Using Positron Emission Tomography and Florbetapir F 18 to Image Cortical Amyloid in Patients With Mild Cognitive Impairment or Dementia Due to Alzheimer Disease

Abstract

To characterize quantitative florbetapir F 18 (hereafter referred to as simply florbetapir) positron emission tomographic (PET) measurements of fibrillar ␤-amyloid (A␤) burden in a large clinical cohort of participants with probable Alzheimer disease (AD) or mild cognitive impairment (MCI) and older healthy controls (OHCs). Design: Cerebral-to-whole-cerebellar florbetapir standard uptake value ratios (SUVRs) were computed. Mean cortical SUVRs were compared. A threshold of SUVRs greater than or equal to 1.17 was used to reflect pathological levels of amyloid associated with AD based on separate antemortem PET and postmortem neuropathology data from 19 end-of-life patients. Similarly, a threshold of SUVRs greater than 1.08 was used to signify the presence of any identifiable A␤ because this was the upper limit from a separate set of 46 individuals 18 to 40 years of age who did not carry apolipoprotein E (APOE) ε4. Setting: Multiple research imaging centers. Participants: A total of 68 participants with probable AD, 60 participants with MCI, and 82 OHCs who were 55 years of age or older. Main Outcome Measure: Florbetapir-PET activity. Results: All of the participants (ie, those with probable AD or MCI and those who were OHCs) differed significantly in mean (SD) cortical florbetapir SUVRs (1.39 [0.24], 1.17 [0.27], and 1.05 [0.16], respectively; P Ͻ1.0ϫ10 −7), in percentage meeting levels of amyloid associated with AD by SUVR criteria (80.9%, 40.0%, and 20.7%, respectively; P Ͻ 1.0 ϫ 10 −7), and in percentage meeting SUVR criteria for the presence of any identifiable A␤ (85.3%, 46.6%, and 28.1%, respectively; P Ͻ 1.0 ϫ 10 −7). Among OHCs, the percentage of florbetapir positivity increased linearly by age decile (P=.05). For the 54 OHCs with available APOE genotypes, APOE ε4 carriers had a higher mean (SD) cortical SUVR than did noncarriers (1.14 [0.2] vs 1.03 [0.16]; P =.048). Conclusions: The findings of our analysis confirm the ability of florbetapir-PET SUVRs to characterize amyloid levels in clinically probable AD, MCI, and OHC groups using continuous and binary measures of fibrillar A␤ burden. It introduces criteria to determine whether an image is associated with an intermediate-to-high likelihood of pathologic AD or with having any identifiable cortical amyloid level above that seen in low-risk young controls.

Use of Standardized Uptake Value Ratios Decreases Interreader Variability of [18F] Florbetapir PET Brain Scan Interpretation

“…5,11 These findings motivated quantitative analysis of [ 18 F] florbetapir PET brain images, comparing differential binding between these cortical regions to the whole cerebellum, a site not prone to amyloid deposition, expressed as cerebral-to-whole-cerebellar standardized uptake value ratios (SUVr). 5,12 Subsequent pathologic analysis demonstrated high sensitivity (97%), specificity (100%), and accuracy (98%) between [ 18 F] florbetapir PET SUVr and postmortem immunohistochemical measurements of ␤-amyloid. 5,7,12 These studies showed that a mean [ 18 F] florbetapir SUVr value of Ͼ1.17 was strongly associated with an intermediate-to-high likelihood of a neuropathologic diagnosis of AD.…”

Amyloid-β imaging with PET in Alzheimer’s disease: is it feasible with current radiotracers and technologies?

“…This was reflected in a recent study using florbetapir, which showed significant overlap between scans of patients with probable AD, patients with MCI, and older healthy controls (Fig. 4) [8]. These observations severely limit the utility of this PET imaging approach for accurately diagnosing the presence or absence of MCI, let alone early AD.…”

“…Patients with MCI, early AD, and late AD are assumed to have roughly 0.1%, 1%, and 6% of total cortical area (i.e., area fractions f a ) occupied by β-amyloid, respectively, and corresponding volume fractions (f v ) of roughly 0.03%, 0.33%, and 2.0%, respectively Fig. 4 A scatterplot of mean cortical SUV ratios in individuals with probable AD (PAD) and mild cognitive impairment (MCI), as well as older healthy controls (OHC) [8]. Noteworthy false-negative and false-positive rates can be seen in AD patients and controls, respectively (reproduced with permission from Archives of Neurology, [8]) established, the claim of causation is still a matter of debate and has recently been challenged by developments in the clinical trials of antiamyloid pharmaceuticals.…”

“…However, the advent of three new radiotracers, which are currently at various stages of FDA assessment and approval, has brought amyloid imaging to the doorstep of clinical use. Recent clinical studies on florbetapir (AV-45), florbetaben (BAY-94), and flutemetamol (GE-067) claim to have demonstrated an ability to discriminate between AD patients and healthy controls with high degrees of sensitivity and specificity [6][7][8][9][10][11]. However, the theoretical bases of and ubiquitous patterns in the reported data raise a host of lingering questions that should be addressed before these radiotracers are clinically approved.…”

“…et al reported significant correlations between quantitative and semiquantitative measures of overall amyloid burden through imaging and histopathology, but the regional localizations of these amyloid deposits do not seem to agree with pre-existing pathological data [5]. Imaging studies conducted with florbetapir, as well as virtually any other amyloid radiotracer, consistently show the frontal lobe to have one of-if not the-highest standardized uptake values (SUVs) [6,8,9,[11][12][13][14]. This implies a preponderant amyloid burden in the frontal lobe, which is not in line with the findings of in vitro studies.…”