[(11)C]PIB-amyloid binding and levels of Abeta40 and Abeta42 in postmortem brain tissue from Alzheimer patients.
ABSTRACT 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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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).Frontiers in Aging Neuroscience 01/2013; 5:45. DOI:10.3389/fnagi.2013.00045 · 2.84 Impact Factor
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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.Neurobiology of aging 01/2012; 33(11):2561-71. DOI:10.1016/j.neurobiolaging.2011.12.024 · 4.85 Impact Factor
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ABSTRACT: Alzheimer's disease (AD), the most common cause of age-related dementia, is a progressive neurodegenerative disorder with an enormous unmet medical need. In recent years, several unexpected longitudinal and cross-sectional epidemiological studies reveal that beta-blockers treatment reduces the prevalence of AD in patients suffering from hypertension. Now, a newly population-based study of individuals with incident AD demonstrates that beta-blockers are also associated with delay of functional decline. Furthermore, accumulated convincing evidences from cell culture experiments and animal studies have also suggested that β-adrenergic receptors (β-ARs) may involve in the AD pathogenesis through effects on amyloid-β (Aβ) production or inflammation. This review explores clinical and experimental studies that might help to explain the roles of β-ARs in the AD pathogenesis and the potential underlying mechanisms and whether treatment with β-ARs antagonists provides a new therapeutic option for AD.Brain research bulletin 02/2011; 84(2):111-7. DOI:10.1016/j.brainresbull.2010.11.004 · 2.97 Impact Factor