Metabolic Syndrome
Conditions
Keywords
Cerebral Blood Flow, CBF, COX, Metabolic Syndrome, MetSyn
Brief summary
This study tests the hypothesis that Metabolic Syndrome (MetSyn) decreases cerebral blood flow (CBF) more in females than males due in part to the sex-specific loss of COX vasodilation. Male and female participants will be enrolled in two groups: Healthy Controls versus participants with MetSyn.
Detailed description
The central hypothesis is that MetSyn decreases CBF more in females than males due in part to the sex-specific loss of COX vasodilation. This hypothesis is based on extensive preliminary data demonstrating MetSyn induces: 1) 3-fold larger reductions in CBF in females that abolish sex differences, 2) region-specific CBF reduction patterns, and 3) a greater loss of COX-mediated vasodilation in females. This hypothesis is tested via three Specific Aims: * Aim 1: Determine the extent of sex differences in MetSyn-driven CBF reductions. The investigators hypothesize females with MetSyn will demonstrate larger decrements in global, grey matter and white matter CBF versus males. * Aim 2: Determine the sex-by-region interactions of MetSyn reductions in CBF. The investigators hypothesize females will demonstrate larger regional CBF declines-particularly in regions known to be impacted very early in brain pathologies and/or specifically impaired by insulin resistance. * Aim 3: Determine the role of COX signaling in mediating CBF changes in MetSyn. The investigators hypothesize COX vasodilation is reduced more in females than males with MetSyn. All consented participants will conduct a screening visit with a blood panel to identify control vs MetSyn eligibility. Once eligible, participants complete three laboratory visits (each lasting about 2 hours): 1. Exercise Visit: VO2 Max, DEXA for adiposity quantification, NIH Toolbox to assess neurocognitive function 2. MRI Visit 1: blinded to either Placebo or Indomethacin 3. MRI Visit 2: blinded to either Placebo or Indomethacin
Interventions
DRUGIndomethacin
Indomethacin is a nonsteroidal anti-inflammatory. It prevents the production of prostaglandins, endogenous signaling molecules known to cause symptoms from inflammation. Indomethacin (1.5 mg/kg) will be taken orally prior to one MRI study visit.
DRUGPlacebo
Participants will be screened for lactose intolerance. Total dosing will be calculated to match the mg needed for the indomethacin study visit.
DIAGNOSTIC_TESTMRI
CBF testing will be performed on 3T MRI scanners (GE Healthcare)
Sponsors
University of Wisconsin, Madison
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
Participants are randomized to Placebo vs Indomethacin for 2 MRI visits such that they are their own control.
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
(Healthy Controls): * 18-45 years old * Normal fasting values for blood glucose (less than 100 g/dl) * Normal values for lipids (LDL cholesterol less than 130 mg/dl, triglycerides less than 150 mg/dl) and HDL (men greater than 40, women greater than 50 mg/dl) * Women must have a predictable menstrual cycle. Females will be studied on cycle days 1-7 to minimize sex hormone differences and their potential confounding effects on vascular outcomes. Oral contraceptives are allowed, and women will be studied during their placebo phase. Inclusion Criteria (Participants with Metabolic Syndrome): * 18-45 years old * Meet at least 3 of the 5 ATP MetSyn criteria. These are: 1. Waist circumference greater than 102 cm (males) or 82 cm (females) 2. Triglycerides greater than 150 mg/dL 3. HDL cholesterol less than 40 mg/dL (males) or 50 mg/dL (females) 4. Blood pressure greater than or equal to 130/85 mmHg 5. Fasting plasma glucose greater than 110 mg/dL
Exclusion criteria
(Healthy Controls): * Body Mass Index (BMI) greater than or equal to 25 kg/m2 * Blood pressure over 130/80 mmHg * Meeting any of the 5 MetSyn criteria listed above.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cerebral Blood Flow | data collected over 2 study visits that must be completed within 6 months | Data collected via MRI under one of 2 conditions: placebo or indomethacin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Body Fat Mass | data collected at one study visit (must be completed within 6 months) | Dual-energy x-ray absorptiometry (DEXA) to measure fat mass. |
| Cognitive Testing: Flanker Inhibitory Control and Attention | data collected at one study visit (must be completed within 6 months) | NIH Toolbox to assess neurocognitive function. The Flanker test is a measure of executive function and is scored using a T-score where 100 is the average, higher scores indicate better performance. |
| Cognitive Testing: Pattern Comparison Processing Speed Test | data collected at one study visit (must be completed within 6 months) | NIH Toolbox to assess neurocognitive function. The Pattern Comparison Processing Speed Test measures how many correct responses the participant has within 90 seconds. There is a maximum of 130 items. |
| Cardiorespiratory Fitness: VO2 max | data collected at one study visit (must be completed within 6 months) | Graded exercise test to assess maximal aerobic capacity, reported as VO2 max (milliliters of oxygen consumed per kilogram of body weight per minute) |
| Cognitive Testing: Dimensional Change Card Sort Test | data collected at one study visit (must be completed within 6 months) | NIH Toolbox to assess neurocognitive function. The Dimensional Change Card Sort Test measures accuracy: the number of accurate responses, up to a maximum of 40. |
| Cognitive Testing: Picture Vocabulary Test | data collected at one study visit (must be completed within 6 months) | NIH Toolbox to assess neurocognitive function. The Picture Vocabulary Test has the participant hear a word and then pick from one of four pictures that best represents the word. It is scored using a T-score where 100 is the average, higher scores indicate better performance. |
| Cognitive Testing: List Sorting Working Memory Test | data collected at one study visit (must be completed within 6 months) | NIH Toolbox to assess neurocognitive function. The List Sorting Working Memory Test is a measure of recall and sorting. Participants scores reflect the number of items recalled and appropriately sorted up to 28 items maximum. |
Countries
United States
Contacts
CONTACTShawn Bolin, MS
PRINCIPAL_INVESTIGATORWilliam Schrage, PhD
UW Madison
Outcome results
None listed