Clinical trial NCT01953705: n-3 PUFA for Vascular Cognitive Aging
Official title: Omega 3 PUFA for the Vascular Component of Age-related Cognitive Decline
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Age Related Cognitive Decline
Alzheimer's Disease
Vascular Dementia
Endothelial Dysfunction
Executive Dysfunction
Keywords: omega 3 fatty acids
cognitive decline
MRI
endothelial function
white matter
executive function
prevention
DTI
ASL
Lead sponsor: Oregon Health and Science University
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2013-10-01
Enrollment: 102
Sex: ALL
Minimum age (years): 75
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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.)

Primary outcomes:
measure: total cerebral white matter hyperintensity volume
timeFrame: annual over 3 years
Secondary outcomes:
measure: biomarkers of endothelial health
timeFrame: annual over 3 years
measure: total brain atrophy
timeFrame: annual over 3 years
measure: medial temporal lobe atrophy
timeFrame: annual over 3 years
measure: ventricular expansion
timeFrame: annual over 3 years
Other outcomes:
measure: trail making test part B
timeFrame: annual over 3 years
measure: digit symbol WAIS-R
timeFrame: annual over 3 years
measure: cerebral blood flow
timeFrame: annual over 3 years
measure: fractional anisotropy within frontal gyri
timeFrame: annual over 3 years
Locations:
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
Study officials:
affiliation: Oregon Health and Science University
name: Gene Bowman, ND, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Oregon Health and Science University
name: Lynne Shinto, ND, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.