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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes Mellitus; Cognitive Impairment
• Intervention / Treatment: Behavioral: Cognitive assessments; Other: Olfactory function measurements; Other: Functional magnetic resonance imaging

Detailed Description

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.

• Study Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

• Study Contact: Name: Wen Zhang, MD, PhD; Phone Number: 86-15950576908; Email: zw7830254@163.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210008
      • Recruiting
      • Department of Radiology, the Affiliated Drum Tower Hospital of Nanjing University
      • Contact: Bing Zhang, MD, PhD; Phone Number: 86-15851803070; Email: zhangbing_nanjing@vip.163.com
      • Principal Investigator: Bing Zhang, MD, PhD
      • Sub-Investigator: Wen Zhang, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

T2DM patients will be recruited from the outpatient and inpatient units of the endocrinology department of the investigator's hospital. Healthy control will be recruited in the community.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Type 2 Diabetes Mellitus; 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; 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).; Other: Olfactory function measurements; Olfactory Threshold, Odor Identification Score, Odor Memory Score.; Other: Functional magnetic resonance imaging; resting-state fMRI, odor-induced fMRI.; Other Names: fMRI
Healthy Control; 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; 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).; Other: Olfactory function measurements; Olfactory Threshold, Odor Identification Score, Odor Memory Score.; Other: Functional magnetic resonance imaging; resting-state fMRI, odor-induced fMRI.; Other Names: fMRI

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Study record dates

Study Major Dates

• Study Start (Anticipated): October 18, 2022
• Primary Completion (Anticipated): June 30, 2025
• Study Completion (Anticipated): August 31, 2025

Study Registration Dates

• First Submitted: September 9, 2022
• First Submitted That Met QC Criteria: September 14, 2022
• First Posted (Actual): September 16, 2022

Study Record Updates

• Last Update Posted (Actual): October 26, 2022
• Last Update Submitted That Met QC Criteria: October 23, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Glucose Metabolism Disorders; Metabolic Diseases; Neurocognitive Disorders; Endocrine System Diseases; Cognition Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 2; Cognitive Dysfunction
• Other Study ID Numbers: 2022-LCYJ-PY-15

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: IPD sharing will be made during the 12 months after the end of study, and the original data can be obtained from the PI if necessary.
• IPD Sharing Time Frame: during the 12 months after the end of study
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No