Cognitive Impairment, Executive Dysfunction, Endothelial Dysfunction, Cardiovascular Disease
Conditions
Keywords
Cognitive impairment, Executive function, Arterial stiffness, Endothelial function, Menopause, Women's health, Hormone therapy, functional MRI
Brief summary
Complaints about memory and thinking are common in women as they go through menopause and estrogen levels fall. The ovarian hormone estrogen is important for supporting normal cognitive function, and changes in brain activity and function occur when estrogen levels are decreased. Estrogen is also important for maintaining healthy blood vessels which also support normal cognitive function. In Alzheimer's disease and other types of dementia, there is significant damage to the blood vessels in the brain. This study will test whether changes in brain activity and function with the loss of estrogen are related to changes in vascular function. The investigators will measure vascular function using ultrasound, and brain activity using MRI scans in women who are enrolled in the Females, Aging, Metabolism and Exercise (FAME) study (NCT01712230). In the FAME study, healthy premenopausal women either take a medication to decrease their estrogen levels, or a placebo. This sub-study may provide new information about how estrogen affects vascular function and cognitive function, and lead to new ways to prevent or delay cognitive impairment or dementia.
Interventions
DRUGLeuprolide acetate
Lupron 3.75 mg for depot suspension delivered by monthly intramuscular injection for 9 months. First 6 months under parent study (FAME) protocol (NCT01712230); months 6-9 under sub-study.
DRUGEstradiol
Climara transdermal patch 0.075mg/day applied weekly months 6-9
Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
DRUGPlacebo
placebo
Sponsors
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
1. Volunteers will be healthy women aged 40 to 60 years 2. Are enrolled in the parent FAME study (NCT01712230). The Investigators will consent up to 80 subjects with the aim of enrolling 17 in each of the 2 groups (placebo, GnRH agonist).
Exclusion criteria
1. mini-mental state examination (MMSE) score 27 or less 2. history of neurologic disease or major psychiatric illness 3. major depressive episode within the past 12 months 4. history of learning disability 5. less than high-school education 6. current smoking 7. use of psychoactive medications in the past 3 months (stable use of anti- depressant medication is allowed) 8. contraindications to MRI scanning
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Prefrontal Cortex Brain Activation at 6 Months | Baseline, 6 months | Changes in patterns of brain activation in the prefrontal cortex using functional magnetic resonance imaging (fMRI) during a task of working memory will be measured at baseline, 6 months, and 9 months (GnRH agonist arm only). Beta weight is the percent signal change on the FMRI from one condition to another. The FMRI is measuring blood oxygen levels and blood flow in different regions of the brain and using that to determine activity changes in the brain. A positive number/increase indicates more blood flow and brain activity in that area. |
| Changes in Prefrontal Cortex Brain Activation at 9 Months | Baseline, 9 months | Changes in patterns of brain activation in the prefrontal cortex using functional magnetic resonance imaging (fMRI) during a task of working memory will be measured at baseline, 6 months, and 9 months (GnRH agonist arm only). Beta weight is the percent signal change on the FMRI from one condition to another. The FMRI is measuring blood oxygen levels and blood flow in different regions of the brain and using that to determine activity changes in the brain. A positive number/increase indicates more blood flow and brain activity in that area. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Artery Compliance at 6 Months | Baseline, 6 months | Changes in carotid artery compliance will be measured using ultrasound in at baseline, 6 months. |
| Changes in Artery Compliance at 9 Months | Baseline, 9 months | Changes in carotid artery compliance will be measured using ultrasound in at baseline, 9 months. |
| Changes in Executive Cognitive Function: Trails A, 6 Months | Baseline, 6 months | Change in time (seconds) to complete Trails A test between baseline and 6 months. Negative value indicates faster time (better performance) at 6 months compared to baseline. |
| Changes in Executive Cognitive Function: Trails A, 9 Months | Baseline, 9 months | Change in time (seconds) to complete Trails A test between baseline and 9 months. Negative value indicates faster time (better performance) at 9 months compared to baseline. |
| Changes in Executive Cognitive Function: RAVLT, 6 Months | Baseline, 6 months | Change in Rey Auditory Verbal Learning Test from baseline to 6 months. Score is the change in the number of items correct on delayed recall trial. Scores on the RAVLT range from 0-15 with higher scores indicating better performance. A positive change indicates improvement in recall. |
| Changes in Executive Cognitive Function: RAVLT, 9 Months | Baseline, 9 months | Change in Rey Auditory Verbal Learning Test from baseline to 9 months. Score is the change in the number of items correct on delayed recall trial. Scores on the RAVLT range from 0-15 with higher scores indicating better performance. A positive change indicates improvement in recall. |
| Changes in Executive Cognitive Function: Trails B, 6 Months | Baseline, 6 months | Change in time (seconds) to complete Trails B test between baseline and 6 months. Negative value indicates faster time (better performance) at 6 months compared to baseline. |
| Changes in Endothelial Function at 6 Months | Baseline, 6 months | Changes in endothelial function will be measured using brachial artery flow-mediated dilation at baseline, 6 months |
| Changes in Executive Cognitive Function: Stroop, 6 Months | Baseline, 6 months | Change in number of correct responses in one minute on Stroop Color Word Interference test between baseline and 6 months. A positive number indicates more items correct indicating better performance. There is no maximum score because the test measures how many correct responses a participant can return within one minute (minimum = 0), however 40 or fewer is considered low. The change in the number of correct responses is reported, and so a positive number indicates more correct responses and better/improved cognitive function. |
| Changes in Executive Cognitive Function: Stroop, 9 Months | Baseline, 9 months | Change in number of correct responses in one minute on Stroop Color Word Interference test between baseline and 9 months. Positive number indicates more items correct indicating better performance. There is no maximum score because the test measures how many correct responses a participant can return within one minute (minimum = 0), however 40 or fewer is considered low. The change in the number of correct responses is reported, and so a positive number indicates more correct responses and better/improved cognitive function. |
| Changes in Executive Cognitive Function: Digits Span Forward and Backward, 6 Months | Baseline, 6 months | Change in score on the Digit Span Test between baseline and 6 month. Raw scores on the Digit Span test range from 0-16 (Digits Forward) and 0-10 (Digits Backward) with higher scores indicating better performance. A positive change score indicates improved performance. |
| Changes in Executive Cognitive Function: Digits, 9 Months | Baseline, 9 months | Change in score on the Digit Span Test between baseline and 9 months. Raw scores on the Digit Span test range from 0-16 (Digits Forward) and 0-10 (Digits Backward) with higher scores indicating better performance. A positive change score indicates improved performance. |
| Changes in Executive Cognitive Function: Controlled Oral Word Association Test, 6 Months | Baseline, 6 months | Change in sum of scores on 3 COWAT trials (letters, F, A, and S) between baseline and 6 months. Participants are given one minute to think up as many words as they can associated with each letter (F, A, or S). Raw scores are the total number of words generated across all trials. Higher scores indicate more words generated and better performance. Positive change score indicates an increase in words generated, or improved performance. |
| Changes in Executive Cognitive Function: Controlled Oral Word Association Test, 9 Months | Baseline, 9 months | Change in sum of scores on 3 COWAT trials (letters, F, A, and S) between baseline and 9 months. Participants are given one minute to think up as many words as they can associated with each letter (F, A, or S). Raw scores are the total number of words generated across all trials. Higher scores indicate more words generated and better performance. Positive change score indicates an increase in words generated, or improved performance. |
| Changes in Executive Cognitive Function: Trails B, 9 Months | Baseline, 9 months | Change in time (seconds) to complete Trails B test between baseline and 9 months. Negative value indicates faster time (better performance) at 9 months compared to baseline. |
| Changes in Endothelial Function at 9 Months | Baseline, 9 months | Changes in endothelial function will be measured using brachial artery flow-mediated dilation at baseline, 9 months |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Monthly placebo injections for 6 months under parent study (FAME) protocol (NCT01712230)
Placebo: placebo | 5 |
| GnRH Agonist Monthly injections of leuprolide acetate 3.75mg for 9 months; first 6 months under parent study (FAME) protocol (NCT01712230); months 6-9 under sub-study protocol.
Weekly application of estradiol patch 0.075mg/d months 6-9.
Daily medroxyprogesterone acetate 5mg by mouth for 12 days at week 30.
Leuprolide acetate: Lupron 3.75 mg for depot suspension delivered by monthly intramuscular injection for 9 months. First 6 months under parent study (FAME) protocol (NCT01712230); months 6-9 under sub-study.
Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9
Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30. | 12 |
| Total | 17 |
Baseline characteristics
| Characteristic | GnRH Agonist | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 47.7 years STANDARD_DEVIATION 4 | 47.1 years STANDARD_DEVIATION 3.7 | 45.6 years STANDARD_DEVIATION 2.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 15 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 14 Participants | 3 Participants |
| Sex: Female, Male Female | 12 Participants | 17 Participants | 5 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 12 |
| other Total, other adverse events | 0 / 5 | 1 / 12 |
| serious Total, serious adverse events | 0 / 5 | 0 / 12 |
Outcome results
Primary
Changes in Prefrontal Cortex Brain Activation at 6 Months
Changes in patterns of brain activation in the prefrontal cortex using functional magnetic resonance imaging (fMRI) during a task of working memory will be measured at baseline, 6 months, and 9 months (GnRH agonist arm only). Beta weight is the percent signal change on the FMRI from one condition to another. The FMRI is measuring blood oxygen levels and blood flow in different regions of the brain and using that to determine activity changes in the brain. A positive number/increase indicates more blood flow and brain activity in that area.
Time frame: Baseline, 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Changes in Prefrontal Cortex Brain Activation at 6 Months | Frontal Pole (L) | 90.64 beta-weight | Standard Deviation 3.88 |
| Placebo | Changes in Prefrontal Cortex Brain Activation at 6 Months | Frontal Orbital Cortex (L) | 28.07 beta-weight | Standard Deviation 37.48 |
| Placebo | Changes in Prefrontal Cortex Brain Activation at 6 Months | Superior Frontal Gyrus (R) | 92.45 beta-weight | Standard Deviation 33.66 |
| GnRH Agonist | Changes in Prefrontal Cortex Brain Activation at 6 Months | Frontal Pole (L) | -62.20 beta-weight | Standard Deviation 57.61 |
| GnRH Agonist | Changes in Prefrontal Cortex Brain Activation at 6 Months | Frontal Orbital Cortex (L) | -79.04 beta-weight | Standard Deviation 71.85 |
| GnRH Agonist | Changes in Prefrontal Cortex Brain Activation at 6 Months | Superior Frontal Gyrus (R) | -53.05 beta-weight | Standard Deviation 41.13 |
Primary
Changes in Prefrontal Cortex Brain Activation at 9 Months
Changes in patterns of brain activation in the prefrontal cortex using functional magnetic resonance imaging (fMRI) during a task of working memory will be measured at baseline, 6 months, and 9 months (GnRH agonist arm only). Beta weight is the percent signal change on the FMRI from one condition to another. The FMRI is measuring blood oxygen levels and blood flow in different regions of the brain and using that to determine activity changes in the brain. A positive number/increase indicates more blood flow and brain activity in that area.
Time frame: Baseline, 9 months
Population: This outcome measure was only collected for a subset of the GnRH Agonist group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Changes in Prefrontal Cortex Brain Activation at 9 Months | Frontal Pole (L) | -27.15 beta-weight | Standard Deviation 67.37 |
| Placebo | Changes in Prefrontal Cortex Brain Activation at 9 Months | Frontal Orbital Cortex (L) | -88.87 beta-weight | Standard Deviation 0.34 |
| Placebo | Changes in Prefrontal Cortex Brain Activation at 9 Months | Superior Frontal Gyrus (R) | -77.23 beta-weight | Standard Deviation 68.22 |
Secondary
Changes in Artery Compliance at 6 Months
Changes in carotid artery compliance will be measured using ultrasound in at baseline, 6 months.
Time frame: Baseline, 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Artery Compliance at 6 Months | -0.048 mm^2/mmhgx10^-1 | Standard Deviation 0.057 |
| GnRH Agonist | Changes in Artery Compliance at 6 Months | -0.095 mm^2/mmhgx10^-1 | Standard Deviation 0.011 |
Secondary
Changes in Artery Compliance at 9 Months
Changes in carotid artery compliance will be measured using ultrasound in at baseline, 9 months.
Time frame: Baseline, 9 months
Population: Outcome measure was only collected for a subset of the GnRH agonist arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Artery Compliance at 9 Months | -0.002 mm^2/mmhgx10^-1 | Standard Deviation 0.006 |
Secondary
Changes in Endothelial Function at 6 Months
Changes in endothelial function will be measured using brachial artery flow-mediated dilation at baseline, 6 months
Time frame: Baseline, 6 months
Population: This outcome cannot be reported due to corruption of the collected image data.
Secondary
Changes in Endothelial Function at 9 Months
Changes in endothelial function will be measured using brachial artery flow-mediated dilation at baseline, 9 months
Time frame: Baseline, 9 months
Population: Outcome measure was collected for a subset of the GnRH agonist arm only. This outcome cannot be reported due to corruption of the collected image data.
Secondary
Changes in Executive Cognitive Function: Controlled Oral Word Association Test, 6 Months
Change in sum of scores on 3 COWAT trials (letters, F, A, and S) between baseline and 6 months. Participants are given one minute to think up as many words as they can associated with each letter (F, A, or S). Raw scores are the total number of words generated across all trials. Higher scores indicate more words generated and better performance. Positive change score indicates an increase in words generated, or improved performance.
Time frame: Baseline, 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Executive Cognitive Function: Controlled Oral Word Association Test, 6 Months | -5.33 words generated | Standard Deviation 7.77 |
| GnRH Agonist | Changes in Executive Cognitive Function: Controlled Oral Word Association Test, 6 Months | 0.25 words generated | Standard Deviation 9.5 |
Secondary
Changes in Executive Cognitive Function: Controlled Oral Word Association Test, 9 Months
Change in sum of scores on 3 COWAT trials (letters, F, A, and S) between baseline and 9 months. Participants are given one minute to think up as many words as they can associated with each letter (F, A, or S). Raw scores are the total number of words generated across all trials. Higher scores indicate more words generated and better performance. Positive change score indicates an increase in words generated, or improved performance.
Time frame: Baseline, 9 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Executive Cognitive Function: Controlled Oral Word Association Test, 9 Months | 7.33 words generated | Standard Deviation 5.51 |
Secondary
Changes in Executive Cognitive Function: Digits, 9 Months
Change in score on the Digit Span Test between baseline and 9 months. Raw scores on the Digit Span test range from 0-16 (Digits Forward) and 0-10 (Digits Backward) with higher scores indicating better performance. A positive change score indicates improved performance.
Time frame: Baseline, 9 months
Population: Outcome measure was only collected for a subset of the GnRH agonist arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Changes in Executive Cognitive Function: Digits, 9 Months | Digits Backward (trials correct) | 1.0 number of trials correct | Standard Deviation 1 |
| Placebo | Changes in Executive Cognitive Function: Digits, 9 Months | Digits Forward (trials correct) | 1.00 number of trials correct | Standard Deviation 3.61 |
Secondary
Changes in Executive Cognitive Function: Digits Span Forward and Backward, 6 Months
Change in score on the Digit Span Test between baseline and 6 month. Raw scores on the Digit Span test range from 0-16 (Digits Forward) and 0-10 (Digits Backward) with higher scores indicating better performance. A positive change score indicates improved performance.
Time frame: Baseline, 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Changes in Executive Cognitive Function: Digits Span Forward and Backward, 6 Months | Digits Forward (trials correct) | 1.00 number of correct trials | Standard Deviation 1 |
| Placebo | Changes in Executive Cognitive Function: Digits Span Forward and Backward, 6 Months | Digits Backward (trials correct) | -0.67 number of correct trials | Standard Deviation 3.06 |
| GnRH Agonist | Changes in Executive Cognitive Function: Digits Span Forward and Backward, 6 Months | Digits Forward (trials correct) | -0.88 number of correct trials | Standard Deviation 1.89 |
| GnRH Agonist | Changes in Executive Cognitive Function: Digits Span Forward and Backward, 6 Months | Digits Backward (trials correct) | 0.00 number of correct trials | Standard Deviation 1.51 |
Secondary
Changes in Executive Cognitive Function: RAVLT, 6 Months
Change in Rey Auditory Verbal Learning Test from baseline to 6 months. Score is the change in the number of items correct on delayed recall trial. Scores on the RAVLT range from 0-15 with higher scores indicating better performance. A positive change indicates improvement in recall.
Time frame: Baseline, 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Executive Cognitive Function: RAVLT, 6 Months | -1.00 number of items recalled | Standard Deviation 2.65 |
| GnRH Agonist | Changes in Executive Cognitive Function: RAVLT, 6 Months | -1.38 number of items recalled | Standard Deviation 1.85 |
Secondary
Changes in Executive Cognitive Function: RAVLT, 9 Months
Change in Rey Auditory Verbal Learning Test from baseline to 9 months. Score is the change in the number of items correct on delayed recall trial. Scores on the RAVLT range from 0-15 with higher scores indicating better performance. A positive change indicates improvement in recall.
Time frame: Baseline, 9 months
Population: Outcome measure was only collected for a subset of the GnRH agonist arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Executive Cognitive Function: RAVLT, 9 Months | 0 number of items recalled | Standard Deviation 2 |
Secondary
Changes in Executive Cognitive Function: Stroop, 6 Months
Change in number of correct responses in one minute on Stroop Color Word Interference test between baseline and 6 months. A positive number indicates more items correct indicating better performance. There is no maximum score because the test measures how many correct responses a participant can return within one minute (minimum = 0), however 40 or fewer is considered low. The change in the number of correct responses is reported, and so a positive number indicates more correct responses and better/improved cognitive function.
Time frame: Baseline, 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Executive Cognitive Function: Stroop, 6 Months | -0.67 number correct in one minute | Standard Deviation 10.97 |
| GnRH Agonist | Changes in Executive Cognitive Function: Stroop, 6 Months | 0.25 number correct in one minute | Standard Deviation 13.76 |
Secondary
Changes in Executive Cognitive Function: Stroop, 9 Months
Change in number of correct responses in one minute on Stroop Color Word Interference test between baseline and 9 months. Positive number indicates more items correct indicating better performance. There is no maximum score because the test measures how many correct responses a participant can return within one minute (minimum = 0), however 40 or fewer is considered low. The change in the number of correct responses is reported, and so a positive number indicates more correct responses and better/improved cognitive function.
Time frame: Baseline, 9 months
Population: Outcome measure was only collected for a subset of the GnRH agonist arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Executive Cognitive Function: Stroop, 9 Months | 7.33 number correct in one minute | Standard Deviation 3.06 |
Secondary
Changes in Executive Cognitive Function: Trails A, 6 Months
Change in time (seconds) to complete Trails A test between baseline and 6 months. Negative value indicates faster time (better performance) at 6 months compared to baseline.
Time frame: Baseline, 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Executive Cognitive Function: Trails A, 6 Months | 2.79 seconds | Standard Deviation 8.54 |
| GnRH Agonist | Changes in Executive Cognitive Function: Trails A, 6 Months | -5.82 seconds | Standard Deviation 3.11 |
Secondary
Changes in Executive Cognitive Function: Trails A, 9 Months
Change in time (seconds) to complete Trails A test between baseline and 9 months. Negative value indicates faster time (better performance) at 9 months compared to baseline.
Time frame: Baseline, 9 months
Population: Outcome measure was only collected for a subset of the GnRH agonist arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Executive Cognitive Function: Trails A, 9 Months | -5.46 time (seconds) | Standard Deviation 7.12 |
Secondary
Changes in Executive Cognitive Function: Trails B, 6 Months
Change in time (seconds) to complete Trails B test between baseline and 6 months. Negative value indicates faster time (better performance) at 6 months compared to baseline.
Time frame: Baseline, 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Executive Cognitive Function: Trails B, 6 Months | 14.23 time (seconds) | Standard Deviation 4.77 |
| GnRH Agonist | Changes in Executive Cognitive Function: Trails B, 6 Months | -4.32 time (seconds) | Standard Deviation 16.27 |
Secondary
Changes in Executive Cognitive Function: Trails B, 9 Months
Change in time (seconds) to complete Trails B test between baseline and 9 months. Negative value indicates faster time (better performance) at 9 months compared to baseline.
Time frame: Baseline, 9 months
Population: Outcome measure was only collected for a subset of the GnRH agonist arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Executive Cognitive Function: Trails B, 9 Months | 14.14 time (seconds) | Standard Deviation 12.09 |