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

Sylvia Villeneuve, Gil D. Rabinovici, Brendan I. Cohn-Sheehy, Cindee Madison, Nagehan Ayakta, Pia M. Ghosh, Renaud La Joie, Samia Kate Arthur-Bentil, Jacob W. Vogel, Shawn M. Marks, Manja Lehmann, Howard J. Rosen, Bruce R Reed, John M Olichney, Adam L. Boxer, Bruce L. Miller, Ewa Borys, Lee-Way Jin, Eric J. Huang, Lea T. GrinbergCharles DeCarli, William W. Seeley, William Jagust

Research output: Contribution to journalArticle

152 Scopus citations

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 ratio<inf>low</inf> = 1.21, distribution volume ratio<inf>low</inf> = 1.08) that represent the earliest detectable Pittsburgh compound-B signal, as well as high thresholds (standard uptake value ratio<inf>high</inf> = 1.40, distribution volume ratio<inf>high</inf> = 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 ratio<inf>low</inf> 81.0%, standard uptake value ratio<inf>low</inf> 83.3%; distribution volume ratio<inf>high</inf> 61.9%, standard uptake value ratio<inf>high</inf> 62.5%) for CERAD moderate-to-frequent neuritic plaques, with similar specificity (distribution volume ratio<inf>low</inf> 95.8%; standard uptake value ratio<inf>low</inf>, distribution volume ratio<inf>high</inf> and standard uptake value ratio<inf>high</inf> 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 ratio<inf>low</inf> and standard uptake value ratio<inf>low</inf>. In summary, we found that frequently applied thresholds for Pittsburgh compound-B positivity (typically at or above distribution volume ratio<inf>high</inf> and standard uptake value ratio<inf>high</inf>) are overly stringent in defining amyloid positivity. Lower thresholds in this study resulted in higher sensitivity while not compromising specificity.

Original languageEnglish (US)
Pages (from-to)2020-2033
Number of pages14
JournalBrain
Volume138
Issue number7
DOIs
StatePublished - Jul 1 2015

Keywords

  • Alzheimer's disease
  • beta-amyloid
  • biomarkers
  • dementia
  • neurodegeneration

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Fingerprint Dive into the research topics of 'Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: Statistical and pathological evaluation'. Together they form a unique fingerprint.

  • Cite this

    Villeneuve, S., Rabinovici, G. D., Cohn-Sheehy, B. I., Madison, C., Ayakta, N., Ghosh, P. M., La Joie, R., Arthur-Bentil, S. K., Vogel, J. W., Marks, S. M., Lehmann, M., Rosen, H. J., Reed, B. R., Olichney, J. M., Boxer, A. L., Miller, B. L., Borys, E., Jin, L-W., Huang, E. J., ... Jagust, W. (2015). Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: Statistical and pathological evaluation. Brain, 138(7), 2020-2033. https://doi.org/10.1093/brain/awv112