Longitudinal PET Monitoring of Amyloidosis and Microglial Activation in a Second-Generation Amyloid-β Mouse Model

Sacher, Christian; Blume, Tanja; Beyer, Leonie; Peters, Finn; Eckenweber, Florian; Sgobio, Carmelo; Deußing, Maximilian; Albert, Nathalie L.; Unterrainer, Marcus; Lindner, Simon; Gildehaus, Franz-Josef; Ungern-Sternberg, Barbara von; Brzak, Irena; Neumann, Ulf; Saito, Takashi; Saido, Takaomi C.; Bartenstein, Peter; Rominger, Axel; Herms, Jochen; Brendel, Matthias

doi:10.2967/jnumed.119.227322

Cited by 48 publications

(71 citation statements)

References 32 publications

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“…Our data clearly indicate that µPET with the TSPO tracer 18 We show that transfer of TSPO µPET technology from different amyloid-β mouse models [19,23,25] to the present tau mouse model is feasible without major caveats. As in some former studies [16,20], we successfully validated a suitable pseudo-reference region for TSPO µPET in P301S mice and we were again able to show that this methodology reduces variance at the group level. This SUVR approach supported the detection of robust longitudinal increases of TSPO expression in different target regions of the P301S mouse model, which were matched with increases of microglial activation markers measured later by IHC.…”

Section: Discussionsupporting

confidence: 68%

“…Mice intended for IHC were deeply anaesthetized prior to transcardial perfusion with saline followed by 4% paraformaldehyde and subsequent brain extraction. We reprocessed historical µPET 18 F-GE-180 scans from amyloid-β APP/PS1 [19] and App NL−G−F mice [20] for comparison of their longitudinal microglial activation with present findings associated with tau accumulation in P301S mice.…”

Section: Animals and Study Designmentioning

confidence: 99%

“…Behavioral Testing n = 22 P301S and n = 18 WT mice were subjected to a MWM test for spatial learning and memory deficits, which was performed according to a standard protocol [20]. On training days one through five each mouse had to perform four trials per day in the test basin, with maximum time set to 70 seconds.…”

Section: Spm Analysismentioning

confidence: 99%

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Longitudinal Microglial Activation in Tau Transgenic P301S Mice Predicts Increased Tau Accumulation and Deteriorated Spatial Learning

Eckenweber

Luque

Blume

et al. 2020

Preprint

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Background: P301S tau transgenic mice show age-dependent accumulation of neurofibrillary tangles in brainstem, hippocampus, and neocortex, leading to neuronal loss and cognitive deterioration. However, there is hitherto only sparse documentation of the role of neuroinflammation in tau mouse models. Thus, we analyzed longitudinal microglial activation by small animal 18kDa translocator protein positron-emission-tomography (TSPO µPET) imaging in vivo , in conjunction with terminal assessment of tau pathology, spatial learning, and cerebral glucose metabolism. Methods: Transgenic P301S (n=33) and wild-type (n=18) female mice were imaged by 18 F-GE-180 TSPO µPET at the ages of 1.9, 3.9 and 6.4 months. We conducted behavioral testing in the Morris water maze, 18 F-fluordesoxyglucose ( 18 F-FDG) µPET and AT8 tau immunohistochemistry at 6.3-6.7 months. Terminal microglial immunohistochemistry served for validation of TSPO µPET results in vivo, applying target regions in brainstem, cortex, cerebellum and hippocampus. We compared the results with our historical data in amyloid -β mouse models. Results: TSPO expression in all target regions of P301S mice increased exponentially from 1.9 to 6.4 months, leading to significant differences in the contrasts with wild-type mice at 6.4 months (+11-23%, all p<0.001), but the apparent microgliosis proceeded more slowly than in our experience in amyloid-β mouse models. Spatial learning and glucose metabolism of AT8-positive P301S mice were significantly impaired at 6.3/6.5 months compared to the wild-type group. Longitudinal increases in TSPO expression predicted greater tau accumulation and lesser spatial learning performance at 6.7/6.3 months. Conclusions: Monitoring of microglial activation in P301S tau transgenic mice by TSPO µPET indicates a delayed time course when compared to amyloid-β mouse models. Detrimental associations of microglial activation with outcome parameters are opposite to earlier data in amyloid-β mouse models. The contribution of microglial response to pathology accompanying amyloid-β and tau over-expression merits further investigation.

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Section: Discussionsupporting

confidence: 68%

Section: Animals and Study Designmentioning

confidence: 99%

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Longitudinal Microglial Activation in Tau Transgenic P301S Mice Predicts Increased Tau Accumulation and Deteriorated Spatial Learning

Eckenweber

Luque

Blume

et al. 2020

Preprint

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“…TSPO PET imaging is now becoming a useful tool in neuroin ammation evaluation, as well as in diagnosis and therapy evaluation for many neurological diseases. In the longitudinal studies of neurological diseases, TSPO density evaluation with different radiotracers and analytical approaches have been performed to increase the sensitivity of TSPO expression characterization, and thus to elucidate the relationship between the disease progression and TSPO density [32][33][34][35]. In these studies, semi-quantitative parameters like %ID/cc and SUV are widely evaluated in both clinical and preclinical studies.…”

Section: Discussionmentioning

confidence: 99%

18F-VUIIS1009B Features a Superior Imaging Performance to 18F-DPA-714 in TSPO Density Characterization for Neuroinflammatory PET Imaging

Huang¹,

Fan²,

Hao³

et al. 2020

Preprint

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Abstract Purpose Translocator protein (TSPO), an out-mitochondrial membrane protein, is regarded as a key biomarker for neuroinflammation in a variety of neurodegenerative diseases. In this study, we aim to evaluate two highly specific TSPO radiotracers 18F-VUIIS1009A and 18F-VUIIS1009B in a mild cerebral ischemic rat model, and to compare their in vivo performance to the well-established TSPO probe 18F-DPA-714 for neuroinflammation imaging. With multiple graphic analytical methods tested and macro parameters determined, we propose to find a suitable and best quantification method to profile neuroinflammation and measure TSPO density with the three TSPO radiotracers. Methods Cerebral ischemia rat model was created and imaged using 18F-VUIIS1009A, 18F-VUIIS1009B and 18F-DPA-714. Displacement studies using cold analogs were performed to evaluate the binding specificities of 18F-VUIIS1009A and 18F-VUIIS1009B individually. Imaging analysis using arterial plasma input functions (AIFs) was employed to generate Logan plots and parametric images of total distribution volume (VT) for each radiotracer. Reference Logan model using healthy brain as a reference region was introduced to generate parametric images for binding potential (BPND). Results When compared to 18F-DPA-714, 18F-VUIIS1009B demonstrated higher in vitro binding specificity, binding potential (BPND) and distribution volume ratio (DVR). Parameter images of BPND and VT also indicate 18F-VUIIS1009B has a superior imaging profile when compared with other two radiotracers in TSPO imaging. Correlation analysis between BPND for 18F-VUIIS1009B and 18F-DPA-714 also indicates 18F-VUIIS1009B is more sensitive than 18F-DPA-714 in TSPO density measurement. Conclusions This study demonstrates the superiority of 18F-VUIIS1009B to 18F-VUIIS1009A and 18F-DPA-714 in the neuroinflammation imaging. It also demonstrates that 18F-VUIIS1009B PET imaging coupled with parameter mapping (VT and BPND) and graphic analysis holds great promise for neuroinflammation characterization and TSPO density measurement.

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“…The concentration of Aβ plaques in the brain was longitudinally monitored by means of the non-invasive, ultra-sensitive in vivo imaging technique Positron Emission Tomography (PET). The validated radiotracer [ 18 F]florbetaben,previously used for imaging Aβ plaques in AD patients(40), different transgenic AD mouse models(41)(42)(43)(44)(45)(46) and also in longitudinal therapeutic efficacy studies of AD transgenic mouse models(47), was used for assessing protein aggregates distribution.…”

mentioning

confidence: 99%

Oral treatment with iododiflunisal delays beta amyloid plaque formation in a transgenic mouse model of Alzheimer Disease: a Longitudinal in vivo molecular imaging study

Rejc

Gómez‐Vallejo

Rios

et al. 2020

Preprint

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Background: Transthyretin (TTR) is a tetrameric, Amyloid-beta (Aβ)-binding protein, which has been shown to reduce Aβ toxicity both in vitro and in vivo. The ability of TTR to interact with Aβ can be enhanced by a series of small molecules that stabilize its tetrameric form. Because of this, TTR stabilizers might act as disease modifying drugs in Alzheimer Disease (AD). In this work, we monitored the therapeutic efficacy of two TTR stabilizers, iododiflunisal (IDIF) and the repurposed drug tolcapone, by longitudinal assessment of Aβ deposition in an animal model of AD using positron emission tomography (PET) with [ 18 F]florbetaben.Methods: Mice (AβPPswe/PS1A246E/TTR+/-; n=21) were divided into 3 groups (n=7 per group): iododiflunisal (IDIF)-treated, tolcapone-treated and non-treated. The treatment, administered in the drinking water at a dose of 100 mg/Kg/day, was started at 5 months of age. The level of Aβ deposition was assessed at ages=5, 9, 11, and 14 months by PET imaging using [ 18 F]florbetaben. Treatment efficacy was determined based on radiotracer uptake in the hippocampus (HIP) and the cortex (CTX) with respect to the cerebellum (CB) and presented as standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analysis was performed at 14 months of age to further support in vivo results. Results: SUVr of [ 18 F]florbetaben in CTX and HIP of non-treated animals progressivelyincreased from age=5 to 11 months and stabilized afterwards. In contrast, [ 18 F]florbetaben uptake in HIP of IDIF-treated animals remained constant between ages=5 and 11 months and significantly increased at 14 months. At age=11 months, IDIF-treated group showed significantly lower SUVr values than those obtained for nontreated animals. In tolcapone-treated group, SUVr progressively increased with time, but at lower rate than in non-treated group. Moderate treatment effect of tolcapone suggests different mechanism of action than IDIF. No significant treatment effect was observed in CTX of IDIF-or tolcapone-treated animals. Results from IHC matched the in vivo data at age=14 months. Conclusions:The TTR stabilizer IDIF shows good Aβ-protective effect. Nevertheless, Aβ levels in treated and control animals reached similar values at the end of the study. Furthermore, differences in efficacy between IDIF and tolcapone, suggest different mechanisms of action.

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Longitudinal PET Monitoring of Amyloidosis and Microglial Activation in a Second-Generation Amyloid-β Mouse Model

Cited by 48 publications

References 32 publications

Longitudinal Microglial Activation in Tau Transgenic P301S Mice Predicts Increased Tau Accumulation and Deteriorated Spatial Learning

Longitudinal Microglial Activation in Tau Transgenic P301S Mice Predicts Increased Tau Accumulation and Deteriorated Spatial Learning

18F-VUIIS1009B Features a Superior Imaging Performance to 18F-DPA-714 in TSPO Density Characterization for Neuroinflammatory PET Imaging

Oral treatment with iododiflunisal delays beta amyloid plaque formation in a transgenic mouse model of Alzheimer Disease: a Longitudinal in vivo molecular imaging study

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