The Association Between Midlife Cardiorespiratory Fitness Levels and Later-Life Dementia

1. The Association Between Midlife Cardiorespiratory Fitness Levels and Later-Life Dementia April 9th, 2013 Journal Club University of Southern California José L González, MD

2. Introduction

3. Why this study? • Prevalence • 1/8 Americans > 65yoa • $200b/yr • Why this study? • Prevention of cognitive disability • Lifestyle modification = most cost-effective • Current evidence insufficient • No public health recommendation

4. Previous Studies • Increased fitness protects against • All-cause mortality • Stroke • Diabetes • HTN • Other studies linked to dementia • Only associated dancing • Only vascular dementia • Only Alzheimers

5. Previous Studies • Intermediate outcomes • Brain atrophy – med. Temporal lobe vol. • MMSE • NIH consensus statement “physical activity may prevent dementia” • Self-reported physical activity • Canadian study of health and aging • 5-yr f/u, n= 4615

6. Study Objectives • Assess association between objectively measured fitness and all-cause dementiaw/ long-duration of follow-up. • Hypothesized: pts w/ greater midlife fitness = lower risk for dementia later in life • Independent of antecedent cerebrovascular disease

7. Methods

8. Methods • Study Design: Prospective, observational cohort study • Cooper Longitudinal Study • Non-profit, independent research organization • Assessing lifestyle behavior on health outcomes • Observational database of 28,968 community-dwelling participants • Dallas, TX

9. Participants • Generally healthy self-referred/employee referred for preventative health (midlife) exam. • Midlife exam: • H&P (HTN, DM, smoker, level of education) • Physical Exam • Fasting labs (blood glucose, lipids) • Anthropomorphic measurements (Ht, Wt, BMI) • ETT between 1971 - 2001 • Cooper database: n = 28,968 and matched w/ indivdiuals w/ Medicare claims = 25,995

10. Participants • w/ the following exclusions @ time of midlife exam: • MI or stroke • Chronic illness leading to disability • On renal dialysis • >65yoa • Prior dx of dementia before 1999 • Final cohort, N = 19,458

11. Measurement of Cardiorespiratory Fitness • Fitness level = Max time on treadmill  METs • Adjusted for age and sex, classified into quintiles • 1 = lowest level • 5= highest level • No categorization or definition of fitness

12. Outcome Variables • Diagnosis from Chronic Condition Data Warehouse • Data from Medicare beneficiaries for research purposes • Used to identify chronic diseases • Primary Outcome of Interest: diagnosis of all-cause dementia defined by claim filed from • SNF, home health, hospital outpatient or inpatient, physician or supplier claim • 24 different ICD-9 codes for types of dementia: • Alzheimers • Senile • Pre-senile • Vascular

13. Statistical Analysis

14. Statistical Analysis • Hazard Ratios = (chance of an event occuring)tx group (chance of an event occuring)control group • Resolution depicted on Kaplan-Meir curve • Proportion of each group where end-point has not been reached • End-point = dx of dementia • Cox-proportional hazards model: estimate of tx effect on survival after adjustment for other explanatory variables

15. Cox-Proportional Hazards Model • disease-free survival vs 5-level categorical covariate corresponding to age and sex-adjusted quintiles of fitness • Adjusted for demographic and study variables • Sex, exam age, exam year • Adjusted for clinical variables • HTN, fasting glucose level, current tobacco use, BMI, total cholesterol, SBP, DM) • Repeated analysis w/ midlife fitness as a continuous variable (METs) rather than by category (quintile)

16. Results

17. Results • Mean follow-up from CCLS data = 24 years • Mean 7.2 years on Medicare data • 1659 cases of all-cause dementia • Prevalence of dementia increased w/ age

18. Table 1 • Incidence of different variables amongst the 5 quintiles • Raw numbers sorted by clinical variables (HTN, DM, smoker, level of education, FLP, glucose level) • Sorted by quintiles (1 lowest, 5 highest) • Decreased incidence of all variables in higher quintiles • Except etoh intake and education

19. Figure 1 • Higher fitness levels = lower risk for incident dementia • Similar findings when fitness was modeled on a continuous scale (i.e. by METs) • Figure 1: Kaplan-Meier curve • y-axis: probability of dementia-free survival (%) • x-axis: Age

21. Table 2 • Derived hazard ratio for each quintile, reference = 1 • Lowest HR in quintile 5 • Statistical significance reached in quintile 3 (CI and P-value) • Adjusted for sex, age and listed RFs • Statistical significance reached in quintile 3 • Adjusted for individual RFs • Only HTN was statistically significant

22. Results • Association similar among pts w/ & w/o hx of previous stroke • HR w/o stroke 0.74 [CI 0.61-0.90] • HR w/ stroke 0.74 [CI 0.53-1.04]

23. Discussion

24. Discussion • Generally healthy community-dwelling pts + association between • Midlife fitness levels (as measured by ETT) • Independent of other RFs • Association present w/ and w/o stroke suggesting a non-vascular MOA • No statistical significance between dementia and education • Homogenous group (see table 1)

25. Discussion: MOA • Previous studies confirm: ↑fitness = ↓risk DM, HTN • Established RFs for dementia • Previous studies • Brain atrophy • ↑ # small caliber vessels, ↓ tortuosity = ? ↑ blood flow • ↓ prod. Neurotoxins • Enhanced neuroplasticity w/ exercise

26. Strengths & Weaknesses • Strengths • Large cohort study size • Long duration of f/u • Weaknesses • Not randomized: unmeasured cofounder, such as lifestyle factors could lead to ↑ exercise & ↓ dementia • Based on Medicare claims data • 85% sens, 89% spec

27. Limitations • Homogenous population (Medicare, non-Hispanic, mid to upper-mid class) • Initial exclusion criteria limits applicability • Can’t give specific recommendations about activity level due to breakdown into quintiles • Future studies should focus on dose-specific relationship to give recs

28. Sources: • Defina LF, Willis BL, Radford NB, Gao, A, Leonard, D, Haskell, WL et al. The Association Between Midlife Cardiorespiratory Fitness Levels and Later Life Dementia: A Cohort Study. Ann Intern Med. 2013;158:162-168