Establish Diagnostic Models Based on Olfactory Function and Odor-induced Brain Activation for Diabetes-Related Cognitive Impairment

Study Overview
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Brief Summary
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This is a cross-sectional and longitudinal study to establish diagnostic models based on olfactory function assessments and odor-induced brain activation for cognitive impairment in patients with type 2 diabetes mellitus.

Detailed Description
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Patients with diabetes have increased risks of cognitive impairment and dementia, which affecting the quality of life and diabetes management. Therefore, it is an urgent challenge to identify non-invasive biomarkers for early diagnosis and prognosis of the cognitive decline in patients with diabetes. Previous research has shown that both olfactory dysfunction and decreased odor-induced brain activation are present before clinically measurable cognitive decrements in type 2 diabetes. This is a cross-sectional and longitudinal study to establish diagnostic models based on olfactory function assessments and odor-induced brain activation for cognitive impairment in patients with type 2 diabetes mellitus. The investigators will recruit 200 patients with type 2 diabetes in the outpatient and inpatient departments. Health controls will be recruited from the community. At the baseline, clinical information collection, 100g-steamed bread meal test, biochemical measurement, cognitive assessments, olfactory test and functional magnetic resonance imaging(fMRI) scan will be conducted for all participants. Study duration was 3 years with a follow-up every 18 months. In the longitudinal study, all of the assessments will be repeated to evaluate changes of observational parameters.

Official Title
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A Cross-sectional and Longitudinal Study to Establish Diagnostic Models Based on Olfactory Function and Odor-induced Brain Activation for Diabetes-Related Cognitive Impairment

Conditions
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Type 2 Diabetes Mellitus, Cognitive Impairment

Intervention / Treatment
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* Behavioral: Cognitive assessments
* Other: Olfactory function measurements
* Other: Functional magnetic resonance imaging


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 40-75 years Right handedness Possessed over 6-year education Provision of informed consent prior to any study specific procedures Disease duration of T2DM patients >1 year Exclusion Criteria: Control participants would be excluded if they had a fasting blood glucose level >7.0 mmol/L; glucose level> 7.8 mmol/L after oral glucose tolerance test (OGTT); HbA1c>5.7% Control participants would be excluded if they had a Montreal Cognitive Assessment (MoCA, Beijing edition) score of < 26 Any acute disease History of neurologic or psychological illness Abnormal results of thyroid hormones, vitamin B12, and folate Metal implants, unable to complete the MR scanning Partial or complete olfactory dysfunction associated with sinusitis, allergic rhinitis, and deviated nasal septum Pregnant or lactating women Participating in other clinical trials at the same time or within 6 months prior to the start of the trial

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Type 2 Diabetes Mellitus<br>These patients must have a definite diagnosis of type 2 diabetes mellitus (T2DM) according to the American Diabetes Association (ADA) standards. Some of these patients have symptoms of cognitive impairment, while others have normal cognition. All T2DM patients will undergo physical exam, cognitive and olfactory test as well as structural and brain functional MRI at baseline and follow-up time points. | Behavioral: Cognitive assessments<br>* Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Rey Auditory Verbal Learning Test (RAVLT), Boston Naming Test (BNT), Digit Span Test (DST), Trail Making Test (TMT).<br>Other: Olfactory function measurements<br>* Olfactory Threshold, Odor Identification Score, Odor Memory Score.<br>Other: Functional magnetic resonance imaging<br>* resting-state fMRI, odor-induced fMRI.<br>* Other names: fMRI;|
| Healthy Control<br>These participants have normal glucose tolerance and normal cognition. All HC subjects will undergo physical exam, cognitive and olfactory test as well as structural and brain functional MRI at baseline and follow-up time points. | Behavioral: Cognitive assessments<br>* Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Rey Auditory Verbal Learning Test (RAVLT), Boston Naming Test (BNT), Digit Span Test (DST), Trail Making Test (TMT).<br>Other: Olfactory function measurements<br>* Olfactory Threshold, Odor Identification Score, Odor Memory Score.<br>Other: Functional magnetic resonance imaging<br>* resting-state fMRI, odor-induced fMRI.<br>* Other names: fMRI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline cognitive performance | The Montreal Cognitive Assessment (MoCA) score, ranges from 0 to 30, and higher scores mean better cognition. | Day 1 of entry study | 
| Baseline olfactory threshold | Olfactory threshold test: score range 1-13.5, which is determined based on a series of binary dilutions of the N-butanol solution in light mineral oil. The higher the score is, the more sensitive the participant is in detecting an odor. Scores of 8-10 were considered normal olfactory sensitivity, whereas scores of 1-3 signified olfactory dysfunction or anosmia, and scores of ≥10 indicate better olfactory sensitivity. | Day 1 of entry study | 
| Baseline olfactory memory | Olfactory memory test: Part A: Participants are shown 4 pictures for each odor (10 odors in total), then they need to select what they sniffed. Have a 10-minute break. Part B: Participants sniff 20 different odors, 10 of which are the same odors as in Part A. They need to select the picture and figure out whether the odor is old or new. | Day 1 of entry study | 
| Baseline odor-induced brain fMRI activation | Each participant underwent a series of task fMRI scans to measure temporal brain response to four increasing concentrations of lavender odors (0.032%, 0.10%, 0.32%, and 1.0) diluted in 1,2-propanediol (Sigma-Aldrich, St. Louis, MO). The visual cues of + and smell were used for baseline and odor stimulation, respectively. Each concentration was assessed three times, with fresh air and scent occurring alternately. Participants were instructed to press a button once they smelled the lavender scent. A general linear model was used to estimate odor-induced brain activation. Contrasts between fresh air > rest and scent > rest for each participant were made to get odor-induced brain activation value. Bilateral parahippocampus, amygdala, piriform cortex, insula, orbitofrontal cortex, entorhinal cortex, and hippocampus were extracted and merged as olfactory regions of interest (ROIs) for further analyses. | Within 1 week after cognitive assessments | 
| Longitudinal changes of cognitive performance | Compare the change of MoCA score from baseline to each follow-up time points (18 months' follow-up, 36 months' follow-up). The Montreal Cognitive Assessment (MoCA) score, ranges from 0 to 30, and higher scores mean better cognition. | From baseline to 18 months' follow-up and 36 months' follow-up | 
| Longitudinal changes of olfactory threshold | Compare the change of olfactory threshold tests score from baseline to each follow-up time points (18 months' follow-up, 36 months' follow-up). Olfactory threshold test: score range 1-13.5, which is determined based on a series of binary dilutions of the N-butanol solution in light mineral oil. The higher the score is, the more sensitive the participant is in detecting an odor. Scores of 8-10 were considered normal olfactory sensitivity, whereas scores of 1-3 signified olfactory dysfunction or anosmia, and scores of ≥10 indicate better olfactory sensitivity. | From baseline to 18 months' follow-up and 36 months' follow-up | 
| Longitudinal changes of olfactory memory | Compare the change of olfactory memory tests score from baseline to each follow-up time points (18 months' follow-up, 36 months' follow-up). Olfactory memory test: Part A: Participants are shown 4 pictures for each odor (10 odors in total), then they need to select what they sniffed. Have a 10-minute break. Part B: Participants sniff 20 different odors, 10 of which are the same odors as in Part A. They need to select the picture and figure out whether the odor is old or new. | From baseline to 18 months' follow-up and 36 months' follow-up | 
| Longitudinal changes of odor-induced brain fMRI activation | Compare the change of odor-induced brain activation beta value from baseline to each follow-up time points (18 months' follow-up, 36 months' follow-up) | From baseline to 18 months' follow-up and 36 months' follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline brain structural MRI scan | Cortical morphology | Within 1 week after cognitive assessments | 
| Baseline brain functional MRI scan | Large-scale network functional connectivity | Within 1 week after cognitive assessments | 
| Longitudinal changes of brain structural MRI scan | Compare the change of cortical morphology from baseline to each follow-up time points (18 months' follow-up, 36 months' follow-up) | From baseline to 18 months' follow-up and 36 months' follow-up | 
| Longitudinal changes of functional MRI scan | Compare the change of large-scale network functional connectivity from baseline to each follow-up time points (18 months' follow-up, 36 months' follow-up) | From baseline to 18 months' follow-up and 36 months' follow-up |