Svedberg, M. M. et al. [11C]PIB-amyloid binding and levels of Aβ40 and Aβ42 in postmortem brain tissue from Alzheimer patients. Neurochem. Int. 54, 347-357

Uppsala University, Department of Biochemistry and Organic Chemistry, Sweden.
Neurochemistry International (Impact Factor: 3.09). 12/2008; 54(5-6):347-57. DOI: 10.1016/j.neuint.2008.12.016
Source: PubMed


beta-Amyloid (Abeta) deposits are one of the major histopathological hallmarks of Alzheimer's disease (AD). The amyloid-imaging positron emission tomography (PET) tracer [(11)C]PIB (N-methyl[(11)C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole) is used in the assessment of Abeta deposits in the human brain. [(11)C]PIB-amyloid interaction and insoluble Abeta40 and Abeta42 peptide levels in the brain were quantified in postmortem tissue from nine AD patients and nine age-matched control subjects in the temporal, frontal and parietal cortices and the cerebellum. Autoradiographical studies showed significantly higher densities of specific [(11)C]PIB-amyloid binding in gray matter in the temporal and parietal cortex (62fmol/mg tissue) in AD patients as compared to control subjects, whereas the density was somewhat lower in the frontal cortex (56fmol/mg tissue). No specific binding could be detected in the AD cerebellum or in the tissues from the control subjects (< or =5fmol/mg tissue). Insoluble Abeta40 and total Abeta levels (i.e. sum of Abeta40 and Abeta42) were significantly higher in patients than in controls in all measured cortical regions as determined using ELISA, which was confirmed using immunohistochemistry. The present findings show a more regional selective distribution of [(11)C]PIB amyloid binding than previously reported. Moreover, it is suggested that some of the [(11)C]PIB binding and insoluble Abeta seen in control subjects may be amyloid in the blood vessels.

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    • "For example, it has been reported that PIB may bind differentially to polymorphic Aβ aggregates in some humans as well as in animals (Rosen et al., 2010; Ikonomovic et al., 2012). Additionally, apparent retention of PIB is evident in cerebral white matter both in vivo by PET (Fodero-Tavoletti et al., 2009) and in vitro by postmortem auto-radiography (Klunk et al., 2004; Svedberg et al., 2009). "
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    ABSTRACT: Rapid clearance and disappearance of a tracer from the circulation challenges the determination of the tracer's binding potentials in brain (BP ND) by positron emission tomography (PET). This is the case for the analysis of the binding of radiolabeled [(11)C]Pittsburgh Compound B ([(11)C]PIB) to amyloid-β (Aβ) plaques in brain of patients with Alzheimer's disease (AD). To resolve the issue of rapid clearance from the circulation, we here introduce the flow-independent Washout Allometric Reference Method (WARM) for the analysis of washout and binding of [(11)C]PIB in two groups of human subjects, healthy aged control subjects (HC), and patients suffering from AD, and we compare the results to the outcome of two conventional analysis methods. We also use the rapid initial clearance to obtain a surrogate measure of the rate of cerebral blood flow (CBF), as well as a method of identifying a suitable reference region directly from the [(11)C]PIB signal. The difference of average absolute CBF values between the AD and HC groups was highly significant (P < 0.003). The CBF measures were not significantly different between the groups when normalized to cerebellar gray matter flow. Thus, when flow differences confound conventional measures of [(11)C]PIB binding, the separate estimates of CBF and BP ND provide additional information about possible AD. The results demonstrate the importance of data-driven estimation of CBF and BP ND, as well as reference region detection from the [(11)C]PIB signal. We conclude that the WARM method yields stable measures of BP ND with relative ease, using only integration for noise reduction and no model regression. The method accounts for relative flow differences in the brain tissue and yields a calibrated measure of absolute CBF directly from the [(11)C]PIB signal. Compared to conventional methods, WARM optimizes the Aβ plaque load discrimination between patients with AD and healthy controls (P = 0.009).
    Full-text · Article · Nov 2013 · Frontiers in Aging Neuroscience
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    • "In addition, both [11C]AZD2995 and [11C]AZD2184 were evaluated with the reference Logan (refLogan) method using the cerebellum as the reference region. The cerebellum was chosen since it is known to be devoid of substantial amounts of fibrillar amyloid-β [27, 28], and has previously been successfully used as a reference region [14, 29–31]. To obtain the VT, the same number of frames (six) were used in the linear part of the curve for [11C]AZD2995 (13 to 45 min after injection) and [11C]AZD2184 (30 to 60 min). "
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    ABSTRACT: Purpose The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer’s disease (AD). Methods In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [11C]AZD2995 and [11C]AZD2184 in three healthy control subjects and seven AD patients. Results AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [3H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [11C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [11C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus. Conclusion Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [11C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [11C]AZD2995. However, the very low nonspecific binding of [11C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy.
    Full-text · Article · Apr 2013 · European journal of nuclear medicine and molecular imaging
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    • "However , some instances of unexpectedly high uptake in nondemented cases (Rowe et al., 2007) or poor enhancement in clinically diagnosed AD cases (Edison et al., 2007; Li et al., 2008) have been reported. Furthermore, some A␤ lesions appear to be refractory to PIB binding (Svedberg et al., 2009). The short half-life of [11C] (t 1/2 ϭ 20.4 minutes) limits the use of [11C]-PIB and emphasizes the need for [18F]-labeled selective amyloid tracers to envisage largescale imaging studies. "
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    ABSTRACT: Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is characterized by the accumulation of β-amyloid peptide. In man, [18F]AV-45 with positron emission tomography (PET) is currently studied and used to track in vivo amyloid accumulation. Here, [18F]-AV45-PET was used to visualize amyloid deposition in a transgenic murine model of amyloidosis (APP/PS1-21). Studies were performed ex vivo by autoradiography and in vivo by microPET. Autoradiograms of the brain sections highlighted an increased uptake of [18F]AV-45 in APP/PS1-21 mice compared with age-matched control mice. From 8 months, an intense labeling was observed in cortex, hippocampus, and striatum. The marked accumulation of radiotracer was found in close association with thioflavin S-positive amyloid plaques. The longitudinal microPET assessment, performed from 3 to 12 months of age, demonstrated an increased [18F]AV-45 uptake in APP/PS1-21 compared with control mice. The elevated tracer uptake was increased in association with age. This study opens the possibility of [18F]AV-45, coupled with microPET, to visualize and quantitatively measure amyloid deposits in the brains of living APP/PS1 mice.
    Full-text · Article · Jan 2012 · Neurobiology of aging
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