Inorganic Nitrate Supplementation on Cerebrovascular Aging and Arterial Stiffness Study

Reduced nitric oxide bioavailability with aging contributes in part to increased large
central artery stiffness and cerebrovascular dysfunction. Large central artery stiffness is a
risk factor for cognitive decline mediated in part by the development of cerebrovascular
dysfunction. This study will investigate the degree to which improving nitric oxide
bioavailability using dietary inorganic nitrate supplementation improves cerebrovascular
function through reductions in large central artery stiffness in middle-aged and older
adults.

Inclusion Criteria:

- Age 50-79 years

- Cognitively healthy, having mild cognitive impairment

- Able to undergo cardiovascular testing procedures including fasting overnight and
holding selected morning medication doses.

- Ability to understand and willingness to sign a written informed consent document.

- Ability to lie comfortably for up to 90 minutes

- Women only: Post-menopausal

Exclusion Criteria:

- Current or history of cardiovascular disease disease (heart attack, stroke, heart
failure, cardiomyopathy or peripheral artery disease, heart angioplasty/stent or
bypass surgery, valve replacement, carotid endarterectomy, heart transplant.

- Medical history of stroke or other neurological disorder or systemic illness that
could potentially affect cognition or brain function (outside of a diagnosis of Mild
Cognitive impairment, Alzheimer's Disease) or could affect their safety or comfort
while undergoing the imaging or cardiovascular studies.

- Subjects with evidence of cardiovascular disease at baseline or during the exercise
test (evidence of myocardial infarction, abnormal cardiac arrhythmia, myocardial
ischemia, conduction delays, >1mm S-T segment depression or elevation; >3 beat
ventricular tachycardia; atrial fibrillation) will be excluded from the study.

- Wilson's disease, hemochromatosis

- Individuals taking clonidine or other short-acting beta blocker

- Resting blood pressure > 200/ 110 mmHg or systolic <90 mmHg

- Medical history of chronic major psychiatric or current diagnosis of major psychiatric
disease (other than dementia).

- Systemic illness or neurological disorder potentially affecting cognition or cerebral
blood flow other than mild cognitive impairment

- Unable to provide informed consent due to cognitive impairment

- Currently taking medications that may affect cerebral blood flow (e.g. papaverine,
indomethacin, acetazolamide, etc) or efficacy of beetroot juice (proton pump
inhibitors)

- Current clinically abnormal thyroid function not adequately regulated by thyroid
hormone supplementation or medication.

- Allergic to beets

- Current tobacco user or history of tobacco use within the past 3 months (cigarettes,
cigars, chewing tobacco, hookah, electronic cigarettes) or living with someone who
smokes/has smoked in the past 3 months.

- Current diagnosis of insulin-dependent diabetes (Type I or insulin dependent Type II)

- Current diagnosis of chronic obstructive lung disease, cystic fibrosis, emphysema,
chronic bronchitis

- History of renal failure, dialysis or kidney transplant

- Current diagnosis or history of liver disease or HIV/AIDS, or cancer (other than
non-melanoma skin cancers).

- Current diagnosis or history of rheumatoid arthritis, systemic lupus erythematosus,
Wegener's granulomatosis

- Vulnerable populations (prisoners, etc) will not be eligible.

- Unwillingness to wash out from a vitamin or dietary supplement regime prior to
enrollment and maintain throughout the duration of the study.

- Inability to comply with experimental instructions.

- Uncontrolled intercurrent illness that would limit compliance with study requirements
per investigator.

- Inability to fast or hold morning medications doses until after testing is complete.

- Hormone replacement use within the past 6 months

- Currently enrolled in another study using an study medication, supplement, device or
intervention.