Age- and transgene-related changes in regional cerebral metabolism in PSAPP mice

Abstract

In parallel to imaging studies in humans with Alzheimer's disease (AD), we have mapped brain metabolic activity in transgenic mouse models of AD. Our aim in both is to provide new surrogate markers of progression to help clarify disease mechanisms and rapidly screen candidate therapeutics. Since previous findings of preferential reductions in posterior cingulate glucose metabolism may have been confounded by morphological abnormalities in previously studied "PDAPP" transgenic mice, we first assessed hippocampal and callosal anatomy in PSAPP (PS1×APP) mice, another transgenic mouse model of AD, and found no major abnormalities. We then used fluorodeoxyglucose (FDG) autoradiography in older and younger PSAPP and wildtype mice to assess the functional state of 56 regions-of-interest across group, age and increasing amyloid load. Reductions in FDG uptake in aged transgenic mice, with significant interactions between group and age, were found in retrosplenial cingulate gyrus, found to be metabolically affected in persons affected by or at risk for AD, and in brain regions known to participate with retrosplenial cingulate in networks contributing to spatial learning deficits found in these animals. Like patients with AD, PSAPP mice have agerelated metabolic reductions in posterior cingulate cortex, a finding that does not appear to be related to morphological abnormalities. If longitudinal studies support these progressive and preferential reductions in retrosplenial metabolism in PSAPP mice, these reductions could provide an indicator of disease progression, help bridge the gap between human and animal studies of AD, and aid in clarification of disease mechanisms and screening of promising treatments.

Limitations of Small Animal PET Imaging with [18F]FDDNP and FDG for Quantitative Studies in a Transgenic Mouse Model of Alzheimer’s Disease

“…In humans, most prominent reductions of FDG uptake were observed in the posterior cingulate cortex, precuneus, and parietotemporal areas, extending to the frontal cortex [9]. Similar findings have been reported for two different transgenic mouse models of AD (PDAPP and PSAPP), where significant reductions in [ 14 C]FDG uptake (∼−15%) as measured by ex vivo autoradiography were found in posterior cingulate cortex of aged transgenic as compared to wild-type mice [22,23]. In our study, these previous findings could not be confirmed as regional radioactivity uptake and ratios to whole brain were similar in both groups of animals after injection of FDG (Table 2).…”

“…In our study, these previous findings could not be confirmed as regional radioactivity uptake and ratios to whole brain were similar in both groups of animals after injection of FDG (Table 2). Our failure to detect regionally increased [ 18 F]FDDNP retention and regionally decreased FDG retention in any brain area analyzed of transgenic animals is in all likelihood related to the limitations in spatial resolution of small animal PET as compared to 14 C-autoradiography [22,23]. Possible partial volume effects can lead to difficulties in volume definition and radioactivity measurements for small VOIs of mouse brain.…”

Mapping Changes in Mouse Brain Metabolism with PET/CT

“…Although a given recording technique or analysis technique may reveal highly reliable differences for a specific region, it cannot automatically be concluded that this method is generally superior. Our study found areas of reduced activity in the caudal brain stem, cerebellum, and midbrain matching those identified in other studies (21). In addition, because the clusters of most significance were in the same place regardless of registration method and were away from the brain-skull interface, they were unlikely to be an artifact caused by misregistration, for example.…”

“…The ability to follow single animals or groups of animals using repeated scans should improve accuracy (by potentially reducing the effect of variability between animals) and reduce the number of animals required for studies, with the corollary of a significant lowering of costs when working with transgenic cohorts. However, attempts to measure changes in mouse brain metabolism have met with mixed results: uptake of 18 F-FDG correlated well with 14 C-DG uptake in normoglycemic animals (10), and 18 F-FDG PET has been used to reveal metabolic phenotypes in models of epilepsy (11,12) and Alzheimer disease (13)(14)(15)(16)(17)(18)(19)(20)(21). However, others have failed to detect differences in mouse models of Alzheimer disease (22,23) and the question may be raised of whether phenotypes are due to different acquisition and analysis methods yielding different sensitivities in identifying neuronal alterations.…”

“…This method was based and validated in a mouse cohort on an inbred C57BL/6 background undergoing a longitudinal study starting at age 6 mo and ending at 14 mo. The choice of this cohort is in keeping with autoradiography data, which have underlined subtle changes in 18 F-FDG uptake in certain brain regions as mice age (21). However, we envisage our methodology to be more sensitive (since it measures changes in individual animals) and to be applicable to other metabolic changes related to a range of models, phenotypes, or therapy.…”