IC‐P‐098: ALTERNATIVE CEREBRAL GLUCOSE UPTAKE METRICS DETECT EARLY METABOLIC CHANGES IN THE 5XFAD MOUSE MODEL OF ALZHEIMER'S DISEASE

Despite concerted efforts towards identifying brain imaging biomarkers in Alzheimer's Disease (AD), early and definitive diagnosis of AD during life remains elusive. Characteristic neurometabolic dysfunction, as revealed by 18 FDG PET imaging, is profound in later stages of AD. However, altered metabolism at early stages of the disease has been difficult to observe. This may be due, in part, to the variable representation and interpretation of such data using standardized uptake values (SUVs) and relative SUVs (SUVRs). We posit that alternative metrics of 18 FDG uptake may provide new insight into early aberrant metabolic regulation in the AD brain. Male 5XFAD (n=24) and age-matched wild-type (WT) mice (n=13) at 2, 5 and 13 months underwent PET scanning 30 min after 18 FDG administration, and subsequently imaged using CT/MRI. PET/CT/MRI data were co-registered and MR-based ROIs of specific brain regions were generated including amygdala, basal forebrain, cerebellum, hippocampus, hypothalamus, neocortex and thalamus. SUVs were reported and a series of relative SUVs (SUVRs) were iteratively generated to evaluate the sensitivity of each brain region as a candidate reference tissue. 5XFAD animals demonstrated a global decrease in 18 FDG SUVs compared to WT controls at 13 months in each of the brain structures investigated (p ≤ 0.002). 5XFAD mice at 2 and 5 months showed no significant difference in SUVs compared to their control counterparts. Importantly, employing alternative SUVR metrics to express relative 18 F-FDG uptake revealed an early and significant SUVR increase in 5XFAD mice at 2 months when using neocortex as the reference region (p ≤ 0.03) - a feature that could not distinguish 5XFAD and WT mice using SUVs alone, or the frequently employed cerebellar reference SUVR. As in human AD, significant decreases in brain 18 F-FDG uptake are directly observable only in late disease stages in the 5XFAD model. However, determining alternative regional brain glucose metabolism SUVRs in young animals was found to distinguish 5XFAD from WT mice. We conclude 18 FDG uptake could represent a sensitive biomarker for early detection of brain dysfunction in AD mouse models when alternative SUVR metrics are utilized. Further study utilizing the ADNI database will help determine applicability in human AD.

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