Back to resultsThe Interaction Between Diabetes and Estradiol on Human Brain Metabolism in Postmenopausal Women (E2T2D)
Primary Purpose
Diabetes Type 2, Dementia
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Estradiol patch
Sponsored by
About this trial
This is an interventional other trial for Diabetes Type 2 focused on measuring women's health, estradiol, postmenopausal
Eligibility Criteria
Inclusion Criteria:
- Willing to provide written informed consent
- Stated willingness to comply with all study procedures and availability for the duration of the study
- Female, postmenopausal, aged 60-80
- Normal results on recommended healthcare screenings (e.g., mammogram, pap smear, colonoscopy)
- BMI 20-35 kg/m2
- No evidence of dementia or mild cognitive impairment (MoCA score >25)
- Able to access reliable transportation to study and intervention visits
Exclusion Criteria:
- Use of hormone replacement therapy within the past 3 months
- History of renal, heart, liver, or neurological disease; head injury with loss of consciousness in the past 5 years; chronic pain, anxiety or depression
- Presence of medical conditions that might contraindicate estrogen use (e.g., unexplained vaginal bleeding, history of reproductive tissue cancer, thrombosis)
- Currently taking insulin, metformin, or any other drug or medication judged by the study physician to affect safety or research outcomes of interest
- Involved in another research study
- Contraindications for MRI or PET scanning
- Current smoker
Sites / Locations
- Wake Forest University Health Sciences
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Post menopausal women with diabetes
Post menopausal women without diabetes
Arm Description
8-week administration of transdermal 17β-estradiol (Climara) patch in postmenopausal women with type 2 diabetes
8-week administration of transdermal 17β-estradiol (Climara) patch in postmenopausal women without type 2 diabetes.
Outcomes
Primary Outcome Measures
Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)--Whole Brain
Brain metabolism will be measured using PET tracers to examine brain glucose uptake (FDG PET). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of FDG will be quantified.
FDG PET--Whole Brain
Brain metabolism will be measured using PET tracers to examine brain glucose uptake (FDG PET). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of FDG will be quantified.
Acetoacetate Uptake (AcAc) PET--Whole Brain
Brain metabolism will be measured using PET tracers to examine brain ketone body (acetoacetate) uptake (AcAc). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of AcAc tracers will be quantified.
AcAc PET--Whole Brain
Brain metabolism will be measured using PET tracers to examine brain ketone body (acetoacetate) uptake (AcAc). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of AcAc tracers will be quantified.
Change in Uptake of Glucose and Ketone Bodies in Whole Brain and Alzheimer's Disease-related Regions of Interest.
Brain metabolism will be measured using PET tracers to examine brain glucose uptake (FDG PET) and ketone body (acetoacetate) uptake (AcAc). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of FDG and AcAc tracers will be quantified, as well as uptake of AcAc relative to FDG to find potential regions of compensatory ketone use
Secondary Outcome Measures
Short-Term Memory Composite Score
A composite memory score was created by averaging z-scores for CVLT delayed recall, BVRT delayed recall, and prospective memory. A composite executive function score was created by averaging digit span forwards total correct, digit span backwards total correct, and both verbal fluency scores. Summed z-score ranging from -2 to 2 where higher score indicates better performance.
Executive Function Composite Score
The California Verbal Learning Test (CVLT) is a word list recall task that can be used to test immediate and delayed verbal memory. Free recall after the short delay (immediately after learning lists) and long delay (25 minutes) are reported. Summed z-score ranging from -2 to 2 where higher score indicates better performance.
California Verbal Learning Task (CVLT) Long Delay Free Recall
The CVLT is a word list recall task that can be used to test immediate and delayed verbal memory. Free recall after long delay (25 minutes). The minimum score is 0. The maximum score is 16 and a higher score represents better performance.
CVLT Short Delay Free Recall
The CVLT is a word list recall task that can be used to test immediate and delayed verbal memory. Short delay free recall is immediately after learning lists. The minimum score is 0. The maximum score is 16 and a higher score represents better performance.
Benton Visual Retention Task (BVRT) Total Score
The BVRT tests figural memory by testing memory for a line drawing. The minimum score is 0. The scoring used is total correct, the maximum score is 10, and a higher score represents better performance. The total score is reported.
Prospective Memory
The Prospective Memory test is a test of everyday memory where participants are given instructions for 3 tasks that will occur later on during the testing session. The minimum score is 0. The maximum score is 12 points, a higher score represents better performance, and the total score is reported
Verbal Fluency (Letters)
Participants were given a letter and asked to say aloud as many words as they could think of beginning with that letter. The three letters were F, A, and S, and the participant had one minute per letter to list words. The total score reported is the sum of the correct words generated for all three letters. Although there is no set maximum score, based on published data, it was anticipated that scores could range from 1 to no more than 120. A higher value reflects better performance.
Verbal Fluency Score (Fruits and Vegetables)
Participants were given one minute to say aloud as many fruits as possible and one minute to list as many vegetables as possible. The total score reported is the sum of all correct fruits and vegetables listed. Although there is no set maximum score, it was anticipated that scores could range from 0 to no more than 60. A higher value reflects better performance.
Digit Span Forward Total Correct
Participants listened to a sequence of two to nine numbers and were asked to repeat each sequence back to the tester in the same order the numbers were presented. The outcome measure reported here is the total number of correct responses (range of scores 0-9). Higher scores reflect better performance.
Digit Span Backward Total Correct
Participants listened to a sequence of two to nine numbers and were asked to repeat each sequence back to the tester in reverse order. The outcome measure reported here is the longest span of numbers recalled (range of scores 0-9). Higher scores reflect better performance.
Finger Tapping Score--Dominant Hand
The Finger Tapping test assesses fine motor speed by asking participants to tap a button as many times as possible. Seven trials were administered. The highest and lowest scores were dropped, and the reported score is the average of the remaining 5 trials. Results for the dominant hand are reported here. There is no set maximum score. However, published averages for women in this age range suggest that a value over 57 would be highly unusual. A higher value (more taps) is better performance.
Finger Tapping Score--Non-Dominant Hand
The Finger Tapping test assesses fine motor speed by asking participants to tap a button as many times as possible. Seven trials were administered. The highest and lowest scores were dropped, and the reported score is the average of the remaining 5 trials. Results for the non-dominant hand are reported here. There is no set maximum score. However, published averages for women in this age range suggest that a value over 57 would be highly unusual. A higher value (more taps) is better performance.
Card Rotations Test Score
The Card Rotations Test is used to assess the ability to mentally rotate figures in space. The test has two parts, each of which last 3 minutes. During each part, the participant is given a sheet of paper with 10 simple geometric figures. Next to each figure is a row of 8 similar figures. Participants are asked to mark whether each of the figures in the row is the same or different than the first figure in the row. The score reported is the number of correct responses. The minimum score is 0. The maximum possible score is 160 and a higher score reflects better performance.
Change in Short-term Memory and Executive Function Composite Scores.
A battery of cognitive tasks will be administered before and after estrogen administration. Composite z-scores will be calculated by calculating a z-score for each cognitive task and summing z-scores from -5 (low) to 5 (high) for the tasks designated as short-term memory and executive function.Higher scores denotes better outcomes.
Full Information
NCT ID
NCT03681691
First Posted
September 10, 2018
Last Updated
September 1, 2022
Sponsor
Wake Forest University Health Sciences
Collaborators
National Institute on Aging (NIA)
1. Study Identification
Unique Protocol Identification Number
NCT03681691
Brief Title
The Interaction Between Diabetes and Estradiol on Human Brain Metabolism in Postmenopausal Women
Acronym
E2T2D
Official Title
The Interaction Between Diabetes and Estradiol on Human Brain Metabolism in Postmenopausal Women
Study Type
Interventional
2. Study Status
Record Verification Date
July 2022
Overall Recruitment Status
Completed
Study Start Date
May 13, 2019 (Actual)
Primary Completion Date
July 19, 2021 (Actual)
Study Completion Date
July 19, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Wake Forest University Health Sciences
Collaborators
National Institute on Aging (NIA)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The primary aim of this study is to test whether type 2 diabetes interacts with estradiol on brain metabolism in vivo in humans. This will be accomplished by imaging brain metabolism using positron emission tomography before and after short-term administration of transdermal 17β-estradiol in 10 postmenopausal women with diabetes and 10 non-diabetic postmenopausal women.
Detailed Description
Epidemiological studies suggest there may be an interaction between type 2 diabetes and estrogen in postmenopausal women, such that diabetes may interact with estrogen levels over time to increase risk for dementia. The mechanism for this effect is now known. However, animal research suggests that it may occur through estrogen's effects on cellular metabolism of glucose and ketone bodies. The primary aim of this study is to test whether type 2 diabetes interacts with estradiol on brain metabolism in vivo in humans. This will be accomplished by imaging brain metabolism using positron emission tomography before and after short-term administration of transdermal 17β-estradiol in 10 postmenopausal women with diabetes and 10 non-diabetic postmenopausal women.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Type 2, Dementia
Keywords
women's health, estradiol, postmenopausal
7. Study Design
Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
Primary Objective: The primary objective is to determine whether the effects of glucose and ketone body uptake to the brain in response to 8-week administration of transdermal 17β-estradiol differ in postmenopausal women with and without type 2 diabetes.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
12 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Post menopausal women with diabetes
Arm Type
Experimental
Arm Description
8-week administration of transdermal 17β-estradiol (Climara) patch in postmenopausal women with type 2 diabetes
Arm Title
Post menopausal women without diabetes
Arm Type
Experimental
Arm Description
8-week administration of transdermal 17β-estradiol (Climara) patch in postmenopausal women without type 2 diabetes.
Intervention Type
Drug
Intervention Name(s)
Estradiol patch
Other Intervention Name(s)
Climara patch
Intervention Description
transdermal 17β-estradiol patch
Primary Outcome Measure Information:
Title
Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)--Whole Brain
Description
Brain metabolism will be measured using PET tracers to examine brain glucose uptake (FDG PET). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of FDG will be quantified.
Time Frame
Baseline
Title
FDG PET--Whole Brain
Description
Brain metabolism will be measured using PET tracers to examine brain glucose uptake (FDG PET). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of FDG will be quantified.
Time Frame
Week 8
Title
Acetoacetate Uptake (AcAc) PET--Whole Brain
Description
Brain metabolism will be measured using PET tracers to examine brain ketone body (acetoacetate) uptake (AcAc). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of AcAc tracers will be quantified.
Time Frame
Baseline
Title
AcAc PET--Whole Brain
Description
Brain metabolism will be measured using PET tracers to examine brain ketone body (acetoacetate) uptake (AcAc). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of AcAc tracers will be quantified.
Time Frame
Week 8
Title
Change in Uptake of Glucose and Ketone Bodies in Whole Brain and Alzheimer's Disease-related Regions of Interest.
Description
Brain metabolism will be measured using PET tracers to examine brain glucose uptake (FDG PET) and ketone body (acetoacetate) uptake (AcAc). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of FDG and AcAc tracers will be quantified, as well as uptake of AcAc relative to FDG to find potential regions of compensatory ketone use
Time Frame
Baseline and 8 weeks
Secondary Outcome Measure Information:
Title
Short-Term Memory Composite Score
Description
A composite memory score was created by averaging z-scores for CVLT delayed recall, BVRT delayed recall, and prospective memory. A composite executive function score was created by averaging digit span forwards total correct, digit span backwards total correct, and both verbal fluency scores. Summed z-score ranging from -2 to 2 where higher score indicates better performance.
Time Frame
Baseline and Week 8
Title
Executive Function Composite Score
Description
The California Verbal Learning Test (CVLT) is a word list recall task that can be used to test immediate and delayed verbal memory. Free recall after the short delay (immediately after learning lists) and long delay (25 minutes) are reported. Summed z-score ranging from -2 to 2 where higher score indicates better performance.
Time Frame
Baseline and Week 8
Title
California Verbal Learning Task (CVLT) Long Delay Free Recall
Description
The CVLT is a word list recall task that can be used to test immediate and delayed verbal memory. Free recall after long delay (25 minutes). The minimum score is 0. The maximum score is 16 and a higher score represents better performance.
Time Frame
Baseline and Week 8
Title
CVLT Short Delay Free Recall
Description
The CVLT is a word list recall task that can be used to test immediate and delayed verbal memory. Short delay free recall is immediately after learning lists. The minimum score is 0. The maximum score is 16 and a higher score represents better performance.
Time Frame
Baseline and Week 8
Title
Benton Visual Retention Task (BVRT) Total Score
Description
The BVRT tests figural memory by testing memory for a line drawing. The minimum score is 0. The scoring used is total correct, the maximum score is 10, and a higher score represents better performance. The total score is reported.
Time Frame
Baseline and Week 8
Title
Prospective Memory
Description
The Prospective Memory test is a test of everyday memory where participants are given instructions for 3 tasks that will occur later on during the testing session. The minimum score is 0. The maximum score is 12 points, a higher score represents better performance, and the total score is reported
Time Frame
Baseline and Week 8
Title
Verbal Fluency (Letters)
Description
Participants were given a letter and asked to say aloud as many words as they could think of beginning with that letter. The three letters were F, A, and S, and the participant had one minute per letter to list words. The total score reported is the sum of the correct words generated for all three letters. Although there is no set maximum score, based on published data, it was anticipated that scores could range from 1 to no more than 120. A higher value reflects better performance.
Time Frame
Baseline and Week 8
Title
Verbal Fluency Score (Fruits and Vegetables)
Description
Participants were given one minute to say aloud as many fruits as possible and one minute to list as many vegetables as possible. The total score reported is the sum of all correct fruits and vegetables listed. Although there is no set maximum score, it was anticipated that scores could range from 0 to no more than 60. A higher value reflects better performance.
Time Frame
Baseline and Week 8
Title
Digit Span Forward Total Correct
Description
Participants listened to a sequence of two to nine numbers and were asked to repeat each sequence back to the tester in the same order the numbers were presented. The outcome measure reported here is the total number of correct responses (range of scores 0-9). Higher scores reflect better performance.
Time Frame
Baseline and Week 8
Title
Digit Span Backward Total Correct
Description
Participants listened to a sequence of two to nine numbers and were asked to repeat each sequence back to the tester in reverse order. The outcome measure reported here is the longest span of numbers recalled (range of scores 0-9). Higher scores reflect better performance.
Time Frame
Baseline and Week 8
Title
Finger Tapping Score--Dominant Hand
Description
The Finger Tapping test assesses fine motor speed by asking participants to tap a button as many times as possible. Seven trials were administered. The highest and lowest scores were dropped, and the reported score is the average of the remaining 5 trials. Results for the dominant hand are reported here. There is no set maximum score. However, published averages for women in this age range suggest that a value over 57 would be highly unusual. A higher value (more taps) is better performance.
Time Frame
Baseline and Week 8
Title
Finger Tapping Score--Non-Dominant Hand
Description
The Finger Tapping test assesses fine motor speed by asking participants to tap a button as many times as possible. Seven trials were administered. The highest and lowest scores were dropped, and the reported score is the average of the remaining 5 trials. Results for the non-dominant hand are reported here. There is no set maximum score. However, published averages for women in this age range suggest that a value over 57 would be highly unusual. A higher value (more taps) is better performance.
Time Frame
Baseline and Week 8
Title
Card Rotations Test Score
Description
The Card Rotations Test is used to assess the ability to mentally rotate figures in space. The test has two parts, each of which last 3 minutes. During each part, the participant is given a sheet of paper with 10 simple geometric figures. Next to each figure is a row of 8 similar figures. Participants are asked to mark whether each of the figures in the row is the same or different than the first figure in the row. The score reported is the number of correct responses. The minimum score is 0. The maximum possible score is 160 and a higher score reflects better performance.
Time Frame
Baseline and Week 8
Title
Change in Short-term Memory and Executive Function Composite Scores.
Description
A battery of cognitive tasks will be administered before and after estrogen administration. Composite z-scores will be calculated by calculating a z-score for each cognitive task and summing z-scores from -5 (low) to 5 (high) for the tasks designated as short-term memory and executive function.Higher scores denotes better outcomes.
Time Frame
Baseline and 8 weeks
Other Pre-specified Outcome Measures:
Title
Regional Ratio of Ketone/Glucose Uptake
Time Frame
Baseline and Week 8
Title
Number of White Matter Hypertensities
Description
Attained from a T2-weighted FLAIR image, an indicator of small-vessel disease correlated with diabetes status and hypertension
Time Frame
Baseline and Week 8
Title
Number of Microbleeds
Description
Attained from a susceptibility-weighted image
Time Frame
Baseline and Week 8
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
60 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Willing to provide written informed consent
Stated willingness to comply with all study procedures and availability for the duration of the study
Female, postmenopausal, aged 60-80
Normal results on recommended healthcare screenings (e.g., mammogram, pap smear, colonoscopy)
BMI 20-35 kg/m2
No evidence of dementia or mild cognitive impairment (MoCA score >25)
Able to access reliable transportation to study and intervention visits
Exclusion Criteria:
Use of hormone replacement therapy within the past 3 months
History of renal, heart, liver, or neurological disease; head injury with loss of consciousness in the past 5 years; chronic pain, anxiety or depression
Presence of medical conditions that might contraindicate estrogen use (e.g., unexplained vaginal bleeding, history of reproductive tissue cancer, thrombosis)
Currently taking insulin, metformin, or any other drug or medication judged by the study physician to affect safety or research outcomes of interest
Involved in another research study
Contraindications for MRI or PET scanning
Current smoker
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christina Hugenschmidt, PhD
Organizational Affiliation
Wake Forest Health Sciences
Official's Role
Principal Investigator
Facility Information:
Facility Name
Wake Forest University Health Sciences
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Undecided
IPD Sharing Plan Description
Undecided at the present time.
Learn more about this trial
The Interaction Between Diabetes and Estradiol on Human Brain Metabolism in Postmenopausal Women
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