Transcript Healthy vs. pathological cognitive aging

External Advisory Board Meeting
June 19,2013
MISSION:
T O C O N D U C T C U T T I N G - E D G E I N T E R D I S C I P L I N A RY
C L I N I C A L N E U R O S C I E N C E A N D T R A N S L AT I O N A L
R E S E A R C H , O N A G E - A S S O C I AT E D C O G N I T I V E ,
B E H AV I O R A L A N D E M O T I O N A L F U N C T I O N I N G ,
FA C TO R S T H AT C O N T R I B U T E T O I M PA I R M E N T S A N D
F U N C T I O N A L D E C L I N E , A N D F U T U R E AV E N U E S F O R
I N T E RV E N T I O N .
PRIMARY OBJECTIVE:
T R A N S L AT E B A S I C S C I E N C E D I S C O V E R I E S I N T O
C L I N I C A L A P P L I C AT I O N S I N O R D E R TO S L O W,
AV E R T O R R E S TO R E A G E - R E L AT E D C O G N I T I V E
DECLINE AND MEMORY LOSS.
Healthy vs. Pathological Cognitive Aging
• What are the characteristics of “normal” cognitive aging?
• How does it differ from pathological cognitive decline?
• Do all cognitive functions eventually decline?
• Why are some functions spared from age-associated
decline?
• Do certain cognitive function improve as people age?
• What occurs as people reach very advanced age?
• What is the trajectory of cognitive changes in the very
old?
• Are these changes linked to specific brain changes?
The Aging Brain: Unresolved Questions
• What distinguishes normal from pathological brain aging as people
reach advanced age?
• To what extent is AD pathophysiology involved in cognitive decline
with advanced age?
• What are the contribution of other systemic metabolic and vascular
factors?
Continued…..
• Is age-associated cognitive decline bound to occur due to apoptosis
or other epigenetic mechanisms even in the absence of AD or
vascular and metabolic disturbances?
• Are certain structural and functional brain changes avoidable if other
risk factors are not present?
• What biomarkers will be most useful in identifying risk factors and
predicting change?
• To what extent are these factors modifiable?
Neuroimaging
as a Biomarker
• How sensitive are structural and functional neuroimaging measures
to these changes?
• Do structural and functional MRI provide useful measures for
predicting late-life cognitive change?
• Which measures are the best predictive biomarkers?
• To what extent do vascular and metabolic factors contribute to these
changes?
• Can cerebral blood flow and metabolic neuroimaging be useful in
assessing these factors and predicting subsequent decline?
• Can neuroimaging provide a s , along with structural and functional
MRI, useful in assessing modifiable risk factors?
So What is Needed?
• Normative cognitive, neuroimaging, and biological data from people
who have reached advanced
• Longitudinal measures over two time points (initially) to enable
examination of rates of change by domains
• Cognitive data sensitive to individual cognitive domains and change
in the very old
• Multimodal neuroimaging measures to characterize changes in
brain structure and function, and cerebral hemodynamic and
metabolic health.
Continued….
• These measures should be obtainable within a single session
enabling co-registration of structural, functional and
pathophysiological MRI indices.
• Neuroimaging measures should be collected along with cognitive
measures outside the scanner providing validation of the MBI
cognitive battery
• Biological samples, including blood, should be obtained at each visit
enabling epigenetic and proteomic analyses relative to the
neuroimaging and cognitive measures.
A Paradigm Shift is Needed
• Rather than starting from the perspective of neurodegenerative
disease, we propose to initially focus on people who have
successfully aged.
• By this we mean that they have survived to reach relatively
advanced age in relatively good physical health, without significant
cognitive or functional problems.
• This will require being quite selective in our recruitment necessitating the involvement of the four MBI programs.
CAM-CTRP SCOPE
• Normal Memory and Cognitive Aging
• Advanced age (> 70 years)
• People with and without medical co-morbidities
• Cognitive aging studies grounded in basic research
• Broad range of cognitive functions besides memory
(e.g. semantics, social cognition, decision making, creativity, etc.)
• Neuroimaging and other neuroscientific methods
• Clinical translation and interventions
Relationship to UF Institutes
McKnight Brain Research Foundation (MBRF)
•
Cognitive Aging
and MemoryClinical
Translational
Research Program
McKnight
(CAM-CTRP)
Dr. R. Cohen
Brain Institute
(MBI)
Dr. T. Ashizawa
Clinical
Translational
Science Institute
Dr. D. Nelson
Institute
on Aging (IoA)
Pepper Center
Dr. M. Pahor
CAM-CTRP Faculty
Ronald A. Cohen, Ph.D.
Natalie Ebner, Ph.D.
John Williamson, Ph.D.
Adam Woods, Ph.D.
Recruitment
Simon Davis, Ph.D.
CAM-CTRP Core Leaders
Marco Pahor, M.D.
Lauren Crump, M.P.H.
Steve Anton, Ph.D.
Christiaan Leeuwenburgh, Ph.D.
Christy S. Carter, Ph.D.
Michael Marsiske, Ph.D.
Hani Doss, Ph.D.
Todd Manini,Ph.D.
Song Lai, Ph.D.
Adam Woods, Ph.D.
CAM-CTRP Affiliate Faculty
• T. Ashizawa, M.D.
• Adam Falchook, M.D.
• Russell Bauer, Ph.D.
• Tom Foster, Ph.D.
• Jennifer Bizon, Ph.D.
• Kenneth Heilman, M.D.
• Dawn Bowers, Ph.D.
• Christina McCrae Ph.D.
• Robert Cook, MD,
Ph.D.
• Steven Nadeau, M.D .
• Ming-Zhao Ding, Ph.D.
• Vonetta Dotson, Ph.D.
• Natalie Ebner, Ph.D.
• Michael Okun, M.D.
• Cate Price, Ph.D.
• Ranganatha Sitaram, Ph.D.
Fellows and Students
• Eric Porges, PhD (Univ. of Chicago) Post-doctoral fellow
• Talia Seider, BSc (Univ. of Calif.) Graduate Student
•
• Six doctoral dissertations
Where do we go from here?”
Answering the need
for studies of healthy cognitive
aging
Initiatives:
• Neurocognitive Task Development
• Biomarker Development
•
•
•
•
Neuroimaging
Electrophysiological
Proteomic
Genomic
• Translational Research
• Clinical Trials
• Assemble supporting Cores
• Assemble Affiliate Faculty
• Equip new Building
Neurocognitive Approaches:
• Implementation of MBI battery and NIH Cognitive Toolbox
(core CAM-CTRP cognitive assessment)
• Trajectory of change analyses -CAM-CTRP
• Social cognition – Ebner
• Cognitive-affective assessment – Dodson
• Attention – Cohen, Heilman, Williamson, Woods, Falchook,
• Semantic network analysis – Cohen, Heilman, Nadeau
• Creativity – Heilman
Neuroimaging
• Setup of CAM-CTRP Neuroimaging
Analysis Laboratory
• Interface with new UF CTSI computing systems
• Implementation of standard multimodal neuroimaging
protocol for CAM-CTRP studies
• MRI standardization across MBI institutes
• Collection of neuroimaging data: LIFE cohort
• Advance metabolic neuroimaging (MRS)
• Plan NIA proposal for inter-institute project
Neuroimaging Assessment
• Scout + parameter setup =~ 3 min
• SENSITIVITY Reference scan =~2.5 min
• MPRAGE =~ 5 min x 2
• FLAIR =~ 3 min
• ASL =~ 5 min
• Phase contrast =~ 2min +1.5 min locator
• BOLD =~ 2 * 5 min resting state
OR 18 min for Task +rest
• DTI = ~ 10 min
• MRS =~ 7 min for ~1 ROI
• (phantoms acquired at beginning of each day)
Laboratory Biomarker Initiatives
• Proteomics and metabolomics
• (e.g., cytokines)
• Genomics
• genetic
• epigenetic
Laboratory Biomarker Plan
• Blood sample collection on CAM-CTRP
participants
• CSF collection in a limited sample
• Other tissues?
• CTSI Bio specimen repository
Translational Research
(some examples)
• Inflammation – neuroimaging mouse models
• Phosphorus and carbon MRS imaging methods
• Induced pluripotent stem cell (iPSC) initiative
• MBI initiatives: ARML translation efforts
• Computational neuroscience: Neural networks
• Combined electrophysiology-FMRI
• Drug challenges methodologies
• Combined studies of cognitive and physical function
Clinical Trials for Cognitive Aging
• Pharmaceutical
• Vitamin D
• Methotrexate
• Behavioral – Lifestyle
• Testosterone
• The Active Brain
• Resveratrol
• CHORES-XL
• Oxytocin
• Bariatric Surgery Study
• Neuroprotective Agents
• LIFE
• Cognitive Enhancers
• LIFE-ES
• Vascular Function
Enhancers
• LIFE-ARISE
• Performance Enhancers
• Cognitive Training
• VITAL- Bowers/Marsiske
• Vigorous Mind- Cohen
• Neurofeedback- Sitaram
CAM-CTRP Core Protocol
• Neurocognitive measures
• Neuroimaging and physiological
• Laboratory biomarkers (blood, tissue, CSF)
• Genomic sequencing (Leonid Moroz)
• CTSI Bio Specimen Repository
“The Active Brain” Cohort
• An inter-institutional cohort consisting of successful agers
• People who have reached advanced age (75 – 90 years)
• No evidence of significant cognitive or functional decline
• No history of major medical problems (CVD, Stroke, etc.)
• Well controlled vascular and metabolic risk factors
• We estimate that a sample size of 500 (125 per site) assessed
twice will provide sufficient power for initial analyses of
cognitive aging effects.
SPECIFIC OBJECTIVES: Year 2
• Faculty recruitment
• Transition to new IOA building
•
program
•
• Integration with Pepper cores
• Recruit cognitive aging cohort:
LIFE-ancillary study
• Support current IOA studies
Implement junior scholars
Facilitate proteomic and genomic
initiatives
•
Continue integration with ARML
•
MBI Inter-Institute Initiative
•
Continue current R01-P01
supported research
• Initiate multimodal neuroimaging
initiative
•
• Initiate pilot study program
•
Resubmission of Bariatric Grant
and two new submissions
Branding of CAM-CTRP
IOA-CAM Brain Wellness Clinic
• Multi-disciplinary program
• Geriatrics, Neurology, Psychiatry, Neuropsychology,
Social Work and other supportive services
• Provide assessment for older adults with concerns about
cognitive decline
• Receive referrals from community, psychiatry and other
sources
• Triage to the AD, PD, and other UF clinical programs
• Provide support and interventions
• Clinical trials
• Facilitated by arrival of Dr. Solberg
to direct clinical geriatrics at UF
IOA- CAM INTERFACE
Clinic
Research
Cohort Development
Study Recruiting
Sponsored Clinical Trials
Integrated Clinical and Research
Operation
Center Branding
Questions ?