Cerebrovascular and Cognitive Improvement by Resveratrol (resVida) and Fruitflow-II (CCIRF-II)

Accumulating evidence suggests that tomato consumption has cardiovascular benefits,
primarily through increasing blood flow in vivo; the active ingredient in tomato, or its
extract (Fruitflow) have been shown to inhibit glycoprotein IIb/IIIa, similar to aspirin
(which has antiplatelet activity and is used for secondary prevention of cardiovascular and
cerebrovascular events in patients). Considering the fact that Fruitflow can improve the
platelet function and peripheral blood flow, we hypothesized that Fruitflow can also
increase the blood flow in the brain and thereby possibly enhance memory and cognitive
function in middle-aged or elderly people who have memory complaints. Therefore, the initial
goal of our study is to evaluate the effects of Fruitflow on brain blood and cardiovascular
function by using Transcranial Doppler ultrasound (to check for changes in cerebral blood
flow), cardiovascular fitness testing (to check for changes in VO2-max and stroke volume),
and neurocognitive evaluation (to check for changes in memory and executive function).

Many pathways such as inflammation and oxidative stress are involved in the pathophysiology
of memory loss with ageing. Recent studies have shown that a natural compound found in the
skin of red grapes and also in wine, called "Resveratrol", have beneficial effects for
prevention of cognitive decline by reducing inflammation and improving cardiovascular
function. Therefore, our next goal is to evaluate whether administration of Resveratrol, by
itself or in combination with Fruitflow, can improve brain blood flow, VO2-max, and
cognitive performance.

Thus our clinical trial will have the following 4 arms: Fruitflow, Resveratrol,
Fruitflow/Resveratrol combination, and placebo for each supplement.

The results of the study will potentially provide evidence that these natural supplements
can have significant cardioprotective and neuroprotective properties in middle-aged and
elderly adults.

Subjects (between 50 and 80 years old) complaining of memory problem who have MMSE
(Mini-Mental State Examination) above 27 will be recruited from patients of Dr. Majid Fotuhi
(PI at the Neurology Institute for Brain Health and Fitness). Flyers at the institute and
advertisement in Baltimore will provide information about the opportunity to enroll in an
observational study for 3 months, along with eligibility criteria. Participants will
continue to receive routine and standard care, while data on outcome (i.e., dependent)
variables and mediators will be collected over three study visits:

Day 1: at the onset of their participation: Assessment of memory and Cardiovascular Fitness
Testing (CFT)

Day 2: Blood Test and Transcranial Doppler (TCD) Ultrasound at time 0 and 3 hours after
taking the first dose of the supplements;

Month 3: Assessment of memory, Cardiovascular Fitness Testing, and Transcranial Doppler
Ultrasound 3 months after daily treatment with supplements in each group.

Inclusion Criteria:

1. Between the ages of 50 and 80;

2. Having a primary care physician;

3. Ability to speak, read, and write English;

4. Logical Memory subtest (of the Wechsler Memory Scale - IV [WMS-IV]) raw score one
standard deviation or greater below the mean of a younger population;

5. Be in stable overall health based on medical history and physical examination;

6. Sedentary or moderately active (< 2 aerobic session / week);

7. Suspend, for at least one month before participating in the study, the use of dietary
supplements (fish oil, seed oils, ginkgo biloba, ginseng, resveratrol, fruit powder
extracts and DHA; subjects who have high intake of these products are asked to take
off these products for 4 weeks and after this washout period they will be recruited
in the study). No more than one multivitamins per day is acceptable;

8. Wine intake not more than 2 glasses per day

Exclusion Criteria:

1. Patients reporting severe depression with or without suicidal ideation [Beck
Depression Inventory (BDI) > 30 and BDI item #9 >1];

2. Patients with a severe language or hearing and/or vision impairment;

3. Pregnancy;

4. Patients presenting with delirium, dementia, or cognitive impairment (Mini-Mental
Status Examination score < 26);

5. Current alcohol or substance abuse/dependence;

6. Major neurological and psychiatric diseases including Parkinson's disease,
Alzheimer's disease, epilepsy, multiple sclerosis, concussion/traumatic brain injury,
schizophrenia, bipolar disorder, psychosis, eating disorders;

7. Uncontrolled high blood pressure (> 180/100 mmHg) or a documented record of
uncontrolled high blood pressure-related complications such as cerebral vascular
disease (CVD), and/or large strokes with disability, uncontrolled diabetes mellitus
(medical report of blood HbA1c > 7 during the last three months; in diabetic patients
without this record HbA1c will be measured in the first blood testing), or history of
major cardiopulmonary disease such as congestive heart failure, pulmonary disorders
(COPD [emphysema or chronic bronchitis] and pulmonary embolism);

8. Documented evidence of the following findings in the current medical history of
subjects:

8-1- Low platelet number (< 170 x 10^9/ L); 8-2- Hematocrit below 40% for males or
30% for females; 8-3- Haemoglobin below 120 g/L for males or 110 g/L for females;
8-4- Prothrombin time (PT) values outside normal range of approximately 10-16 s;

9. Current hepatic failure, renal failure, bleeding disorders (hemophilia, Von
Willebrand disease, esophageal varicoses);

10. Subjects who have given 500 ml of blood or more for transfusion purposes in the past
month before entry into the study

11. Patients who take aspirin more than 325 mg/day

12. Current medications for cognition such as acetylcholine esterase inhibitors (e.g.,
tacrine, donepezil, galantamine, rivastigmin) and memantine;

13. Known history of allergies to tomatoes or tomato-based products;

14. High habitual intake of tomatoes, grapes, and tomato-based products confirmed by food
frequency questionnaire (>5 times per day). Subjects who have high intake of these
products are asked to take off these products for 4 weeks and after this washout
period they will be reconsidered to participate in the study.