Correlation of Amyloid PET Ligand Florbetapir F 18 Binding With Aβ Aggregation and Neuritic Plaque Deposition in Postmortem Brain Tissue

Abstract

Background Florbetapir F 18 (18F-AV-45) is a positron emission tomography (PET) imaging ligand for the detection of amyloid aggregation associated with Alzheimer’s disease. Earlier data showed that florbetapir F 18 binds with high affinity to β-amyloid plaques in human brain homogenates (Kd = 3.7 nM) and has favorable imaging pharmacokinetic properties, including rapid brain penetration and washout. The present study used human autopsy brain tissue to evaluate the correlation between in vitro florbetapir F 18 binding and β-amyloid density measured by established neuropathological methods. Methods The localization and density of florbetapir F 18 binding in frozen and formalin-fixed paraffin-embedded sections of postmortem brain tissue from 40 subjects with a varying degree of neurodegenerative pathology was assessed by standard florbetapir F 18 autoradiography and correlated with the localization and density of β-amyloid identified by silver staining, thioflavin S staining, and immunohistochemistry. Results There were strong quantitative correlations between florbetapir F 18 tissue binding and both β-amyloid plaques identified by light microscopy (sliver staining and thioflavin S fluorescence) and by immunohistochemical measurements of β-amyloid using three antibodies recognizing different epitopes of the β-amyloid peptide (Aβ). Florbetapir F 18 did not bind to neurofibrillary tangles. Conclusion Florbetapir F 18 selectively binds β-amyloid in human brain tissue. The binding intensity was quantitatively correlated with the density of β-amyloid plaques identified by standard neuropathological techniques and correlated with the density of Aβ measured by immunohistochemistry. Since β-amyloid plaques are a defining neuropathological feature for Alzheimer’s disease, these results support the use of florbetapir F 18 as an amyloid PET ligand to identify the presence of AD pathology in patients with signs and symptoms of progressive late-life cognitive impairment.

Longitudinal Assessment of Cerebral β-Amyloid Deposition in Mice Overexpressing Swedish Mutant β-Amyloid Precursor Protein Using 18F-Florbetaben PET

“…In those studies, progressive contamination of the cerebellum reference tissue signal contributed importantly to a systematic underestimation of the magnitude of the ligand BP ND in the striatum region of interest, despite an optimized iterative reconstruction procedure. Others have resorted to factor analysis for the correction of spill-in (29) or pharmacologic suppression of the pathway for radioligand defluorination (30). In the only previous rodent study using the 18 F-labeled amyloid tracer flutemetamol considering this issue (9), no significant defluorination was detected in rats in vivo, and the uptake in bone and brain were comparable at 120 min after injection.…”

A Quantitative Analysis of Brain Soluble Tau and the Tau Secretion Factor

“…Thioflavin S is one of the methods recommended and validated for neuritic plaque density grading by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (19); Braak NFT staging was originally described using the Gallyas stain (20). The validity and accuracy of this combination of stains for estimating the density of Ab deposits has also been established through strong correlations with autoradiographic binding of the amyloid imaging ligand Florbetapir (Spearman rho ¼ 0.95) to postmortem human brain sections from AD subjects (21), with biochemical measures (ELISA) of Ab in human cerebral cortex extracts (Spearman rho ¼ 0.89) and with quantitative immunohistochemical stains for Ab (Spearman rho ¼ 0.86) (22).…”

Quantification of Blood Flow-Dependent Component in Estimates of Beta-Amyloid Load Obtained Using Quasi-Steady-State Standardized Uptake Value Ratio

“…In recent years, radioligands binding specifically to fibrillar amyloid-β (Aβ) have been successfully applied. 1 The radioligands have enabled in vivo detection of amyloid deposits [2][3][4][5] and have been implemented in clinical research including longitudinal amyloid imaging such as in the Alzheimer's Disease Neuroimaging Initiative (ADNI) or in the Australian Imaging Biomarkers and Lifestyle study. 6,7 Importantly, cross-sectional results indicate that the prevalence of high amyloid binding is 15% to 25% in cognitively normal (CN) elderly controls, 50% to 70% in patients with mild cognitive impairment (MCI), and 85% to 95% in those with probable AD.…”