Cognitive Impairment in Diabetes: Endothelial Mechanisms & Intervention
Diabetes doubles the risk vascular cognitive impairment and dementia (VCID), a disease spectrum ranging from mild cognitive impairment to dementia and is associated with small vessel disease (SVD) of the brain, especially deep in the white matter that further complicates the disease by causing infarctions due to the occlusion of terminal arterioles. Yet, early mechanisms contributing to amplified SVD and cognitive decline remain unknown. Given that diabetes mediates early cerebrovascular dysfunction, and microemboli are quite common in the cerebral circulation and can penetrate into the brain parenchymal arterioles without causing an infarction, with the support of a 2017 DiaComp award, we started testing the hypothesis that entrapment of microemboli in dysfunctional vessel walls leads to the development of SVD ultimately resulting in VCID in diabetes. Phase III Lacunar Intervention Trial (LACI-2) that was announced in early 2018 to assess the safety and efficacy of isosorbide mononitrate (ISMN) and cilostazol, two commonly prescribed drugs to improve vascular function, in the prevention of lacunar strokes and progression of SVD provided a translational direction for our exciting preliminary data. Therefore, the objective of this pilot application is to refine the microemboli model of VCID and begin preclinical testing with ISMN and cilostazol for the prevention/treatment of SVD and VCID in diabetes. The working hypothesis is that early endothelial dysfunction in diabetes facilitates entrapment of microemboli leading to SVD and VCID. In 2 aims, by using histopathological assessment and longitudinal MRI imaging & behavioral testing, we will determine 1) the impact of microemboli on temporal development of SVD and VCID in diabetes, and 2) the effectiveness of ISMN and cilostazol combination in the prevention of SVD and cognitive decline in diabetes. The data of this study will provide essential evidence that endothelial dysfunction plays a critical role in the pathogenesis of SVD in diabetes. We also will establish a clinically relevant model to develop further studies on neurovascular protection in the high risk groups. Finally, we will provide crucial preclinical data specific for diabetes with therapeutics that are on clinical trials for the prevention of SVD in general population. Given that cognitive impairment is a wide spectrum that can start early in life and diabetes is the most rapidly increasing risk factor for cognitive decline, we believe that this translational study will provide critical data to fully develop this project to advance the field and make a significant positive impact on public health.