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Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer's disease.

ABSTRACT: Radiolabeled Pittsburgh compound B (PIB) is a benzothiazole imaging agent that usually binds with high affinity, specificity, and stoichiometry to cerebral beta-amyloid (Abeta) in patients with Alzheimer's disease. Among a cohort of ten AD subjects examined postmortem, we describe a case of idiopathic, end-stage Alzheimer's disease with heavy Abeta deposition yet substantially diminished high-affinity binding of (3)H-PIB to cortical homogenates and unfixed cryosections. Cortical tissue samples were analyzed by immunohistochemistry, electron microscopy, ELISA, immunoblotting, MALDI-TOF mass spectrometry, in vitro (3)H-PIB binding and (3)H-PIB autoradiography. The PIB-refractory subject met the histopathological criteria for AD. However, cortical tissue from this case contained more vascular beta-amyloidosis, higher levels of insoluble Abeta40 and Abeta42, and a higher ratio of Abeta40:Abeta42 than did tissue from the nine comparison AD cases. Furthermore, cerebral Abeta from the PIB-refractory subject displayed an unusual distribution of low- and high-molecular weight Abeta oligomers, as well as a distinct pattern of N- and C-terminally truncated Abeta peptides in both the soluble and insoluble cortical extracts. Genetically, the patient was apolipoprotein-E3/4 heterozygous, and exhibited no known AD-associated mutations in the genes for the beta-amyloid precursor protein, presenilin1 or presenilin2. Our findings suggest that PIB may differentially recognize polymorphic forms of multimeric Abeta in humans with Alzheimer's disease. In addition, while the prevalence of PIB-refractory cases in the general AD population remains to be determined, the paucity of high-affinity binding sites in this AD case cautions that minimal PIB retention in positron-emission tomography scans of demented patients may not always rule out the presence of Alzheimer-type Abeta pathology.

SUBMITTER: Rosen RF

PROVIDER: S-EPMC3045810 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer's disease.

Rosen Rebecca F RF Ciliax Brian J BJ Wingo Thomas S TS Gearing Marla M Dooyema Jeromy J Lah James J JJ Ghiso Jorge A JA LeVine Harry H Walker Lary C LC

Acta neuropathologica 20090819 2

Radiolabeled Pittsburgh compound B (PIB) is a benzothiazole imaging agent that usually binds with high affinity, specificity, and stoichiometry to cerebral beta-amyloid (Abeta) in patients with Alzheimer's disease. Among a cohort of ten AD subjects examined postmortem, we describe a case of idiopathic, end-stage Alzheimer's disease with heavy Abeta deposition yet substantially diminished high-affinity binding of (3)H-PIB to cortical homogenates and unfixed cryosections. Cortical tissue samples w ...[more]

PMID: 19690877

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Project description:Amyloid-?, 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-? 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-? 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-?-positive or amyloid-?-negative based on Pittsburgh compound-B index uptake; (iii) a k-means cluster approach that clustered subjects into amyloid-?-positive or amyloid-?-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-? 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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Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer's disease.

Publications

Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer's disease.

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