Compared with patients undergoing complete operative IPMN clearance, patients with residual IPMN after segmental pancreatectomy do not demonstrate increased risk for the development of invasive disease or reduced survival. In patients without residual IPMN who later develop new IPMN, the risk for invasive IPMN is increased.
The reference standard IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from tert-butyl (S)-5-oxopyrrolidine-2-carboxylate, fluoroethylbromide, and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 12% in three steps. The target tracer [F]IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-[F]fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from desmethyl-GSK1482160 with 2-[F]fluoroethyl tosylate, prepared from 1,2-ethylene glycol-bis-tosylate and K[F]F/Kryptofix2.2.2, in two steps and isolated by HPLC combined with SPE in 1-3% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity at end of bombardment (EOB) was 74-370 GBq/μmol. The potency of IUR-1601 in comparison with GSK1482160 was determined by a radioligand competitive binding assay using [C]GSK1482160, and the binding affinity K values for IUR-1601 and GSK1482160 are 4.31 and 5.14 nM, respectively.
Obesity is recognized as a significant risk factor for Alzheimer’s disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies, to date, have focused on the use of early-onset AD models. Here, we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed with a high fat/high sugar diet (HFD). We focused on three mouse models created through the IU/JAX/PITT MODEL-AD Center. These included a combined risk model with APOE4 and a variant in triggering receptor expressed on myeloid cells 2 (Trem2R47H). We have termed this model, LOAD1. Additional variants including the M28L variant in phospholipase C Gamma 2 (Plcg2M28L) and the 677C > T variant in methylenetetrahydrofolate reductase (Mthfr677C >T) were engineered by CRISPR onto LOAD1 to generate LOAD1.Plcg2M28L and LOAD1.Mthfr677C >T. At 2 months of age, animals were placed on an HFD that induces obesity or a control diet (CD), until 12 months of age. Throughout the study, blood was collected to assess the levels of cholesterol and glucose. Positron emission tomography/computed tomography (PET/CT) was completed prior to sacrifice to image for glucose utilization and brain perfusion. After the completion of the study, blood and brains were collected for analysis. As expected, animals fed a HFD, showed a significant increase in body weight compared to those fed a CD. Glucose increased as a function of HFD in females only with cholesterol increasing in both sexes. Interestingly, LOAD1.Plcg2M28L demonstrated an increase in microglia density and alterations in regional brain glucose and perfusion on HFD. These changes were not observed in LOAD1 or LOAD1.Mthfr677C >T animals fed with HFD. Furthermore, LOAD1.Plcg2M28L but not LOAD1.Mthfr677C >T or LOAD1 animals showed transcriptomics correlations with human AD modules. Our results show that HFD affects the brain in a genotype-specific manner. Further insight into this process may have significant implications for the development of lifestyle interventions for the treatment of AD.
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