Use of Florbetapir-PET for Imaging beta-Amyloid Pathology

Avid Radiopharmaceuticals, Philadelphia, Pennsylvania, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 30.39). 01/2011; 305(3):275-83. DOI: 10.1001/jama.2010.2008
Source: PubMed

ABSTRACT The ability to identify and quantify brain β-amyloid could increase the accuracy of a clinical diagnosis of Alzheimer disease.
To determine if florbetapir F 18 positron emission tomographic (PET) imaging performed during life accurately predicts the presence of β-amyloid in the brain at autopsy.
Prospective clinical evaluation conducted February 2009 through March 2010 of florbetapir-PET imaging performed on 35 patients from hospice, long-term care, and community health care facilities near the end of their lives (6 patients to establish the protocol and 29 to validate) compared with immunohistochemistry and silver stain measures of brain β-amyloid after their death used as the reference standard. PET images were also obtained in 74 young individuals (18-50 years) presumed free of brain amyloid to better understand the frequency of a false-positive interpretation of a florbetapir-PET image.
Correlation of florbetapir-PET image interpretation (based on the median of 3 nuclear medicine physicians' ratings) and semiautomated quantification of cortical retention with postmortem β-amyloid burden, neuritic amyloid plaque density, and neuropathological diagnosis of Alzheimer disease in the first 35 participants autopsied (out of 152 individuals enrolled in the PET pathological correlation study).
Florbetapir-PET imaging was performed a mean of 99 days (range, 1-377 days) before death for the 29 individuals in the primary analysis cohort. Fifteen of the 29 individuals (51.7%) met pathological criteria for Alzheimer disease. Both visual interpretation of the florbetapir-PET images and mean quantitative estimates of cortical uptake were correlated with presence and quantity of β-amyloid pathology at autopsy as measured by immunohistochemistry (Bonferroni ρ, 0.78 [95% confidence interval, 0.58-0.89]; P <.001]) and silver stain neuritic plaque score (Bonferroni ρ, 0.71 [95% confidence interval, 0.47-0.86]; P <.001). Florbetapir-PET images and postmortem results rated as positive or negative for β-amyloid agreed in 96% of the 29 individuals in the primary analysis cohort. The florbetapir-PET image was rated as amyloid negative in the 74 younger individuals in the nonautopsy cohort.
Florbetapir-PET imaging was correlated with the presence and density of β-amyloid. These data provide evidence that a molecular imaging procedure can identify β-amyloid pathology in the brains of individuals during life. Additional studies are required to understand the appropriate use of florbetapir-PET imaging in the clinical diagnosis of Alzheimer disease and for the prediction of progression to dementia.

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Available from: Carl H Sadowsky, Mar 20, 2014
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    • "The brain amyloid burden could be sensitively detected by some amyloid-related phenotypes. Cerebrospinal fluid (CSF) A␤ 1-42 and florbetapir 18 F amyloid positron emission tomography (AV45-PET) have both shown high specificity in reflecting brain amyloid burden, and are proposed as established endophenotypes for AD [5] [6]. Moreover, AD pathology could be found in the brains of nondemented elderly and mild cognitive impairment (MCI) patients, and genetic factors might play different roles at different levels of disease severity. "
    Journal of Alzheimer's disease: JAD 05/2015; 46(2):491-495. DOI:10.3233/JAD-150110 · 3.61 Impact Factor
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    • "In order to assess Ab burden across a wide sampling of cortical areas, standardized uptake value ratios (SUVRs) were computed by normalizing counts from eight bilateral cortical regions (precuneus, posterior and anterior cingulate , dorsolateral prefrontal, orbital frontal, temporal, parietal , and occipital cortices) to cerebellar hemisphere (excluding peduncles). These eight cortical regions were selected because they are regions in which in vivo Ab deposition has been shown to discriminate Alzheimer's patients from healthy controls [Clark et al., 2011], and these regions are commonly used in Ab-imaging studies of preclinical AD [Clark et al., 2011; Rodrigue et al., 2012]. All regions were defined using Automated Anatomical Labeling (AAL; Tzourio-Mazoyer et al., 2002] masks modified to minimize nonspecific white matter binding [see Rodrigue et al., 2012 for more detail and an illustration of these regions]. "
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    ABSTRACT: The recent ability to measure in vivo beta-amyloid (Aβ), a marker of Alzheimer's disease (AD), has led to an increased focus on the significance of Aβ deposition in clinically normal adults. Evidence suggests that healthy adults with elevated cortical Aβ show differences in neural activity associated with memory encoding-specifically encoding of face stimuli. Here, we examined if Aβ deposition in clinically normal adults was related to differences in neural activity in ventral visual cortex during face viewing. Our sample included 23 high-Aβ older adults, 23 demographically matched low-Aβ older adults, and 16 young adults. Participants underwent cognitive testing, Aβ positron emission tomography imaging with (18) F-Florbetapir, and functional magnetic resonance imaging to measure neural activity while participants passively viewed photographs of faces. Using barycentric discriminant analysis-a between-groups classification technique-we found that patterns of neural activity in the left fusiform gyrus, a region highly responsive to faces, distinguished Aβ status of participants. Older adults with elevated Aβ were characterized by decreased activity in left fusiform compared to Aβ-negative older adults. Further, we found that the degree to which older adults expressed decreased fusiform activity was related to worse performance on tasks of processing speed. Our results provide unique evidence that, in addition to previously studied memory and default regions, decreased neural activity in a region important for face perception was associated with elevated Aβ and may be an early manifestation of AD. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 04/2015; DOI:10.1002/hbm.22788 · 6.92 Impact Factor
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    • "Given the importance of a stable reference region in order to detect small changes in cortical amyloid, it is critical to identify regions with little or no amyloid accumulation to serve as reference regions. Although the SWM and the PON both appeared to be good candidates in our analyses, the development of novel tracers with increased binding to non-amyloid structure in SWM [9] may make the pons a better alternative reference region, provided that pons is relatively spared from non-specific uptake. Conventional cut-offs to demarcate amyloidpositive from amyloid-negative have been developed using cerebellum normalization. "
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    ABSTRACT: Background: Pittsburgh Compound B (PiB) positron emission tomography (PET) neuroimaging is a powerful research tool to characterize amyloid evolution in the brain. Quantification of amyloid load critically depends on (i) the choice of a reference region (RR) and (ii) on the selection of regions of interest (ROIs) to derive the standard uptake value ratios (SUVRs). Objective: To evaluate the stability, i.e., negligible amyloid accumulation over time, of different RRs, and the performance of different PiB summary measures defined by selected ROIs and RRs for their sensitivity to detecting longitudinal change in amyloid burden. Methods: To evaluate RRs, cross-sectional and longitudinal analyses of focal regional and composite measures of amyloid accumulation were carried out on the standardized PiB-PET regional data for cerebellar grey matter (CER), subcortical white matter (SWM), and pons (PON). RRs and candidate composite SUVR measures were further evaluated to select regions and develop novel composites, using standardized 2-year change from baseline. Results: Longitudinal trajectories of PiB4-average of anterior cingulate (ACG), frontal cortex (FRC), parietal cortex, and precuneus-demonstrated marked variability and small change from baseline when normalized to CER, larger changes and less variability when normalized to SWM, which was further enhanced for the composite in PON-normalized settings. Novel composite PiB3, comprised of the average SUVRs of lateral temporal cortex, ACG, and FRC was created. Conclusion: PON and SWM appeared to be more stable RRs than the CER. PiB3 showed compelling sample size reduction and gains in power calculations for clinical trials over conventional PiB4 composite.
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