April 9th, 2013 Journal Club

University of Southern California José L González, MD

Prevalenceo 1/8 Americans > 65yoa o $200b/yr

Why this study?o Prevention of cognitive disabilityo Lifestyle modification = most cost-effectiveo Current evidence insufficiento No public health recommendation

Increased fitness protects againsto All-cause mortalityo Strokeo Diabeteso HTN

Other studies linked to dementiao Only associated dancingo Only vascular dementiao Only Alzheimers

Intermediate outcomeso 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 agingo 5-yr f/u, n= 4615

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 lifeo Independent of antecedent cerebrovascular disease

Study Design: Prospective, observational cohort study

Cooper Longitudinal Studyo Non-profit, independent research organizationo Assessing lifestyle behavior on health outcomes

o Observational database of 28,968 community-dwelling participants

o Dallas, TX

Generally healthy self-referred/employee referred for preventative health (midlife) exam.

Midlife exam:o H&P (HTN, DM, smoker, level of education)o Physical Examo 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

w/ the following exclusions @ time of midlife exam:o MI or strokeo Chronic illness leading to disabilityo On renal dialysiso >65yoao Prior dx of dementia before 1999

Final cohort, N = 19,458

Fitness level = Max time on treadmill METs Adjusted for age and sex, classified into quintiles

o 1 = lowest levelo 5= highest level

No categorization or definition of fitness

Diagnosis from Chronic Condition Data Warehouseo Data from Medicare beneficiaries for research purposeso Used to identify chronic diseases

Primary Outcome of Interest: diagnosis of all-cause dementia defined by claim filed fromo 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

Hazard Ratios = (chance of an event occuring)tx group (chance of an event occuring)control group

Resolution depicted on Kaplan-Meir curveoProportion of each group where end-point has not been reachedoEnd-point = dx of dementia

Cox-proportional hazards model: estimate of tx effect on survival after adjustment for other explanatory variables

disease-free survival vs 5-level categorical covariate corresponding to age and sex-adjusted quintiles of fitness

Adjusted for demographic and study variableso Sex, exam age, exam year

Adjusted for clinical variableso 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)

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) 70 75 80 85

Dementia Prevalence

0.8% 2.9% 8.3% 14.8%

Incidence of different variables amongst the 5 quintileso 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

Quintile

1 2 3 4 5 All

METs 8.1 9.4 10.4 11.3 13.3 10.6

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 curveo y-axis: probability of dementia-free survival (%)o x-axis: Age

Derived hazard ratio for each quintile, reference = 1o Lowest HR in quintile 5o Statistical significance reached in quintile 3 (CI and P-

value)

Adjusted for sex, age and listed RFso Statistical significance reached in quintile 3

Adjusted for individual RFso Only HTN was statistically significant

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]

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 educationo Homogenous group (see table 1)

Previous studies confirm: ↑fitness = ↓risk DM, HTNo Established RFs for dementia

Previous studieso Brain atrophyo ↑ # small caliber vessels, ↓ tortuosity = ? ↑ blood flowo ↓ prod. Neurotoxinso Enhanced neuroplasticity w/ exercise

Strengthso Large cohort study sizeo Long duration of f/u

Weaknesseso Not randomized: unmeasured cofounder, such as

lifestyle factors could lead to ↑ exercise & ↓ dementiao Based on Medicare claims data

• 85% sens, 89% spec

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

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