Exploratory Dual PET imaging of [F] fluorodeoxyglucose and [C]acetoacetate in type 2 diabetic nonhuman primates.

Despite recent advancements in imaging (amyloid-PET & tau-PET) and fluid (Aβ42/Aβ40 & Aβ42/ptau) biomarkers, the current standard for in vivo assessment of AD, diagnosis and prediction of Alzheimer's disease (AD) remains challenging. We demonstrated in nonhuman primates (NHP) that increased plasma and cerebrospinal fluid (CSF) glucose correlated with decreased CSF Aβ42 and CSF Aβ40, a hallmark of plaque promoting pathogenesis. Together, our findings demonstrate that altered glucose homeostasis and insulin resistance are associated with Aβ and amyloid in rodent and NHP models. This warranted further exploration into the dynamics of altered brain metabolism in the NHP model of T2D, cross referenced with CSF and blood-based AD markers. Preliminary dual PET ([C]acetoacetate ([C]AcAc) and [F]fluorodeoxyglucose ([F]FDG) imaging studies were conducted in an aged cohort of NHPs classified as T2D (n = 5) and pre-diabetic (n = 1) along with corresponding plasma and CSF samples for metabolite analysis. [C]AcAc and [F]FDG PET brain standard uptake values (SUV) were highly positively associated (r = 0.88, p = 0.02) in the T2D and pre-diabetic NHPs. Age was not significantly associated with brain SUV (age range 16.5-23.5 years old). Metabolic measures were positively correlated with brain [F]FDG and CSF Aβ42:40 was positively correlated to fasting glucose values. Although our findings suggest moderate correlations, this study further elucidates that peripheral insulin resistance and poor glycemia control alter AD-related pathology, illustrating how T2D is a risk factor for AD.