Physical Exercise and Mild Cognitive Impairment: A Population-Based Study

SETTING AND STUDY DESIGN

We conducted a population-based case-control study comparing subjects with MCI with cognitively normal subjects. This study was derived from the Mayo Clinic Study of Aging, which was described in detail elsewhere.²¹ Briefly, it is a population-based study designed to estimate the prevalence and incidence of MCI in Olmsted County, Minnesota. Elderly individuals were recruited using stratified random sampling from the target population of nearly 10 000 elderly individuals living in Olmsted County on October 1, 2004. The sampling involved equal allocation of men and women in 2 age strata, 70 to 79 years old and 80 to 89 years old. During the first follow-up performed from 2006 through 2008, subjects were asked to complete a self-reported questionnaire on physical exercise; therefore, the sample of this study was restricted to the 1324 non-demented study participants who completed the questionnaire.

DEFINITION OF CASES AND CONTROLS

Each participant in the Mayo Clinic Study of Aging underwent a baseline face-to-face evaluation including 3 components: (1) a neurological evaluation by a physician; (2) a risk factor assessment by a nurse or study coordinator; and (3) neuropsychological testing which was interpreted by a neuropsychologist. The interview by the nurse or study coordinator included administration of the Clinical Dementia Rating Scale (CDR)²² to the participant and to an informant. The neurological evaluation was performed by a physician and included administration of the Short Test of Mental Status (STMS),²³ medical history review, and a complete neurological examination.

Neuropsychological testing was performed using 9 cognitive tests to assess 4 cognitive domains: (1) Memory (Logical Memory-II [delayed recall] and Visual Reproduction-II [delayed recall] from Wechsler Memory Scale-Revised, and delayed recall from the Auditory Verbal Learning Test);^24–27 (2) Executive Function (Trail Making Test B,²⁸ and Digit Symbol Substitution from Wechsler Adult Intelligent Scale-Revised); (3) Language (Boston Naming Test,²⁹ and category fluency);³⁰ and (4) Visuospatial Skills (Picture Completion and Block Design from WAIS-R). We transformed the raw scores on each test into age-adjusted scores using Mayo’s Older American Normative Studies (MOANS) normative data. These adjusted scores were also scaled to have a mean of 10 and a standard deviation of 3.^24–27

Domain scores were obtained for every subject by summing the age-adjusted scores within each domain. Because different numbers of tests were used to compute domain scores (ie, 2 tests for the executive function, language, and visuospatial domains vs 3 for memory), the domain scores were also scaled to allow comparisons across domains. In summary, the performance of a person in a particular domain was measured by comparing the person’s domain score with the score in normals, available from previous normative work in this same population.^{24–27,31,32} However, the final decision about impairment in any cognitive domain was made by consensus agreement between the examining physician, nurse, and neuropsychologist taking into account years of education, prior occupation, and other information.²¹

We considered as cases all the participants who met the revised Mayo Clinic criteria for MCI: (1) cognitive concern expressed by a physician, informant, participant, or nurse; (2) cognitive impairment in 1 or more domains (executive function, memory, language, or visuospatial); (3) normal functional activities; and (4) not demented.^4,5 Subjects with MCI could have a Clinical Dementia Rating Scale score of 0 or 0.5; however, the final diagnosis of MCI was not based exclusively on the clinical dementia rating, but rather on all available data. We considered as controls all the participants who were cognitively normal according to published normative data developed on this community.^24–27

MEASUREMENT OF PHYSICAL EXERCISE

We studied frequency and intensity of physical exercise using a self-reported questionnaire with ordinal responses. We used questions from 2 previously validated instruments, the 1985 Health Interview Survey,³³ and the Minnesota Heart Survey intensity codes.³⁴ The participants were asked directly to provide information about physical exercise carried out within 1 year of the date of cognitive assessment (late life physical exercise), and carried out at ages 50–65 years (midlife physical exercise). The questionnaire inquired about light, moderate, and vigorous exercise.

Light physical exercise was defined as bowling, leisurely walking, stretching, slow dancing, and golfing with a golf cart. Moderate physical exercise was defined as brisk walking, hiking, aerobics, strength training, golfing without a golf cart, swimming, tennis doubles, moderate use of exercise machines (eg, exercise bike), yoga, martial arts, and weight lifting. Vigorous physical exercise was defined as jogging, backpacking, bicycling uphill, tennis singles, racquetball, intense/extended use of exercise machines, and skiing. For each category of intensity, further inquiry was made as to the frequency of exercise (times per month or per week).

MEASUREMENT OF COVARIATES

We considered as covariates age, sex, years of education, medical comorbidity, and depression. We measured medical comorbidity using the weighted Charlson index, which takes into account both number and severity of diseases (range, 0 to 33).³⁵ We measured depression using the Beck Depression Inventory (BDI–II).³⁶

STATISTICAL ANALYSIS

We conducted a set of primary analyses considering only intensity of physical exercise to test whether any frequency of exercise was associated with MCI. The “once a month or less” category served as the reference. Prompted by the results of the primary analyses, we also conducted a set of secondary analyses considering both intensity and frequency. The strength of the association between physical exercise and MCI was measured using ORs and corresponding 95% confidence intervals (95% CI) after adjusting for age (continuous variable), sex, years of education (continuous variable), medical comorbidity (weighted Charlson index as a continuous variable), and depression (BDI-II score <13 vs ≥13).

Analyses were conducted separately for physical exercise carried out at ages 50–65 years, and for physical exercise carried out within 1 year of the date of cognitive assessment. We considered 3 levels of intensity of exercise (light, moderate, and vigorous) and 6 levels of frequency of exercise (once a month or less, 2 to 3 times per month, 1 to 2 times per week, 3 to 4 times per week, 5 to 6 times per week, and daily exercise). Since the 3 categories of intensity of exercise were not mutually exclusive, it was not possible to collapse these categories.

We also conducted a set of sensitivity analyses using a composite score obtained by assigning a numeric score to frequency of physical exercise and adding the scores across the light, moderate, and vigorous strata (equal weighting to all strata). The scores were 0 for once a month or less, 0.5 for 2 to 3 times per month, 1.5 for 1 to 2 times per week, 3.5 for 3 to 4 times per week, 5.5 for 5 to 6 times per week, and 7 for daily. The total composite score ranged between 0 and 21. We consider these analyses as secondary (sensitivity analyses) because the results varied noticeably depending on the assumptions made in computing the scores (weights assigned to different responses).

Statistical testing was done at the conventional 2-tailed alpha level of 0.05. All analyses were performed by using SAS®, version 8 (SAS Institute, Cary, NC).

CHARACTERISTICS OF STUDY SUBJECTS

Table 1 summarizes the demographic characteristics of the 198 subjects with MCI and the 1126 subjects with normal cognition. Among the cognitively normal subjects, there were an equal number of men and women, whereas among the MCI group there were more men. The median age was 83 years (interquartile range, 78 to 86 years) for the MCI group and 80 years (interquartile range, 76 to 84 years) for the cognitively normal group.

RELIABILITY OF THE PHYSICAL EXERCISE QUESTIONNAIRE

We assessed the reliability of the physical exercise questionnaire in 2 ways. First, we studied its internal consistency using Cronbach’s alpha and observed a value of 0.71 (in the moderate to good range). Second, in a sub-sample of 87 subjects who completed the questionnaire at 2 successive visits, we computed a test-retest Spearman’s correlation coefficient. The correlation in the overall group was 0.47 for light exercise, 0.50 for moderate exercise, and 0.33 for vigorous exercise. Interestingly, the test-retest correlations were similar in the 73 cognitively normal subjects and in the 14 subjects affected by MCI (out of the 87 subjects with 2 interviews; data not shown).

PRIMARY ANALYSES STRATIFIED BY INTENSITY OF EXERCISE

Table 2 shows results of primary analyses dichotomizing physical exercise into any frequency of exercise vs none. Light intensity exercise had an OR of 0.90 (95% CI, 0.55–1.47; P=.68) for midlife and 0.69 (95% CI, 0.47–1.00; P=.048) for late life. Moderate intensity exercise had an OR of 0.61 (95% CI, 0.43–0.88; P=.008) for midlife and 0.68 (95% CI, 0.49–0.93; P=.02) for late life. The findings were consistent for men and women (Table 2, footnotes b and c). Vigorous exercise had an OR of 0.82 (95% CI, 0.59–1.15; P=.25) for midlife and 1.14 (95% CI, 0.72–1.81; P=.58) for late life. As expected, relatively fewer people reported vigorous exercise in late life; therefore, the non-significant associations for this analysis may be caused in part by lack of statistical power. Results using a composite score of physical exercise were comparable (Table 2, footnote a).

SECONDARY ANALYSES CONSIDERING BOTH INTENSITY AND FREQUENCY OF EXERCISE

Table 3 shows our case-control analyses considering both intensity and frequency for physical exercise carried out in midlife (aged 50–65 years). The point estimates for nearly all frequencies of both light-intensity and vigorous-intensity exercise were between 0 and 1, suggesting a potential “protective” effect. However, none of these associations were statistically significant. On the other hand, several frequencies of moderate-intensity exercise were significantly associated with MCI. Table 4 shows our case-control analyses considering both intensity and frequency for physical exercise carried out in late life (within 1 year of the date of cognitive assessment). There was no significant association between physical exercise and MCI in any of the analyses except 1.