| Part 1 Altered Odor-Induced Brain Activity as an Early Manifestation of Cognitive Decline in Type 2 DiabetesAims:The mechanisms underlying diabetes related cognitive decline remain uncovered,while early diagnosis helps to delay the decline process.Olfactory dysfunction has been reported to be associated with neurodegenerative disorders such as Alzheimer's disease in many studies,and is considered as an important early sign for evaluating preclinical cognitive impairment and also determining the cognitive decline process.This study thus aimed to evaluate the olfactory function and brain olfactory network alterations,and to determine the associations of odor-induced brain activation with cognitive function,olfactory behavior and metabolic parameters in patients with type 2 diabetes.Methods:According to the inclusion criteria,92 subjects with normal cognition including 51 patients with T2DM and 41 non-diabetic control subjects were enrolled.These two groups were matched for age,sex and educational years.Detailed clinical and biochemical information were collected,and neuropsychological assessment was performed.Meanwhile,a computerized battery of olfactory function tests assessing olfactory threshold,odor identification and memory was investigated.Neural activation intensity in response to lavender odor stimuli was assessed with high-resolution functional magnetic resonance imaging(fMRI)scanning.Olfactory brain regions showing significantly different activation between the two groups were extracted as seed regions for resting-state functional connectivity analyses.Partial correlation and mediation analyses with age,sex and educational years corrected were performed to determine the relationships of olfaction with cognitive function and metabolic parameters in diabetes.Results:The olfactory threshold score was significantly lower in patients with type 2 diabetes than the control group(8.7±3.2 vs.11.0±2.5,P<0.05).Task fMRI scanning demonstrated the olfactory-induced bilateral brain activation of the olfactory circuit in all subjects.Compared with the control,patients with diabetes demonstrated significantly decreased brain activation in the left hippocampus and parahippocampus,and the disrupted seed-regions functional connectivity with the right orbitofrontal cortex in the olfactory network.Positive associations of the disrupted functional connectivity with decreased neuropsychology test scores and reduced pancreatic function were observed in diabetic patients with adjustment for age,sex and education(r=0.323,0.299,both P<0.05).Notably,the association between pancreatic function with executive function was mediated by olfactory behavior and olfactory functional connectivity.Conclusions:This is the first study to indicate that the alteration of odor-induced brain activation is present before clinical symptoms of cognitive decrements in patients with type 2 diabetes.Olfactory brain functional connectivity positively associated with cognitive and olfactory function,indicating potential early functional neuroimaging markers for type 2 diabetes related cognitive decline.Part 2 Olfactory dysfunction mediates adiposity in cognitive impairment of type 2 diabetesAims:The prevalence of type 2 diabetes is mainly attributed to weight gain and adiposity.Both diabetes and obesity are important risk factors and also modifiable lifestyle factors for dementia.Olfactory dysfunction is an early predictive sign of cognitive decline and has been reliably associated with late-life dementia.Both diabetic and obese patients had decreased olfactory acuity,however,changes in cognition and related olfactory brain function in obese people with diabetes have not been characterized.Here,we investigated cognition,olfactory function and odor-induced brain alterations in these patients,and therapeutic effects of glucagon-like peptide-1 receptor agonists(GLP-1Ras)on their psychological behavior and olfactory networks.Methods:According to the inclusion criteria,a total of 105 participants including 35 control subjects,35 non-obese type 2 diabetic and 35 obese diabetic patients matched for age,sex and education years.These three groups underwent detailed cognitive assessment,the computerized olfactory function tests assessing odor threshold,identification and memory,and odor-induced functional MRI(fMRI)scan.One-way analysis of covariance(ANCOVA)was performed to determine the differences in brain activation with correction for age,sex,education and vascular risk factors among three groups.Brain regions showing significantly different activations among controls and non-obese and obese diabetic patients were selected as seed-regions for functional connectivity analyses.Among them,20 obese diabetic individuals with inadequately glycemic control and metformin monotherapy received GLP-1Ras treatment for 3 months and were reassessed for metabolic,cognitive,olfactory,and neuroimaging changes.Results:Obese patients with type 2 diabetes demonstrated lower MMSE scores of general cognition(28.4±1.2 vs.29.0±1.3 vs 29.2±0.8,P<0.05)and olfactory threshold(8.3±2.8 vs.9.7 ±2.4 vs.10.6±2.7,P<0.05)than non-obese diabetes and controls.Odor-induced fMRI showed obese diabetes had decreased left hippocampal activation and disrupted seed-based functional connectivity with the right insula when compared with non-obese diabetes and controls.Negative associations were found between adiposity and episodic memory,and between fasting insulin and processing speed test time in patients with diabetes after adjustment for age,sex and education(r=-0.300,-0.319,both P<0.05).Mediation analyses showed olfactory function and left hippocampus activation mediated these correlations.With 3-month GLP-1Ras treatment,obese diabetes exhibited enhanced MoCA,olfactory test total score and odor-induced right parahippocampus activation.Conclusions:Obese patients with type 2 diabetes showed more pronounced impaired cognitive function,decreased olfactory threshold,and disrupted olfactory brain activation and functional connectivity.Such olfactory dysfunction mediated adiposity in cognitive impairment of diabetes.GLP-1Ras ameliorated cognitive and olfactory abnormalities in obese patients with diabetes,providing new perspectives for early diagnosis and therapeutic approaches for cognitive decrements in these patients. |
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