External Advisory Board MeetingJune 19,2013

MISSION:TO CONDUCT CUTTING-EDGE INTERDISCIPLINARY

CLINICAL NEUROSCIENCE AND TRANSLATIONAL

RESEARCH, ON AGE-ASSOCIATED COGNIT IVE,

BEHAVIORAL AND EMOTIONAL FUNCTIONING,

FACTORS THAT CONTRIBUTE TO IMPAIRMENTS AND

FUNCTIONAL DECLINE, AND FUTURE AVENUES FOR

INTERVENTION.

PRIMARY OBJECTIVE:TRANSLATE BASIC SCIENCE DISCOVERIES INTO

CLINICAL APPLICATIONS IN ORDER TO SLOW, AVERT

OR RESTORE AGE-RELATED COGNIT IVE 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

McKnight Brain Research Foundation (MBRF)

Cognitive Aging and Memory-

Clinical Translational

Research Program(CAM-CTRP) Institute

on Aging (IoA)Pepper Center

McKnight Brain Institute

(MBI) Clinical Translational

Science Institute

Relationship to UF Institutes

•

Dr. T. Ashizawa

Dr. D. Nelson

Dr. R. Cohen

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.

• Russell Bauer, Ph.D.

• Jennifer Bizon, Ph.D.

• Dawn Bowers, Ph.D.

• Robert Cook, MD, Ph.D.

• Ming-Zhao Ding, Ph.D.

• Vonetta Dotson, Ph.D.

• Natalie Ebner, Ph.D.

• Adam Falchook, M.D.

• Tom Foster, Ph.D.

• Kenneth Heilman, M.D.

• Christina McCrae Ph.D.

• Steven Nadeau, M.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

• Testosterone

• Resveratrol

• Oxytocin

• Neuroprotective Agents

• Cognitive Enhancers

• Vascular Function Enhancers

• Performance Enhancers

• Behavioral – Lifestyle• The Active Brain

• CHORES-XL

• Bariatric Surgery Study

• LIFE

• LIFE-ES

• LIFE-ARISE

• 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

• Integration with Pepper cores

• Recruit cognitive aging cohort: LIFE-ancillary study

• Support current IOA studies

• Initiate multimodal neuroimaging initiative

• Initiate pilot study program

• Implement junior scholars

program• Facilitate proteomic and genomic

initiatives• Continue integration with ARML • MBI Inter-Institute Initiative• Continue current R01-P01

supported research• 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

Cohort Development

Study Recruiting

Clinic Research

Sponsored Clinical Trials

Integrated Clinical and Research Operation

Center Branding

Questions ?