n-3 PUFA for Vascular Cognitive Aging

Omega 3 PUFA for the Vascular Component of Age-related Cognitive Decline

Brain scans can help identify changes that appear to increase risk for cognitive decline and dementia. Some of these brain changes are thought to reflect actual damage to the small blood vessels that support normal brain function. This clinical trial will determine whether an omega 3 polyunsaturated fatty acid (PUFA) therapy can promote brain health by supporting the small blood vessels in the brain over 3 years in older adults at high risk for cognitive decline and dementia of Alzheimer's type.

Study Overview

• Status: Unknown
• Conditions: Endothelial Dysfunction; Vascular Dementia; Executive Dysfunction; Alzheimer's Disease; Age Related Cognitive Decline
• Intervention / Treatment: Drug: Placebo; Drug: Omega 3 PUFA

Detailed Description

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 100 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.

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 75 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: omega 3 polyunsaturated fatty acids; 1.65 grams of EPA+DHA taken daily over 3 years	Drug: Omega 3 PUFA; fish oil concentrate standardized to long chain n-3 PUFA content; Other Names: Fish Oil
Placebo Comparator: Soybean oil; 1.65 grams of soybean oil taken daily over 3 years	Drug: Placebo; Other Names: Soybean Oil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
total cerebral white matter hyperintensity volume	quantitative MRI	annual over 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
biomarkers of endothelial health	blood based	annual over 3 years
total brain atrophy	quantitative MRI	annual over 3 years
medial temporal lobe atrophy	quantitative MRI	annual over 3 years
ventricular expansion	quantitative MRI	annual over 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
trail making test part B	neuropsych	annual over 3 years
digit symbol WAIS-R	neuropsyh	annual over 3 years
cerebral blood flow	arterial spin labeling	annual over 3 years
fractional anisotropy within frontal gyri	diffusion tensor imaging	annual over 3 years

Collaborators and Investigators

• Sponsor: Oregon Health and Science University
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Gene Bowman, ND, MPH, Oregon Health and Science University

Publications and helpful links

General Publications

• Bowman GL, Dayon L, Kirkland R, Wojcik J, Peyratout G, Severin IC, Henry H, Oikonomidi A, Migliavacca E, Bacher M, Popp J. Blood-brain barrier breakdown, neuroinflammation, and cognitive decline in older adults. Alzheimers Dement. 2018 Dec;14(12):1640-1650. doi: 10.1016/j.jalz.2018.06.2857. Epub 2018 Aug 14. Erratum In: Alzheimers Dement. 2019 Feb;15(2):319.
• Alber J, Alladi S, Bae HJ, Barton DA, Beckett LA, Bell JM, Berman SE, Biessels GJ, Black SE, Bos I, Bowman GL, Brai E, Brickman AM, Callahan BL, Corriveau RA, Fossati S, Gottesman RF, Gustafson DR, Hachinski V, Hayden KM, Helman AM, Hughes TM, Isaacs JD, Jefferson AL, Johnson SC, Kapasi A, Kern S, Kwon JC, Kukolja J, Lee A, Lockhart SN, Murray A, Osborn KE, Power MC, Price BR, Rhodius-Meester HFM, Rondeau JA, Rosen AC, Rosene DL, Schneider JA, Scholtzova H, Shaaban CE, Silva NCBS, Snyder HM, Swardfager W, Troen AM, van Veluw SJ, Vemuri P, Wallin A, Wellington C, Wilcock DM, Xie SX, Hainsworth AH. White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities. Alzheimers Dement (N Y). 2019 Apr 9;5:107-117. doi: 10.1016/j.trci.2019.02.001. eCollection 2019.
• Dayon L, Cominetti O, Wojcik J, Galindo AN, Oikonomidi A, Henry H, Migliavacca E, Kussmann M, Bowman GL, Popp J. Proteomes of Paired Human Cerebrospinal Fluid and Plasma: Relation to Blood-Brain Barrier Permeability in Older Adults. J Proteome Res. 2019 Mar 1;18(3):1162-1174. doi: 10.1021/acs.jproteome.8b00809. Epub 2019 Feb 15.
• Bowman GL, Dodge HH, Guyonnet S, Zhou N, Donohue J, Bichsel A, Schmitt J, Hooper C, Bartfai T, Andrieu S, Vellas B; MAPT/DSA Study Group. A blood-based nutritional risk index explains cognitive enhancement and decline in the multidomain Alzheimer prevention trial. Alzheimers Dement (N Y). 2019 Dec 28;5:953-963. doi: 10.1016/j.trci.2019.11.004. eCollection 2019. Erratum In: Alzheimers Dement (N Y). 2020 Jul 14;6(1):e12042.
• Hooper C, De Souto Barreto P, Coley N, Causse E, Payoux P, Salabert AS, Cesari M, Andrieu S, Bowman GL, Weiner M, Vellas B. Cross-Sectional Associations of Total Plasma Homocysteine with Cortical beta-Amyloid Independently and as a Function of Omega 3 Polyunsaturated Fatty Acid Status in Older Adults at Risk of Dementia. J Nutr Health Aging. 2017;21(10):1075-1080. doi: 10.1007/s12603-017-0989-x.
• Bowman GL, Dodge HH, Mattek N, Barbey AK, Silbert LC, Shinto L, Howieson DB, Kaye JA, Quinn JF. Plasma omega-3 PUFA and white matter mediated executive decline in older adults. Front Aging Neurosci. 2013 Dec 16;5:92. doi: 10.3389/fnagi.2013.00092. eCollection 2013.
• Bowman GL, Silbert LC, Dodge HH, Lahna D, Hagen K, Murchison CF, Howieson D, Kaye J, Quinn JF, Shinto L. Randomized Trial of Marine n-3 Polyunsaturated Fatty Acids for the Prevention of Cerebral Small Vessel Disease and Inflammation in Aging (PUFA Trial): Rationale, Design and Baseline Results. Nutrients. 2019 Mar 29;11(4):735. doi: 10.3390/nu11040735.

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Anticipated): December 1, 2020
• Study Completion (Anticipated): June 1, 2021

Study Registration Dates

• First Submitted: September 24, 2013
• First Submitted That Met QC Criteria: September 30, 2013
• First Posted (Estimate): October 1, 2013

Study Record Updates

• Last Update Posted (Actual): September 4, 2020
• Last Update Submitted That Met QC Criteria: September 2, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: MRI; prevention; cognitive decline; DTI; executive function; endothelial function; white matter; omega 3 fatty acids; ASL
• Additional Relevant MeSH Terms: Mental Disorders; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cognition Disorders; Intracranial Arterial Diseases; Intracranial Arteriosclerosis; Leukoencephalopathies; Alzheimer Disease; Cognitive Dysfunction; Dementia, Vascular
• Other Study ID Numbers: R01AG043398 (U.S. NIH Grant/Contract); R01AG043398-01A1 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No