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: 10.23). 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, Aug 23, 2015
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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 · 3.80 Impact Factor
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    • "In the context of current models of the AD pathophysiologic cascade ( Jack et al., 2013 ), these findings suggest that A β may exert both local and remote effects on brain metabolism, the latter potentially due to deafferentation of remote areas ( Bourgeat et al., 2010 ). Traditional univariate approaches have similarly demonstrated both local and remote correlations between PiB and FDG ( Cohen et al., 2009 ; Edison et al., 2007 ; Engler et al., 2006 ). Our results are further congruent with a recent report in mild cognitive impairment, which showed via pICA that increased amyloid-β burden in the left precuneus / cuneus and medial-temporal regions was associated with increased brain atrophy rates in the left medial-temporal and parietal regions, while increased amyloid-β burden in bilateral precuneus / cuneus and parietal regions was associated with increased brain atrophy rates in the right medial temporal regions ( Tosun et al., 2011 ). "
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    Clinical neuroimaging 03/2014; 4. DOI:10.1016/j.nicl.2014.03.005 · 2.53 Impact Factor
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    • "Patients with subtle cognitive deficits, who will later develop AD, can be identified with [ 11 C]PIB-PET [5]. However, in longitudinal studies, clinically deteriorating AD patients demonstrated a largely unchanged [ 11 C]PIB-PET-signal [7] [8]. Thus the ability to monitor disease progression or assess therapeutic efficacy with [ 11 C]PIB-PET-imaging seems rather limited. "
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    ABSTRACT: Evidence suggests that amyloid-β (Aβ) protofibrils/oligomers are pathogenic agents in Alzheimer's disease (AD). Unfortunately, techniques enabling quantitative estimates of these species in patients or patient samples are still rather limited. Here we describe the in vitro and ex vivo characteristics of a new antibody-based radioactive ligand, [125I]mAb158, which binds to Aβ protofibrils with high affinity. [125I]mAb158 was specifically taken up in brain of transgenic mice expressing amyloid-β protein precursor (AβPP) as shown ex vivo. This was in contrast to [125I]mAb-Ly128 which does not bind to Aβ. The uptake of intraperitoneally-administered [125I]mAb158 into the brain was age- and time-dependent, and saturable in AβPP transgenic mice with modest Aβ deposition. Brain uptake was also found in young AβPP transgenic mice that were devoid of Aβ deposits, suggesting that [125I]mAb158 targets soluble Aβ protofibrils. The radioligand was diffusely located in the parenchyma, sometimes around senile plaques and only occasionally colocalized with cerebral amyloid angiopathy. A refined iodine-124-labeled version of mAb158 with much improved blood-brain barrier passage and a shorter plasma half-life might be useful for PET imaging of Aβ protofibrils.
    Journal of Alzheimer's disease: JAD 06/2013; 37(1). DOI:10.3233/JAD-130029 · 4.15 Impact Factor
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