Etablierung eines neuen Modells an der Ratte mit extrakorporaler Zirkulation und zerebralen Luftembolien wobei der Einfluss von Xenon auf neuropsychologische Leistungsfähigkeit und Mortalität mit untersucht werden soll

In der vorliegenden Studie gelang erstmalig die Integration der Untersuchung über die Inkorporation zerebraler Luftembolien in ein Modell der extrakorporalen Zirkulation bei der Ratte. Mit diesem Modell wurde auch der Einfluss von Xenon auf neuropsychologische Leistungsfähigkeit und Mortalität untersucht. Mit dem modifizierten Hole Board (mHB) Test kann die kognitive Leistungsfähigkeit sowie Verhaltensänderungen bewertet und ermittelt werden. Die Auswertung von Mortalität, Kognition und Verhalten ergibt Dosis-Wirkungs-Beziehungen zwischen unterschiedlichen Luftvolumina und nachweisbaren Defiziten. Diese Studie diente auch als Dosis-Findungs-Studie in Vorbereitung auf eine Langzeitüberlebensstudie (14 Tage), in der der Einfluss von Xenon auf zentralnervöse Leistungen der Ratte untersucht werden soll. Zu diesem Zweck sollte ein geeigneter Luftbolus gefunden werden, der vereinbar mit langfristigem Überleben ist und zugleich eine deutliche zentralnervöse Schädigung hervorruft

Automated Spatial Brain Normalization and Hindbrain White Matter Reference Tissue Give Improved [F-18]-Florbetaben PET Quantitation in Alzheimer's Model Mice

Preclinical PET studies of 13-amyloid (A beta) accumulation are of growing importance, but comparisons between research sites require standardized and optimized methods for quantitation. Therefore, we aimed to evaluate systematically the (1) impact of an automated algorithm for spatial brain normalization, and (2) intensity scaling methods of different reference regions for A beta-PET in a large dataset of transgenic mice. PS2APP mice in a 6 week longitudinal setting (N = 37) and another set of PS2APP mice at a histologically assessed narrow range of A beta burden (N = 40) were investigated by florbetaben PET Manual spatial normalization by three readers at different training levels was performed prior to application of an automated brain spatial normalization and inter -reader agreement was assessed by Fleiss Kappa (kappa). For this method the impact of templates at different pathology stages was investigated. Four different reference regions on brain uptake normalization were used to calculate frontal cortical standardized uptake value ratios (SUVRc-rx/REF) relative to raw SUVCTX. Results were compared on the basis of longitudinal stability (Cohen's d), and in reference to gold standard histopathological quantitation (Pearson's R). Application of an automated brain spatial normalization resulted in nearly perfect agreement (all If kappa >= 0.99) between different readers, with constant or improved correlation with histology. Templates based on inappropriate pathology stage resulted in up to 2.9% systematic bias for SUVRc-Fx, /REF " All SUVRG-Fx, /REF methods performed better than SUVGTx both with regard to longitudinal stability (d >= 1.21 vs. d = 0.23) and histological gold standard agreement (R >= 0.66 vs. R >= 0.31). Voxel-wise analysis suggested a physiologically implausible longitudinal decrease by global mean scaling. The hindbrain white matter reference (R-mean = 0.75

Cross-Sectional Comparison of Small Animal [F-18]-Florbetaben Amyloid-PET between Transgenic AD Mouse Models

We aimed to compare [F-18]-florbetaben PET imaging in four transgenic mouse strains modelling Alzheimer's disease (AD), with the main focus on APPswe/PS2 mice and C57Bl/6 mice serving as controls (WT). A consistent PET protocol (N = 82 PET scans) was used, with cortical standardized uptake value ratio (SUVR) relative to cerebellum as the endpoint. We correlated methoxy-X04 staining of beta-amyloid with PET results, and undertook ex vivo autoradiography for further validation of a partial volume effect correction (PVEC) of PET data. The SUVR in APPswe/PS2 increased from 0.95 +/- 0.04 at five months (N = 5) and 1.04 +/- 0.03 (p < 0.05) at eight months (N = 7) to 1.07 +/- 0.04 (p < 0.005) at ten months (N = 6), 1.28 +/- 0.06 (p < 0.001) at 16 months (N = 6) and 1.39 +/- 0.09 (p < 0.001) at 19 months (N = 6). SUVR was 0.95 +/- 0.03 in WT mice of all ages (N = 22). In APPswe/PS1G384A mice, the SUVR was 0.93/0.98 at five months (N = 2) and 1.11 at 16 months (N = 1). In APPswe/PS1dE9 mice, the SUVR declined from 0.96/0.96 at 12 months (N = 2) to 0.91/0.92 at 24 months (N = 2), due to beta-amyloid plaques in cerebellum. PVEC reduced the discrepancy between SUVR-PET and autoradiography from -22% to +2% and increased the differences between young and aged transgenic animals. SUVR and plaque load correlated highly between strains for uncorrected (R = 0.94, p < 0.001) and PVE-corrected (R = 0.95, p < 0.001) data. We find that APPswe/PS2 mice may be optimal for longitudinal amyloid-PET monitoring in planned interventions studies

Monitoring of Tumor Growth with [F-18]-FET PET in a Mouse Model of Glioblastoma: SUV Measurements and Volumetric Approaches

Noninvasive tumor growth monitoring is of particular interest for the evaluation of experimental glioma therapies. This study investigates the potential of positron emission tomography (PET) using O-(2-F-18-fluoroethyl)-L-tyrosine ([F-18]-FET) to determine tumor growth in a murine glioblastoma (GBM) model including estimation of the biological tumor volume (BTV), which has hitherto not been investigated in the pre-clinical context. Fifteen GBM bearing mice (GL261) and six control mice (shams) were investigated during 5 weeks by PET followed by autoradiographic and histological assessments. [F-18]-FET PET was quantitated by calculation of maximum and mean standardized uptake values within a universal volume-of-interest (VOI) corrected for healthy background (SUVmax/BG, SUVmean/BG). A partial volume effect correction (PVEC) was applied in comparison to ex vivo autoradiography. BTVs obtained by predefined thresholds for VOI definition (SUV/BG: >= 1.4;>= 1.6;>= 1.8;>= 2.0) were compared to the histologically assessed tumor volume (n = 8). Finally, individual-optimal" thresholds for BTV definition best reflecting the histology were determined. In GBM mice SUVmax/BG and SUVmean/BG clearly increased with time, however at high inter-animal variability. No relevant [F-18]-FET uptake was observed in shams. PVEC recovered signal loss of SUVmean/BG assessment in relation to autoradiography. BTV as estimated by predefined thresholds strongly differed from the histology volume. Strikingly, the individual "optimal" thresholds for BTV assessment correlated highly with SUVmax/BG (rho = 0.97, p < 0.001), allowing SUVmax/BG-based calculation of individual thresholds. The method was verified by a subsequent validation study (n = 15, p = 0.88, p < 0.01) leading to extensively higher agreement of BTV estimations when compared to histology in contrast to predefined thresholds. [F-18]-FET PET with standard SUV measurements is feasible for glioma imaging in the GBM mouse model. PVEC is beneficial to improve accuracy of [F-18]-FET PET SUV quantification. Although SUVmax/BG and SUVmean/BG increase during the disease course, these parameters do not correlate with the respective tumor size. For the first time, we propose a histology-verified method allowing appropriate individual BTV estimation for volumetric in vivo monitoring of tumor growth with [F-18]-FET PET and show that standardized thresholds from routine clinical practice seem to be inappropriate for BTV estimation in the GBM mouse model

Increase of TREM2 during Aging of an Alzheimer's Disease Mouse Model Is Paralleled by Microglial Activation and Amyloidosis

Heterozygous missense mutations in the triggering receptor expressed on myeloid cells 2 (TREM2) have been reported to significantly increase the risk of developing Alzheimer's disease (AD). Since TREM2 is specifically expressed by microglia in the brain, we hypothesized that soluble TREM2 (sTREM2) levels may increase together with in vivo biomarkers of microglial activity and amyloidosis in an AD mouse model as assessed by small animal positron-emission-tomography (it PET). In this cross-sectional study, we examined a strong amyloid mouse model (PS2APP) of four age groups by mu PET with H-18-GE180 (glial activation) and F-18]-florbetaben (amyloidosis), followed by measurement of sTREM2 levels and amyloid levels in the brain. Pathology affected brain regions were compared between tracers (dice similarity coefficients) and pseudo-longitudinally. (PET results of both tracers were correlated with terminal TREM2 levels. The brain sTREM2 levels strongly increased with age of PS2APP mice (5 vs. 16 months: +211%, p 0.001), and correlated highly with mu PET signals of microglial activity (R = 0.89, p < 0.001) and amyloidosis (R = 0.92, p < 0.001). Dual p,,PET enabled regional mapping of glial activation and amyloidosis in the mouse brain, which progressed concertedly leading to a high overlap in aged PS2APP mice (dice similarity 67%). Together, these results substantiate the use of in vivo mu PET measurements in conjunction with post mortem sTREM2 in future anti-inflammatory treatment trials. Taking human data into account sTREM2 may increase during active amyloid deposition

Correlation of Perfusion MRI and F-18-FDG PET Imaging Biomarkers for Monitoring Regorafenib Therapy in Experimental Colon Carcinomas with Immunohistochemical Validation

Objectives To investigate a multimodal, multiparametric perfusion MRI/F-18-fluoro-deoxyglucose (F-18-FDG)-PET imaging protocol for monitoring regorafenib therapy effects on experimental colorectal adenocarcinomas in rats with immunohistochemical validation. Materials and Methods Human colorectal adenocarcinoma xenografts (HT-29) were implanted subcutaneously in n = 17 (n = 10 therapy group;n = 7 control group) female athymic nude rats (Hsd: RH-Foxn1(mu)). Animals were imaged at baseline and after a one-week daily treatment protocol with regorafenib (10 mg/kg bodyweight) using a multimodal, multiparametric perfusion MRI/F-18-FDG-PET imaging protocol. In perfusion MRI, quantitative parameters of plasma flow (PF, mL/100 mL/min), plasma volume (PV,%) and endothelial permeability-surface area product (PS, mL/100 mL/min) were calculated. In F-18-FDG-PET, tumor-to-background-ratio (TTB) was calculated. Perfusion MRI parameters were correlated with TTB and immunohistochemical assessments of tumor microvascular density (CD-31) and cell proliferation (Ki-67). Results Regorafenib significantly (p<0.01) suppressed PF (81.1 +/- 7.5 to 50.6 +/- 16.0 mL/100mL/min), PV (12.1 +/- 3.6 to 7.5 +/- 1.6%) and PS (13.6 +/- 3.2 to 7.9 +/- 2.3 mL/100mL/min) as well as TTB (3.4 +/- 0.6 to 1.9 +/- 1.1) between baseline and day 7. Immunohistochemistry revealed significantly (p<0.03) lower tumor microvascular density (CD-31, 7.0 +/- 2.4 vs. 16.1 +/- 5.9) and tumor cell proliferation (Ki-67, 434.0 +/- 62.9 vs. 663.0 +/- 98.3) in the therapy group. Perfusion MRI parameters Delta PF, Delta PV and Delta PS showed strong and significant (r = 0.67-0.78;p<0.01) correlations to the PET parameter Delta TTB and significant correlations (r = 0.57-0.67;p<0.03) to immunohistochemical Ki-67 as well as to CD-31-stainings (r = 0.49-0.55;p<0.05). Conclusions A multimodal, multiparametric perfusion MRI/PET imaging protocol allowed for non-invasive monitoring of regorafenib therapy effects on experimental colorectal adenocarcinomas in vivo with significant correlations between perfusion MRI parameters and F-18-FDG-PET validated by immunohistochemistry

Impact of partial volume effect correction on cerebral Beta-amyloid imaging in APP-Swe mice using [18F]-florbetaben PET

Highlights - We explored the magnitude of partial volume effects (PVE) in small animal PET. - We performed correction of PVE in longitudinal [18F]-florbetaben PET data. - Longitudinal group differences resulted higher with PVE correction. - Discrepancies with autoradiography decreased with PVE correction. - The method should increase sensitivity of longitudinal studies with treatment arms. Abstract We previously investigated the progression of β-amyloid deposition in brain of mice over-expressing amyloid-precursor protein (APP-Swe), a model of Alzheimer's disease (AD), in a longitudinal PET study with the novel β-amyloid tracer [18F]-florbetaben. There were certain discrepancies between PET and autoradiographic findings, which seemed to arise from partial volume effects (PVE). Since this phenomenon can lead to bias, most especially in the quantitation of brain microPET studies of mice, we aimed in the present study to investigate the magnitude of PVE on [18F]-florbetaben quantitation in murine brain, and to establish and validate a useful correction method (PVEC). Phantom studies with solutions of known radioactivity concentration were performed to measure the full-width-at-half-maximum (FWHM) resolution of the Siemens Inveon DPET and to validate a volume-of-interest (VOI)-based PVEC algorithm. Several VOI-brain-masks were applied to perform in vivo PVEC on [18F]-florbetaben data from C57BL/6(N = 6) mice, while uncorrected and PVE-corrected data were cross-validated with gamma counting and autoradiography. Next, PVEC was performed on longitudinal PET data set consisting of 43 PET scans in APP-Swe (13–20 months) and age-matched wild-type (WT) mice using the previously defined masks. VOI-based cortex-to-cerebellum ratios (SUVR) were compared for uncorrected and PVE-corrected results. Brains from a subset of transgenic mice were ultimately examined by autoradiography ex vivo and histochemistry in vitro as gold standard assessments, and compared to VOI-based PET results. The phantom study indicated a FWHM of 1.72 mm. Applying a VOI-brain-mask including extracerebral regions gave robust PVEC, with increased precision of the SUVR results. Cortical SUVR increased with age in APP-Swe mice compared to baseline measurements (16 months: + 5.5%, p 18F]-florbetaben uptake in aging APP-Swe mice in planned studies of disease modifying treatments on amyloidogenesis

Cross-sectional Comparison of Small Animal [18F]-Florbetaben Amyloid-PET Between Transgenic AD Mouse Models

PET imaging of cerebral β-amyloid in small animal models of Alzheimer’s disease (AD) now offers the possibility of experimental treatment monitoring in vivo. However, there is no consensus concerning the optimal transgenic mouse model or choice of β-amyloid radiotracers. Therefore, we aimed to compare cross-sectional PET findings in four established AD models using the previously evaluated β-amyloid ligand [18F]-florbetaben (FBB). In addition, we carried out further validation of our partial volume effect correction (PVEC) for FBB in mouse brain. We investigated a total of 20 mice using a standardized FBB PET protocol: APPswe/PS2 (N = 5; 8, 12 and 19 mo), APPswe/PS1dE9 (N = 4; 12 and 24 mo), APPswe/PS1G384A (N = 3; 5 and 16 mo), and C57Bl/6 controls (WT) at a range of ages (N = 8; 6 - 22 mo), and used historical data from APPswe (N = 10; 13 - 20 mo). For each mouse, we calculated volume-of-interest (VOI)-based cortical standard-uptake-value-ratios (SUVR) and applied PVEC. We carried out hemispheric autoradiography ex vivo for comparison with PET results in representative mice, and carried out histological analysis of β-amyloid using methoxy-X04 staining in all 20 mice. Compared to WT (SUVR: 0.95), APPswe/PS2 animals had elevated SUVR (1.03) at eight mo, with further increases to 1.17 at 12 mo and 1.31 at 19 mo. APPswe/PS1G384A mice had normal SUVR (0.95) at 5 mo which increased to 1.11 at 16 mo, a result comparable to our earlier SUVR finding (1.12) in APPswe mice at 20 mo. The SUVR for APPswe/PS1dE9 mice declined from 0.96 to 0.91 at 24 mo due to increasing cerebellar plaque load. PVEC reduced discrepancies between SUVR-PET and autoradiography, such that corrected SUVR was as high as 1.89 in 19 mo APPswe/PS2 mice. There was for all transgenic strains a high correlation between SUVR and histology (R = 0.94, p < 0.001). APPswe/PS2 and APPswe/PS1G384A mice seemed superior to APPswe mice for longitudinal imaging due to earlier onset of amyloidosis. The cerebellar labelling in APPswe/PS1dE9 mice interferes with quantitation by SUVR. PVEC improved accuracy of PET results relative to autoradiographic gold standard