and quantitative results agreed (κ = 0.92). Visual analysis had a lower sensitivity (79% vs 85%) but higher specificity (96% vs 90%), respectively, compared with SUVR. The conversion rate was 15.2% within a mean of 1.6 years, and a positive [18F] florbetapir baseline scan was associated with a 6.91-fold (SUVR) or 11.38-fold (visual) greater hazard for AD conversion, which changed only modestly after covariate adjustment for apolipoprotein ε4, concurrent fludeoxyglucose F 18 PET scan, and baseline cognitive status.

Conclusions and Relevance  Visual and SUVR Aβ PET analysis may be equivalently used to determine Aβ status for individuals with MCI participating in clinical trials, and both approaches add significant value for clinical course prognostication.

Figures in this Article

Figures

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Figure 1.
Grayscale Positron Emission Tomographic Images of Exemplary Participants With Mild Cognitive Impairment (MCI) With Discordant Results for Visual Florbetapir F 18 [18F] Analysis and [18F] Florbetapir Standardized Uptake Value Ratio (SUVR) Measurements

A, An early MCI (EMCI) nonconverter with a borderline SUVR value of 1.131 ([18F] florbetapir positive) close to the threshold of 1.11 is demonstrated. Well-preserved contrast between white and gray matter with high nonspecific white matter florbetapir binding and absent cortical tracer uptake resulted in a visual [18F] florbetapir-negative scan assessment among both readers; no cerebrospinal fluid (CSF) β-amyloid peptide (Aβ) values were available for this participant. B and C, Participants with EMCI who had high focal and asymmetric [18F] florbetapir retention in the temporal cortex (B, arrowheads) and the temporooccipital cortex (C, arrowheads); both readers rated both scans as visual [18F] florbetapir positive. The SUVR and CSF Aβ1-42 values for scan B were 1.097 ([18F] florbetapir negative) and 164.5 pg/mL (CSF Aβ positive). For scan C, SUVR was 1.106 ([18F] florbetapir negative) and CSF Aβ was 145.6 pg/mL (CSF Aβ positive). Participant B was a nonconverter; participant C converted to AD at age 72.7 years after a 12-month follow-up-period. D, An EMCI nonconverter’s scan with slightly reduced contrast between white and gray matter; both readers rated the image as [18F] florbetapir negative; the SUVR value of 1.242 indicated quantitative [18F] florbetapir positivity. No CSF Aβ values were available for this participant. E and F, An EMCI nonconverter with noncortical [18F] florbetapir uptake (arrowheads). Visual [18F] florbetapir-negative scan assessment between both readers agreed with an Aβ-negative CSF value of 233.4 pg/mL; SUVR measurement of 1.117 was borderline [18F] florbetapir positive.

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Figure 2.
Agreement Between Visual Interpretation, Quantitative Standardized Uptake Value Ratio (SUVR), and Cerebrospinal Fluid (CSF) β-Amyloid Peptide (Aβ) Measurement for 256 Participants With Early Mild Cognitive Impairment (EMCI) and Late MCI (LMCI)

Sector I and sector III demonstrate participants with concordant visual (reader 1) and quantitative florbetapir F 18 [18F]–positive (sector I) and [18F] florbetapir–negative (sector III) scan assessments (n = 221). Sector II and sector IV represent participants with discordant visual and quantitative florbetapir positron emission tomography (PET) data (n = 35). If visual and SUVR measures agreed, CSF Aβ data were highly concordant, particularly in case of scan assessment as [18F] florbetapir positive (orange diamonds, sector I). If visual and quantitative PET analyses were discordant, agreement with CSF Aβ data was poor. When [18F] florbetapir scans were assessed as positive, agreement between PET and CSF was very high (97% concordance for visual reads [orange diamonds in sectors I and II] and 94% concordance for SUVR measures [orange diamonds in sectors I and IV]). When scans were assessed as negative, concordance between PET and CSF was lower (71% concordance for visual reads [blue diamonds in sectors III and IV] and 76% concordance for SUVR measures [blue diamonds in sectors II and III]). The SUVR threshold of 1.11 (borders between sectors I and II and sectors III and IV) was derived from an independent sample.

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Figure 3.
Intermethod Agreement (Visual, Quantitative, Cerebrospinal Fluid [CSF]) and Interrater Agreement for a Subsample of Participants With Mild Cognitive Impairment (MCI) Visually Rated by Both Readers

The graph demonstrates all participants with available CSF β-amyloid peptide (Aβ) data (n = 77) of 125 cases rated by both readers. Sectors I and III illustrate individuals with MCI whose scan assessments were concordant between visual florbetapir F 18 [18F] analysis of reader 1 and [18F] florbetapir standardized uptake value ratio (SUVR) measurements. Sectors II and IV represent patients with MCI whose scan assessments were discordant between visual [18F] florbetapir analysis of reader 1 and [18F] florbetapir SUVR measurements. If visual and quantitative Aβ positron emission tomography evaluation agreed, interrater reliability was high (circles in sectors I and III) as was the concordance with CSF data (orange symbols in sector I, blue symbols in sector III). If visual and SUVR measures disagreed, concordance between both readers was only moderate (circles in sectors II and IV) and agreement with CSF data was very poor (orange symbols in sector II and blue symbols in sector IV for visual analysis, blue symbols in sector II and orange symbols in sector IV for SUVR analysis). The SUVR threshold of 1.11 (borders between sectors I and II and sectors III and IV) was derived from an independent sample.

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