n-3 PUFA for Vascular Cognitive Aging

The main objective of this study is to determine if omega 3 PUFA can slow the accumulation of
brain MRI derived white matter hyper-intensities (WMH) over 3 years in a population at risk
for dementia. This trial is designed to collect preliminary data into the mechanism by which
PUFA therapy operates on the brain with special attention to the vascular components.

The randomized, double-blind and controlled trial will rigorously test PUFA effects versus a
placebo in non-demented elders over 3 years. This biomarker based trial will enroll 150
elders. Aim 1 will assess PUFA effects on neuroimaging parameter changes. Aim 2 will assess
PUFA effects on blood-based biomarkers of endothelial health, and Aim 3 will collect
preliminary data on PUFA effects on neuropsychological and functional parameters with special
attention to the executive and speed of processing skills and gait speed.

Inclusion Criteria:

1. Non-demented or mild cognitive impairment, defined as Clinical Dementia Rating =0 or
0.5 and MMSE >=24.

2. Age 75 and older, male and female

3. Total WMH volume ≥ 5 cc

4. Plasma PUFA index (EPA + DHA) < 110 ug/ml or < 5.5 weight percent

5. Sufficient English language skills to complete all tests

6. Geriatric Depression Scale - 15 < 6 documenting absence of a significant depressive
syndrome

7. Sufficient vision and hearing to complete all tests

8. Informant available with frequent (at least 1 hour/day or 1 day/week) contact with
subject to verify functional status and CDR rating

9. General health status that will not interfere with the ability to complete the
prospective study (these conditions are listed below in the study exclusion list)

Exclusion Criteria:

1. Any dementing illness (AD, vascular dementia, normal pressure hydrocephalus, or
Parkinson's disease); dementia defined by CDR ≥ 1, MMSE < 24

2. Significant disease of the CNS such as brain tumor, seizure disorder, subdural
hematoma, cranial arteritis

3. Alcohol or substance abuse according to DSM-IV criteria within the last 2 years

4. Major depression, schizophrenia, or other major psychiatric disorder defined by DSM-IV
criteria

5. Abnormal labs indicating vitamin B12 deficiency, thyroid disease, or UTI (documented
bacterial colonization is acceptable)

6. Unstable or significantly symptomatic CVD (e.g. CAD with frequent angina, CHF with
dyspnea at rest)

7. Hypertension: defined as uncontrolled BP > 150/90

8. Clinical symptomatic orthostatic hypotension

9. Diabetes mellitus that requires insulin injections

10. History of cortical stroke

11. Cancer within the last 5 years, with the exception of localized prostate cancer
(Gleason Grade < 3) and non-metastatic skin cancers (melanoma).

12. Illness that requires >1 visit /month to a clinician

13. Contraindications to MRI (i.e., heart pacemaker, metal plates or objects in head, ,
claustrophobia)

14. Medications:

1. CNS active meds that have not been on stable doses for at least 2 months
(cimetidine, beta-blockers, and SSRIs)

2. Neuroleptics, antiparkinsonian agents, systemic corticosteroids, and narcotic
analgesics; in the case where these were used for a self-limited time they must
have been discounted for a period of five half-lives prior to baseline visit

3. Over the counter supplements are not by themselves exclusionary, however,
subjects are asked not to change the dosing regimen over the course of the trial
unless medically indicated; the presence and dose of these agents are recorded

4. A baseline screen plasma PUFA > 5.5 weight percent of total fatty acids for
EPA+DHA will confirm supplementation of O3PUFA history. If patient indicates
regular supplementation with fish oil on phone screen, can wash out for 4 months
prior to study visit one.

5. Cholinesterase inhibitors (i.e., Aricept)

6. Investigational drugs within five half-lives prior to baseline

7. Anticoagulation therapy: Vitamin K antagonist: warfarin (Coumadin, jantoven),
Factor Xa inhibitors: rivaroxaban (xarelto), fondaparinux (arixtra), dibigatran
(pradaxa), apixaban (eliquis); Low molecular weight heparins: dalteparin
(fragmin), enoxaparin (lovenox)(Incident use of anticoagulant therapy will
exclude further study drug allocation. However, subjects will be asked to
complete all follow-up visits.)