Long-Term Effects of Walnut Consumption on Brain Function (WalBrain)

Long-Term Effects of Walnut Consumption on Brain Function in Men and Women With Abdominal Obesity

Rationale: Healthy foods, including mixed nuts, may improve brain function, which is essential for cognitive and metabolic health, and may contribute to improved food intake regulation. It is therefore important to investigate the specific effects of walnuts on cerebral blood flow responses before and after intranasal insulin administration, as well as their associated functional benefits. The investigators hypothesize that long-term walnut consumption improves vascular function and insulin-sensitivity in the brain, thereby enhancing cognitive performance and appetite control in abdominally obese men and women. Objective: The primary objectives are to investigate in abdominally obese adults the effects of 24-week walnut consumption on (regional) vascular function and insulin-sensitivity in the brain, while the investigators will also assess changes in cognitive performance and appetite-related brain reward activity (secondary objectives). Cerebral blood flow responses before (brain vascular function) and after the administration of intranasal insulin spray (brain insulin-sensitivity) will be quantified by the non-invasive gold standard magnetic resonance imaging (MRI)-perfusion method Arterial Spin Labeling (ASL). Study design: This intervention study will have a randomized, controlled parallel design. The total study duration will be 24 weeks. Study population: Fifty-five abdominally obese men and (postmenopausal) women (aged 45-75 years) without a history of cardiovascular diseases or complaints will participate. This study population is expected to have a decreased cerebral blood flow at baseline and are also at increased risk of cognitive impairment, allowing for improvement by the intervention. Intervention: Study participants will receive daily 50 g (about 15% of energy) of raw walnuts (walnut intervention) or no walnuts (control intervention) for 24 weeks. Main study parameters/endpoints: At baseline and after 24 weeks (follow-up), participants will visit the research facilities for assessments. The primary endpoint is the difference in the cerebral blood flow response before and after intranasal insulin administration between the walnut and control intervention. Cognitive performance will be assessed, while the investigators will also focus on appetite-related brain reward activity (secondary outcomes).

Study Overview

• Status: Not yet recruiting
• Conditions: Healthy; Cerebral Blood Flow; Cognitive Decline; Cognitive Performance; Abdominal Obesity; Food Reward; Brain Vascular Function; Satiety and Food Intake; Brain Insulin Sensitivity
• Intervention / Treatment: Dietary supplement: Walnuts

• Study Type: Interventional
• Enrollment (Estimated): 55
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Peter J. Joris, PhD; Phone Number: +31883887250; Email: p.joris@maastrichtuniversity.nl
• Study Contact Backup: Name: Linda J. Kehr, MSc; Phone Number: +31433883931; Email: linda.kehr@maastrichtuniversity.nl

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6200MD
      • Maastricht University, Department of Nutrition and Movement Sciences
      • Contact: Peter J. Joris, PhD; Phone Number: +31883887250; Email: p.joris@maastrichtuniversity.nl
      • Contact: Linda J. Kehr, MSc; Phone Number: +31433883931; Email: linda.kehr@maastrichtuniversity.nl
      • Principal Investigator: Peter J. Joris, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Men and women, aged between 45-75 years
• Women postmenopausal: two or more years after last menstruation
• Waist circumference of ≥102 cm for men and ≥88 cm for women (abdominal obesity)
• Fasting plasma glucose < 7.0 mmol/L
• Fasting serum total cholesterol < 8.0 mmol/L
• Fasting serum triacylglycerol < 4.5 mmol/L
• Systolic blood pressure < 160 mmHg and diastolic blood pressure < 100 mmHg
• Stable body weight (weight gain or loss < 3 kg in the past three months)
• Willingness to give up being a blood donor from 8 weeks before the start of the study, during the study and for 4 weeks after completion of the study
• No difficult venipuncture as evidenced during the screening visit

Exclusion Criteria:

• Allergy or intolerance to walnuts
• Left-handedness (effects on brain function differ between left- and right-handed adults)
• Current smoker, or smoking cessation < 12 months
• Diabetic patients
• Familial hypercholesterolemia
• Abuse of drugs
• More than 3 alcoholic consumptions per day
• Use of products or dietary supplements (e.g., dietary fiber or antioxidant dietary supplements (vitamin C and E), fish or seaweed oil capsules) known to interfere with the main outcomes as judged by the principal investigators
• Use of medication to treat blood pressure, lipid, or glucose metabolism
• Use of an investigational product within another biomedical intervention trial within the previous 1-month
• Severe medical conditions that might interfere with the study, such as epilepsy, asthma, kidney failure or renal insufficiency, chronic obstructive pulmonary disease, inflammatory bowel diseases, auto inflammatory diseases, and rheumatoid arthritis
• Active cardiovascular disease like congestive heart failure or cardiovascular event, such as an acute myocardial infarction or cerebrovascular accident
• Contra-indications for MRI imaging (e.g., pacemaker, surgical clips/material in body, metal splinter in eye, claustrophobia)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Walnut; Receive 50g walnuts per day	Dietary supplement: Walnuts; 24-week consumption of 50 g/day of walnuts as part of a healthy diet according to the Dutch dietary guidelines
No Intervention: Control; Does not receive walnuts and is supposed to refrain from nut consumption

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebral blood flow (CBF) prior to and after application of intranasal insulin	CBF will be non-invasively measured using the gold-standard methodology pseudo-continuous arterial spin labeling magnetic resonance imaging (pCASL MRI)	From enrollment to the end of treatment at 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bloodoxygen level-dependent (BOLD) functional MRI (fMRI) activity to measure appetite-related brain reward activity	BOLD fMRI activity will be measured before and while participants watch food pictures	From enrollment to the end of treatment at 24 weeks
Cognitive performance	Cognitive performance measurement of the following cognitive domains: memory, executive function and psychomotor speed. Measurements will be performed using the Cambridge Neuropsychological Test Automated Battery (CANTAB).	From enrollment to the end of treatment at 24 weeks.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endothelial function - Flow Mediated Dilation	Changes in diameter during Flow-Mediated Dilation (FMD) of the brachial artery will be assessed using ultrasound.	From enrollment to the end of treatment at 24 weeks.
Endothelial function - Carotid Artery Reactivity	Changes in diameter during Carotid Artery Reactivity (CAR) in response to a cold stressor will be assessed using ultrasound	From enrollment to the end of treatment at 24 weeks.
Markers related to arterial stiffness	Pulse Wave Analysis (PWA) of the radial artery and Femoral-to-carotid Pulse Wave Velocity (PWV) in m/s will be measured with a tonometer using Sphygomocor	From enrollment to the end of the intervention at 24 weeks.
Peripheral insulin sensitivity	7-point oral glucose tolerance test (OGTT) to determine insulin sensitivity based on insulin and glucose concentrations, Matsuda index and 2h glucose tolerance (2h glucose concentrations)	From enrollment to the end of the intervention at 24 weeks.
Brain perfusion	Cerebral blood flow velocity (CBFv) of the medial cerebral artery will be measured with transcranial Doppler ultrasound (TCD)	From enrollment to the end of treatment at 24 weeks.
Markers related to gut microbiota activity	Fecal and fasting plasma short-chain fatty acids (acetate, butyrate, propionate), fecal bile acids (cholic acid, chenodeoxycholic acid, doxycholic acid, lithocholic acid), fecal lipid (non-esterified fatty acids, triacylglycerides, total cholesterol)	From enrollment to the end of treatment at 24 weeks.
Perceived hunger and satiety	Visual analogue scales (VAS) questionnaires	From enrollment to the end of treatment at 24 weeks.
Mental health	Beck Depression Inventory (BDI), State-Trait Anxiety Inventories (STAI)	From enrollment to the end of the intervention at 24 weeks.
Mood	Profile of Mood States (POMS) questionnaire	From enrollment to the end of the intervention at 24 weeks.
Stress	Perceived Stress Scale (PSS) questionnaire	From enrollment to the end of the intervention at 24 weeks.
Sleep characteristics	Pittsburgh Sleep Quality Index (PSQI) questionnaire to assess sleep duration, quality, latency, and efficiency	From enrollment to the end of the intervention at 24 weeks.
Office blood pressure	Office blood pressure and heart rate	From enrollment to the end of the intervention at 24 weeks.
24h ambulatory blood pressure	24h ambulatory blood pressure measured every 15 min	From enrollment to the end of the intervention at 24 weeks.
Lipid metabolism	Circulating triacylglycerol, High-Density Lipoprotein (HDL) cholesterol, Low-Density Lipoprotein (LDL) cholesterol, and Total Cholesterol concentrations	From enrollment to the end of the intervention at 24 weeks"
Markers related to low-grade systemic inflammation	Interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)a, monocyte chemo attractant protein (MCP)-1, C-reactive protein (hsCRP) and serum amyloid A (SAA)	From enrollment to the end of the intervention at 24 weeks.
Markers related to arterial stiffness	Pulse Wave Velocity (PWV) in m/s measured with a tonometer using Sphygomocor	From enrollment to the end of the intervention at 24 weeks.
Structural brain status	High-resolution anatomical MPRAGE scan	From enrollment to the end of the intervention at 24 weeks.
Body Composition - Fat Mass	BodPod will be used to measure fat mass (weight)	From enrollment to the end of the intervention at 24 weeks.
Body Composition - Fat Free Mass	BodPod will be used to measure fat free mass (weight).	From enrollment to the end of treatment at 24 weeks.
Ad libitum food intake - weight	Ad libitum food intake (weight) in the fasted state	From enrollment to the end of the intervention at 24 weeks.
Ad libitum food intake - Caloric content	Ad libitum food intake (caloric content) in the fasted state.	From enrollment to the end of the intervention at 24 weeks.
Satiety hormones related to food intake	Plasma levels of GLP-1 before and after ad libitum food intake at time points 0, 15, 30, 60, 90 minutes.	From enrollment to the end of the intervention at 24 weeks.
Retinal microvasculature	Retinal microvascular calibers will be measured using retinal images made with a fundus camera	From enrollment to the end of the intervention at 24 weeks.
Weight	Weight in kilograms	From enrollment to the end of the intervention at 24 weeks.
Waist circumference	Waist circumference in centimeters	From enrollment to the end of the intervention at 24 weeks.
Hip circumference	Hip circumference in centimeters	From enrollment to the end of the intervention at 24 weeks.
Food intake	Food intake will be assessed using the Food Frequency Questionnaire	From enrollment to the end of the intervention at 24 weeks.

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: California Walnut Commission

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2026
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: October 2, 2025
• First Submitted That Met QC Criteria: February 18, 2026
• First Posted (Actual): February 19, 2026

Study Record Updates

• Last Update Posted (Actual): February 19, 2026
• Last Update Submitted That Met QC Criteria: February 18, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Cognitive decline; fMRI; Cognitive performance; Satiety; CANTAB; Intranasal insulin; Abdominal obesity; Walnuts; Food cues; Brain vascular function; Juglans; Brain insulin sensitivity; Food reward mechanisms; pCASL MRI
• Additional Relevant MeSH Terms: Mental Disorders; Nutrition Disorders; Overnutrition; Body Weight; Neurocognitive Disorders; Cognition Disorders; Overweight; Obesity; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Cognitive Dysfunction; Obesity, Abdominal
• Other Study ID Numbers: METC 25-018

Drug and device information, study documents

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