Longitudinal Characterization of [18F]-FDG and [18F]-AV45 Uptake in the Double Transgenic TASTPM Mouse Model

Abstract

We aimed to monitor the timing of amyloid-β deposition in relation to changes in brain function using in vivo imaging with [18F]-AV45 and [18F]-FDG in a mouse model of Alzheimer's disease. TASTPM transgenic mice and wild-type controls were scanned longitudinally with [18F]-AV45 and [18F]-FDG before (3 months of age) and at multiple time points after the onset of amyloid deposition (6, 9, 12, and 15 months of age). As expected with increasing amyloidosis, TASTPM mice demonstrated progressive age-dependent increases in [18F]-AV45 uptake that were significantly higher than for WT from 9 months onwards and correlated to ex vivo measures of amyloid burden. The metabolism of [18F]-AV45 produces several brain penetrant radiometabolites and normalization to a reference region helps to negate this non-specific binding and improve the sensitivity of [18F]-AV45. The observed trajectory of [18F]-FDG alterations deviated from our proposed hypothesis of gradual decreases with worsening amyloidosis. While [18F]-FDG uptake in TASTPM mice was significantly lower than that of WT at 9 months, reduced [18F]-FDG was not associated with aging in TASTPM mice. Moreover, [18F]-FDG uptake did not correlate to measures of ex vivo amyloid burden. Our findings suggest that while amyloid-β is sufficient to induce hypometabolism, these pathologies are not linked in a dose-dependent manner in TASTPM mice.

Keywords: Alzheimer’s disease; [18F]-AV45; [18F]-FDG; longitudinal; small animal imaging; transgenic mice.

Fig.1

[¹⁸F]-AV45 is rapidly metabolized with production of several radiometabolites. Young WT mice were injected with 37 Mbq i.v of [¹⁸F]AV45 and sacrificed at multiple time points p.i. The graphs show the average percentage of intact [¹⁸F]-AV45 and radiometabolites in (A) the plasma and (B) the brain as a function of time. Data is presented as % peak area (mean) in the radiochromatogram. Data is presented as the mean.

Fig.2

Longitudinal imaging of [¹⁸F]-AV45 uptake in WT and TASTPM mice. Average μPET images of [¹⁸F]-AV45 uptake in WT and TASTPM mice at each time point. [¹⁸F]-AV45 uptake was corrected for injected dose and normalized to the cerebellum. μPET images are overlaid on a T₂-weighted MRI template for anatomic localization. 3 months (TASTPM = 22, WT = 22), 6 months (TASTPM = 15, WT = 19), 9 months (TASTPM = 12, WT = 16), 12 months (TASTPM = 8, WT = 13), 15 months (TASTPM = 5, WT = 10).

Fig.3

TASTPM mice demonstrate age-related increases in [¹⁸F]-AV45 uptake. Figures A-D show regional uptake values of [¹⁸F]-AV45 in both genotypes over time. [¹⁸F]-AV45 uptake in each region was presented as a ratio to the cerebellum (CBnorm). Data is shown as mean±standard deviation. Differences between genotypes at each time point were evaluated with t-tests (with Sidak-Bonferroni correction), ****p < 0.0001, ***p < 0.001.

Fig.4

Longitudinal imaging of [¹⁸F]-FDG uptake in WT and TASTPM mice. Average μPET images of [¹⁸F]-FDG uptake in WT and TASTPM mice at each time point. [¹⁸F]-FDG uptake was corrected for injected dose, body weight and pre-scan blood glucose, (tissue uptake[kBq/cc] * blood glucose/injected dose[kBq] * body weight). μPET images are overlaid on a T₂-weighted MRI template for anatomic localization. 3 months (TASTPM = 22, WT = 22), 6 months (TASTPM = 13, WT = 19), 9 months (TASTPM = 12, WT = 14), 12 months (TASTPM = 8, WT = 13), 15 months (TASTPM = 5, WT = 10).

Fig.5

TASTPM mice demonstrate lower [¹⁸F]-FDG uptake in comparison to WT that does not worsen with disease progression. Panels A-D show regional uptake values of [¹⁸F]-FDG in both genotypes over time. [¹⁸F]-FDG uptake is quantified as glucose-corrected SUV (tissue uptake[kBq/cc] * blood glucose[mg/dl]/injected dose[kBq] * body weight[g]). Data is shown as mean±standard deviation. Differences between genotypes at each time point were evaluated with t-tests (with Sidak-Bonferroni correction), ^**p < 0.01.

Fig.6

Comparison of in vivo amyloid imaging and ex vivo quantification of amyloid burden. Graphs A-D show correlation analysis of regional [¹⁸F]-AV45 uptake and amyloid burden detected by 4G8 immunostaining. Panel E shows representative 4G8 immunohistochemistry in TASTPM mice at each age. Scale bar = 500 μm.