DHS MIND Metabolomics
DHS MIND Metabolomics
The study team will evaluate whether metabolomic signatures of neurocognitive decline
 trajectories are exacerbated by the presence of type 2 diabetes mellitus (T2D) and whether
 these signatures contribute in part, to ethnic disparities in cognitive decline between
 European Americans and African Americans with T2D.
Aim 1. Re-examine the Diabetes Heart Study Memory IN Diabetes (DHS MIND) cohort for
 progression of neurocognitive decline using an established cognitive battery, literacy
 testing, and adjudicated physician diagnosis of dementia.Another neurocognitive evaluation
 will be completed in European-American and African-American DHS MIND participants, providing
 longitudinal follow-up more than eight years after initial assessment. The cognitive battery
 will reassess domains of executive function, memory, and global cognition. In addition, a
 clinical exam will include a literacy evaluation to circumvent the shortcomings of
 differences in educational attainment among participants. A physician adjudicated assessment
 of cognitively normal, mild cognitive impairment, or dementia will be obtained. Cognitive
 evaluations will inform epidemiological analyses regarding cross-sectional and trajectories
 of cognition decline relative to existing and repeat measures of cardio-metabolic risk
 factors.

 Aim 2. Examine the metabolomic basis of neurocognitive measures in people with T2D. The
 presence of T2D, cardiovascular disease and reduced kidney function are significant risk
 factors for development of cognitive impairment. These risk factors are enriched in the DHS
 and lack early diagnostic tools. Untargeted metabolomic profiling offers the potential to
 identify relevant biomarkers that could impact the diagnosis, prognosis, and treatment of
 cognitive decline. This will be accomplished through untargeted metabolomic analysis of
 European American and African American DHS MIND participants using stored samples from
 baseline visits acquired more than 10 years prior to the current (repeat) neurocognitive
 assessment. These data will be used to A) provide information on novel mechanistic insights
 into cognition and trajectories of cognitive decline, B) develop a risk prediction model
 using the baseline exam, and C) validate extremes of neurocognitive performance using
 longitudinal assessments while examining ancestry/ethnic-specific differences.

 Aim 3. Comprehensive genetic analysis of DHS participants to examine the genetic architecture
 of metabolomic signatures associated with the trajectories of neurocognitive decline.
 Existing genome-wide data will be used to map regions of the human genome that contain loci
 contributing to measures of neurocognition and metabolomics signatures of change in these
 variables through longitudinal assessment. Causal effect modeling will validate the
 association of modifiable exposures, i.e. genetic markers and metabolites on the outcome
 (i.e. trajectories of neurocognitive decline).
Inclusion Criteria:

 • At the baseline visit, European American and African American individuals with T2D must
 have had diabetes diagnosed after the age of 30, 3 years disease duration and lack
 historical evidence of diabetic ketoacidosis.

 Exclusion Criteria:

 -  At the baseline visit, participants with pre-existing kidney disease, defined as a
 serum creatinine concentration >1.5 mg/dl or blood urea nitrogen >35 mg/dl were
 excluded due to the elevation of serum AGE levels in individuals with kidney disease.