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

TitleExisting Pittsburgh Compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation.
Publication TypeJournal Article
Year of Publication2015
AuthorsVilleneuve S, Rabinovici GD, Cohn-Sheehy BI, Madison C, Ayakta N, Ghosh PM, La Joie R, Arthur-Bentil SKate, Vogel JW, Marks SM, Lehmann M, Rosen HJ, Reed B, Olichney J, Boxer AL, Miller BL, Borys E, Jin L-W, Huang EJ, Grinberg LT, DeCarli C, Seeley WW, Jagust W
JournalBrain
Volume138
IssuePt 7
Pagination2020-33
Date Published2015 Jul
ISSN1460-2156
KeywordsAged, Alzheimer Disease, Amyloid beta-Peptides, Aniline Compounds, Female, Humans, Image Interpretation, Computer-Assisted, Male, Positron-Emission Tomography, Radiopharmaceuticals, Reference Values, Thiazoles, Young Adult
Abstract

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 volume ratiolow and standard uptake value ratiolow. In summary, we found that frequently applied thresholds for Pittsburgh compound-B positivity (typically at or above distribution volume ratiohigh and standard uptake value ratiohigh) are overly stringent in defining amyloid positivity. Lower thresholds in this study resulted in higher sensitivity while not compromising specificity.

DOI10.1093/brain/awv112
Alternate JournalBrain
PubMed ID25953778
Grant ListK23-AG031861 / AG / NIA NIH HHS / United States
K24-AG045333 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P01-AG12435 / AG / NIA NIH HHS / United States
P01-AG1972403 / AG / NIA NIH HHS / United States
P30-AG10129 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
P50-AG023501 / AG / NIA NIH HHS / United States
R01 AG045611 / AG / NIA NIH HHS / United States
R01-AG021028 / AG / NIA NIH HHS / United States
R01-AG031563 / AG / NIA NIH HHS / United States
R01-AG032306 / AG / NIA NIH HHS / United States
R01-AG034570 / AG / NIA NIH HHS / United States
R01-AG045611 / AG / NIA NIH HHS / United States
R01AG038791 / AG / NIA NIH HHS / United States