Type 2 Diabetes Mellitus and Blood Brain Barrier Function Improvement- A Randomized Clinical Trial - PROJECT SUMMARY/ ABSTRACT Type 2 diabetes mellitus (T2DM) patients make up 90-95% of all diagnosed diabetes mellitus and show serious cognitive and mood deficits that are associated with increased morbidity and mortality, poor self-care, and decreased life quality. These deficits are linked to brain tissue changes, potentially resulting from impaired blood brain barrier (BBB) function. However, it is unclear whether BBB function can be repaired in T2DM adults, reducing impaired cognition and mood functions and early risks of dementia and Alzheimer’s disease. The BBB restricts diffusion of microscopic objects (such as bacteria) and large (e.g., antibodies and many drugs) or hydrophilic molecules (e.g., salt) from crossing into brain tissue and protects from harmful substances. Although multiple methods, including positron emission tomography, single photon emission computed tomography, and contrast-based magnetic resonance imaging (MRI) can examine BBB function, they are either invasive or pose significant health risks on humans. Using non-invasive MRI based diffusion- weighted pseudo-continuous arterial spin labeling (DW-pCASL), BBB function status can be examined, which has been validated to examine BBB breakdown in pre-clinical and in pilot T2DM studies. Several pre-clinical studies suggest the possibility for BBB function repair, including low-cost thiamine intervention. Thiamine is an essential component for carbohydrate metabolism and adequate or higher levels promote aerobic metabolism. In addition, reduced thiamine levels are shown contributing to impaired endothelial cell functions, leading to BBB dysfunction, and higher doses improve endothelial functions. Although the majority of T2DM adults show thiamine deficiency that may contribute to impaired BBB function, but it is unclear if the thiamine treatment can improve BBB function. Therefore, using 52 T2DM adults with randomized clinical trial, the specific aims are to: 1) compare BBB function, using DW-pCASL, and blood serum BBB (S100β levels) biomarkers in T2DM adults with and without thiamine treatment and 2) examine cognition (Wide Range Assessment of Memory and Learning 2 and Montreal Cognitive Assessment) and mood (Beck Depression Inventory II and Beck Anxiety Inventory) between T2DM adults with thiamine treatment compared to T2DM adults without thiamine treatment. In summary, low-cost thiamine treatment will be performed to assess whether impaired BBB function and mood and cognition deficits are improved in T2DM adults. If successful, the information from this clinical trial might serve as a novel and innovative treatment strategy to repair BBB function, affecting less cognition and mood function, and hence better outcomes in T2DM adults. This R21 clinical trial study will provide required data regarding the benefits of a low-cost thiamine intervention that could be implemented on a large-scale clinical trial to repair BBB function, and thus, decrease early dementia and Alzheimer’s disease, reduce morbidity and mortality, and increase quality of life in T2DM adults.
