OBJECTIVE The comparative neuroprotective effects of different antidiabetes drugs have not been characterized in randomized controlled trials. Here, we investigated the therapeutic effects of liraglutide, dapagliflozin, or acarbose treatment on brain functional alterations and cognitive changes in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Thirty-six patients with type 2 diabetes inadequately controlled with metformin monotherapy were randomized to receive liraglutide, dapagliflozin, or acarbose treatment for 16 weeks. Brain functional MRI (fMRI) scan and a battery of cognitive assessments were evaluated pre- and postintervention in all subjects. RESULTS The 16-week treatment with liraglutide significantly enhanced the impaired odor-induced left hippocampal activation with Gaussian random field correction and improved cognitive subdomains of delayed memory, attention, and executive function (all P < 0.05), whereas dapagliflozin or acarbose did not. Structural equation modeling analysis demonstrated that such improvements of brain health and cognitive function could be partly ascribed to a direct effect of liraglutide on left hippocampal activation (β = 0.330, P = 0.022) and delayed memory (β = 0.410, P = 0.004) as well as to the metabolic ameliorations of reduced waist circumference, decreased body fat ratio, and elevated fasting insulin (all P < 0.05). CONCLUSIONS Our head-to-head study demonstrated that liraglutide enhanced impaired brain activation and restored impaired cognitive domains in patients with type 2 diabetes, whereas dapagliflozin and acarbose did not. The results expand the clinical application of liraglutide and provide a novel treatment strategy for individuals with diabetes and a high risk of cognitive decline.

Few studies have investigated the associations between diabetic peripheral neuropathy (DPN) and cognitive decline. Olfactory impairment is related to neurodegenerative diseases and type 2 diabetes mellitus (T2DM); however, the cognitive alterations of patients with DPN and the role of olfactory function in DPN are not known. We explored alterations in cognition with DPN and the associations of neuropathy parameters with cognition and olfaction. Methods: Healthy controls (HCs) and patients with T2DM underwent nerve-conduction tests, detailed cognitive assessment, olfactory-behavior tests, and odor-induced functional magnetic resonance imaging (fMRI). T2DM patients were divided into two groups (non-DPN [NDPN] and DPN). Olfactory brain regions showing different activation between the two groups were selected for functional connectivity (FC) analyses. A structural equation model (SEM) was also generated to demonstrate the association among cognition, olfactory, and neuropathy parameters. Results: One hundred individuals (36 HCs, 36 NDPN, and 28 DPN) were matched for age, sex, and educational level. Compared with the NDPN group, the DPN group had significantly lower scores for memory and processing speed, as well as lower olfactory identification and memory scores, decreased activation of the left frontal lobe, and reduced seed-based functional connectivity in the right insula. The nerve conduction velocity in patients with T2DM was associated with cognitive functions. The association between nerve conduction and executive function was mediated by olfactory behavior. Conclusion:Patients with DPN had worse cognition than the NDPN patients in the domains of memory and processing speed. Cognitive dysfunction could be predicted by olfactorybehavior tests and electrophysiological examination.

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Context Although cognitive impairment in nonalcoholic fatty liver disease (NAFLD) has received attention in recent years, little is known about detailed cognitive functions in histologically diagnosed individuals. Objective This study aimed to investigate the association of liver pathological changes with cognitive features, and further explore the underlying brain manifestations. Methods and patients We performed a cross-sectional study in 320 subjects who underwent liver biopsy. Among the enrolled participants, 225 individuals underwent assessments of global cognition and cognitive subdomains. Furthermore, 70 individuals received functional magnetic resonance imaging (fMRI) scans for neuroimaging evaluations. The associations among liver histological features, brain alterations and cognitive functions were evaluated using structural equation model. Results Compared with controls, patients with NAFLD had poorer immediate memory and delayed memory. Severe liver steatosis (OR = 2.189, 95% CI: 1.020-4.699) and ballooning (OR = 3.655, 95% CI: 1.419 -9.414) was related to a higher proportion of memory impairment. Structural MRI showed that patients with nonalcoholic steatohepatitis exhibited volume loss in left hippocampus and its subregions of subiculum and presubiculum. Task-based MRI showed that patients with nonalcoholic steatohepatitis had decreased left hippocampal activation. Path analysis demonstrated that higher NAFLD activity scores were associated with lower subiculum volume and reduced hippocampal activation, and such hippocampal damage contributed to lower delayed memory scores. Conclusion We are the first to report the presence and severity of NAFLD to be associated with an increased risk of memory impairment and hippocampal structural and functional abnormalities. These findings stress the significance of early cognitive evaluation in patients with NAFLD.