PIB is a non-specific imaging marker of amyloid-beta (A ) peptide-related cerebral amyloidosis

The University of Edinburgh, Edinburgh, Scotland, United Kingdom
Brain (Impact Factor: 9.2). 11/2007; 130(Pt 10):2607-15. DOI: 10.1093/brain/awm191
Source: PubMed


The in vivo imaging probe [11C]-PIB (Pittsburgh Compound B, N-methyl[11C]2-(4'-methylaminophenyl-6-hydroxybenzathiazole) is under evaluation as a key imaging tool in Alzheimer's disease (AD) and to date has been assumed to bind with high affinity and specificity to the amyloid structures associated with classical plaques (CPs), one of the pathological hallmarks of the disease. However, no studies have systematically investigated PIB binding to human neuropathological brain specimens at the tracer concentrations achieved during in vivo imaging scans. Using a combination of autoradiography and histochemical techniques, we demonstrate that PIB, in addition to binding CPs clearly delineates diffuse plaques and cerebrovascular amyloid angiopathy (CAA). The interaction of PIB with CAA was not fully displaceable and this may be linked to the apolipoprotein E-epsilon4 allele. PIB was also found to label neurofibrillary tangles, although the overall intensity of this binding was markedly lower than that associated with the amyloid-beta (Abeta) pathology. The data provide a molecular explanation for PIB's limited specificity in diagnosing and monitoring disease progression in AD and instead indicate that the ligand is primarily a non-specific marker of Abeta-peptide related cerebral amyloidosis.

Download full-text


Available from: Andrew Lockhart
  • Source
    • "There are two main subtypes of senile plaques; non-classic plaques including diffuse and primitive plaques are not clearly associated with neurodegerative changes, while neuritic (classic/typical) plaques are often concurrent with dystrophic neurites and activation of inflammatory microglia (Bobinski et al. 1996; Rapp et al. 2010). Interestingly, it might be possible to differentially detect amyloid subpopulations by PET imaging tracers, as exemplified by PiB binding with both diffuse and neuritic plaques (Lockhart et al. 2007; Ikonomovic et al. 2008), whereas 11 C-BF-227 (Kudo et al. 2007), 18 F- FACT (Ito et al. 2014), and 125 I-DRM106 (Chen et al. 2015) have been shown to bind more selectively to neuritic plaques. These initial observations may suggest that there are at least two different amyloid components unequally distributed in non-classic and classic plaques providing distinct binding sites for imaging agents. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Non-invasive determination of amyloid-β peptide (Aβ) deposition with radioligands serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). The polymorphic binding site on multimeric Aβ for current radioligands, however, is little understood. In the present study, we investigated the binding of several radioligands including (11) C-Pittsburgh Compound B ((11) C-PiB), (3) H-AZD2184, and two recently developed compounds, (125) I-DRM106 and (125) I-DRK092, with unique presubicular Aβ deposits lacking interaction with the commonly used amyloid dyes FSB. (11) C-PiB, (3) H-AZD2184 and (125) I-DRK092 showed overt binding to presubicular Aβ deposits, while (125) I-DRM106 barely bound to these aggregates, despite its strong binding in the hippocampal CA1 sector. Unlike neuritic plaques in the CA1, Aβ lesions in the presubiculum were not accompanied by inflammatory gliosis enriched with 18-kDa translocator protein (TSPO). Thus, there are at least two different components in Aβ aggregates providing distinct binding sites for the current amyloid radioligands, and one of these binding components is distinctly present in the presubicular Aβ deposits. Amyloid radioligands lacking affinity for this component, such as (125) I-DRM106, may selectively capture Aβ deposits tightly associated with TSPO-positive neuroinflammation and neurodegeneration as exemplified by CA1 neuritic plaques. Hence, comparative autoradiographic assessments of radioligand binding in CA1 and presubiculum could serve for the development of an amyloid PET imaging agent visualizing neurotoxicity-related Aβ pathologies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Aug 2015 · Journal of Neurochemistry
  • Source
    • "CERAD does not capture the severity of diffuse plaques (non-fibrillar amyloid), which are commonly found at autopsy in ageing brains (Nelson et al., 2012). There is evidence, however, that PiB binds to diffuse plaques, as well as cerebral amyloid angiopathy in the vessels and parenchyma (Johnson et al., 2007; Lockhart et al., 2007; Ikonomovic et al., 2008; Niedowicz et al., 2012). Thal amyloid phase does not discriminate among plaque types, but neither does it consider cerebral amyloid angiopathy. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer's disease, was incorporated into the latest National Institute of Ageing - Alzheimer's Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer's disease dementia published by the National Institute of Ageing - Alzheimer's Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem (11)C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of (11)C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. (11)C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical (11)C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer's disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer's disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted (11)C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to (11)C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer's disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer's disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with (11)C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The (11)C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1-2. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.
    Full-text · Article · Mar 2015 · Brain
  • Source
    • "11C-PiB could label β-amyloid in living brains, and it was used in patients suffering from AD since the earliest investigations [52]. It lacks specificity to these classic plaques, as it also binds to diffuse amyloid plaques that can be found in a substantial proportion of healthy elderly and are not specific for AD [53]. Further, PiB binds to cerebrovascular amyloid in cerebral amyloid angiopathy (CAA), mainly in posterior parietal and occipital cortex. "
    [Show abstract] [Hide abstract]
    ABSTRACT: PET based tools can improve the early diagnosis of Alzheimer's disease (AD) and differential diagnosis of dementia. The importance of identifying individuals at risk of developing dementia among people with subjective cognitive complaints or mild cognitive impairment has clinical, social, and therapeutic implications. Within the two major classes of AD biomarkers currently identified, that is, markers of pathology and neurodegeneration, amyloid- and FDG-PET imaging represent decisive tools for their measurement. As a consequence, the PET tools have been recognized to be of crucial value in the recent guidelines for the early diagnosis of AD and other dementia conditions. The references based recommendations, however, include large PET imaging literature based on visual methods that greatly reduces sensitivity and specificity and lacks a clear cut-off between normal and pathological findings. PET imaging can be assessed using parametric or voxel-wise analyses by comparing the subject's scan with a normative data set, significantly increasing the diagnostic accuracy. This paper is a survey of the relevant literature on FDG and amyloid-PET imaging aimed at providing the value of quantification for the early and differential diagnosis of AD. This allowed a meta-analysis and GRADE analysis revealing high values for PET imaging that might be useful in considering recommendations.
    Full-text · Article · Mar 2014
Show more