CHRONIC CEREBRAL HYPOPERFUSION: A TRANSLATIONAL MODEL William J Mack, MD August 31, 2012

1. CHRONIC CEREBRAL HYPOPERFUSION: A TRANSLATIONAL MODEL William J Mack, MD August 31, 2012 Complement Mediated Injury in a Translation model of Chronic Cerebral Hypoperfusion. NIH KL2 : Los Angeles Basin Clinical Translational Science Institute. 1KL2RR031991-01 The Role of the C5 Complement Protein in Chronic Cerebral Hypoperfusion. NIH 5 P50 Center Alzheimer Disease Research Center Pilot grant. 2 P50 AG005142-26A1

2. PRESENTATION GOALS 1. Outline the way in which I developed a research interest/question and designed a study to examine this question • Question in Neurosurgery Practice: • Cerebral Hypoperfusion • Relevant Clinical Studies: • Carotid Endarterectomy • Translational Experimental Model: • Murine model of Bilateral Carotid Artery Stenosis 2. Discuss my pathway to a career in Academic Neurosurgery and Translational Science

3. MY RESEARCH • Research Question: Can modulation of inflammatory mediators improve outcomes following Chronic Cerebral Hypoperfusion? • Approach: Examine a clinical problem and develop a reproducible laboratory animal model to assess mechanism and potential therapies • Brain Ischemia • Neurocognitive Deficits • Inflammatory Modulation

4. THE PROBLEM: CAROTID STENOSIS Carotid Endarterectomy before (above) and during (below) plaque removal Carotid Stenosis before (left) and after (right) stent deployment

5. CLINICAL STUDIES: COGNITIVE ASSESSMENT • Studies have demonstrated that conventional neurological assessment is insufficient for determining neurocognitive sequelae of CEA • Neuropsychometric tests (NPMTs) are sensitive measures of cerebral functioning and indicators of neurological injury • Cognitive decline, not revealed on routine examination, can be demonstrated through a relevant battery of NPMTs • Our group designed a clinical CEA model that affords a controlled paradigm in which to critically examine the mechanisms of cerebral ischemia and resultant cognitive decline

6. CLINICAL STUDIES: COGNITIVE ASSESMENT • Patients undergoing CEA and lumbar spine surgery (control cohort) admitted to the Clinical Research Center one day prior to surgery • Structured neurological examination and detailed NPMT • Peripheral serum specimens for baseline biochemical marker levels • Buccal swab sample was obtained for genetic testing

7. CEA AND COGNITIVE DECLINE • To determine the incidence of neurocognitive decline after CEA • Examined the changes in neuropsychological test performance in patients following CEA vs. an age matched control group undergoing lumbar spine surgery Heyer et al. Arch Neurol, 2002

8. CEA AND COGNITIVE DECLINE Cognitive dysfunction was seen in 28% of the CEA group on day 1 and 23% on day 30 Subtle cognitive decline following CEA is evident postoperatively and persists for at least several weeks following surgery. This decline is absent in the control group Heyer et al. Arch Neurol, 2002

9. MARKERS OF COGNITIVE INJURY Apolipoprotein E (APOE)- ε4 Transcranial Doppler MCP-1 Serum S100-B MR Imaging Heyer et al. Neurosurgery, 2006 Heyer et al. Neurology, 2005 Mocco et al. Stroke, 2005 Mack et al. Acta Neurochir, 2008

10. TRANSLATIONAL MODEL: BACKGROUND • Cognitive impairment and dementia are disabling conditions that are increasingly common with advancing age. • An estimated 5-10% of individuals over sixty-five, and 40% of individuals older than eighty-five are likely to be affected. • Clinical imaging, epidemiological and pharmacotherapeutical studies have supported a strong association between cortical hypoperfusion and cognitive decline and suggest an inflammatory mechanism • In a clinical CEA model of cerebral hypoperfusion, research has demonstrated a roughly 25% incidence of subtle cognitive decline in the absence of overt neurologic change or radiographic evidence of stroke Mack et al. Neurosurgery 2009 Heyer et al. Arch Neurol 2002

11. EXPOSURE: BILATERAL CAROTID STENOSIS 0.18 millimeter microcoil Bilateral Common Carotid Arteries Laser Doppler Flowmetry SHAM BCAS Shibata et al. Stroke2004

12. OUTCOME: WHITE MATTER ISCHEMIA KB SHAM KB BCAS

13. OUTCOME: WHITE MATTER ISCHEMIA KB SHAM KB BCAS

14. OUTCOME: HYPOXYPROBE 6% 15% 31% SHAM BCAS 0.18mm BCAS 0.16mm Hypoxia gradient via 2-nitroimidazole hypoxia marker : pimonidazole hydrochloride

15. OUTCOME: DECLARATIVE MEMORY Significant differences in both frequency and latency between groups Nature Protocols 1, 1306 - 1311 (2006)

16. OUTCOME: COMPLEMENT C5a DEPOSITION BCAS SHAM C5a 125KD GAPDH 37KD BCAS SHAM

17. BEDSIDE TO BENCH: AND BACK Reverse Translation CLINIC BENCH Continuous Modification/ Refinement

18. TRANSLATIONAL SCIENCE: CCH • T0: Identification of opportunities and approaches to health problem. • Basic research question • Complement C5 in murine model of CCH • T1: Discovery of candidate health application. • Phase I and II clinical trials; observational studies • Neurocognitive decline in CEA model • T2: Health application to evidence-based practice guidelines. • Phase III clinical trials; observational studies; evidence synthesis and guidelines development. • Inflammatory/ genetic markers of cognitive decline in CEA • T3: Practice guidelines to health practices. • Dissemination research; implementation research; diffusion research; Phase IV clinical trials • Neuroprotection in CEA: RCT • T4: Practice to population health impact • Outcomes research (includes many disciplines); population monitoring of morbidity, mortality, benefits, and risks studies • Outcomes following implementation of therapy Khoury et al. Genet Med 2007

19. MY PATHWAY: ACADEMIC NEUROSURGERY Academic Neurosurgery: What is that? Vascular Endovascular Neurosurgery Cerebrovascular Research From Training to Recruitment to Practice: Body of Work Institutional Support: ZNI, Neurosurgery Department Protected Research Time ADRC Pilot Grant CTSI KL2 Grant

20. DIFFICULTIES/ CHANGES ALONG THE WAY “Speaking the Language:” Understanding all of the complex parts to translational research and team science Masters in Clinical and Biomedical Investigation Biostatistics Regulatory Science CTR I, II, II Roberta Brinton, PhD; Director Center for Scientific Translation, USC Clinical and Translational Science Institute: “Find a research niche” that has clinical application and for which you are optimally positioned Change in focus and addition to mentorship team

21. MENTORING TEAM Helena Chui, MD: Chair, Department of Neurology, Raymond and Betty McCarron Chair in Neurology, and Professor of Neurology and Gerontology, Keck School of Medicine, USC Caleb Finch, PhD: ARCO/ Keischnick Professor of Gerontology and Biological Science and University Professor, Director, Gerontology Research Institute Berislav Zlokovic, MD, PhD: Professor and Chair, Department of Physiology & Biophysics; Director, Zilkha Neurogenetic Institute Intellectual and Physical Proximity

22. BENEFITS OF TRANSLATIONAL RESEARCH Interdisciplinary Team: Neurosurgeons, Neurologists, Neuroscientists, Statisticians, Behavioral Scientists, Fellows, Residents, Medical Students, College Students, Technicians Expertise in a Specialized field Fun and Exciting workday, week, year: no two days are similar Bedside to bench and back

23. ACKNOWLEDGEMENTS SC CTSI: Jonathan Samet, MD; Cecilia Patino Sutton, MD, MeD, PhD Berislav Zlokovic, MD, PhD Helena Chui, MD Caleb Finch, PhD Marco Bortolato, MD, PhD Leonid Groysman, MD Jonathan Russin, MD Qinghai Lui, MD TC Scotton Shuhan He David Shaked