Mechanisms of Impaired Brain Blood Flow With Aging

Study Overview
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Brief Summary
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Aging is the primary risk factor for Alzheimer's disease (AD), which is a rapidly growing public health concern. Understanding the mechanisms of normal brain aging may provide insight into the factors linking advancing age to increased risk for AD and thereby lead to new therapeutic targets for preventing or slowing AD progression. Cardiovascular changes, including impaired cerebrovascular function, occur with aging and may increase risk for AD; however, the mechanisms by which cerebrovascular function becomes impaired in older adults are incompletely understood. The overall goal of this project is to examine potential mechanisms of age-related declines in cerebrovascular function in humans. The investigators hypothesize that brain macro-vascular endothelial dysfunction, secondary to oxidative stress, plays an important role in mediating age-related changes in brain blood flow and cerebrovascular reactivity. The results of this pilot study have the potential to identify novel targets of cerebrovascular aging and will help guide the design of future clinical trials aimed at improving cerebral blood flow in older adults.

Official Title
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Mechanisms of Impaired Brain Blood Flow With Aging

Conditions
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Aging

Intervention / Treatment
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* Other: Ascorbic Acid
* Other: Normal Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-29 or 55-79 years old Exclusion Criteria: Pregnancy or breastfeeding; Blood chemistries indicative of abnormal renal, liver, thyroid and adrenal function (i.e., outside of normal reference range); estimated glomerular filtration rate using the MDRD prediction equation must be >60 ml/min/1.73 m2; Abnormal blood chemistry that is clinically relevant or any blood chemistry marker that is +/-2.5x the upper or lower limit; Lack of a suitable temporal window for cerebrovascular assessments; Current smoking; Chronic clinical diseases (e.g., coronary artery, peripheral artery, or cerebrovascular diseases, diabetes, chronic kidney disease, COPD); Major psychiatric disorder (e.g. Alzheimer's disease or other form of dementia, schizophrenia, bipolar disorder, major depression within past two years); Neurological or autoimmune conditions affecting cognition (e.g. Parkinson's disease, epilepsy, multiple sclerosis, head trauma with loss of consciousness greater than 30 min, large vessel infarct); Current medication use likely to affect CNS functions (e.g. long active benzodiazepines); Having past or present alcohol dependence or abuse, as defined by the American Psychiatry Association, Diagnostic and Statistical Manual of Mental Disorders; Body mass index (BMI) >40 kg/m2 (FMD measurements can be inaccurate in severely obese patients).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Normal saline will be infused by the research nurse into an antecubital vein using an IV infusion pump. | Other: Normal Saline<br>* Normal saline will be infused by the research nurse into an antecubital vein using an IV infusion pump.<br>|
| Active Comparator: Ascorbic Acid<br>Ascorbic acid will be measured into sterile syringes by the research nurse and infused into an antecubital vein using a IV infusion pump beginning with a priming bolus of 0.06 g Ascorbic Acid per kg fat-free mass dissolved in 100 ml of saline or lactated ringers followed by a drip-infusion of 0.02 g Ascorbic Acid per kg fat-free mass dissolved in 30 ml of saline. | Other: Ascorbic Acid<br>* Ascorbic acid will be infused into an antecubital vein using a IV infusion pump beginning with a priming bolus of 0.06 g Ascorbic Acid per kg fat-free mass dissolved in 100 ml of saline followed by a drip-infusion of 0.02 g Ascorbic Acid per kg fat-free mass dissolved in 30 ml of saline.<br>* Other names: Vitamin C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in internal carotid artery (ICA) diameter after acute infusion of the antioxidant ascorbic acid | Cerebrovascular reactivity to hypercapnia | Change from baseline to 30 minutes post-infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in middle cerebral artery (MCA) diameter after acute infusion of the antioxidant ascorbic acid | Cerebrovascular reactivity to hypercapnia | Change from baseline to 30 minutes post-infusion |