Metabrain: Brain Health in Youth With Normal Weight, Overweight and Obesity at Risk for Type 2 Diabetes (T2D)
Study Details
Study Description
Brief Summary
Investigators propose to study youth across the spectrum of body mass index (BMI) and dysglycemia. This approach will allow investigators to disentangle the relationship of key features of type 2 diabetes (T2D) risk (e.g. obesity) with intermediary physiologic changes (e.g. insulin resistance, inflammation, β-cell dysfunction and dysglycemia) that pose a risk for the brain. Investigators will determine which of these factors are most associated with differences in brain structure and function among groups, over time, and how these effects differ from normal neurodevelopment.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Detailed Description
Investigators will study three groups of pubertal youth, ages 12-17 yrs old (n=31 each): a group with normal weight and normal glucose tolerance (NW-NGT), a group with overweight/obesity and normal glucose tolerance (O-NGT), and a group with overweight/obesity and dysglycemia (O-DG). Groups will be comparable in age, sex, race/ethnicity, and socio-economic status (SES). Brain structure and function will be examined in all groups using magnetic resonance imaging (MRI) and cognitive tests at study entry (time 1/baseline), and after 21 months (time 2), focusing on a limited number of key outcome variables known to be consistently impaired in obesity or T2D. Targeted MRI measures will be regional volumes (e.g. hippocampus), neuroinflammation via restricted ratio from diffusion basis spectrum imaging (DBSI); hippocampus and white matter tracts), whole-brain cerebral blood flow via arterial spin labeling (ASL). Targeted cognitive measures will be delayed memory, processing speed, and executive function. The ultimate goal of this study is to determine how metabolic factors during neurodevelopment set the stage for the potentially profound, long-term impact of T2D on the brain and its functions. Given that the disease occurs at a time when brains are undergoing dramatic developmental processes, the aggressive nature of youth-onset T2D progression and complications in other organ systems, these results may provide guidance and justification for longer follow-up, interventional and/or mechanistic studies, and have important clinical implications.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Normal Weight-Normal Glucose Tolerant (NW-NGT) (1) a group that is the normal weight (BMI<85th%) and has normal glucose tolerance (NW-NGT) |
Other: Observational
Investigators are observing brain health over time (21 months) in these groups
|
| Overweight and/or obese and has normal glucose tolerance (O-NGT) (2) a group that is overweight and/or obese (BMI >85th%) and has normal glucose tolerance (O-NGT) |
Other: Observational
Investigators are observing brain health over time (21 months) in these groups
|
| Overweight and/or Obese and has dysglycemia (O-DG) (3) group that is overweight and/or obese (BMI >85th%) and has dysglycemia (O-DG; fasting plasma glucose ≥100 mg/dl and/or 2-hour glucose ≥140 mg/dl oral glucose tolerance test (OGTT) and laboratory-based HbA1c ≥5.8 and ≤8.0%, if treatment naïve). |
Other: Observational
Investigators are observing brain health over time (21 months) in these groups
|
Outcome Measures
Primary Outcome Measures
- hippocampal volume [21 months - Visit 1 and Visit 2 are 21 months apart]
To determine hippocampal volumes, investigators will use the validated, objective and semi-automatic segmentation program Automated MRI Brain Volumetry System (volBrain). Hippocampal volumes will be obtained for each subject at each visit for primary analyses. Left and right volumes will be averaged, since lateralized findings are not hypothesized.
- restricted fraction [21 months - Visit 1 and Visit 2 are 21 months apart]
Investigators will use Diffusion Basis Spectrum Imaging (DBSI) models on diffusion weighted images (DWI) to assess restricted fraction within the hippocampus and throughout white matter tracts.
- Whole brain cerebral blood flow [21 months - Visit 1 and Visit 2 are 21 months apart]
Pseudo-continuous arterial spin labeling (pCASL) will be used to measure cerebral blood flow (CBF) implemented with an arterial spin labeling (ASL) sequence 228 and volume navigators (vNavs) to minimize motion artifact. Global CBF across pairs of frames will be scaled additively to the median value. Investigators will assess the number of voxels that statistically deviate from a normative value ('distributed deviating voxels') and compared between groups.
- Declarative Memory [21 months - Visit 1 and Visit 2 are 21 months apart]
Investigators will use the total score from the Paired Associates Memory Test, an experimental cognitive task measuring delayed declarative memory
- Processing speed [21 months - Visit 1 and Visit 2 are 21 months apart]
Investigators will use the raw scores from the NIH Toolbox Pattern Comparison Processing Speed task.
- Executive Function [21 months - Visit 1 and Visit 2 are 21 months apart]
Investigators will use an average of the (z scores) from the NIH Toolbox Flanker Inhibitory Control & Attention, Dimensional Change Card Sort and List Sorting tasks.
Eligibility Criteria
Criteria
Inclusion Criteria:
- 12-17 yrs. old at visit 1, 12-19 yrs. old at visit 2, Tanner II or above (determined through an exam by a pediatric endocrinologist or certified nurse practitioner trained in pediatric endocrinology), otherwise healthy except for obesity, <450 lbs. (due to MRI scanner limits), able and willing to lie flat within the MRI scanner and do cognitive testing, fluent in English.
Exclusion Criteria:
- Syndromic obesity, history of bariatric surgery, insulin treatment (metformin allowed if < 6 months) for T2D, contraindications for MRI (metal, claustrophobia), braces, pregnant (pregnancy test will be done on post-menarchal girls) or breastfeeding, inability to participate in cognitive testing due to sensory or language issues, intellectual disability, special education, pharmacologic treatment for Attention Deficit Hyperactivity Disorder (ADHD), prematurity (<36 weeks gestation), complications at birth, neurologic co-morbidities (e.g., seizures, stroke, head injury with >10 min loss of consciousness), significant psychiatric disorders (e.g., schizophrenia, bipolar disorder, current major depression), taking psychoactive medications (e.g., antipsychotics) that would interfere with testing or reporting illegal drug use. Self-reported smoking and alcohol use and length of time with obesity will be assessed by history (although these measures may not be fully reliable).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110 |
| 2 | UPMC Children's Hospital of Pittsburgh | Pittsburgh | Pennsylvania | United States | 15224 |
Sponsors and Collaborators
- Washington University School of Medicine
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
- Principal Investigator: Tamara A Hershey, PhD, Washington University School of Medicine
- Principal Investigator: Silva Arslanian, MD, UPMC Children's Hospital of Pittsburgh
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 202107019
- 1R01DK126826-01A1