Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation

Arnyloid-beta, a hallmark or Alzheimer's disease, begins accumulating up to two decades before me onset of dementia, and can be detected in vivo applying amyloid-beta positron emission tomography tracers such as carbon-11-labelled Pittsburgh compound-B A variety of threshold,: have been applied in the literature to define Pittsburgh compound-B positron emission tomography positivity, but the ability of these thresholds to detect early amyloid-beta deposition is unknown, and validation studies comparing Pittsburgh compound-B thresholds to post-mortem amyloid burden are lacking. In this study we first derived threshold for amyloid positron emission tomography positivity using Pittsburgh compound-B positron emission tomography in 154 cognitively normal older adult,: with four complementary approaches: (i) reference values from a young control group aged between 2(1 and 31 years; jii) a Gaussian mixture model that assigned each subject a probability of being amyloid-p-positive or amyloid-beta-negative based on Pittsburgh compound-B index uptake; (iii) a k-means cluster approach that clustered subject,: into amyloid-p-positive or amyloid-p-negative based on Pittsburgh compound-B uptake in different brain regions (features); and (iv) an iterative voxel-based analysis that further explored the spatial pattern of early amyloid-beta positron emission tomography signal. Next, we tested the, sensitivity and specificity of the derived thresholds in 50 individuals who underwent Pittsburgh compound-B positron emission tomography during life and brain autopsy mean time positron emission tomography to autopsy 3.1 +/- 1.8 years). Am bid autopsy was classified using Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria, unadjusted for age. The analytic approaches yielded low thresholds standard uptake value ratio(low) = 1.21, distribution volume ratio(low) = 1.08) that represent the earliest detectable Pittsburgh compound-B signal, as well as high thresholds (standard uptake value ratio(high) = 1.40, distribution volume ratio(high) = 1.20) that are more conservative in defining Pittsburgh compound-B positron emission tomography positivity. In voxel-wise contrasts, elevated Pittsburgh compound-B retention was first noted in the medial frontal cortex, then the precuneus, lateral frontal and parietal lobes, and finally the lateral temporal lobe. When compared to post-mortem amyloid burden, tow proposed thresholds were more sensitive than high thresholds (sensitivities: distribution volume ratio(low) 81.0% standard uptake value ratio(low) 83.3%; distribution volume ratio(high) 61.9%, standard uptake value ratio(high) 62.5%) for GERM moderate-to-frequent neuritic plaques, with similar specificity (distribution volume ratio(low) 95.8%; standard uptake value ratio: distribution volume ratio(high), and standard uptake value ratio(high) 100.0%). A receiver operator characteristic analysis identified optimal distribution volume ratio (1.06) and standard uptake value ratio;1.20) thresholds that were nearly identical to the a prior distribution volume ratio(low) and standard uptake value ratio(low). In summary, We found that frequently applied thresholds for Pittsburgh compound-B positivity (typically at or above distribution volume ratio(high) and standard uptake value ratio(high)) are overly stringent in defining amyloid positivity. Lower thresholds in this study resulted in higher sensitivity while not comprimising specificity.