title: Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation.
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.
authors.affiliation: 1 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley CA, USA villeneuve.sylvia@gmail.com.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Villeneuve
authors.affiliation: 1 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley CA, USA 2 Lawrence Berkeley National Laboratory, Berkeley, California, USA 3 Memory and Aging Centre, Department of Neurology, University of California, San Francisco, USA.
authors.forename: Gil D
authors.initials: GD
authors.lastname: Rabinovici
authors.affiliation: 1 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley CA, USA 2 Lawrence Berkeley National Laboratory, Berkeley, California, USA 3 Memory and Aging Centre, Department of Neurology, University of California, San Francisco, USA.
authors.forename: Brendan I
authors.initials: BI
authors.lastname: Cohn-Sheehy
authors.affiliation: 1 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley CA, USA.
authors.forename: Cindee
authors.initials: C
authors.lastname: Madison
authors.affiliation: 1 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley CA, USA 3 Memory and Aging Centre, Department of Neurology, University of California, San Francisco, USA.
authors.forename: Nagehan
authors.initials: N
authors.lastname: Ayakta
authors.affiliation: 1 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley CA, USA 2 Lawrence Berkeley National Laboratory, Berkeley, California, USA 3 Memory and Aging Centre, Department of Neurology, University of California, San Francisco, USA.
authors.forename: Pia M
authors.initials: PM
authors.lastname: Ghosh
authors.affiliation: 1 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley CA, USA.
authors.forename: Renaud
authors.initials: R
authors.lastname: La Joie
authors.affiliation: 1 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley CA, USA 2 Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors.forename: Samia Kate
authors.initials: SK
authors.lastname: Arthur-Bentil
authors.affiliation: 1 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley CA, USA.
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Vogel
authors.affiliation: 1 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley CA, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Marks
authors.affiliation: 1 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley CA, USA 3 Memory and Aging Centre, Department of Neurology, University of California, San Francisco, USA.
authors.forename: Manja
authors.initials: M
authors.lastname: Lehmann
authors.affiliation: 3 Memory and Aging Centre, Department of Neurology, University of California, San Francisco, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Rosen
authors.affiliation: 4 Department of Neurology, School of Medicine, University of California, Davis, USA 5 Veterans Affairs Northern California Health Care System, Martinez, CA, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Reed
authors.affiliation: 4 Department of Neurology, School of Medicine, University of California, Davis, USA.
authors.forename: John
authors.initials: J
authors.lastname: Olichney
authors.affiliation: 3 Memory and Aging Centre, Department of Neurology, University of California, San Francisco, USA.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Boxer
authors.affiliation: 3 Memory and Aging Centre, Department of Neurology, University of California, San Francisco, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: 6 Department of Pathology, Stritch School of Medicine, Loyola University Chicago, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Borys
authors.affiliation: 7 Department of Pathology and Laboratory Medicine, University of California, Davis, USA.
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
authors.affiliation: 8 Department of Pathology, University of California, San Francisco, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.affiliation: 3 Memory and Aging Centre, Department of Neurology, University of California, San Francisco, USA 8 Department of Pathology, University of California, San Francisco, USA.
authors.forename: Lea T
authors.initials: LT
authors.lastname: Grinberg
authors.affiliation: 4 Department of Neurology, School of Medicine, University of California, Davis, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: DeCarli
authors.affiliation: 3 Memory and Aging Centre, Department of Neurology, University of California, San Francisco, USA 8 Department of Pathology, University of California, San Francisco, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: 1 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley CA, USA 2 Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors.forename: William
authors.initials: W
authors.lastname: Jagust
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging*; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000814:Aniline Compounds; D005260:Female; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008297:Male; D049268:Positron-Emission Tomography / Q000592:standards*; D019275:Radiopharmaceuticals; D012016:Reference Values; D013844:Thiazoles; D055815:Young Adult
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D019275:Radiopharmaceuticals; D013844:Thiazoles
keywords: Alzheimer's disease; beta-amyloid; biomarkers; dementia; neurodegeneration