CHRONIC CEREBRAL HYPOPERFUSION: A TRANSLATIONAL MODEL

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• 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
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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

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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

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

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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

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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
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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
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MARKERS OF COGNITIVE INJURY
Apolipoprotein E (APOE)- e4
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
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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
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EXPOSURE BILATERAL CAROTID STENOSIS
0.18 millimeter microcoil Bilateral Common
Carotid Arteries Laser Doppler Flowmetry
SHAM
BCAS
Shibata et al. Stroke2004
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OUTCOME WHITE MATTER ISCHEMIA
KB SHAM
KB BCAS
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OUTCOME WHITE MATTER ISCHEMIA
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OUTCOME HYPOXYPROBE
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SHAM
BCAS 0.18mm
BCAS 0.16mm
Hypoxia gradient via 2-nitroimidazole hypoxia
marker pimonidazole hydrochloride
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OUTCOME DECLARATIVE MEMORY
Significant differences in both frequency and
latency between groups
Nature Protocols 1, 1306 - 1311 (2006)
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OUTCOME COMPLEMENT C5a DEPOSITION
BCAS SHAM
C5a 125KD
GAPDH 37KD
BCAS
SHAM
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BEDSIDE TO BENCH AND BACK
Reverse Translation
CLINIC
BENCH
Continuous Modification/ Refinement
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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
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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
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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
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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
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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
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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