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
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
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
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
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
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
THE PROBLEM: CAROTID STENOSIS
Carotid Endarterectomy before (above) and
during (below) plaque removal
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Clinical and Translational Science Institute
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Carotid Stenosis before (left) and after (right)
stent deployment
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
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
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
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
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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Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
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
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
MARKERS OF COGNITIVE INJURY
Apolipoprotein E
(APOE)- ε4
Transcranial Doppler
Serum S100-B
MR Imaging
Heyer et al. Neurosurgery, 2006
Heyer et al. Neurology, 2005
MCP-1
Mocco et al. Stroke, 2005
Mack et al. Acta Neurochir, 2008
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Clinical and Translational Science Institute
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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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Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
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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Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
OUTCOME: WHITE MATTER ISCHEMIA
KB SHAM
KB BCAS
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
OUTCOME: WHITE MATTER ISCHEMIA
KB SHAM
KB BCAS
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
OUTCOME: HYPOXYPROBE
6%
15%
SHAM
BCAS 0.18mm
31%
BCAS 0.16mm
Hypoxia gradient via 2-nitroimidazole hypoxia marker : pimonidazole hydrochloride
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
OUTCOME: DECLARATIVE MEMORY
Significant differences in both
frequency and latency
between groups
Nature Protocols 1, 1306 - 1311 (2006)
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Clinical and Translational Science Institute
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OUTCOME: COMPLEMENT C5a DEPOSITION
BCAS
SHAM
C5a 125KD
GAPDH 37KD
BCAS
C5a/GAPDH Whole Brain
0.06
0.05
0.04
0.03
0.02
0.01
SHAM
0
BCAS DAY 30
SHAM DAY 30
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Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
BEDSIDE TO BENCH: AND BACK
Reverse
Translation
CLINIC
Continuous
Modification/ Refinement
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BENCH
TRANSLATIONAL SCIENCE: CCH
Khoury et al. Genet Med 2007
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
•
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
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
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
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
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
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
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
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
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health
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
Southern California
Clinical and Translational Science Institute
Translating Science into Solutions for Better Health