Increased small vessel disease in the brain and cognitive impairment in diabetes
Diabetes is an increasing risk factor for vascular cognitive impairment (VCI), which is defined as cognitive deficits associated with small vessel disease (SVD) and/or lacunar infarction due to the occlusion of terminal arterioles by emboli in the brain. Microemboli even in sizes that would not cause complete occlusion are quite common in the cerebral circulation and are more so in patients with diabetes that present with a hypercoagulable state. Lack of understanding of the role and mechanisms by which microemboli can contribute to increased disease burden in diabetes is a critical gap in our knowledge. The objectives of this DiaComp Pilot & Feasibility Program grant application are to begin addressing this important clinical problem by establishing a novel animal model and gathering proof-of-concept data to implicate the vascular dysfunction and microemboli interaction in the development of cerebral SVD preceding the VCI in diabetes. We propose that the microemboli injected through the internal carotid artery will accelerate the development of cerebral SVD in diabetes ultimately resulting in VCI without increasing microinfarcts in a sex independent manner. We will examine the cerebral neuronal and vascular changes by neuropathology assay in both male and female animals. We will also examine the neurological and cognitive behavioral tests, and brain imaging to assess the cognitive function. The results of this translational study first will provide the proof-of-concept pilot data that microemboli are pathological even in the absence of increased microinfarction in diabetes. Second, we will establish a new clinically relevant model to study the mechanisms of VCI, which will enable us to develop the studies on neurovascular protection strategies especially in the high-risk groups. Third, we will provide novel data regarding the impact of sex on the development of VCI in diabetes.

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.

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