Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study

Summary

Background

Results of previous studies have shown associations between PET imaging of amyloid plaques and amyloid-β pathology measured at autopsy. However, these studies were small and not designed to prospectively measure sensitivity or specificity of amyloid PET imaging against a reference standard. We therefore prospectively compared the sensitivity and specificity of amyloid PET imaging with neuropathology at autopsy.

Methods

This study was an extension of our previous imaging-to-autopsy study of participants recruited at 22 centres in the USA who had a life expectancy of less than 6 months at enrolment. Participants had autopsy within 2 years of PET imaging with florbetapir (¹⁸F). For one of the primary analyses, the interpretation of the florbetapir scans (majority interpretation of five nuclear medicine physicians, who classified each scan as amyloid positive or amyloid negative) was compared with amyloid pathology (assessed according to the Consortium to Establish a Registry for Alzheimer's Disease standards, and classed as amyloid positive for moderate or frequent plaques or amyloid negative for no or sparse plaques); correlation of the image analysis results with amyloid burden was tested as a coprimary endpoint. Correlation, sensitivity, and specificity analyses were also done in the subset of participants who had autopsy within 1 year of imaging as secondary endpoints. The study is registered with ClinicalTrials.gov, number NCT 01447719 (original study NCT 00857415).

Findings

We included 59 participants (aged 47–103 years; cognitive status ranging from normal to advanced dementia). The sensitivity and specificity of florbetapir PET imaging for detection of moderate to frequent plaques were 92% (36 of 39; 95% CI 78–98) and 100% (20 of 20; 80–100%), respectively, in people who had autopsy within 2 years of PET imaging, and 96% (27 of 28; 80–100%) and 100% (18 of 18; 78–100%), respectively, for those who had autopsy within 1 year. Amyloid assessed semiquantitatively with florbetapir PET was correlated with the post-mortem amyloid burden in the participants who had an autopsy within 2 years (Spearman ρ=0·76; p<0·0001) and within 12 months between imaging and autopsy (0·79; p<0·0001).

Interpretation

The results of this study validate the binary visual reading method approved in the USA for clinical use with florbetapir and suggest that florbetapir could be used to distinguish individuals with no or sparse amyloid plaques from those with moderate to frequent plaques. Additional research is needed to understand the prognostic implications of moderate to frequent plaque density.

Funding

Avid Radiopharmaceuticals.

Introduction

PET imaging biomarkers such as Pittsburgh compound B (¹¹C-PIB),¹ florbetaben (¹⁸F),² flutemetamol (¹⁸F),³ and florbetapir (¹⁸F)⁴ provide the potential for in-vivo identification of amyloid-β pathology in patients being assessed for Alzheimer's disease or other causes of cognitive decline. We have shown a strong relation between amyloid-β density estimated from florbetapir PET imaging (with semiquantitative visual interpretation and quantitative standard uptake value ratio [SUVR]) and that assessed by use of immunohistochemistry or silver stain at autopsy.⁵ Results of other studies with ¹¹C-PIB and flutemetamol have similarly shown associations between amyloid burden estimated by use of PET imaging and amyloid levels at autopsy or after biopsy.6, 7, 8, 9, 10 However, so far, these studies have all been small and their results have not established the sensitivity or specificity of these PET tracers compared with a defined pathology reference standard.

Our previous study⁵ was designed to continue until 35 autopsy assessments had been obtained. The current study is a continuation of the previous one. Participants who were alive and therefore did not have an autopsy in the original study were followed up to autopsy or for an additional year (maximum of 2 years) after the PET scan. Images and histopathological results from the original and extended follow-up were analysed together to test the sensitivity and specificity of a binary visual interpretation (ie, amyloid positive or amyloid negative) of florbetapir PET scans by comparison with the reference standard of neuritic plaque density at autopsy. We also aimed to confirm, in this larger population, the correlation previously noted between the PET scan and a quantitative immunohistochemical assessment of brain amyloid β.