Role of cerebral amyloid angiopathy on cerebral blood flow, cerebral ischemia, cerebral hemorrhage, and dementia; Pathophysiology and novel therapeutic approaches for aneurysmal subarachnoid hemorrhage
My research focuses on investigating the molecular pathophysiology of cerebrovascular dysfunction, ischemic brain injury, and subarachnoid hemorrhage. One main focus of the lab is investigating the role of amyloid-beta peptide (A-beta) and apolipoprotein E (ApoE) in these conditions. In particular, we are interested in the pathologic vascular effects of these agents. Compelling experimental evidence indicates that both soluble A-beta and insoluble vascular deposits of A-beta (i.e. cerebral amyloid angiopathy) promote cerebral vessel dysfunction, which could heighten sensitivity to acute neurologic insults such as ischemic brain injury and/or subarachnoid hemorrhage. Moreover, apolipoprotein E – a key genetic risk factor in Alzheimer’s disease – is known to differentially influence A-beta metabolism and clearance and in so doing could significantly modulate these A-beta-mediated vascular effects. We hypothesize that A-beta and ApoE, through discreet and/or synergistic vascular mechanisms, contribute to neural injury following ischemic brain injury and/or subarachnoid hemorrhage.
Another focus of the lab is investigating novel approaches toward ameliorating a devastating condition known cerebral vasospasm, which commonly occurs after subarachnoid hemorrhage. Vasospasm is defined by delayed narrowing of large cerebral arteries that often leads to ischemic brain injury. It is a well known risk factor for poor patient outcome after SAH. We are investigating several new molecular targets and therapeutic appraoches to this disease, including MMP-9 and MMP-9 inhibitors, cGMP and phosphodiesterase inhibitors, as well as vascular preconditioning strategies.
We utilize a variety of basic, translational, and clinical experimental techniques to investigate these hypotheses. These include in vivo assessment of cerebral arteriole function and cerebral blood flow in transgenic and knockout mice; in vivo mouse models of focal cerebral ischemia and subarachnoid hemorrhage/vasospasm; microdialysis to measure brain A-beta levels in mice and humans; a prospective observational study in humans evaluating the effect of ApoE isoforms on subarachnoid hemorrhage-induced vasospasm; and a Phase I trial investigating the effect of phosphodiesterase inhibitors on cerebral blood flow and oxygen metabolism in patients with subarachnoid hemorrhage.