In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18)

Abstract

An (18)F-labeled PET amyloid-beta (Abeta) imaging agent could facilitate the clinical evaluation of late-life cognitive impairment by providing an objective measure for Alzheimer disease (AD) pathology. Here we present the results of a clinical trial with (E)-4-(2-(6-(2-(2-(2-(18)F-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine ((18)F-AV-45 or florbetapir [corrected] F 18).

Methods: An open-label, multicenter brain imaging, metabolism, and safety study of (18)F-AV-45 was performed on 16 patients with AD (Mini-Mental State Examination score, 19.3 +/- 3.1; mean age +/- SD, 75.8 +/- 9.2 y) and 16 cognitively healthy controls (HCs) (Mini-Mental State Examination score, 29.8 +/- 0.45; mean age +/- SD, 72.5 +/- 11.6 y). Dynamic PET was performed over a period of approximately 90 min after injection of the tracer (370 MBq [10 mCi]). Standardized uptake values and cortical-to-cerebellum standardized uptake value ratios (SUVRs) were calculated. A simplified reference tissue method was used to generate distribution volume ratio (DVR) parametric maps for a subset of subjects.

Results: Valid PET data were available for 11 AD patients and 15 HCs. (18)F-AV-45 accumulated in cortical regions expected to be high in Abeta deposition (e.g., precuneus and frontal and temporal cortices) in AD patients; minimal accumulation of the tracer was seen in cortical regions of HCs. The cortical-to-cerebellar SUVRs in AD patients showed continual substantial increases through 30 min after administration, reaching a plateau within 50 min. The 10-min period from 50 to 60 min after administration was taken as a representative sample for further analysis. The cortical average SUVR for this period was 1.67 +/- 0.175 for patients with AD versus 1.25 +/- 0.177 for HCs. Spatially normalized DVRs generated from PET dynamic scans were highly correlated with SUVR (r = 0.58-0.88, P < 0.005) and were significantly greater for AD patients than for HCs in cortical regions but not in subcortical white matter or cerebellar regions. No clinically significant changes in vital signs, electrocardiogram, or laboratory values were observed.

Conclusion: (18)F-AV-45 was well tolerated, and PET showed significant discrimination between AD patients and HCs, using either a parametric reference region method (DVR) or a simplified SUVR calculated from 10 min of scanning 50-60 min after (18)F-AV-45 administration.

Figures

Figure 1

Representative [18F]AV-45 PET images. Average of two consecutive 5 minute PET brain images (obtained 50 – 60 minutes post injection) from a 77 year old female mild AD patient with an MMSE of 24 (top) and an 82 year old male cognitively healthy control with an MMSE of 30 (bottom), following injection with 10 mCi [18F]AV-45. Experimental conditions and imaging and computational parameters were identical for the two subjects. Counts are shown as ratio to the average of the grey matter in cerebellum for each subject (SUVR).

Figure 2

Mean time activity curves. Mean Precuneus, Cortical Average and Cerebellum Standard Uptake Values (SUV) are shown for cognitively healthy controls (HC, left panel) and patients with Alzheimer’s disease (AD, right panel). Subjects were scanned for approximately 90 minutes (horizontal axis represents the beginning of each imaging time point, e.g., 80–90 min)

Figure 3

Mean cortical average SUVR for cognitively healthy controls (HC) and patients with Alzheimer’s disease (AD). As would be expected from the SUV time activity curves (Figure 2), the cortical target to cerebellum SUVRs for both AD patients and HC subjects approached asymptote at 50 minutes and remained essentially unchanged between 50 and 90 minutes post injection of [18F]AV-45. Subjects were scanned for approximately 90 minutes (horizontal axis represents the beginning of each imaging time point, e.g., 80–90 min).

Figure 4

Precuneus (left panel) and cortical average (right panel) SUVR relative to cerebellum for individual AD patients and cognitively healthy controls for all 3 imaging sites.