Abstract
IntroductionRadioligand imaging is a powerful in vivo method to assess the molecular basis of Alzheimer’s Disease. We therefore aimed to visualize the pathological deposition of fibrillar amyloid-β and neuronal dysfunction in aged double transgenic mice.MethodsUsing non-invasive positron emission tomography (PET) we assessed brain glucose utilization with [18F]FDG and fibrillar amyloidosis with [11C]PiB and [18F]AV45 in 12 month old APPPS1-21 (n = 10) mice and their age-matched wild-type controls (n = 15). PET scans were analyzed with statistical parametric mapping (SPM) to detect significant differences in tracer uptake between genotypes. After imaging, mice were sacrificed and ex vivo measures of amyloid-β burden with immunohistochemistry as well as glucose utilization with [14C]-2DG autoradiography were obtained as gold standards.ResultsVoxel-wise SPM analysis revealed significantly decreased [18F]FDG uptake in aged APPPS1-21 mice in comparison to WT with the thalamus (96.96 %, maxT = 3.35) and striatum (61.21 %, maxT = 3.29) demonstrating the most widespread reductions at the threshold of p < 0.01. [11C]PiB binding was significantly increased in APPPS1-21 mice, most notably in the hippocampus (87.84 %, maxT = 7.15) and cortex (69.08 %, maxT = 7.95), as detected by SPM voxel-wise analysis at the threshold of p < 0.01. Using the same threshold [18F]AV45 uptake was comparably lower with less significant differences. Compared to their respective ex vivo equivalents [18F]FDG demonstrated significant positive correlation to [14C]2-DG autoradiography (r = 0.67, p <0.0001) while [11C]PiB and [18F]AV45 binding did not correlate to ex vivo immunohistochemistry for amyloid-β (r = 0.25, p = 0.07 and r = 0.17, p = 0.26 respectively). Lastly no correlation was observed between regions of high amyloid burden and those with decreased glucose utilization (r = 0.001, p = 0.99).ConclusionsOur findings support that fibrillar amyloid-β deposition and reduced glucose utilization can be visualized and quantified with in vivo μPET imaging in aged APPPS1-21 mice. Therefore, the combined use of [18F]FDG and amyloid μPET imaging can shed light on the underlying relationship between fibrillar amyloid-β pathology and neuronal dysfunction.
Highlights
Radioligand imaging is a powerful in vivo method to assess the molecular basis of Alzheimer’s Disease
VOI analysis (Fig. 1b) demonstrated increased retention of [11C]Pittsburgh compound B (PiB) in APPPS1-21 mice with the cortex (p = 8.35e-005) and hippocampus (p = 1.54e-005) showing the greatest significant difference. [18F]AV45 retention was increased in APPPS1-21 mice but did not reach significance
We investigated the association between regional Micro-positron emission tomography (μPET) micro-positron emission tomography, FDG fluorodeoxyglucose, 2-DG 2-deoxy-D-glucose, PiB Pittsburgh compound B
Summary
Radioligand imaging is a powerful in vivo method to assess the molecular basis of Alzheimer’s Disease. A number of transgenic mouse models of cerebral amyloidosis are readily available and are generally created by the manipulation of the genes involved in amyloid processing [9] While investigation of these models has led to a greater understanding of amyloid-related disease mechanisms, they are limited by the primary use of ex vivo methods to assess brain pathology. Investigations of glucose utilization in transgenic models with [18F]FDG focused on the highresolution technique of ex vivo autoradiography With this method a number of models were shown to have reductions in [18F]FDG uptake in brain regions with homology to those affected in clinical AD [19,20,21,22,23]. More recently in vivo hypometabolism in amyloidosis models has been described [31,32,33]
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