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. Grinberg & 3 others Charles DeCarli, William W. Seeley, William Jagust

Research output: Contribution to journalArticle

121 Citations (Scopus)

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

Fingerprint

Amyloid
Positron-Emission Tomography
Autopsy
Alzheimer Disease
Parietal Lobe
Frontal Lobe
2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
Evaluation
Pittsburgh
Positron Emission Tomography
Registries
Aptitude
Validation Studies
Amyloid Plaques
Brain
Temporal Lobe
Dementia
Reference Values
Positivity
Carbon

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Villeneuve, S., Rabinovici, G. D., Cohn-Sheehy, B. I., Madison, C., Ayakta, N., Ghosh, P. M., ... 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

Existing Pittsburgh Compound-B positron emission tomography thresholds are too high : Statistical and pathological evaluation. / Villeneuve, Sylvia; Rabinovici, Gil D.; Cohn-Sheehy, Brendan I.; Madison, Cindee; Ayakta, Nagehan; Ghosh, Pia M.; La Joie, Renaud; Arthur-Bentil, Samia Kate; Vogel, Jacob W.; Marks, Shawn M.; Lehmann, Manja; Rosen, Howard J.; Reed, Bruce R; Olichney, John M; Boxer, Adam L.; Miller, Bruce L.; Borys, Ewa; Jin, Lee-Way; Huang, Eric J.; Grinberg, Lea T.; DeCarli, Charles; Seeley, William W.; Jagust, William.

In: Brain, Vol. 138, No. 7, 01.07.2015, p. 2020-2033.

Research output: Contribution to journalArticle

Villeneuve, S, Rabinovici, GD, Cohn-Sheehy, BI, Madison, C, Ayakta, N, Ghosh, PM, La Joie, R, Arthur-Bentil, SK, Vogel, JW, Marks, SM, Lehmann, M, Rosen, HJ, Reed, BR, Olichney, JM, Boxer, AL, Miller, BL, Borys, E, Jin, L-W, Huang, EJ, Grinberg, LT, DeCarli, C, Seeley, WW & Jagust, W 2015, 'Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: Statistical and pathological evaluation', Brain, vol. 138, no. 7, pp. 2020-2033. https://doi.org/10.1093/brain/awv112
Villeneuve S, Rabinovici GD, Cohn-Sheehy BI, Madison C, Ayakta N, Ghosh PM et al. Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: Statistical and pathological evaluation. Brain. 2015 Jul 1;138(7):2020-2033. https://doi.org/10.1093/brain/awv112
Villeneuve, Sylvia ; Rabinovici, Gil D. ; Cohn-Sheehy, Brendan I. ; Madison, Cindee ; Ayakta, Nagehan ; Ghosh, Pia M. ; La Joie, Renaud ; Arthur-Bentil, Samia Kate ; Vogel, Jacob W. ; Marks, Shawn M. ; Lehmann, Manja ; Rosen, Howard J. ; Reed, Bruce R ; Olichney, John M ; Boxer, Adam L. ; Miller, Bruce L. ; Borys, Ewa ; Jin, Lee-Way ; Huang, Eric J. ; Grinberg, Lea T. ; DeCarli, Charles ; Seeley, William W. ; Jagust, William. / Existing Pittsburgh Compound-B positron emission tomography thresholds are too high : Statistical and pathological evaluation. In: Brain. 2015 ; Vol. 138, No. 7. pp. 2020-2033.
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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.",
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T1 - Existing Pittsburgh Compound-B positron emission tomography thresholds are too high

T2 - Statistical and pathological evaluation

AU - Villeneuve, Sylvia

AU - Rabinovici, Gil D.

AU - Cohn-Sheehy, Brendan I.

AU - Madison, Cindee

AU - Ayakta, Nagehan

AU - Ghosh, Pia M.

AU - La Joie, Renaud

AU - Arthur-Bentil, Samia Kate

AU - Vogel, Jacob W.

AU - Marks, Shawn M.

AU - Lehmann, Manja

AU - Rosen, Howard J.

AU - Reed, Bruce R

AU - Olichney, John M

AU - Boxer, Adam L.

AU - Miller, Bruce L.

AU - Borys, Ewa

AU - Jin, Lee-Way

AU - Huang, Eric J.

AU - Grinberg, Lea T.

AU - DeCarli, Charles

AU - Seeley, William W.

AU - Jagust, William

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N2 - 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.

AB - 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.

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KW - beta-amyloid

KW - biomarkers

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