Effects of Ad Libitum Ultra-Processed Diet on Brain Dopamine in Humans

Study Description:

In this single-site study, we will recruit a cohort of 32 adult volunteers to a randomized crossover diet study to investigate change in dopamine D2 receptor availability (via \[11C\]raclopride binding potential). During their participation, after a 2-day outpatient stabilization diet, participants will be admitted for a 14-day, 13-night inpatient stay at the NIH Clinical Center. Following 2 days of inpatient stabilization diet, participants will consume two ad libitum test diets with distinct proportions of ultra-processed food for 5 days each in random order separated by 1 day of stabilization diet. We will collect information via Positron Emission Tomography (PET) about dopamine D2 receptor availability under fasting conditions and dopamine response to an oral stimulus solution. Additionally, magnetic resonance spectroscopy and imaging (MRS, MRI) will be used to collect information on changes in brain GABA tone, white matter hyperintensities, brain iron content, and brain activity in response to the two test diets. Further, we will additionally recruit a cohort of 36 adult volunteers for a 2 day/1night stay at the Clinical Center to measure dopamine D2 receptor availability in the extended post ingestive state to determine whether dopamine release may be quantified in this period of the postprandial state.

Objectives:

• Primary Objective: To determine the impact of two 5-day ad libitum test diets differing in proportion of ultra-processed, energy-dense, hyper-palatable foods on fasting striatal \[11C\]raclopride dopamine D2 receptor binding potential (D2BP) as well as the magnitude of any change from baseline.
• Secondary Objective: To determine differences in spatiotemporal components of striatal dopamine response (rDA) to a milkshake after two 5-day ad libitum test diets matched for presented nutrients but different in proportion of ultra-processed, energy-dense, hyperpalatable foods.
• Secondary Objective: To determine change in whole striatal dopamine D2BP in the extended post-ingestive period, beginning 1.5 - 3 hours following consumption of a UPF milkshake, as measured by \[11C\]raclopride

Endpoints:

• Primary Endpoint: Dopamine D2 receptor binding potential (D2BP) in the striatum after two test diets will be quantified during steady state portion of 20mCi \[11C\]raclopride infusion PET neuroimaging.
• Secondary Endpoint: Regionally and temporally specific dopamine response to in-scanner milkshake consumption and digestion after 5 days of each test diet will be determined voxelwise (spatial) over a duration of \[11C\]raclopride infusion (temporal), compared to equivalent endpoints for "tasteless" oral stimulus.
• Secondary Endpoint: D2BP in the striatum will be quantified using a bolus of 20mCi \[11C\]raclopride in both the overnight fasted state and delayed post-ingestive state for each participant.

Participants will be randomized to the one of two diet sequences (study arms: UPF-MPF vs MPF-UPF) by NIH dietitians after enrollment, in advance of admission. A total of n=32 participants will be evenly grouped into 16 batches according to date of inpatient admission. Within each batch of 2 participants, participants will be randomly assigned to one of the two diet sequences, ensuring any order effects will be counterbalanced and maintaining balance across diet sequence assignments.

Drug: [11C] raclopride · Other: liquid nutritive stimulus · Other: Tasteless Oral Stimulus Solution · Other: Minimally Processed Diet · Other: Baseline Diet

Participants will be randomized to the one of two diet sequences (study arms: UPF-MPF vs MPF-UPF) by NIH dietitians after enrollment, in advance of admission. A total of n=32 participants will be evenly grouped into 16 batches according to date of inpatient admission. Within each batch of 2 participants, participants will be randomly assigned to one of the two diet sequences, ensuring any order effects will be counterbalanced and maintaining balance across diet sequence assignments.

Drug: [11C] raclopride · Other: liquid nutritive stimulus · Other: Tasteless Oral Stimulus Solution · Other: Ultra Processed Diet · Other: Baseline Diet

The drug is intended for use as a radiopharmaceutical for positron emission tomography (PET) administered at a maximum prescribed dose of 20mCi and will be administered intravenously via indwelling catheter

The \~8 oz liquid meal will be high in both dietary fat and sugar and ultra-processed designation based on ingredients and will be prepared by the NIH Clinical Center Metabolic Kitchen for participant consumption during the PET scans at the end of both test dietary intervention periods (Cohort 1) or for consumption between the PET scans (Cohort 2).

The control stimulus is a non-rewarding tasteless solution with viscosity distinct from pure water (i.e., artificial saliva). Four dilutions of 25mM potassium chloride + 2.5mM sodium bicarbonate will be prepared by NIH Clinical Center Pharmacy for participant oral stimulus taste test

The minimally processed diet will derive \~80% of calories from minimally processed foods and will contain no ultra-processed foods, (NOVA 1-3), as defined by the degree, extent, and purpose of processing according to the NOVA classification system. The minimally processed diet will be matched to the ultra-processed diet for presented macronutrients, sugar, sodium, and fiber. This diet will be low in both non-beverage energy density and hyper-palatable foods

The ultra-processed diet will derive \~80% of energy from ultra-processed foods (NOVA 4), as defined by the degree, extent, and purpose of processing according to the NOVA classification system. The ultra processed diet will be matched to the minimally processed diet for presented macronutrients, sugar, sodium, and fiber. This diet will be high in both non-beverage energy density and hyper-palatable foods.

The baseline (control) diet will be composed of 50% of energy from ultra-processed foods while matching distribution of macronutrients presented in test diets and total sugar, sodium, and fiber). Energy needs will be estimated using resting energy expenditure multiplied by an appropriate activity factor collected at screening visit to facilitate production by the NIH Metabolic Kitchen.

Plazo: 5 days

Fasting (steady state) whole striatal dopamine D2 receptor binding at the conclusion of three diet periods (on 4th day of control diet, after 5 full days ad libitum UPF, and after 5 full days ad libitum MPF)

Plazo: 5 days

Measured at the conclusion of three diet periods (on 4th day of control diet, after 5 full days ad libitum UPF, and after 5 full days ad libitum MPF).

Plazo: 90-180 minutes

Measured while fasting and 1.3 -3 hours after a palatable liquid meal (Cohort 2).

Effects of Ad Libitum Ultra-Processed Diet on Brain Dopamine in Humans