WelcomeAlzheimer’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 CenterSilberstein Alzheimer’s InstituteCenter for Cognitive Neurology

Body Fat and Muscle: Relationship to Cognitive and Physical Decline

James E. Galvin, MD, MPHNYU Alzheimer’s Disease Center

Supported by grants from the National Institute on Aging, Morris and Alma Schapiro Fund and Michael J Fox Foundation

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

DefinitionsPhysical 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

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

Cognitive Physical Impairment

Rajan KB et al., JGMS 67:1419-1426, 2012

low

highlow

high

Earlier Onset Faster Progression

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

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

Body Composition

Bone

Water

Lean Muscle

Fat

Body Visceral

Measurement Tools

Body Composition - ImpedanceDynamometer – Grip Strength

Tape Measure – Girth

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• 8-11 Mild • 5-7 Moderate• 0-4 Severe

MoCA– 30 point, 10 minute

cognitive screen to detect MCI and AD1

• Memory, constructions, attention, executive function, language and orientation1

• Score less than 26 suggests impairment2

– Utility in an office setting established1,3

– Also sensitive to PD-related dementia2

– 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.

AD8

All participants Mean AD8 score (+ SD)

CDR N Informant Patient

0 149 0.64 (1.19) 1.01 (1.52)

0.5 102 3.49 (2.32) 2.80 (2.19)

1 50 6.64 (1.74) 2.40 (2.51)

2 23 6.22 (2.66) 3.00 (2.66)

Only CDR 0 and 0.5 participantsCohen’s d 1.66 0.98

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%

Biophysiological Markers of Health in a Multicultural Community

Variable White Black Hispanic PHealthCo-morbid conditions, # 6.2 (3.2) 6.0 (3.4) 5.0 (2.5) 0.058Mean Blood Pressure 117.5 (18.8) 117.5 (15.5) 114.7 (14.4) 0.530Resting Heart Rate 71.3 (15.1) 71.3 (13.9) 71.4 (9.8) 0.893Lung Volume (FEV1), L 3.3 (1.4) 2.3 (0.9) 2.5 (0.8) <0.001HbA1c 5.7 (0.7) 6.4 (1.3) 6.1 (0.7) 0.146StrengthMini-PPT 12.3 (2.6) 9.6 (3.7) 11.8 (2.4) 0.004Grip strength 58.6 (24.0) 46.6 (16.5) 46.2 (19.6) 0.003Body CompositionBody Mass Index (BMI) 27.0 (4.5) 30.0 (6.8) 28.2 (5.0) 0.035Bone Mass, lb 8.1 (13.9) 5.0 (0.9) 4.8 (0.9) <0.001Body Water, % 49.6 (5.7) 43.5 (6.8) 45.5 (5.9) <0.001Muscle Mass, lb 113.4 (27.0) 95.9 (17.6) 90.6 (17.8) <0.001Body Fat, % 31.2 (8.2) 39.5 (9.5) 36.1 (7.9) 0.004Visceral Fat, lb 12.3 (4.4) 12.8 (3.1) 13.8 (12.8) 0.307Abdominal Girth, cm 124.8 (15.8) 98.7 (14.1) 97.7 (13.6) <0.001Hip Girth, cm 108.2 (9.3) 112.7 (12.7) 106.5 (10.1) <0.001Basal Metabolic Rate, kcal 1.6 (0.4) 1.4 (0.2) 1.3 (0.2) <0.001

Galvin and Tolea In preparation 2014

Distribution Across Community Sample

% Body Fat Visceral Fat

Distribution Across Community Sample

% Body Water Lean Muscle Mass

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

None Either Both PAge 62.9 (±9.7) 66.5 (±10.3) 74.3 (±7.6) <0.001Education, yrs. 14.8 (±3.2) 14.2 (±3.9) 10.8 (±4.7) <0.001Female, % 62.7 55.9 81.8 0.005White race, % 60.3 39.0 25.9 0.006BMI 27.6 (±6.2) 27.8 (±5.3) 29.2 (±5.3) 0.278Muscle mass 106.4 (±24.7) 105.8 (±22.9) 91.6 (±22.1) <0.001Grip strength 64.3 (±26.7) 58.7 (±24.9) 42.3 (±13.6) <0.001Walking speed 13.6 (±2.2) 14.8 (±3.9) 20.1 (±4.2) <0.001MoCA 27.8 (±1.3) 21.9 (±4.9) 19.4 (±4.2) <0.001AD8 1.1 (±1.8) 1.8 (±1.9) 2.0 (±1.8) 0.012

Sarcopenia and Impairment

No sarcopenia Pre-sarcopenia Sarcopenia0

10

20

30

40

50

60

70% dual impairment

% single impairment

% no impairment

Tolea and Galvin, In Preparation 2014

Odd Ratio of having both cognitive impairment and physical impairment

Unadjusted Adjusted 1 Adjusted 2Controls 1.0 1.0 1.0Pre-sarcopenia 0.94 (0.43-2.09) 1.29 (0.47-3.55) 1.89 (0.63-5.71)Sarcopenia 5.92 (2.51-13.96) 4.21 (1.41-12.51) 3.40 (1.07-11.46)

p<0.001

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

Stage of Function and Cognition

* *

No impairment UEimpairment

LE extremity impairment

UE and LE impairment

P value

Age 62.0 (±10.9) 66.5 (±8.7) 69.5 (±7.9) 75.1 (±8.2)7 <0.001Education 14.8 (±3.0) 13.8 (±4.6) 13.9 (±3.2) 11.2 (±5.0) <0.001Race, % 0.015 White, non-Hispanic 52.8 40.9 20.0 29.0 Black, non-Hispanic 19.4 15.2 50.0 21.0 Hispanic 27.8 43.9 30.0 50.0 BMI 27.9 (±5.7) 27.5 (5.6) 29.6 (±5.6) 28.7 (±5.4) 0.546Visceral fat, % 12.7 (±4.5) 10.6 (±3.7) 14.6 (±3.7) 12.1 (±3.3) 0.002Muscle mass 121.7 (±21.0) 91.9 (±15.5) 115.3 (±24.5) 88.4 (±17.6) <0.001

Relationship of BMI to Function

Mini-PPT r=.14

MoCA r=.02

Differences: Visceral and Body FatVisceral FatBody Fat

Worse Cognitive PerformanceWorse Physical Performance

MoCA r=.03

Mini-PPT r=.36Mini-PPT r=.13

MoCA r=.19

Abdomen/Hip Ratio as Proxy Marker

Worse OutcomesMini-PPT r=.07

MoCA r=.23

Falls RiskCognitive vs. Physical Status

Cognitive Status Impaired Normal P valuePhysical Status Normal Impaired Normal Impaired

Age, y 64.4 (9.3) 74.5 (8.9) 62.4 (9.3) 72.6 (7.2) <0.001Education, y 13.89 (4.4) 11.9 (5.2) 15.5 (3.3) 15.5 (3.4) <0.001

Female, % 44.8 71.9 52.9 77.8 0.003White, % 66.1 69.6 71.1 59.3 0.425Latino, % 46.6 47.3 21.2 14.8 <0.001

Co-morbidities 4.3 (2.5) 6.5 (3.0) 5.4 (2.8) 6.7 (3.1) <0.001Body Mass Index 27.5 (5.4) 28.6 (5.6) 27.3 (5.6) 28.5 (5.1) 0.543

Body Fat 30.2 (9.5) 36.6 (8.2) 29.8 (9.7) 36.6 (9.0) <0.001Visceral Fat 12.1 (4.4) 12.9 (4.1) 10.8 (4.1) 12.3 (2.7) 0.026Bone mass 5.8 (1.2) 5.0 (1.1) 5.8 (1.43) 5.3 (1.2) 0.001

Muscle mass 111.6 (23.5) 96.0 (20.6) 111.0 (24.4) 100.7 (23.3) 0.001Grip strength 63.9 (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

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

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– 1st fall increases risk of 2nd fall and may further drive cognitive and physical

decline– Our initial work developed a profile of individuals at risk for falls

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

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