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.