Correspondence between in vivo (11)C-PiB-PET amyloid imaging and postmortem, region-matched assessment of plaques

Abstract

The definitive Alzheimer's disease (AD) diagnosis requires postmortem confirmation of neuropathological hallmarks-amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The advent of radiotracers for amyloid imaging presents an opportunity to investigate amyloid deposition in vivo. The (11)C-Pittsburgh compound-B (PiB)-PET ligand remains the most widely studied to date; however, regional variations in (11)C-PiB binding and the extent of agreement with neuropathological assessment have not been thoroughly investigated. Sojkova and colleagues [35] reported variable agreement between CERAD-based neuropathologic diagnosis of AD lesions and mean cortical PiB, suggesting the need for a more direct quantification of regional Aβ in relation to in vivo imaging. In the present study, we extend these findings by examining the correspondence among regional (11)C-PiB load, region-matched quantitative immunohistological assessments of Aβ and NFTs, and brain atrophy (MRI) in six older Baltimore Longitudinal Study of Aging participants who came to autopsy (imaging-autopsy interval range 0.2-2.4 years). The total number of Aβ plaques (6E10) and NFTs (PHF1) in paraffin sections from hippocampus, orbito-frontal cortex, anterior and posterior cingulate gyrus, precuneus and cerebellum was quantified using a technique guided by unbiased stereological principles. We report a general agreement between the regional measures of amyloid obtained via stereological assessment and imaging, with significant relationships evident for the anterior (r = 0.83; p = 0.04) and posterior (r = 0.94; p = 0.005) cingulate gyri, and the precuneus (r = 0.94; p = 0.005). No associations were observed between (11)C-PiB load and NFT count for any of the regions examined (p > 0.2 in all regions), or between regional Aβ or NFT counts and corresponding brain volumes. The strong associations of PiB retention with region-matched, quantitative analyses of Aβ in postmortem tissue offer support for the validity of (11)C-PiB-PET imaging as a method for evaluation of plaque burden in vivo.

Figure 1

Comparison of regional distribution of A) amyloid load in vivo (¹¹C-PiB DVR; from Sojkova et al., 2011) and B) corresponding Aβ immunohistochemistry (6E10) on a case-by-case basis. A) Voxel-wise ¹¹C-PiB distribution DVR maps are overlaid on the cortical surface and parasagittal slices. B) Area fraction of Aβ by 6E10 immunohistochemistry is represented on the y-axis. Each of six participants are denoted on x-axis corresponding to the labels used for DVR maps in A). Different colors represent each of the six regions examined.

Figure 2

Correspondence between regional amyloid load by ¹¹C-PiB and immunohistochemistry (6E10) in A) the hippocampus, B) orbito-frontal cortex, C) anterior cingulate gyrus, D) posterior cingulate gyrus, and E) the precuneus. Regional PiB DVR is represented on the y-axis; regional area fraction of Aβ by 6E10 immunohistochemistry is represented on the x-axis. F) Aβ by immunohistochemistry (6E10) in the precuneus (original magnification × 10).