Pathophysiology of vascular contributions to cognitive impairment and dementia (VCID), including vascular cognitive impairment, remains enigmatic, and this project will take a novel focus by addressing the possible role of calcification of the intracranial vasculature. We will analyze the consequences of neurovascular calcification (NVC) on brain parenchyma and subsequent impact on cognition in a high-risk population of aging and chronic kidney disease (CKD) subjects/patients. We will delineate the specific pattern of calcification (intimal vs medial arterial/arteriolar and capillary) and analyze ischemic and hemorrhagic injury in autopsy human brain. We will also examine the process of NVC in mouse brain, its impact on parenchymal injury and cognitive impairment, and determine how it may be treated or prevented. Vascular calcification is age-dependent, and we will focus on aging in our studies. Because CKD is known to profoundly advance calcification of vasculature, we will also focus on CKD in our studies. The project team has expertise in stroke neurology, vascular neurobiology, nephrology, neuropathology, and biostatistics, all relevant to the proposal: Specific Aim 1: To determine the relationship between NVC and microvascular disease in CKD of aging.
Hypothesis 1A: NVC (medial vs intimal/capillary) predicts microvascular ischemic injury in autopsy brain of aged CKD subjects.
Hypothesis 1B: NVC (medial vs intimal/capillary) predicts microvascular hemorrhagic injury in autopsy brain of aged CKD subjects.
Specific Aim 2: To determine a) the effects of NVC on brain parenchyma and cognitive performance, and b) the mechanistic treatment of NVC, in aged CKD mice.
Hypothesis 2A: NVC worsens microvascular parenchymal injury and VCID with cognitive decline in aged CKD mice.
Hypothesis 2B: Anti-calcification therapies decrease NVC and parenchymal injury and improve cognitive performance in aged CKD mice.
Our proposed project combines human autopsy investigation with a relevant mouse model, designed to produce project synergy in which observations from the human study inform the mouse investigation and mouse studies suggest targetable mechanisms of NVC in human brain. Incorporation of the mouse model provides the advantage of a trial of targeted therapy for NVC, which is to the best of our knowledge the first such attempt. Our human autopsy study will compare CKD vs non-CKD subjects, and thus insights will be generated for both the CKD and non-CKD population. Completion of this project by our unique mutli- disciplinary team should pave the way for more comprehensive studies of NVC and its treatment, providing new directions in the scientific approach to ameliorating VCID, including vascular cognitive impairment.