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. 2012 Jan-Mar;26(1):8-16.
doi: 10.1097/WAD.0b013e31821300bc.

Correlation of amyloid PET ligand florbetapir F 18 binding with Aβ aggregation and neuritic plaque deposition in postmortem brain tissue

Seok Rye Choi  1 , Julie A Schneider, David A Bennett, Thomas G Beach, Barry J Bedell, Simone P Zehntner, Michael J Krautkramer, Hank F Kung, Daniel M Skovronsky, Franz Hefti, Christopher M Clark
Affiliations

Correlation of amyloid PET ligand florbetapir F 18 binding with Aβ aggregation and neuritic plaque deposition in postmortem brain tissue

Seok Rye Choi et al. Alzheimer Dis Assoc Disord. 2012 Jan-Mar.

Abstract

Background: Florbetapir F 18 (F-AV-45) is a positron emission tomography imaging ligand for the detection of amyloid aggregation associated with Alzheimer disease. Earlier data showed that florbetapir F 18 binds with high affinity to β-amyloid (Aβ) plaques in human brain homogenates (Kd=3.7 nM) and has favorable imaging pharmacokinetic properties, including rapid brain penetration and washout. This study used human autopsy brain tissue to evaluate the correlation between in vitro florbetapir F 18 binding and Aβ density measured by established neuropathologic 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 patients with a varying degree of neurodegenerative pathology was assessed by standard florbetapir F 18 autoradiography and correlated with the localization and density of Aβ identified by silver staining, thioflavin S staining, and immunohistochemistry.

Results: There were strong quantitative correlations between florbetapir F 18 tissue binding and both Aβ plaques identified by light microscopy (Silver staining and thioflavin S fluorescence) and by immunohistochemical measurements of Aβ using 3 antibodies recognizing different epitopes of the Aβ peptide. Florbetapir F 18 did not bind to neurofibrillary tangles.

Conclusions: Florbetapir F 18 selectively binds Aβ in human brain tissue. The binding intensity was quantitatively correlated with the density of Aβ plaques identified by standard neuropathologic techniques and correlated with the density of Aβ measured by immunohistochemistry. As Aβ plaques are a defining neuropathologic feature for Alzheimer disease, these results support the use of florbetapir F 18 as an amyloid positron emission tomography ligand to identify the presence of Alzheimer disease pathology in patients with signs and symptoms of progressive late-life cognitive impairment.

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Figures

Figure 1
Figure 1
Double-labeling of amyloid plaques with thioflavin S fluorescence microscopy (A) and florbetapir F 18 autoradiography (B). Image (C) shows the two figures combined. White bars indicate 100 μm.
Figure 2
Figure 2
In vitro florbetapir F 18. The darkly speckled band around the edge of the positive tissue sections reflects florbetapir F 18 labeling of gray matter β-amyloid, while the light central area of the tissue reflects white matter which is not specifically labeled by florbetapir F 18.
Figure 3
Figure 3
Representative examples of immunohistochemical staining with 4G8 (A), 6F/3D (B), and 10D5 (C).
Figure 4
Figure 4
Anti-Aβ immunohistochemistry with antibody 4G8 and florbetapir F 18 autoradiography on adjacent sections of human brain tissue (numbers correspond to subject numbers in Table 2-1). Top row: Parametric maps of beta-amyloid burden over the entire tissue section generated from PERMITS™ processing of digitized 4G8 IHC data. . The spectral color scale shows gray matter amyloid burden per unit area (0–30%). Bottom row: florbetapir F 18 autoradiography.
Figure 5
Figure 5
(A–G): Correlations of florbetapir F 18 ARG, neuritic plaque density, and β-amyloid tissue density by immunohistochemical staining.
Figure 5
Figure 5
(A–G): Correlations of florbetapir F 18 ARG, neuritic plaque density, and β-amyloid tissue density by immunohistochemical staining.
Figure 5
Figure 5
(A–G): Correlations of florbetapir F 18 ARG, neuritic plaque density, and β-amyloid tissue density by immunohistochemical staining.
Figure 5
Figure 5
(A–G): Correlations of florbetapir F 18 ARG, neuritic plaque density, and β-amyloid tissue density by immunohistochemical staining.
Figure 5
Figure 5
(A–G): Correlations of florbetapir F 18 ARG, neuritic plaque density, and β-amyloid tissue density by immunohistochemical staining.
Figure 5
Figure 5
(A–G): Correlations of florbetapir F 18 ARG, neuritic plaque density, and β-amyloid tissue density by immunohistochemical staining.
Figure 5
Figure 5
(A–G): Correlations of florbetapir F 18 ARG, neuritic plaque density, and β-amyloid tissue density by immunohistochemical staining.
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