1. Welcome Alzheimer’s Disease Research Update: What’s New in 2014 Please take this opportunity to complete the Pre-Test located on the pink form in your folders NYU Alzheimer’s Disease Center Silberstein Alzheimer’s Institute Center for Cognitive Neurology

2. Body Fat and Muscle: Relationship to Cognitive and Physical Decline James E. Galvin, MD, MPH NYU Alzheimer’s Disease Center Supported by grants from the National Institute on Aging, Morris and Alma Schapiro Fund and Michael J Fox Foundation

3. Acknowledgements Galvin Lab – Magdalena Tolea, PhD – Chaim Tarshish, PhD – Arline Faustin, MD – Stephanie Chrisphonte, MD – Yael Zweig, MSN, ANP, GNP – Licet Valois, LMSW, MPS – Crystal Quinn, LMSW – Katty Saravia, CCMA New York University – Stella Karantzoulis, PhD – Victoria Raveis, PhD – Marie Boltz, PhD – Ab Brody, PhD – Els Fieremans, PhD – Tim Shepard, MD, PhD – Jean Bear-Lehman, PhD Washington University – John Morris, MD – Linda Larson-Prior, PhD University of Kansas – David Johnson, PhD

4. Definitions Physical Function Physical Functionality: physical ability to independently carry out activities of daily living Frailty: geriatric syndrome with high risk of declines in health and function – 5 dimensions: weight loss, exhaustion, weakness, slowness, and low activity Muscle weakness: inability to exert force with one's skeletal muscles Sarcopenia: degenerative loss of muscle mass, quality, and strength Functional dependence: disability in one or more of seven basic activities of daily living (toileting, eating, dressing, etc.) Cognitive Function Healthy brain aging: little to no loss of memory or thinking abilities but tend to do things slower Mild Cognitive Impairment: transitional stage between healthy brain aging and dementia Dementia: progressive decline in memory and thinking that interferes with everyday function Alzheimer’s disease: most common cause of dementia

5. What is the evidence? Data support a relationship between physical function and cognition function – Difficult to determine the causal relationship – What comes first? Cognitive evaluation may be difficult for many primary care physicians, who will be the first contact for many patients but physical assessments are already part of what they do If physical impairment can be detected before noticeable cognitive impairment, performance-based assessments may help identify people at-risk for dementia

6. Cognitive Physical Impairment Rajan KB et al., JGMS 67:1419-1426, 2012 low high low high Earlier Onset Faster Progression

7. Mild Physical Impairment Predicts Future AD Controlled for age, ApoE Wilkins CH, et al JAGS 2013 HR: 1.06; 95% CI:1.01-1.12

8. Multicultural Community Dementia Screening Supported by grant from the National Institute on Aging Community-based assessment of older adults (target goal 500) Demographics, financial resources, preferences Cognitive-Behavioral Screening (memory, mood) Medical Screening (blood pressure, diabetes, lung disease, obesity) Physical assessment (balance, frailty, strength) Anthropometric measurements Social work follow-up Subset have Gold Standard testing and biomarkers collected MRI scans PET scans EEG Blood Spinal fluid Rich dataset with over 500,000 individual data points

9. Body Composition Bone Water Lean Muscle Fat BodyVisceral

10. Measurement Tools Body Composition - Impedance Dynamometer – Grip Strength Tape Measure – Girth

11. Mini-PPT Changes in the Mini PPT scores correlate with disability, loss of independence, the risk of falls, and mortality. Cutoff scores of less than 12 imply impaired physical functioning Sensitivity: 86% Specificity: 90% Assessment takes ~7 minutes Range of Scores >12 Unimpaired 8-11Mild 5-7Moderate 0-4Severe

12. MoCA – 30 point, 10 minute cognitive screen to detect MCI and AD 1 Memory, constructions, attention, executive function, language and orientation 1 Score less than 26 suggests impairment 2 – Utility in an office setting established 1,3 – Also sensitive to PD- related dementia 2 – Sensitivity ~90%, Specificity ~87% 1 – http://www.mocatest.org 1. Nasreddine ZS et al, J Am Geriatr Soc. 2005;53:695-699. 2. Zadikoff et al, Mov Disord. 2008;23:297-299. 3. Smith et al, Can J Psych. 2007;52:329-332.

13. AD8 All participants Mean AD8 score (+ SD) CDRNInformantPatient 01490.64 (1.19)1.01 (1.52) 0.51023.49 (2.32)2.80 (2.19) 1506.64 (1.74)2.40 (2.51) 2236.22 (2.66)3.00 (2.66) Only CDR 0 and 0.5 participants Cohen’s d1.660.98 ICC.583 (95% CI:.47-68),p<.001 Detect change in individuals compared to previous level of function – No need for baseline assessment – Patients serve as their own control – Little bias by education, race, gender Brief (< 2 min), Yes/No format – 2 or more “Yes” answers highly correlated with presence of dementia AUC: 0.917 (95% CI: 0.88-0.95) Sensitivity: 92% Positive PV: 93%

14. Biophysiological Markers of Health in a Multicultural Community VariableWhiteBlackHispanicP Health Co-morbid conditions, #6.2 (3.2)6.0 (3.4)5.0 (2.5)0.058 Mean Blood Pressure117.5 (18.8)117.5 (15.5)114.7 (14.4)0.530 Resting Heart Rate71.3 (15.1)71.3 (13.9)71.4 (9.8)0.893 Lung Volume (FEV1), L3.3 (1.4)2.3 (0.9)2.5 (0.8)<0.001 HbA1c5.7 (0.7)6.4 (1.3)6.1 (0.7)0.146 Strength Mini-PPT12.3 (2.6)9.6 (3.7)11.8 (2.4)0.004 Grip strength58.6 (24.0)46.6 (16.5)46.2 (19.6)0.003 Body Composition Body Mass Index (BMI)27.0 (4.5)30.0 (6.8)28.2 (5.0)0.035 Bone Mass, lb8.1 (13.9)5.0 (0.9)4.8 (0.9)<0.001 Body Water, %49.6 (5.7)43.5 (6.8)45.5 (5.9)<0.001 Muscle Mass, lb113.4 (27.0)95.9 (17.6)90.6 (17.8)<0.001 Body Fat, %31.2 (8.2)39.5 (9.5)36.1 (7.9)0.004 Visceral Fat, lb12.3 (4.4)12.8 (3.1)13.8 (12.8)0.307 Abdominal Girth, cm124.8 (15.8)98.7 (14.1)97.7 (13.6)<0.001 Hip Girth, cm108.2 (9.3)112.7 (12.7)106.5 (10.1)<0.001 Basal Metabolic Rate, kcal1.6 (0.4)1.4 (0.2)1.3 (0.2)<0.001 Galvin and Tolea In preparation 2014

15. Distribution Across Community Sample % Body Fat Visceral Fat

16. Distribution Across Community Sample % Body Water Lean Muscle Mass

17. Is Sarcopenia a Risk Factor? Categories – No Sarcopenia: absence of both low muscle mass and grip strength – Pre-sarcopenia: presence of low muscle mass only – Sarcopenia: both low muscle mass and grip strength Cognitive impairment and physical impairment NoneEitherBothP Age62.9 (±9.7)66.5 (±10.3)74.3 (±7.6)<0.001 Education, yrs.14.8 (±3.2)14.2 (±3.9)10.8 (±4.7)<0.001 Female, %62.755.981.80.005 White race, %60.339.025.90.006 BMI27.6 (±6.2)27.8 (±5.3)29.2 (±5.3)0.278 Muscle mass106.4 (±24.7)105.8 (±22.9)91.6 (±22.1)<0.001 Grip strength64.3 (±26.7)58.7 (±24.9)42.3 (±13.6)<0.001 Walking speed13.6 (±2.2)14.8 (±3.9)20.1 (±4.2)<0.001 MoCA27.8 (±1.3)21.9 (±4.9)19.4 (±4.2)<0.001 AD81.1 (±1.8)1.8 (±1.9)2.0 (±1.8)0.012

18. Sarcopenia and Impairment Tolea and Galvin, In Preparation 2014 Odd Ratio of having both cognitive impairment and physical impairment UnadjustedAdjusted 1Adjusted 2 Controls1.0 Pre-sarcopenia0.94 (0.43-2.09)1.29 (0.47-3.55)1.89 (0.63-5.71) Sarcopenia5.92 (2.51-13.96)4.21 (1.41-12.51)3.40 (1.07-11.46) p<0.001

19. Staging Physical Impairment as Risk for Cognitive Impairment Relationship between cognitive and physical functionality is well established at later stages of disability, however it is less clear whether association extends to the earliest stages of impairment Measurements included: – upper extremity (UE) muscle strength (mean grip strength) – lower extremity (LE) function (Mini Physical Performance Test), – Cognition (Montreal Cognitive Assessment) Participants were categorized: – no physical impairment – UE functional impairment – LE functional impairment – both UE and LE impairment

20. Stage of Function and Cognition * * No impairment UE impairment LE extremity impairment UE and LE impairment P value Age62.0 (±10.9)66.5 (±8.7)69.5 (±7.9)75.1 (±8.2)7<0.001 Education14.8 (±3.0)13.8 (±4.6)13.9 (±3.2)11.2 (±5.0)<0.001 Race, % 0.015 White, non-Hispanic52.840.920.029.0 Black, non-Hispanic19.415.250.021.0 Hispanic27.843.930.050.0 BMI27.9 (±5.7)27.5 (5.6)29.6 (±5.6)28.7 (±5.4)0.546 Visceral fat, %12.7 (±4.5)10.6 (±3.7)14.6 (±3.7)12.1 (±3.3)0.002 Muscle mass121.7 (±21.0)91.9 (±15.5)115.3 (±24.5)88.4 (±17.6)<0.001

21. Relationship of BMI to Function Mini-PPT r=.14 MoCA r=.02

22. Differences: Visceral and Body Fat Visceral Fat Body Fat Worse Cognitive Performance Worse Physical Performance MoCA r=.03 Mini-PPT r=.36 Mini-PPT r=.13 MoCA r=.19

23. Abdomen/Hip Ratio as Proxy Marker Worse Outcomes Mini-PPT r=.07 MoCA r=.23

24. Falls Risk Cognitive vs. Physical Status Cognitive StatusImpairedNormalP value Physical StatusNormalImpairedNormalImpaired Age, y64.4 (9.3)74.5 (8.9)62.4 (9.3)72.6 (7.2)<0.001 Education, y13.89 (4.4)11.9 (5.2)15.5 (3.3)15.5 (3.4)<0.001 Female, %44.871.952.977.80.003 White, %66.169.671.159.30.425 Latino, %46.647.321.214.8<0.001 Co-morbidities4.3 (2.5)6.5 (3.0)5.4 (2.8)6.7 (3.1)<0.001 Body Mass Index27.5 (5.4)28.6 (5.6)27.3 (5.6)28.5 (5.1)0.543 Body Fat30.2 (9.5)36.6 (8.2)29.8 (9.7)36.6 (9.0)<0.001 Visceral Fat12.1 (4.4)12.9 (4.1)10.8 (4.1)12.3 (2.7)0.026 Bone mass5.8 (1.2)5.0 (1.1)5.8 (1.43)5.3 (1.2)0.001 Muscle mass111.6 (23.5)96.0 (20.6)111.0 (24.4)100.7 (23.3)0.001 Grip strength63.9 (25.2)43.4 (15.6)66.2 (25.2)52.8 (36.9)<0.001 Falls, events (%)9 (15.5)27 (51.9)21 (25.0)11 (40.7)<0.001

25. Initial Pass of Falls Risk Factor Demographic Variables – Increasing age, female, living alone, self-reported memory problems, self-reported mood problems Clinical/Anthropometric Variables – Body water, fat, visceral fat, bone density, muscle mass, pulse pressure Cognitive Variables – List learning, visuoconstructive, trailmaking Performance Variables – Grip strength, timed walk, flexion, progressive Romberg

26. Summary Relationship between cognitive and physical function is complex and bidirectional – Physical impairments are strong risk factors for future cognitive impairment – Once present, cognitive decline is stronger driver for further physical decline Loss of muscle mass and strength (sarcopenia) may be one of the earliest detectable warning signs of impending cognitive decline – 3 to 6-fold increased risk – Strength testing (via dynamometer) is easy to do – Grip strength earlier and stronger predictor than just testing mobility The association between cognitive and physical functionality follows a pattern from no impairment to loss of UE muscle strength to LE functional impairment – May explain up to 27% of variability in performance on cognitive tests Falls are a significant consequence of both cognitive and physical decline – 1 st fall increases risk of 2 nd fall and may further drive cognitive and physical decline – Our initial work developed a profile of individuals at risk for falls

27. Summary Poorly controlled medical conditions greatly increase the risk of AD – May be multiple pathways to get to Alzheimer’s disease – May also be multiple pathways to prevent or treat Interventions designed to prevent sarcopenia, increase lean muscle mass and improve strength may help reduce the burden of cognitive and physical impairments in community-dwelling older adults Efforts to prevent cognitive decline and development of dementia may be more successful when directed to at at-risk individuals based on their physical functional profile Detection of and interventions addressing physical impairments may offer novel approaches to reducing cognitive decline and falls Prevention measures - Stay mentally alert, physically fit and eat a heart-healthy diet AD is a disease of a lifetime; many ways to build a better brain as we age

28. New York University Resources Pearl I. Barlow Center for Memory Evaluation and Treatment – Specialty Faculty Practice – Multidisciplinary Approach – 212-263-3210 – www.nyulmc.org/barlow Alzheimer Disease Center – Longitudinal Research Project – 212-263-8088 – www.adc.med.nyu.edu Clinical Trials Center – Study New and Exciting Treatments for Dementia – 212-263-5708