Eric J. Heyer - US grants

postoperative state; cerebrovascular imaging /visualization; carotid artery; cardiovascular surgery; stroke; neuropsychological tests; neurologic manifestations; patient oriented research; human subject; ultrasound blood flow measurement; magnetic resonance imaging; clinical research;

DESCRIPTION: (provided by applicant) Carotid endarterectomy (CEA) is extremely efficacious in preventing stroke- and reducing death due to the low incidence of major surgical complications (2-5 percent incidence of stroke). However, at least 30 percent of endarterectomy patients experience cognitive deficits, revealed by a battery of neuropsychometric tests (NPMTs). Although most strokes after CEA are due to FOCAL injury from emboli coming from the surgical field, we hypothesize that some patients without EEG evidence of cerebral ischemia may still have GLOBAL ischemia as indicated by TCD that leads to cognitive deficits and decreases quality of life. We further hypothesize that the incidence and severity of cognitive deficits will be significantly reduced in these patients if CBF is augmented by placement of a shunt across the operative site. Specific Aims: In order to test thehypotheses we propose the following: 1. To demonstrate that a certain percentage of patients with normal EEGs develop significant cognitive deficits due to GLOBAL brain parenchymal damage after CEA by three independent measures of cerebralinjury ury:functional, structural and biochemical 2. To determine prospectively the importance of GLOBAL hypoperfusion by randomizing patients who have normal EEGs but significantly teduced CBF velocity after carotid artery clamping into two groups. One group will have a shunt inserted across the operative site and the other, not (the current standard). Each will be assessed for cognitive deficits, and structural and biochemical changes. Conclusion: We shall demonstrate that cognitive deficits arise from GLOBAL ischemia when the carotid artery is clamped, which can be assessed by TCD ultrasonography and prevented by increasing cerebral perfusion using a shunt across the surgical site. EEG is inadequate to determine this subtle degree of hypoperfusion.

magnesium ion; human therapy evaluation; neuropsychological tests; sulfates; magnesium; drug screening /evaluation; carotid artery; endarterectomy; postoperative state; clinical trials; patient oriented research; human subject; clinical research;

DESCRIPTION (provided by applicant): Carotid endarterectomy prevents stroke and reduces mortality. Despite its low incidence of major medical complications, patients having carotid endarterectomy commonly manifest significant post-surgical cognitive deterioration that is mental deterioration, in ~ 25%. The procedures used during surgery may be critical in reducing or enhancing the likelihood of this post-surgical mental deterioration. Increasingly, carotid artery stenting is a procedure that may replace carotid endarterectomy, but it also has been associated with post-surgical persistent cognitive deterioration in a substantial proportion of patients. We aim to determine whether cognitive function is improved by increasing cerebral blood flow during carotid artery surgery via inserting a shunt. We will randomize patients to either conventional management, which includes increasing systolic blood pressure, or by inserting a shunt while maintaining systolic blood pressure at baseline values. All patients will be examined before and after surgery (1 day, and 1 and 6 months [1 d/1 & 6 m]) with a battery of neuropsychometric tests. This study will test the hypotheses that use of a shunt reduces the rate, extent and persistence of cognitive impairment following carotid endarterectomy with an associated effect on two serum markers of injury to the brain, S100B, a protein from glia, and NSE, a protein from neurons, and that a marker sensitive to blood flow during surgery, namely how much oxygen is extracted by the brain, will show reliable associations with cognitive outcomes and the two biomarkers of tissue injury, S100B and NSE. Also, we aim to determine the incidence of cognitive deterioration associated with carotid artery stenting by comparing cognitive performance in patients having carotid artery stenting to those having coronary artery stenting using a battery of neuropsychometric tests before and after surgery (1 d/ 1 & 6 m). This study will test the hypotheses that the use of stenting does not reduce the rate, extent and persistence of cognitive impairment compared to carotid endarterectomy, and will be associated with elevations in S100B, MRI evidence of focal infarct, and quantitative transcranial Doppler evidence of emboli. Based on the findings from these studies we will reduce cognitive injury, stroke and mortality from these procedures. PUBLIC HEALTH RELEVANCE Carotid artery stenosis is a major cause of stroke and mortality. Its treatment is to remove the stenosis either surgically by performing a carotid endarterectomy or endovascularly by performing carotid artery angioplasty and stenting (stenting). While we have demonstrated that carotid endarterectomy leads to cognitive dysfunction in ~25% of patients, more so in patients with Type 2 diabetes mellitus, no direct comparison of the incidence of cognitive dysfunction has been performed between patients undergoing carotid endarterectomy and carotid artery stenting. The aims of this study are to perform just such a comparison to see if one treatment is safer than the other, and also to determine whether cerebral blood Flow-Enhancement with shunt placement across the surgical site during carotid endarterectomy in patients with diabetes mellitus reduces cognitive dysfunction.

For the past 15 years, we have studied cognitive changes in patients treated for carotid artery stenosis by carotid endarterectomy (CEA) or carotid artery angioplasty and stenting (CAS). Using neurocognitive tests, we have defined post-operative cognitive dysfunction (CD), a subtle measure of cerebral injury. Post-operative cognitive dysfunction is part of a continuum of injury to the brain. Early cognitive dysfunction (eCD) is observed in ~ 25% of patients within 1 day of CEA, and less so 30 days after CEA (delayed CD [dCD]). Over the last 10 years of our NIH grant (RO1 AG17604), we have demonstrated that 1. Asymptomatic patients taking statinspre-operatively exhibit significantly less eCD than those not taking statins, 2. Simvastatin is associated with significantly less eCD than atorvastatin, 3. Statins are also neuroprotective against eCD in CAS patients, 4.Patients with eCD and not taking statins have significantly higher risk of mortality than those with eCD taking statins, 5. Pro-inflammatory polymorphisms and marker concentrations are significantly associated with increased eCD, and 6. Statins are associated with lower levels of pro-inflammatory markers. Based on these findings, we hypothesize that in asymptomatic patients undergoing CEA, 1. Pre-operative statin use is neuroprotective against eCD and lowers the risk of early mortality, 2. Statin type and dose may be important in achieving optimal neuroprotection, and 3. The anti-inflammatory effects of statins may partially account for the observed neuroprotection. To address these hypotheses, we will prospectively evaluate 1000 asymptomatic patients with a neurocognitive battery for eCD and dCD before and after CEA in a multi-center randomized trial. Lipid profiles and markers of systemic inflammation will be obtained before and after statin therapy. Patients will be randomized into one of three arms for 2 weeks pre-operatively and 4 weeks-post operatively depending on their statin status upon enrollment. Arms: 1. Patients on optimal daily doses of either simvastatin (40mg), atorvastatin (80mg) or rosuvastatin (20mg) will be tested and observed, 2. Patients on one of the three statins at less than optimal dosage (simvastatin <40mg, atorvastatin <80mg or rosuvastatin <20mg) will be randomized to receive an optimal dose or remain at their suboptimal dosage using re-encapsulated blinded medication, and 3. Patients who are not already taking statins, will be randomized to a daily dose ofreencapsulated blinded atorvastatin 10mg (suboptimal) or atorvastatin 80mg (optimal). Overall, we expect that high-dose simvastatin, atorvastatin and rosuvastatin will be neuroprotectiveagainst eCD and dCD. We think that statin neuroprotection occurs because of anti-inflammatory mechanisms and will be reflected in reduced levels of systemic inflammatory markers. The findings of this prospective randomized trial will provide important data for clinicians attempting to make this common procedure safer, and will elucidate whether statins are neuroprotective in human ischemic cerebral injury. Our results may guide the development of these agents for other indications.