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The goal of this clinical trial is to learn about the nature of brain abnormalities associated with excess body fat in healthy adults aged 35-55. The main questions it aims to answer are:
Participants will:
We conducted a priori power calculations (80% power, α=0.05) based on published effect sizes (Cohen's d) for the following measures comparing obese to lean participants: hypothalamic neuroinflammation (d=1.52, required n=8/group; Thaler et al. 2012); cerebral metabolic rate of O₂ (d=1.59, required n=8/group; Anwar et al. 2022); oxygen extraction fraction (OEF) (d=0.67, required n=37/group; Anwar et al. 2022); white matter fractional anisotropy (d=0.61, required n=43/group; Daoust et al. 2021); and for the following measures following bariatric surgery: OEF (d=0.47, required n=37; Anwar et al. 2022); cerebral blood flow (d=0.74, required n=17; Anwar et al. 2022); fALFF (d=1.60, required n=6; Zeighami et al. 2021); cortical thickness (d=0.78, required n=8; Bohon et al. 2018).
Based on the above, we will assume a conservative minimum sample size of 43 per group to detect changes in brain health. In line with previous clinical trials for weight loss, where 88% of patients completed the trial but 83% adhered to the treatment regimen, we will assume a 15% attrition rate. Therefore, the minimum sample size providing adequate statistical power for sex-stratified analyses will be 50 men and 50 women. We will enroll 60 participants per group to account for an additional 20% dropout, for a total target sample of 120. At full enrollment, this will allow us to detect small to medium effects in brain health with over 90% power (Cohen's d=0.30), and sex-stratified analyses will be powered to detect medium effect sizes (Cohen's d=0.40) with 80% power.
If enrollment falls below 100 total participants (50 per group) for feasibility reasons, the sample might be considered insufficient to support confirmatory sex-stratified analyses. In this event, analyses will be conducted in the total sample only. Sex differences may then be examined in an exploratory capacity. This decision rule is pre-specified and will be applied without reference to outcome data.
Anwar, Nareen, Wesley J. Tucker, Nancy Puzziferri, T. Jake Samuel, Vlad G. Zaha, Ildiko Lingvay, Jaime Almandoz, et al. 2022. "Cognition and Brain Oxygen Metabolism Improves after Bariatric Surgery-Induced Weight Loss: A Pilot Study." Frontiers in Endocrinology 13 (December): 954127.
Bohon, Cara, Luis C. Garcia, and John M. Morton. 2018. "Changes in Cerebral Cortical Thickness Related to Weight Loss Following Bariatric Surgery." Obesity Surgery 28 (8): 2578-82.
Daoust, Justine, Joelle Schaffer, Yashar Zeighami, Alain Dagher, Isabel García-García, and Andréanne Michaud. 2021. "White Matter Integrity Differences in Obesity: A Meta-Analysis of Diffusion Tensor Imaging Studies." Neuroscience and Biobehavioral Reviews 129 (October): 133-41.
Thaler, Joshua P., Chun Xia Yi, Ellen A. Schur, Stephan J. Guyenet, Bang H. Hwang, Marcelo O. Dietrich, Xiaolin Zhao, et al. 2012. "Obesity Is Associated with Hypothalamic Injury in Rodents and Humans." The Journal of Clinical Investigation 122 (1): 153.
Zeighami, Yashar, Sylvain Iceta, Mahsa Dadar, Mélissa Pelletier, Mélanie Nadeau, Laurent Biertho, Annie Lafortune, et al. 2021. "Spontaneous Neural Activity Changes after Bariatric Surgery: A Resting-State FMRI Study." NeuroImage 241 (November): 118419.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Overweight Group (BMI 27 - 40 kg/m2) | Experimental | semaglutide |
|
| Lean group (BMI 20 - 25 kg/m2) | No Intervention |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| semaglutide | Drug | Treatment will be given for 80 weeks. Dose will be escalated from 0.25 mg to a max of 2.4 mg per week. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Serum C-reactive Protein (CRP) | Fasting serum CRP concentration (mg/L) | Baseline & Change from Baseline |
| Serum Pro-inflammatory Cytokines (Interleukin-6, TNF-α, Interleukin-1β, and IL-1 Receptor Antagonist) | Fasting serum concentrations of IL-6, TNF-α, IL-1β, and IL-1 receptor antagonist (all in pg/mL) | Baseline & Change from Baseline |
| Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) | HOMA-IR is calculated as (fasting glucose [mmol/L] × fasting insulin [μIU/mL]) / 22.5. The resulting dimensionless value estimates insulin resistance; higher values indicate greater insulin resistance. | Baseline & Change from Baseline |
| Fasting Plasma Glucose | Venous plasma glucose concentration (mmol/L) following an overnight fast | Baseline & Change from Baseline |
| Glycated Hemoglobin A1c (HbA1c) | Percentage of glycated hemoglobin (%), reflecting mean blood glucose | Baseline & Change from Baseline |
| Serum Leptin | Fasting serum leptin concentration (ng/mL) | Baseline & Change from Baseline |
| Serum Ghrelin | Fasting serum ghrelin concentration (pg/mL) | Baseline & Change from Baseline |
| Measure | Description | Time Frame |
|---|---|---|
| Delay Discounting Task Score (Impulsive Choice) | The Delay Discounting Task quantifies impulsive choice by measuring preference for smaller immediate versus larger delayed rewards. The discounting rate (k value, log-transformed) is the primary output; higher k values indicate greater impulsivity. | Baseline & Change from Baseline |
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Inclusion Criteria:
Key inclusion criteria for obese group:
Key inclusion criteria for lean control group:
Exclusion Criteria for both groups:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Michael Pileggi, M.Sc. | Contact | 514-396-2085 | michael.pileggi@mcgill.ca | |
| Filip Morys | Contact | filip.morys@mcgill.ca |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Montreal Neurological Institute-Hospital | Montreal | Quebec | H3A 2B4 | Canada |
All anonymised and de-identified IPD (not biological samples) will be available to researchers on a case by case basis after trial completion.
After trial completion with no end date.
Researchers will register to the portal and agree to terms and conditions of data use after which they will gain access to the IPD.
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| ID | Term |
|---|---|
| D015431 | Weight Loss |
| D009765 | Obesity |
| D050177 | Overweight |
| ID | Term |
|---|---|
| D001836 | Body Weight Changes |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C000591245 | semaglutide |
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The population selected for this trial includes adults aged 35 to 55 years with overweight or obesity (BMI 27-40 kg/m²) and an age- and sex-matched lean control group (BMI 20-25 kg/m²).
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| Serum Adiponectin | Fasting serum adiponectin concentration (μg/mL) | Baseline & Change from Baseline |
| Fasting Serum Insulin | Fasting serum insulin concentration (μIU/mL) | Baseline & Change from Baseline |
| Serum Glucagon-Like Peptide-1 (GLP-1) | Serum total GLP-1 concentration (pmol/L) | Baseline & Change from Baseline |
| Serum C-peptide | Fasting serum C-peptide concentration (nmol/L) | Baseline & Change from Baseline |
| Serum Lipid Panel (Total Cholesterol, HDL Cholesterol, LDL Cholesterol, Triglycerides, and Non-Esterified Fatty Acids [NEFA]) | Fasting serum concentrations of total cholesterol, HDL, LDL, triglycerides, and NEFA (mmol/L) | Baseline & Change from Baseline |
| Serum Apolipoprotein B (ApoB) | Fasting serum ApoB concentration (g/L) | Baseline & Change from Baseline |
| Red Blood Cell Phospholipid Fatty Acid Composition | Proportion of individual fatty acid species in red blood cell membrane phospholipids (expressed as % of total fatty acids) | Baseline & Change from Baseline |
| Cerebral Blood Flow as Measured by Pseudo-Continuous Arterial Spin Labeling (pCASL) MRI | Regional and whole-brain cerebral blood flow (mL/100g/min) derived from pCASL sequences at 3T MRI | Baseline & Change from Baseline |
| Oxygen Extraction Fraction (OEF) as Measured by Quantitative Susceptibility Mapping (QSM) and T2* MRI | Whole-brain or regional OEF (dimensionless ratio, 0-1) derived from combined QSM and T2* imaging | Baseline & Change from Baseline |
| Cerebral Metabolic Rate of Oxygen (CMRO₂) as Measured by QSM and T2* MRI | CMRO₂ (μmol/100g/min) estimated from OEF and cerebral blood flow | Baseline & Change from Baseline |
| Cortical Thickness as Measured by Structural MRI | Mean cortical thickness (mm) derived from T1-weighted | Baseline & Change from Baseline |
| Grey Matter Volume as Measured by Structural MRI | Regional and total grey matter volume (cm³) derived from T1-weighted structural MRI | Baseline & Change from Baseline |
| Grey Matter Surface Area as Measured by Structural MRI | Cortical surface area (cm²) derived from T1-weighted structural MRI | Baseline & Change from Baseline |
| White Matter Fractional Anisotropy (FA) as Measured by Diffusion Tensor Imaging (DTI) | FA (dimensionless, 0-1) derived from DTI; higher FA indicates greater white matter tract coherence | Baseline & Change from Baseline |
| White Matter Mean Diffusivity (MD) as Measured by Diffusion Tensor Imaging (DTI) | MD (mm²/s) derived from DTI; higher MD may indicate white matter disruption | Baseline & Change from Baseline |
| White Matter Microstructure as Measured by NODDI (intracellular volume fraction [ICVF], isotropic volume fraction [ISOVF], and Orientation Dispersion Index [ODI]) | ICVF, and ISOVF, ODI (dimensionless, 0-1) derived from NODDI modelling of multi-shell diffusion MRI data | Baseline & Change from Baseline |
| White Matter Hyperintensity Volume as Measured by FLAIR MRI | Total white matter hyperintensity volume (mL) segmented from T2-weighted FLAIR images | Baseline & Change from Baseline |
| Cerebrovascular Reactivity (CVR) as Measured by BOLD fMRI with End-Tidal CO₂ (EtCO₂) Challenge | CVR (expressed as % BOLD signal change per mmHg EtCO₂) derived from BOLD fMRI acquired during a hypercapnic EtCO₂ challenge | Baseline & Change from Baseline |
| Neuroinflammation proxy as Measured by T2* relaxation times | Milliseconds (ms) | Baseline & Change from Baseline |
| Neuromelanin Contrast Ratio in the Substantia Nigra as Measured by Neuromelanin-Sensitive MRI | Ratio of T1 signal intensity in the substantia nigra pars compacta relative to a reference region (dimensionless), used as an indirect in vivo measure of neuromelanin content | Baseline & Change from Baseline |
| Intracranial Artery Lumen Diameter as Measured by Time-of-Flight MRA | Lumen diameter (mm) measured at standardized segments of the ICA, MCA, basilar, and vertebral arteries using 3D TOF-MRA at 3T | Baseline & Change from Baseline |
| Body Mass Index (BMI) | BMI (kg/m²) calculated from measured height (m) and body weight (kg) | Baseline & Change from Baseline |
| Waist Circumference, Hip Circumference | circumference (cm) | Baseline & Change from Baseline |
| Waist-to-height ratio, Waist-to-hip ratio | Unitless | Baseline & Change from Baseline |
| Visceral Adipose Tissue as Measured by MRI | Visceral adipose tissue volume (mL) quantified by MRI Dixon sequence and Bioimpedance Analysis | Baseline & Change from Baseline |
| Subcutaneous Adipose Tissue as Measured by MRI | Subcutaneous adipose tissue volume (mL) quantified by MRI | Baseline & Change from Baseline |
| Body Composition | Whole-body fat as a percentage of total body mass (%), lean mass tissue, muscle mass measured by BIA | Baseline & Change from Baseline |
| Penn Line Orientation Test Score (Visual Processing) |
The Penn Line Orientation Test (PLOT) assesses visuospatial processing by asking participants to match line orientations. Higher scores indicate better visual processing performance. |
| Baseline & Change from Baseline |
| Penn Progressive Matrices Score (Fluid Intelligence) | The Penn Progressive Matrices is a nonverbal test of fluid reasoning and abstract problem-solving. Higher scores indicate greater fluid intelligence. | Baseline & Change from Baseline |
| Oral Reading Recognition Test Score (Language Ability) | The Oral Reading Recognition Test assesses language ability and reading recognition. Scores are reported as raw scores; higher scores indicate better language performance. | Baseline & Change from Baseline |
| Penn Word Memory Test Score (Episodic Memory) | The Penn Word Memory Test assesses verbal episodic memory via a word recognition paradigm. Performance is reported as percentage of words correctly recognized (0-100%); higher values indicate better episodic memory. | Baseline & Change from Baseline |
| Relational Memory Task Score (Executive Function and Attention) | The Relational Task assesses relational reasoning and executive attention. Performance is reported as [% correct / reaction time in ms]; [higher accuracy / lower reaction time] indicates better performance. | Baseline & Change from Baseline |
| Montreal Cognitive Assessment (MoCA) Total Score | The MoCA is a brief cognitive screening tool assessing multiple domains including memory, attention, language, and visuospatial ability. Scores range from 0 to 30; higher scores indicate better global cognitive function. | Baseline & Change from Baseline |
| Patient Health Questionnaire-9 (PHQ-9) Depression Score | The PHQ-9 is a 9-item validated self-report questionnaire measuring depressive symptom severity over the preceding 2 weeks. Scores range from 0 to 27; higher scores indicate greater depressive symptom severity. | Baseline & Change from Baseline |
| Mean Daily Energy Intake, fat, carbohydrate, sugar, protein intake, saturated fatty acids intake as Assessed by 3-Day Food Record. | Daily energy intake from different macronutrients (kcal/day) derived from a 3-day food record and. | Baseline & Change from Baseline |
| Percentage of calories derived from each of NOVA food classification categories | Units: Percentage (%) | Baseline & Change from Baseline |
| Healthy Eating Index | The Healthy Eating Index (HEI) measures diet quality on a scale of 0 to 100, where 100 indicates perfect alignment with the Dietary Guidelines for Americans | Baseline & Change from Baseline |
| Fat Taste Preference Score | Geometric average of a preferred solution from a Monell 2-series forced choice test. | Baseline & Change from Baseline |
| Sweet Taste Preference Score | Geometric average of a preferred solution from a Monell 2-series forced choice test. | Baseline & Change from Baseline |
| Working memory capacity | Digits remembered on the digit span and digit span backwards task | Baseline & Change from Baseline |
| Reinforcement learning outcomes | Choose-A accuracy (reward learning) Proportion of test-phase trials on which participants select stimulus A (the most frequently rewarded stimulus, 80% positive feedback) when paired with novel stimuli, indexing the bias to learn from positive feedback / approach the best option. Avoid-B accuracy (punishment learning) Proportion of test-phase trials on which participants avoid stimulus B (the most frequently punished stimulus, 80% negative feedback) when paired with novel stimuli, indexing the bias to learn from negative feedback / avoid the worst option. | Baseline & Change from Baseline |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |