Engler, H. et al. Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain 129, 2856-2866

Department of Psychology, Stockholm University, Tukholma, Stockholm, Sweden
Brain (Impact Factor: 9.2). 11/2006; 129(Pt 11):2856-66. DOI: 10.1093/brain/awl178
Source: PubMed

ABSTRACT Beta amyloid is one of the major histopathological hallmarks of Alzheimer's disease. We recently reported in vivo imaging of amyloid in 16 Alzheimer patients, using the PET ligand N-methyl[11C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole (PIB). In the present study we rescanned these 16 Alzheimer patients after 2.0 +/- 0.5 years and have described the interval change in amyloid deposition and regional cerebral metabolic rate for glucose (rCMRGlc) at follow-up. Sixteen patients with Alzheimer's disease were re-examined by means of PET, using PIB and 2-[18F]fluoro-2-deoxy-d-glucose (FDG) after 2.0 +/- 0.5 years. The patients were all on cholinesterase inhibitor treatment and five also on treatment with the N-methyl-d-aspartate (NMDA) antagonist memantine. In order to estimate the accuracy of the PET PIB measurements, four additional Alzheimer patients underwent repeated examinations with PIB within 20 days (test-retest). Relative PIB retention in cortical regions differed by 3-7% in the test-retest study. No significant difference in PIB retention was observed between baseline and follow-up while a significant (P < 0.01) 20% decrease in rCMRGlc was observed in cortical brain regions. A significant negative correlation between rCMRGlc and PIB retention was observed in the parietal cortex in the Alzheimer patients at follow-up (r = 0.67, P = 0.009). A non-significant decline in Mini-Mental State Examination (MMSE) score from 24.3 +/- 3.7 (mean +/- standard deviation) to 22.7 +/- 6.1 was measured at follow-up. Five of the Alzheimer patients showed a significant decline in MMSE score of >3 (21.4 +/- 3.5 to 15.6 +/- 3.9, P < 0.01) (AD-progressive) while the rest of the patients were cognitively more stable (MMSE score = 25.6 +/- 3.1 to 25.9 +/- 3.7) (AD-stable) compared with baseline. A positive correlation (P = 0.001) was observed in the parietal cortex between Rey Auditory Verbal Learning (RAVL) test score and rCMRGlc at follow-up while a negative correlation (P = 0.018) was observed between RAVL test and PIB retention in the parietal at follow-up. Relatively stable PIB retention after 2 years of follow-up in patients with mild Alzheimer's disease suggests that amyloid deposition in the brain reaches a plateau by the early clinical stages of Alzheimer's disease and therefore may precede a decline in rCMRGlc and cognition. It appears that anti-amyloid therapies will need to induce a significant decrease in amyloid load in order for PIB PET images to detect a drug effect in Alzheimer patients. FDG imaging may be able to detect a stabilization of cerebral metabolism caused by therapy administered to patients with a clinical diagnosis of Alzheimer's disease.

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Available from: Anna Maria Ringheim, Sep 28, 2015
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    • "Pittsburgh compound B ( 11 C-PiB) is one of the most widely used, and allows for longitudinal and quantitative assessments of Ab accumulation in AD patients. 11 C-PiB has also been demonstrated to facilitate prediction of the conversion from mild cognitive impairment to AD, and serving for evaluation of anti-amyloid therapies (Klunk et al. 2004; Engler et al. 2006; Ikonomovic et al. 2008; Leinonen et al. 2008; Okello et al. 2009b). 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). "
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    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.
    Journal of Neurochemistry 08/2015; DOI:10.1111/jnc.13293 · 4.28 Impact Factor
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    • "-FDG to become a superior measure of disease severity [5] [14] [15]. Thus the combined use of both amyloid and [ 18 F]-FDG PET can aid early diagnosis, disease staging and possibly therapeutic evaluation. "
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    ABSTRACT: Positron emission tomography studies of cerebral glucose utilization and amyloid-β deposition with fluoro-deoxy-D-glucose ([18F]-FDG) and amyloid tracers have shown characteristic pathological changes in Alzheimer's Disease that can be used for disease diagnosis and monitoring. Application of this technology to preclinical research with transgenic animal models would greatly facilitate drug discovery and further understanding of disease processes. The results from preclinical studies with these imaging biomarkers have however been highly inconsistent, causing doubts over whether animal models can truly replicate an AD-like phenotype. In this study we performed in vivo imaging with [18F]-FDG and [18F]-AV45 in double transgenic TASTPM mice, a transgenic model that been previously demonstrated high levels of fibrillar amyloid-β and decreases in cerebral glucose utilization with ex vivo techniques. Our results show widespread and significant retention of [18F]-AV45 (p < 0.0001) in aged TASTPM mice in addition to significantregional decreases in [18F]-FDG uptake (p < 0.05). In vivo quantification of amyloid-β showed a strong (Pearson's r = 0.7078), but not significant (p = 0.1156), positive correlation with ex vivo measures suggesting some limitations on tracer sensitivity. In the case of [18F]-FDG, voxelwise analysis greatly enhanced detection of hypometabolic regions. We further evidenced modest neuronal loss (thalamus p = 0.0318) that could underlie the observed hypometabolism. This research was performed in conjunction with the European Community's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under the PharmaCog Grant Agreement n°115009.
    Current Alzheimer research 07/2015; 12(7). DOI:10.2174/1567205012666150710104713 · 3.89 Impact Factor
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    • "Further, at least in AD, brain amyloid deposition seems to be a very early phenomenon and rather rapidly reaches a “plateau” at the time cognitive deficits become detectable [123], thus mirroring Aβ 1–42 levels in cerebrospinal fluid [124]. As such, the amount of amyloid deposition, along with Aβ 1–42 levels in cerebrospinal fluid, should not be viewed as an accurate index of disease progression. "
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    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.
    03/2014; 2014(17):785039. DOI:10.1155/2014/785039
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