1.  April 9 th, 2013 Journal Club University of Southern California José L González, MD

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

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

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

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

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

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

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

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

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

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

15.  disease-free survival vs 5-level categorical covariate corresponding to age and sex-adjusted quintiles of fitness  Adjusted for demographic and study variables o Sex, exam age, exam year  Adjusted for clinical variables o 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)

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17.  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 Age (years)70758085 Dementia Prevalence0.8%2.9%8.3%14.8%

18.  Incidence of different variables amongst the 5 quintiles o Raw numbers sorted by clinical variables (HTN, DM, smoker, level of education, FLP, glucose level) o Sorted by quintiles (1 lowest, 5 highest) o Decreased incidence of all variables in higher quintiles Except etoh intake and education Quintile12345All METs8.19.410.411.313.310.6

19.  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 o y-axis: probability of dementia-free survival (%) o x-axis: Age

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

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

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

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

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

27.  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.  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