PROJECT SUMMARY
There is a critical need to determine whether premature vascular disease observed in youth with type 2
diabetes (T2D) extends to the brain. This proposal builds on exciting data generated by our team showing
differences in brain structure and clinically meaningful declines in neurocognitive function among adolescents
with youth-onset T2D compared to their obese and lean peers. Our most prominent findings include lower brain
gray matter volume and lower scores on measures of working memory. Importantly, we have also demonstrated
some of the first evidence of cerebrovascular impairment in youth with T2D, manifested as reduced gray matter
cerebral blood flow. Finally, we have preliminary evidence that cerebral blood flow correlates with reduction in
gray matter volume and working memory measures. These findings suggest the breakdown of the neurovascular
unit (NVU), a physiological construct describing the interplay between brain vasculature, neurons, and supporting
glia and a mechanism for reduced brain volume and cognitive impairment. Our overarching hypothesis that
premature vascular disease observed in youth-onset T2D extends to the brain and is associated with structural
brain abnormalities and neurocognitive impairment. Importantly, we aim to differentiate the impact of T2D on the
brain from the effect of obesity. Thus, we will compare NVU in adolescents with T2D to age, sex and race similar
non-diabetic adolescents with obesity (obese controls) and without obesity (lean controls). Aim 1 will
comprehensively assess aspects of NVU structure and function and identify risk factors impacting the NVU; 2)
Aim 2 will determine the relationships between cerebrovascular, neuroanatomical, and cognitive outcomes
cross-sectionally, and 3) Aim 3 will evaluate changes in the NVU, brain structure and cognition over time. Our
team is well positioned to conduct this study as we have generated compelling preliminary data in our laboratory
(m-PI Shah & DiFrancesco), we have expertise in conducting research studies in youth with T2D with
documented ability to recruit and retain participants (m-PI Shah), we developed the state of the art MRI methods
to study the vasculature in our laboratory and have applied these to other diseases with vascular sequelae such
as systemic lupus erythematous (m-PI DiFrancesco), and we have extensive expertise in neurocognition and
brain-behavior research (co-I Beebe & m-PI DiFrancesco). Finally, we have documented collaboration between
the members of the study team over the last five years (Shah, DiFrancesco, Beebe & Altaye). The results of this
proposal will separate the effects of T2D from obesity, identify noninvasive imaging biomarkers of brain health
and treatable risk factors, and explore progression over time, positioning us to test interventions for youth with
T2D and obesity as an immediate next step.
