Performance Characteristics of Amyloid PET with Florbetapir F 18 in Patients with Alzheimer's Disease and Cognitively Normal Subjects

Abstract

The objectives of this study were to examine the effective dose range and the test-retest reliability of florbetapir F 18 using, first, visual assessment by independent raters masked to clinical information and, second, semiautomated quantitative measures of cortical target area to cerebellum standardized uptake value ratios (SUVr) as primary outcome measures. Visual ratings of PET image quality and tracer retention or b-amyloid (Ab) binding expressed as SUVrs were compared after intravenous administration of either 111 MBq (3 mCi) or 370 MBq (10 mCi) of florbetapir F 18 in patients with Alzheimer's disease (AD) (n 5 9) and younger healthy controls (YHCs) (n 5 11). In a separate set of subjects (AD, n 5 10; YHCs, n 5 10), test-retest reliability was evaluated by comparing intrasubject visual read ratings and SUVrs for 2 PET images acquired within 4 wk of each other. Results: There were no meaningful differences between the 111-MBq (3-mCi) and 370-MBq (10-mCi) dose in the visual rating or SUVr. The difference in the visual quality across 111 and 370 MBq showed a trend toward lower image quality, but no statistical significance was achieved (t test; t 1 5 21.617, P 5 0.12) in this relatively small sample of subjects. At both dose levels, visual ratings of amyloid burden identified 100% of AD subjects as Ab-positive and 100% of YHCs as Ab-negative. Mean intrasubject test-retest variability for cortical average SUVrs with the cerebellum as a reference over the 50-to 70-min period was 2.4% 6 1.41% for AD subjects and 1.5% 6 0.84% for controls. The overall SUVr test-retest correlation coefficient was 0.99. The overall k-statistic for test-retest agreement for Ab classification of the masked reads was 0.89 (95% confidence interval, 0.69-1.0). Conclusion: Florbetapir F 18 appears to have a wide effective dose range and a high testretest reliability for both quantitative (SUVr) values and visual assessment of the ligand. These imaging performance properties provide important technical information on the use of florbetapir F 18 and PET to detect cerebral amyloid aggregates.

Quantitation of PET signal as an adjunct to visual interpretation of florbetapir imaging

“…The software packages used in this study, MIM (MIMneuro®), Siemens (Siemens syngo.PET Amyloid Plaque) and Hermes (Hermes Brain Analysis Software Suite™ BRASS, 2.0; CE 0413), are all commercially available and approved in the US and EU for visual examination and quantitation of PET images, with specific routines designed to quantitate 18 F-florbetapir PET images. Although the individual packages use different proprietary algorithms to perform the quantitation, the three packages share the following features:…”

“…PET imaging ligands including Pittsburgh compound B ( 11 C-PIB) [2], 18 F-florbetaben [3], 18 F-flutemetamol [4] and 18 F-florbetapir [5] have been developed for estimation of cortical beta amyloid (Aβ) neuritic plaque deposition, a hallmark pathology, and a required element for the evaluation of neuropathological changes in patients with Alzheimer's disease (AD) [6]. As shown by their respective package inserts/summaries of product characteristics, as well as the published literature [7][8][9], reader accuracy in the pivotal trials for the 18 F-labeled agents averaged close to 90% for discriminating patients found at autopsy to have no or sparse neuritic plaques (amyloid-negative, Aβ−) from those found to have moderate to frequent plaques (amyloid-positive, Aβ+). However, as might be expected, within each of these development programs, there were individual readers with sensitivity or specificity values below the average, and in some with values below 80%.…”

“…Quantitation has been applied extensively in other realms of nuclear medicine imaging including PET [14][15][16][17], and quantitative analyses have proven useful for characterizing amyloid tracer binding and relationships to other biomarkers [18][19][20]. In the case of 18 F-florbetapir, the use of an exploratory quantitative approach resulted in an accuracy of 97% in relation to autopsy [7]. Until recently, approaches to quantitating PET amyloid images have been limited to research methods that are nonstandard and may require manual intervention and technical expertise.…”

A Semiautomated Method for Quantification of F 18 Florbetapir PET Images

“…The threshold lines in Figure 4 indicate the mcSUVr threshold that best classified positive and negative cases obtained from the ROC analysis (1.10 for whole cerebellum, 1.28 for cerebellar gray matter, 0.78 for pons, and 0.68 for the centrum semiovale). The threshold of 1.10 determined on the basis of the ROC analysis in this study is identical to the threshold selected for no detectable amyloid in a prior study (19), based on the upper limit of the 2-sided 95% confidence interval for YCNs. Using the whole cerebellum as a reference region, there was clear classification with no overlap between the 74 YCN/20 pathologynegative group (black and blue dots) and 39 pathology-positive subjects (red dots) except for a single pathology-positive case, clinically diagnosed as AD, quantified with a mcSUVr of 1.02.…”

Tau PET and tauopathies

“…Thus, if the actual signal change during disease progression was similar or better to what is seen with FDG (although in the opposite direction), tau PET may actually provide superior performance as a progression biomarker. Compared to amyloid PET, which also has excellent test-retest reproducibility [7] but appears to reach a kind of plateau already very early during disease progression with little further change and poor correlation with clinical disease severity, tau PET clearly looks more promising.…”