ging

1. The Center For C ognitive A ging M & emory Clinical Translational Research Program External Advisory Board Meeting June 19,2013

2. Mission: To conduct cutting-edge interdisciplinary clinical neuroscience and translational research, on age-associated cognitive, 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 cognitive decline and memory loss.

3. 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?

4. 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…..

5. 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?

6. 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?

7. 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….

8. 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.

9. 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.

10. 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

11. Relationship to UF Institutes Dr. R. Cohen Dr. M. Pahor Dr. T. Ashizawa Dr. D. Nelson

13. 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.

14. 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.

15. 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.

16. Fellows and Students • Eric Porges, PhD (Univ. of Chicago) Post-doctoral fellow • Talia Seider, BSc (Univ. of Calif.) Graduate Student • Six doctoral dissertations

17. Where do we go from here?”Answering the need for studies of healthy cognitive aging

18. Initiatives: • Neurocognitive Task Development • Biomarker Development • Neuroimaging • Electrophysiological • Proteomic • Genomic • Translational Research • Clinical Trials • Assemble supporting Cores • Assemble Affiliate Faculty • Equip new Building

19. 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

20. 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

21. 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)

22. Laboratory Biomarker Initiatives • Proteomics and metabolomics • (e.g., cytokines) • Genomics • genetic • epigenetic

23. Laboratory Biomarker Plan • Blood sample collection on CAM-CTRP participants • CSF collection in a limited sample • Other tissues? • CTSI Bio specimen repository

24. 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

26. 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

27. Cognitive Training • VITAL- Bowers/Marsiske • Vigorous Mind- Cohen • Neurofeedback- Sitaram

28. CAM-CTRP Core Protocol • Neurocognitive measures • Neuroimaging and physiological • Laboratory biomarkers (blood, tissue, CSF) • Genomic sequencing (Leonid Moroz) • CTSI Bio Specimen Repository

29. “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.

30. SPECIFIC OBJECTIVES: Year 2 • 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 • 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

31. 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

33. IOA- CAM INTERFACE Clinic Research Cohort Development Study Recruiting Sponsored Clinical Trials Integrated Clinical and Research Operation Center Branding

34. Questions ?