The Effects of Added Sugar Intake on Brain Blood Flow and Hippocampal Function in Midlife Adults

This study will focus on improving brain health through dietary modification of added sugars in middle aged adults (50- 64 years old). Participants will be fed two 10-day diets (one diet containing 5% of total energy from added sugars and one diet containing 25% of total energy from added sugars) and examine blood vessel function, hippocampus structure using a MRI, and memory performance.

Study Overview

• Status: Completed
• Conditions: Aging; Healthy Diet
• Intervention / Treatment: Other: Low Added Sugar Diet; Other: High Added Sugar Diet

Detailed Description

Aging is the primary risk factor for Alzheimer's disease (AD) which is the most common form of dementia and among the fastest growing causes of morbidity and mortality in the United States. The risk factors for AD emerge during midlife and are similar to cardiovascular and cerebrovascular diseases. The impact of midlife peripheral vascular changes on cardiovascular risk are worsened by poor lifestyle habits, including eating a diet that contains a lot of added sugars (defined as all caloric sweeteners added to food during processing or preparation). One effect of eating a high added sugar diet is an elevation in blood triglycerides (TGs), which impairs blood vessel function by causing inflammation; however, it is not known whether eating a lot of added sugars affects the blood vessels in the brain. The purpose of this project is to determine if there is a link between added sugar intake and brain health in midlife adults. Our hypothesis is that eating excess added sugar impairs the structure and function of an area of the brain called the hippocampus by increasing plasma TGs and systemic inflammation. To test this, we will have people eat a high and low sugar diet for 10 days each (in a random order) and test how each diet affects their blood vessel function, the structure of their hippocampus, and their memory performance. We expect to show that eating a diet that contains a lot of added sugars worsens brain health compared to a diet that contains few added sugars. The data generated from this project will help us better understand risk factors for dementia and will be used to support a future grant proposal to the National Institutes of Health aimed at lowering added sugar intake in mid-life adults and individuals with mild cognitive impairment.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Delaware
    • Newark, Delaware, United States, 19713
      • University of Delaware

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 64 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• ability to provide informed consent;
• men and postmenopausal women aged 50-64 years;
• habitual intake of added sugars ≤15% of total calories;
• systolic BP < 130 mmHg; diastolic BP < 90 mmHg;
• body mass index (BMI) <30 kg/m2 and % body fat < 25% for men and < 33% for women;
• fasting triglycerides < 200 mg/dl (< 2.3 mmol/L);
• LDL cholesterol <160 mg/dl (4.14 mmol/L);
• fasting plasma glucose <126 mg/dl (<7.0 mmol/L) and hemoglobin A1C < 6.5% at screening;
• weight stable in the prior 6 months (≤ 2 kg weight change);
• blood chemistries indicative of normal liver enzymes and renal function (estimated glomerular filtration rate using the Modification of Diet in Renal Disease (MDRD) prediction equation must be >60 ml/min/1.73 m^2).

Exclusion Criteria:

• current use of medications or supplements known to lower blood triglycerides or cholesterol (e.g., fibrates, statins, high dose niacin, high dose omega-3 supplement);
• chronic clinical diseases (e.g., coronary artery/peripheral artery/cerebrovascular diseases, heart failure, diabetes, chronic kidney disease requiring dialysis, neurological or autoimmune conditions affecting cognition (e.g. Alzheimer's disease or other form of dementia, Parkinson's disease, epilepsy, multiple sclerosis, large vessel infarct);
• major psychiatric disorder (e.g. schizophrenia, bipolar disorder);
• major depressive disorder (PHQ-9 ≥ 10);
• current or past (i.e., last 3 months) use of anti-hypertensive or other cardiovascular-acting medications known to influence vascular function and/or arterial stiffness;
• current medication use likely to affect central nervous system (CNS) functions (e.g. long active benzodiazepines);
• concussion within last 2 years and ≥ 3 lifetime concussions;
• heavy alcohol consumption (defined by the Centers for Disease Control and Prevention and United States Department of Agriculture as ≥8 drinks/week for women and ≥15 drinks/week for men).
• claustrophobia, metal implants, pacemaker or other factors affecting feasibility and/or safety of MRI scanning;
• recent major change in health status within previous 6 months (i.e., surgery, significant infection or illness);
• current smoking within the past 3 months;
• High degree of physical activity as defined by ≥ 25 leisure metabolic equivalent (MET)-hours/week, within the past 3 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low Added Sugar Diet; Subjects will be provided with a diet that is low in added sugars.	Other: Low Added Sugar Diet; Consumption of 10 days of a diet low in added sugars (5% of total caloric intake)
Experimental: High Added Sugar Diet; Subjects will be provided with a diet that is high in added sugars.	Other: High Added Sugar Diet; Consumption of 10 days of a diet high in added sugars (25% of total caloric intake)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arterial Compliance (m^2 Kilopascal^-1)	Change in cross-sectional area of the common carotid artery (assessed using ultrasound) per 1 mmHg increase in carotid artery blood pressure (assessed by applanation tonometry). A lower carotid artery compliance is indicative of stiffer elastic arteries.	Day 10 of the diet
Cerebrovascular Reactivity (Percent Increase in Cerebral Perfusion Normalized to the Increase in PETCO2	Cerebrovascular reactivity (CVR) is the relative (percent) change in total cerebral perfusion measured using pseudo-continuous arterial spin labeling per mmHg change in end-tidal carbon dioxide (ETCO2) during a brief period of hypercapnia. Hypercapnia was induced by prospective end-tidal targeting (RespirAct, Thornhill Medical) in which a target change in end-tidal CO2 of +9 millimeters of mercury (mmHg) was set. Data were only analyzed if ETCO2 changed by at least 6.5 mmHg. All data were then normalized to the absolute change in ETCO2.	Day 10 of the diet
Hippocampal Stiffness (kPa)	Noninvasive brain imaging using Magnetic Resonance Elastography (MRE) to estimate tissue mechanical properties. Stiffness values are derived from the propagation of shear waves delivered to the head using vibration at 50 Hertz (Hz) from an acoustic driver system (Resoundant, Inc, Rochester MN) and reflects the distribution and organization of neurons, axons, and glial cells. A higher brain stiffness indicates greater tissue integrity. A nonlinear inversion algorithm estimated mechanical properties in the brain from acquired MRE displacement data to map shear modulus, G = G'+iG", where G' is the storage modulus and G'' is the loss modulus. From these parameters, stiffness is calculated, μ = 2*|G|^2 / (|G|+G')	Day 10 of the diet
Hippocampal Damping Ratio (Unitless Ratio)	Noninvasive brain imaging using Magnetic Resonance Elastography (MRE) to estimate tissue mechanical properties. Damping Ratio is derived from the propagation of shear waves delivered to the head using vibration at 50Hz from an acoustic driver system (Resoundant, Inc, Rochester MN) and reflects the relative elasticity of the brain tissue. A lower damping ratio indicates greater tissue integrity. A nonlinear inversion algorithm estimated mechanical properties in the brain from acquired MRE displacement data to map shear modulus, G = G'+iG", where G' is the storage modulus and G'' is the loss modulus. From these parameters, damping ratio is calculated, ξ = G"/2*G'	Day 10 of the diet
Revised Hopkins Verbal Learning Test (HVLT-R) Total Recall Memory	The Revised Hopkins Verbal Learning Test (HVLT-R) assesses verbal learning and memory, immediate recall and delayed recall from a list of 12 words. Immediate recall takes place over 3 trials (out of 12 correct responses each) Total recall is the sum of trials 1-3 (out of 36 correct responses). Delayed recall takes place 20-25 minutes after trial 3 and the participant must recall the entire list of words (out of 12 correct responses).	Day 10 of the diet
Revised Brief Visuospatial Memory Test (BVMT-R) Total Recall Score	The Revised Brief Visuospatial Memory Test (BVMT-R) assesses visuospatial memory and includes an immediate recall and delayed recall from images. Immediate recall takes place over 3 trials (out of 12 correct responses each) Total recall is the sum of trials 1-3 (out of 36 correct responses). Delayed recall takes place 20-25 minutes after trial 3 and the participant must recall or redraw all the images (out of 12 correct responses).	Day 10 of the diet
Seated Systolic Blood Pressure (mmHg)	Seated systolic blood pressure taken with arm at heart level after a 10-minute rest. Results are average of triplicate measurements	Day 10 of diet
Seated Diastolic Blood Pressure (mmHg)	Seated diastolic blood pressure taken with arm at heart level after a 10-minute rest. Results are average of triplicate measurements	Day 10 of diet

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Carotid-femoral Pulse Wave Velocity (CFPWV) (m/Seconds)	Carotid-femoral pulse wave velocity (CFPWV) assessed using applanation tonometry of the carotid artery and cuff-based assessment of the femoral pulse wave (SphygmoCor XCEL). CFPWV is calculated as the distance between the carotid and femoral pulse divided by the time-delay between pulses. A higher CFPWV is indicative of stiffer elastic arteries.	Day 10 of the diet
Pattern Comparison Processing Speed Test (Raw/Computed Score)	National Institute of Health (NIH) Toolbox Pattern Comparison Processing Speed Test Brief, computer-based assessment of processing speed in which participants quickly determine if two visual patterns are the same or different. For age 50-59, raw/computed score has a mean of 41.53 and standard deviation of 19.42 based on a normative dataset (Range = 11.00 - 65.00). For age 60-69, raw/computed score has a mean of 39.44 and standard deviation of 16.39 based on a normative dataset (Range = 7.00 - 64.00). A higher score indicates a better outcome.	Day 10 of the diet
Flanker Test (Raw/Computed Score)	Brief, standardized assessment of attention and inhibitory control, which are key components of executive function. For age 50-59, raw/computed score has a mean of 8.21 and standard deviation of 1.73 based on a normative dataset (Range = 3.88 - 9.74). For age 60-69, raw/computed score has a mean of 8.16 and standard deviation of 1.60 based on a normative dataset (Range = 3.63 - 9.59). A higher score indicates a better outcome.	Day 10 of the diet
Triglycerides (mg/dL)	Blood biomarkers triglycerides in mg/dL	Day 10 of the diet

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory Cytokines (%)	Biomarkers of inflammation (e.g. cytokines) from peripheral blood mononuclear cells	Day 10 of the diet
Sleep Quality (%)	Sleep quality will be continuously measured for 10 days using an Actiwatch.	Day 10 of the diet
Oxidative Stress	Blood biomarkers of oxidative stress (e.g. superoxide) using Electron Paramagnetic Resonance	Day 10 of the diet

Collaborators and Investigators

• Sponsor: University of Delaware
• Collaborators: National Institute of General Medical Sciences (NIGMS)
• Investigators: Principal Investigator: Christopher Martens, Ph.D., University of Delaware

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2022
• Primary Completion (Actual): May 3, 2024
• Study Completion (Actual): May 3, 2024

Study Registration Dates

• First Submitted: December 21, 2021
• First Submitted That Met QC Criteria: January 14, 2022
• First Posted (Actual): January 27, 2022

Study Record Updates

• Last Update Posted (Actual): June 12, 2025
• Last Update Submitted That Met QC Criteria: May 27, 2025
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: cognitive function; arterial stiffness; added sugars; cerebrovascular function
• Other Study ID Numbers: 1760500; P20GM113125 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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