The Interaction Between Diabetes and Estradiol on Human Brain Metabolism in Postmenopausal Women

Phase 1

Completed

• Conditions: Dementia; Diabetes Type 2
• Interventions: Drug: Estradiol patch

• Registration Number: NCT03681691
• Lead Sponsor: Wake Forest University Health Sciences

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.

Study Timeline

• Study First Submitted: 2018-09-10
• Study First Submitted QC: 2018-09-20
• Study First Posted: 2018-09-24
• Study Start: 2019-05-13
• Primary Completion: 2021-07-19
• Study Completion: 2021-07-19
• Status Verified: 2022-07
• Results First Submitted: 2022-07-18
• Results First Submitted QC: 2022-09-01
• Last Update Submitted: 2022-09-01
• Results First Posted: 2022-09-27
• Last Update Posted: 2022-09-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 12

Inclusion Criteria

1. Willing to provide written informed consent
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Female, postmenopausal, aged 60-80
4. Normal results on recommended healthcare screenings (e.g., mammogram, pap smear, colonoscopy)
5. BMI 20-35 kg/m2
6. No evidence of dementia or mild cognitive impairment (MoCA score >25)
7. Able to access reliable transportation to study and intervention visits

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Exclusion Criteria

1. Use of hormone replacement therapy within the past 3 months
2. History of renal, heart, liver, or neurological disease; head injury with loss of consciousness in the past 5 years; chronic pain, anxiety or depression
3. Presence of medical conditions that might contraindicate estrogen use (e.g., unexplained vaginal bleeding, history of reproductive tissue cancer, thrombosis)
4. Currently taking insulin, metformin, or any other drug or medication judged by the study physician to affect safety or research outcomes of interest
5. Involved in another research study
6. Contraindications for MRI or PET scanning
7. Current smoker

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Post menopausal women without diabetes	Estradiol patch	8-week administration of transdermal 17β-estradiol (Climara) patch in postmenopausal women without type 2 diabetes.
Post menopausal women with diabetes	Estradiol patch	8-week administration of transdermal 17β-estradiol (Climara) patch in postmenopausal women with type 2 diabetes

Primary Outcome Measures

Name	Time	Method
Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)--Whole Brain	Baseline	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	Baseline	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	Week 8	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.
FDG PET--Whole Brain	Week 8	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.
Change in Uptake of Glucose and Ketone Bodies in Whole Brain and Alzheimer's Disease-related Regions of Interest.	Baseline and 8 weeks	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

Name	Time	Method
Executive Function Composite Score	Baseline and Week 8	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	Baseline and Week 8	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.
Benton Visual Retention Task (BVRT) Total Score	Baseline and Week 8	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	Baseline and Week 8	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)	Baseline and Week 8	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)	Baseline and Week 8	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	Baseline and Week 8	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	Baseline and Week 8	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	Baseline and Week 8	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	Baseline and Week 8	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.
Short-Term Memory Composite Score	Baseline and Week 8	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.
CVLT Short Delay Free Recall	Baseline and Week 8	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.
Card Rotations Test Score	Baseline and Week 8	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.	Baseline and 8 weeks	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.

Trial Locations

Locations (1)

Wake Forest University Health Sciences; 🇺🇸 Winston-Salem, North Carolina, United States