Walnuts and Healthy Aging (WAHA)

Effect of Daily Ingestion of Walnuts for 2 Years on Age-related Cognitive Decline and Macular Degeneration in Healthy Elderly Subjects: A Randomized, Single Blind, Dual Center, Controlled Trial

This will be a systematic investigation of the role of walnuts in preventing or slowing age related cognitive decline and age related macular degeneration. 700 subjects will be recruited between 2 sites, Loma Linda University in California, USA and Hospital Clinic in Barcelona, Spain. Participants will be randomly assigned to either the walnut group or the control group for a 2 year intervention. Baseline and annual data will be collected and analyzed.

Study Overview

• Status: Completed
• Conditions: Age Related Macular Degeneration; Age Related Cognitive Decline
• Intervention / Treatment: Dietary supplement: Walnuts; Other: habitual diet

Detailed Description

Epidemiological studies suggest that nutrients such as n-3 polyunsaturated fatty acid, antioxidants and B-vitamins may protect against age related cognitive decline. Small human studies have shown beneficial effects of polyphenol rich foods on cognition and age related macular degeneration. Walnuts are a rich source of n-3 polyunsaturated fatty acid, alpha-linolenic acid, antioxidants, polyphenols and other bioactive compounds. A 2-year intervention will be conducted with healthy, elderly subjects to investigate the role of walnuts in preventing or slowing age related cognitive decline and age related macular degeneration.

350 subjects, age 63 to 79 years, will be recruited at each of 2 sites, Loma Linda University in California and Hospital Clinic in Barcelona. Participants will be randomly assigned to one of two groups: walnut group (habitual diet with 1 or 2 oz/d walnut supplement) or control group (habitual diet only). At baseline and yearly, cardiometabolic risk factors, red blood cell membrane fatty acids, urinary polyphenols and biomarkers of inflammation and oxidation will be measured. Eye exam, blood pressure and cognitive function tests will be measured at the beginning and end of 2 years. At the Barcelona site only, participants will be given a brain MRI and carotid ultrasound.

Descriptive results will be reported as mean plus/minus standard deviation. Primary analysis will be carried out on the basis of groups as randomly assigned. Results will be presented as appropriate effect sizes with a measure of precision (95% CI). Analysis of covariates gender, age, educational status will be conducted.

• Study Type: Interventional
• Enrollment (Actual): 708
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic, University of Barcelona
• United States
  • California
    • Loma Linda, California, United States, 92350
      • Loma Linda University, Department of Nutrition

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 63 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 63 to 79 years old
• healthy men and women
• able to attend clinic at a study sites

Exclusion Criteria:

• illiteracy or inability to understand the protocol
• unable to undergo neurophysiological tests
• morbid obesity (BMI greater than or equal to ≥ 40 kg/m2)
• uncontrolled diabetes (HbA1c>85)
• uncontrolled hypertension
• prior cerebrovascular accident
• any relevant psychiatric illness, including major depression
• advanced cognitive deterioration, dementia
• other neurodegenerative diseases (i.e. Parkinson's disease)
• any chronic illness expected to shorten survival (heart, liver, cancer, etc)
• bereavement in the first year of loss
• bad dentures unless fixable dental prostheses are used
• allergy to walnuts
• customary us of fish oil or flaxseed oil supplements
• eye related exclusion criteria

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Walnut group; This group will have their habitual diet supplemented with 30 to 45g (1 to 1.5 oz) of walnuts daily.	Dietary supplement: Walnuts; 30 to 60g (1 to 2 oz) per day of walnuts
Active Comparator: Control group; This group will eat their habitual diet and refrain from eating walnuts.	Other: habitual diet; Dietary information will be provided

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes from baseline in global cognitive composite score	The composite score will be calculated using the scores from the tests listed below. We will calculate the standardized scores of each test as the score of each participant minus the group mean and divide by its standard deviation. The composite score is the mean of the standardized scores. The 12 tests are: Rey Auditory Verbal Learning Test (RAVLT), Rey-Osterrieth Complex Figure (ROCF), Semantic Fluency (Animals), Boston Naming Test (BNT), Visual Object and Space Perception Battery (VOSP), Block Design section from the Wechsler Adult Intelligence Scale (WAIS-III), Trail Making Test (TMT), FAS Word Fluency, Stroop Color Word Test, Symbol Digit Modalities Test (SMDT) Digit Span from the WAIS-III and Conners Continuous Performance Test (CPT-II).	2 years
Changes from baseline in macular degeneration	This will be assessed: by stereoscopic digitized color fundus images graded by International Classification System for Age-Related Maculopathy (score range. 0 to 4; the higher the score, the worse the condition); by optical coherence tomography (OCT) measurements of macular thickness (in µm); by optical coherence tomography (OCT) measurements of retinal nervous fiber layer thickness (in µm).	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in brain cortical thickness	Changes will be assessed by brain magnetic resonance imaging (MRI) on a randomly selected subset of participants. Only in Barcelona center. Unit of measure is mm2.	2 years
Change from baseline in voxel-based morphometry	Changes will be assessed by brain magnetic resonance imaging (MRI) using GM density maps on a randomly selected subset of participants. Only in Barcelona center. Unit of measure is GM density.	2 years
Change from baseline in white matter hyperintensity volumes	Changes will be assessed by brain magnetic resonance imaging (MRI) on a randomly selected subset of participants. Only in Barcelona center. Unit of measure is mL.	2 years
Change from baseline in perfusion arterial spin labeling	Changes will be assessed by brain magnetic resonance imaging (MRI) on a randomly selected subset of participants. Only in Barcelona center. Unit of measure is ml/100 g/min.	2 years
Changes from baseline in brain activation	Changes will be assessed by Functional MRI (fMRI) on a randomly selected subset of participants. Only in Barcelona center. There are no units of measure.	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in carotid Intima-media thickness (mm)	Changes will be assessed by high-resolution ultrasound. Only in Barcelona center.	2 years
Incidence of plaque presence in carotid artery (yes/no)	Changes will be assessed by high-resolution ultrasound. Only in Barcelona center.	2 years
Change in carotid atheroma plaque height (mm)	Changes will be assessed by high-resolution ultrasound. Only in Barcelona center.	2 years
Change in body mass index (kg/m2)	BMI will be calculated as weight in kilograms divided by height in metres squared	2 years
Change in waist circumference (cm)	Waist circumference will be measured to the nearest 0.5 cm by using an anthropometric tape midway between the lowest rib and at the iliac crest at minimal respiration	2 years
Change in total fat (g)	Changes will be assessed by Dual-energy X-ray absorptiometry. Only in Barcelona center.	2 years
Change in Total lean tissue (g)	Changes will be assessed by Dual-energy X-ray absorptiometry. Only in Barcelona center.	2 years
Change in fasting serum total cholesterol (mg/dL)	Fasting serum total cholesterol will be measured by a standard enzymatic method	2 years
Change in fasting serum LDL-cholesterol (mg/dL)	Fasting serum LDL-cholesterol will be estimated by the Friedewald formula	2 years
Change in fasting serum HDL-cholesterol (mg/dL)	Fasting serum HDL-cholesterol will be measured by a precipitation technique	2 years
Change in fasting serum triglycerides (mg/dL)	Fasting triglycerides will be measured by a standard enzymatic method	2 years
Change in serum brain-derived neurotrophic factor (pg/mL)	Assessed by ELISA	2 years
Change in serum soluble-Selectin (ng/mL)	Assessed by ELISA	2 years
Change in serum soluble-intercellular Adhesion Molecule 1 (ng/mL)	Assessed by ELISA	2 years
Change in serum soluble-vascular cell adhesion molecule 1 (ng/mL)	Assessed by ELISA	2 years
Change in serum amyloid A (ng/mL)	Assessed by ELISA	2 years
Change in serum granulocyte-macrophage colony-stimulating factor (pg/mL)	Assessed by ELISA	2 years
Change in serum interferon-gamma (pg/mL)	Assessed by ELISA	2 years
Change in serum interleukin-1beta (pg/mL)	Assessed by ELISA	2 years
Change in serum interleukin-6 (pg/mL)	Assessed by ELISA	2 years
Change in serum tumor necrosis factor alpha (pg/mL)	Assessed by ELISA	2 years

Collaborators and Investigators

• Sponsor: Loma Linda University
• Collaborators: University of Barcelona; California Walnut Commission
• Investigators: Principal Investigator: Joan Sabate, MD, DrPH, Chair, Department of Nutrition; Principal Investigator: Emilio Ros, MD, PhD, Director Lipid Clinic, Endocrinology & Nutrition Service

Publications and helpful links

General Publications

• Hooper L, Martin N, Jimoh OF, Kirk C, Foster E, Abdelhamid AS. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev. 2020 Aug 21;8(8):CD011737. doi: 10.1002/14651858.CD011737.pub3.
• Hooper L, Martin N, Jimoh OF, Kirk C, Foster E, Abdelhamid AS. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev. 2020 May 19;5(5):CD011737. doi: 10.1002/14651858.CD011737.pub2.
• Nyberg L, Magnussen F, Lundquist A, Baare W, Bartres-Faz D, Bertram L, Boraxbekk CJ, Brandmaier AM, Drevon CA, Ebmeier K, Ghisletta P, Henson RN, Junque C, Kievit R, Kleemeyer M, Knights E, Kuhn S, Lindenberger U, Penninx BWJH, Pudas S, Sorensen O, Vaque-Alcazar L, Walhovd KB, Fjell AM. Educational attainment does not influence brain aging. Proc Natl Acad Sci U S A. 2021 May 4;118(18):e2101644118. doi: 10.1073/pnas.2101644118.
• Fjell AM, Sorensen O, Amlien IK, Bartres-Faz D, Brandmaier AM, Buchmann N, Demuth I, Drevon CA, Duzel S, Ebmeier KP, Ghisletta P, Idland AV, Kietzmann TC, Kievit RA, Kuhn S, Lindenberger U, Magnussen F, Macia D, Mowinckel AM, Nyberg L, Sexton CE, Sole-Padulles C, Pudas S, Roe JM, Sederevicius D, Suri S, Vidal-Pineiro D, Wagner G, Watne LO, Westerhausen R, Zsoldos E, Walhovd KB. Poor Self-Reported Sleep is Related to Regional Cortical Thinning in Aging but not Memory Decline-Results From the Lifebrain Consortium. Cereb Cortex. 2021 Mar 5;31(4):1953-1969. doi: 10.1093/cercor/bhaa332.
• Sorensen O, Brandmaier AM, Macia D, Ebmeier K, Ghisletta P, Kievit RA, Mowinckel AM, Walhovd KB, Westerhausen R, Fjell A. Meta-analysis of generalized additive models in neuroimaging studies. Neuroimage. 2021 Jan 1;224:117416. doi: 10.1016/j.neuroimage.2020.117416. Epub 2020 Oct 2.
• Sala-Vila A, Valls-Pedret C, Rajaram S, Coll-Padros N, Cofan M, Serra-Mir M, Perez-Heras AM, Roth I, Freitas-Simoes TM, Domenech M, Calvo C, Lopez-Illamola A, Bitok E, Buxton NK, Huey L, Arechiga A, Oda K, Lee GJ, Corella D, Vaque-Alcazar L, Sala-Llonch R, Bartres-Faz D, Sabate J, Ros E. Effect of a 2-year diet intervention with walnuts on cognitive decline. The Walnuts And Healthy Aging (WAHA) study: a randomized controlled trial. Am J Clin Nutr. 2020 Mar 1;111(3):590-600. doi: 10.1093/ajcn/nqz328.
• Bartres-Faz D, Gonzalez-Escamilla G, Vaque-Alcazar L, Abellaneda-Perez K, Valls-Pedret C, Ros E, Grothe MJ. Characterizing the Molecular Architecture of Cortical Regions Associated with High Educational Attainment in Older Individuals. J Neurosci. 2019 Jun 5;39(23):4566-4575. doi: 10.1523/JNEUROSCI.2370-18.2019. Epub 2019 Apr 8.
• Domenech M, Serra-Mir M, Roth I, Freitas-Simoes T, Valls-Pedret C, Cofan M, Lopez A, Sala-Vila A, Calvo C, Rajaram S, Sabate J, Ros E. Effect of a Walnut Diet on Office and 24-Hour Ambulatory Blood Pressure in Elderly Individuals. Hypertension. 2019 May;73(5):1049-1057. doi: 10.1161/HYPERTENSIONAHA.118.12766.
• Freitas-Simoes TM, Cofan M, Blasco MA, Soberon N, Foronda M, Corella D, Asensio EM, Serra-Mir M, Roth I, Calvo C, Valls-Pedret C, Casaroli-Marano RP, Domenech M, Rajaram S, Sabate J, Ros E, Sala-Vila A. The red blood cell proportion of arachidonic acid relates to shorter leukocyte telomeres in Mediterranean elders: A secondary analysis of a randomized controlled trial. Clin Nutr. 2019 Apr;38(2):958-961. doi: 10.1016/j.clnu.2018.02.011. Epub 2018 Feb 17.
• Rajaram S, Valls-Pedret C, Cofan M, Sabate J, Serra-Mir M, Perez-Heras AM, Arechiga A, Casaroli-Marano RP, Alforja S, Sala-Vila A, Domenech M, Roth I, Freitas-Simoes TM, Calvo C, Lopez-Illamola A, Haddad E, Bitok E, Kazzi N, Huey L, Fan J, Ros E. The Walnuts and Healthy Aging Study (WAHA): Protocol for a Nutritional Intervention Trial with Walnuts on Brain Aging. Front Aging Neurosci. 2017 Jan 10;8:333. doi: 10.3389/fnagi.2016.00333. eCollection 2016.
• Fernandez-Cabello S, Valls-Pedret C, Schurz M, Vidal-Pineiro D, Sala-Llonch R, Bargallo N, Ros E, Bartres-Faz D. White matter hyperintensities and cognitive reserve during a working memory task: a functional magnetic resonance imaging study in cognitively normal older adults. Neurobiol Aging. 2016 Dec;48:23-33. doi: 10.1016/j.neurobiolaging.2016.08.008. Epub 2016 Aug 20.
• Vaque-Alcazar L, Sala-Llonch R, Valls-Pedret C, Vidal-Pineiro D, Fernandez-Cabello S, Bargallo N, Ros E, Bartres-Faz D. Differential age-related gray and white matter impact mediates educational influence on elders' cognition. Brain Imaging Behav. 2017 Apr;11(2):318-332. doi: 10.1007/s11682-016-9584-8.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): May 1, 2016
• Study Completion (Actual): May 1, 2016

Study Registration Dates

• First Submitted: June 20, 2012
• First Submitted That Met QC Criteria: July 5, 2012
• First Posted (Estimate): July 6, 2012

Study Record Updates

• Last Update Posted (Actual): June 24, 2021
• Last Update Submitted That Met QC Criteria: June 21, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: age related macular degeneration; walnuts; age related cognitive decline; healthy elderly subjects
• Additional Relevant MeSH Terms: Mental Disorders; Eye Diseases; Neurocognitive Disorders; Retinal Degeneration; Retinal Diseases; Cognition Disorders; Macular Degeneration; Cognitive Dysfunction
• Other Study ID Numbers: 5120066; 670715-3833 (Other Identifier: Loma Linda University)