Amyloid-β, a hallmark of Alzheimer's disease, begins accumulating up to two decades before the onset of dementia, and can be detected in vivo applying amyloid-β positron emission tomography tracers such as carbon-11-labelled Pittsburgh compound-B. A variety of thresholds 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-β deposition is unknown, and validation studies comparing Pittsburgh compound-B thresholds to post-mortem amyloid burden are lacking. In this study we first derived thresholds for amyloid positron emission tomography positivity using Pittsburgh compound-B positron emission tomography in 154 cognitively normal older adults with four complementary approaches: (i) reference values from a young control group aged between 20 and 30 years; (ii) a Gaussian mixture model that assigned each subject a probability of being amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B index uptake; (iii) a k-means cluster approach that clustered subjects into amyloid-β-positive or amyloid-β-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-β 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). Amyloid at 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 ratiolow = 1.21, distribution volume ratiolow = 1.08) that represent the earliest detectable Pittsburgh compound-B signal, as well as high thresholds (standard uptake value ratiohigh = 1.40, distribution volume ratiohigh = 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, low proposed thresholds were more sensitive than high thresholds (sensitivities: distribution volume ratiolow 81.0%, standard uptake value ratiolow 83.3%; distribution volume ratiohigh 61.9%, standard uptake value ratiohigh 62.5%) for CERAD moderate-to-frequent neuritic plaques, with similar specificity (distribution volume ratiolow 95.8%; standard uptake value ratiolow, distribution volume ratiohigh and standard uptake value ratiohigh 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 priori distribution volum...

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Background: Emerging evidence suggests that subjective cognitive concerns (SCC) may herald initial cognitive decline at the preclinical stage of Alzheimer's disease (AD). While previous studies have investigated the relationship between SCC and amyloid (A b ) burden and neurodegeneration (ND) separately, it remains unclear if increased SCC correlates with successive stages of preclinical AD. Methods: We studied 186 CN individuals from the Harvard Aging Brain Study (Clinical Dementia Rating Scale ¼ 0, Geriatric Depression Scale <11). A b status was determined with PIB-PET imaging and ND was measured using two a priori imaging markers: hippocampus volume and glucose metabolism extracted from AD-vulnerable regions. A subjective cognitive concerns composite was calculated using subscales from three questionnaires. Linear regression models with A b and ND status as simultaneous predictors were used to predict SCC, controlling for age, education, and gender. A secondary analysis included APOE ε4 carrier status as a predictor. SCC were also examined across groups based on joint A b and ND status (Stage 0: A b -/ND-; Stage 1: A b +/ND-, Stage 2: A b +/ND+, and SNAP: A b -/ND+). Results: SCC was not related to age, gender or education. Both A b (p¼0.002) and ND (p¼0.036) were independently associated with greater SCC. APOE ε4 carrier status was not related to SCC and did not impact results from the initial model. Examination across groups revealed that SCC was greater in stage 2 compared to stage 0 (p<0.001), stage 1 (p¼0.20) and SNAP (p¼0.03). Furthermore, Stage 0 had lower SCC than both SNAP (p ¼ 0.07) and stage 1 (p¼0.03). There was no difference between Stage 1 and SNAP (p¼0.45). Conclusions: We demonstrate independent and additive contribution of A b and ND status in predicting SCC, unaffected by APOE ε4 carrier status, such that individuals who are positive on both biomarkers show the greatest SCC, while individuals positive for a single biomarker show intermediate levels of SCC. This pattern is consistent with the hypothesis that the combination of A b and ND markers increases likelihood of cognitive decline.Background: Alzheimer's disease (AD) is a major public health issue. Atrophy assessed with structural MRI, hypometabolism and amyloid load have been recently proposed as neuroimaging biomarkers for the preclinical diagnosis of the disease, consistently with the amyloid cascade hypothesis. However the meaning and the relevance of each neuroimaging biomarker remain not completely understood. Our objective was to characterize populations defined according to each neuroimaging biomarker (i.e. positive vs negative cases) to further our understanding of their use in the preclinical diagnosis of AD. Methods: We prospectively included 54 healthy controls (HC) over 50 years old who all performed structural MRI, FDG-PET and Florbetapir-PET in the same neuroimaging center. All HC were then dichotomized into positive or negative independently for each of the three biomarkers considering the regions of greatest changes in A...