CRITICALLY APPRAISED TOPICS

Physical Activity Level and Future Risk of Mild Cognitive Impairment or Dementia A Critically Appraised Topic Gretchen E. Schlosser Covell, MD,* Charlene R. Hoffman-Snyder, DNP, RN,* Kay E. Wellik, MLS, AHIP, FMLA,w Bryan K. Woodruff, MD,* Yonas E. Geda, MD, MSc,*z Richard J. Caselli, MD,* Bart M. Demaerschalk, MD, MSc, FRCP(C),* and Dean M. Wingerchuk, MD, MSc, FRCP(C)*

Background: The relationships between physical activity, cognition, and development of neurodegenerative diseases represent an area of intense research interest. Meta-analyses and prospective cohort studies show that greater levels of physical activity are associated with lower dementia risk. Most studies, however, depend on self-report data that are subject to recall and other biases. Obtaining objective and quantitative physical activity data could strengthen observational study validity. Objective: To examine the association between objectively measured daytime activity and mild cognitive impairment (MCI) or Alzheimer disease (AD). Methods: The objective was addressed through the development of a structured, critically appraised topic. We incorporated a clinical scenario, background information, a structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, clinical epidemiologists, a medical librarian, and behavioral neurology and neuropsychiatry content experts. Results: We selected a prospective, single-center cohort study of 716 cognitively normal elderly participants followed for 3.5 years. Greater levels of physical activity, as measured using wrist actigraphy, were associated with a lower risk of incident MCI or AD (hazard ratio, 0.477; 95% confidence interval, 0.273-0.832). Conclusions: Objective measurement confirms that greater levels of physical activity are associated with decreased risk of a future diagnosis of MCI or AD. Further studies are needed to confirm the temporal association of exercise and future cognitive health and understand the relevant underlying biological mechanisms. Key Words: physical activity, actigraphy, evidence-based medicine, mild cognitive impairment, dementia, prognosis

(The Neurologist 2015;19:89–91)

From the *Department of Neurology; wDepartment of Library Services, Division of Education Administration; and zDepartment of Psychiatry, Mayo Clinic, Scottsdale, AZ and Phoenix, AZ. D.M.W. and B.M.D., Co-Directors of Mayo Clinic Evidence Based Clinical Practice, Research, Informatics, and Training (MERIT) Center at Mayo Clinic Arizona were supported by Clinician Educator grants from the Mayo Clinic College of Medicine. The authors declare no conflict of interest. Reprints: Dean M. Wingerchuk, MD, MSc, FRCP(C), Department of Neurology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259. E-mail: [email protected]. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1074-7931/15/1903-0089 DOI: 10.1097/NRL.0000000000000013

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75-year-old healthy male comes to the clinic for baseline cognitive evaluation. He has a mother, aunt, and younger brother with Alzheimer disease (AD) and is concerned he will also develop dementia. He currently manages all activities of daily living, and is an avid competitive marathon runner. His Kokmen Short Test of Mental Status score and neurological examination are normal. Formal neuropsychological testing confirms intact cognition. Four years later, serial neuropsychological testing is unchanged, showing no evidence for mild cognitive impairment (MCI) or AD. He attributes his favorable course in part to the effects of regular physical activity. Does the available evidence support his belief?

BACKGROUND Dementia prevalence increases with age and affects about 14% of people aged 71 years and above.1–3 AD comprises twothirds of these cases and is therefore the most common subtype of dementia. MCI, especially the amnestic subtype, is a transitional stage between normal cognitive function and dementia.2 People with MCI comprise a high-risk group because 10% to 15% develop dementia annually compared with 1% to 2% per annum in the general population. Thus, MCI may be a critical stage in which to identify protective strategies and modifiable risk factors for dementia prevention.2 Physical activity is associated with cognitive health through its impacts on cardiovascular physiology and mental well-being. In a review of 11 prospective cohort studies, all but one showed that mid-life physical activity was correlated with reduced later risk of dementia, with an estimated relative risk of 0.72 (P < 0.001).1 In 1 prospective study examining the baseline participation in physical and cognitive activities and the outcome of incident amnestic MCI, there was a decreased risk of amnestic MCI in those with higher exertion cognitively as part of their daily activity.1,3 This included computer use, reading books, crafting, and other low-impact hobbies. The mechanisms for protection may include promotion of greater cognitive reserve, modification of neurotrophic factors in the hippocampus, attenuating atherosclerotic disease in cerebral vessels, or other direct physiological changes in the brain.1–3 In most studies, data of physical activity is collected through self-report questionnaires. These can be impacted by recall bias, variability in the ordinal scale in validated instruments, and inconsistent subclassifications based on intensity of exercise. Actigraphy is a noninvasive objective measure of daily rest and activity patterns. Through recording of total movements in a daily period for at least 3 days, actigraphs www.theneurologist.org |

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worn on the wrist can measure total physical activity, regardless of duration or intensity. In the process, objective measurement of movement and rest periods eliminates the potential for recall bias or incomplete data from questionnaires while providing a broad picture of total daily expenditure. We sought a review of the published literature to determine whether objectively measured physical activity has been associated with future risk of neurodegenerative disease.

CLINICAL QUESTION In cognitively normal adults, does physical activity level affect future risk of developing MCI or AD?

SEARCH STRATEGY Ovid MEDLINE was searched from 2000 to Week 2, 2012. Two major sets were created and a filter applied. The first set was created using the exploded MeSH (Medical Subject Heading) terms “Alzheimer’s disease” and “Cognition Disorders” joined by the Boolean “OR” with the text words mild cognitive impairment and cognitive decline. The set yielded 88,915 citations. A second set utilized the exploded MeSH terms “motor activity,” “exercise,” “physical exertion,” “physical fitness,” and “actigraphy” joined by the Boolean operator “OR” with the text words “actigraphy” OR “physical activity” yielding 148,109 citations. The 2 major searches were combined and limited to English and human. The Ovid search filter for prognosis maximizing sensitivity was applied with a final set of 120 citations. The Buchman study was chosen due to its relatively large study size, prospective study design, and use of actigraphy to objectively measure physical activity. The search was updated and interim results reviewed in December 2014.

EVIDENCE, RESULTS, AND CRITICAL APPRAISAL We selected the study by Buchman et al2 as the best evidence addressing our clinical question. The investigators initiated a prospective cohort study in 2005 to investigate the relationship between physical activity data and future emergence of MCI or AD. They studied 716 healthy men and women, aged 74 years and above (mean age 81 y), who were determined to be cognitively normal and collected wrist actigraphy data at study onset. The participants included individuals who were part of the Rush Memory and Aging project that recruited individuals from the community.2 This project recruited community-dwelling elderly persons from retirement homes and other housing units in the Chicago region. The study participants were evaluated with a 19-test cognitive battery for memory assessment, both at the start of the study and at follow-up evaluations.3 These tests assessed 5 cognitive abilities, including perceptual speed, episodic memory, working memory, semantic memory, and visuospatial skills. The z-scores of all 19 tests were then averaged and compared with the baseline mean and SD of the entire cohort.3 Wrist actigraphy data were performed on all participants over an average of 10 days. Exclusion criteria included refusal to wear actigraphy watch, self-report of dementia, and presence of clinical AD or non-AD dementia on formal cognitive assessment. An expanded cognitive assessment was completed an average of 3.5 years later, and subjects were then determined to have normal cognition, MCI, or AD based on these results. Outcomes criteria for MCI and AD were based off definitions from the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association Criteria.2

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During an average of 9.3 days of actigraphy data collection, total daily counts of physical activity were measured with an average of 3.06105 counts/d. A Cox proportional hazards model was used to compare total daily physical activity with risk of developing AD. Over the mean follow-up period of 3.5 years, 9.9% of the cohort developed AD. After adjustment for age, sex, and education level, those in the 90th percentile for physical activity level had a more than 2-fold decreased risk for developing AD than those in the 10th percentile for total daily activity [hazard ratio (HR), 0.477; 95% confidence interval (CI), 0.273-0.832]. The association remained significant even when adjusting for a summary measure of motor function (HR, 0.490; 95% CI, 0.264-0.910). Presence of the apolipoprotein (APO) E4 allele did not affect the association of physical activity with risk of AD (HR, 0.511; 95% CI, 0.287-0.909). Other potential confounding variables such as body mass index, depressive symptoms, vascular risk factors, and disease were also explored and did not affect the total physical activity-AD risk relationship. We appraised the methods used by Buchman and colleagues in terms of sampling technique, inclusion criteria, follow-up, reporting, and interpretation. Advantages of the study include prospective design, recruitment of a large, welldefined study cohort, and collection of activity and sleep data using wrist actigraphy. Referral patterns were well described, including participants in the Rush Memory and Aging project. The sample was representative of men and women of various racial backgrounds and APOE4 genotypes. Variations in age, sex, race, education, depression score, comorbidities, and APOE4 allele status were accounted for with multivariable analysis. In addition, the authors controlled for self-reported activity level, social and cognitive activity, and baseline motor function. Appropriate statistical methods were used and HRs were reported. Methodological limitations to the study included that actigraphy was not assessed until several years into the prospective cohort evaluation. Baseline determination of cognition could have led to the inclusion of some subjects with cognitive impairment. Moreover, follow-up averaged 3.5 years, which may not have been sufficiently long.4,5 With the focus of the study being on physical activity before the transition to cognitive impairment, it is critical that the patient’s activity be captured before the neurodegenerative process is well on its way. Thus, a timeline closer to 10 years could potentially limit the number who are already afflicted with preclinical disease. Activity was inclusive of both light-impact and high-impact exertion, which made it difficult to delineate which forms of activity were most optimal for dementia prevention. Finally, using a common expert panel with formal neuropsychological testing and strict guidelines for normal cognition for each participant could have minimized diagnostic variability, especially at the start of the study to ensure only cognitively normal patients were included.

CLINICAL BOTTOM LINES (1) Greater levels of total daily physical activity, as measured by wrist actigraphy, are associated with lower risk of subsequent development of MCI or AD (overall HR, 0.477; 95% CI, 0.273-0.832 for highest 10% activity group compared with the 10% lowest activity group). (2) Larger and longer duration prospective studies that use objective measures of physical activity are needed to understand the magnitude and mechanisms of this effect on cognitive health.

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DISCUSSION—BEHAVIORAL NEUROLOGY AND NEUROPSYCHIATRY PERSPECTIVES This well-designed prospective study adds to the literature that supports an association between greater levels of physical activity and lower future risk of MCI or AD. It has the advantage of including objective measurements of physical activity using wrist actigraphy; therefore, avoiding subjective participant report and recall bias that reduce the internal validity of prior research. The measurement of physical activity, however, was performed only once, at study onset, with the major presumption that the data accurately represent both prior and future average activity levels. It would also have been of interest to know whether there was an effect of wearing the actigraph on physical activity, as participants may have been inclined to be more active while wearing the device. To evaluate this possibility, it would have been an elegant part of the methods to have the participants wear the device for 1 week to acclimate to its presence, but to actually record data even in this acclimation period, unbeknownst to the participants. A significant limitation of this study, and most others of its type, is that it cannot be known whether the less active people at study entry might already have prodromal AD, which would imply that the relationship they contend may actually be the opposite—prodromal AD may lead to decreased physical activity. The authors attempt to address this with a number of analyses; for example, they excluded those subjects who developed clinical AD in the first 2 years after the actigraphy data were collected. Intuitively this makes sense as these individuals almost certainly had prodromal AD at the time of their baseline actigraphy data. However, that only accounted for the obvious cases, and possibly not for the subtly prodromal AD patients who were still scoring borderline well on the battery of tests. On the basis of what is known about amyloid imaging in dominantly inherited AD, the imaging changes develop at least a decade before cognitive change.5–7 The authors further tried to control for this possible relationship by doing a subgroup analysis in 438 individuals with serial cognitive testing demonstrating a decline before their baseline actigraphy data. Of interest, they did not specify how similar or different this subgroup was to the larger study cohort, and they also did not control for APOE status in this analysis. We know there is a dose effect of the E4 allele with respect to risk of developing AD, and without knowing the number of E4 homozygotes in their sample, this could have potentially skewed their results. Also, if these individuals were “declining” before the baseline actigraphy but were not demented, it was not clear how were they classified. Some individuals that are originally cognitively normal or have MCI and later show decline on serial neuropsychological testing can later improve during subsequent cognitive testing epochs.8,9 Without more detail about the clinical diagnosis of this subgroup and the stability of the observed “decline,” it is difficult to interpret this analysis.

CONCLUSIONS The association of physical activity and memory decline is complex. Although causality has not been convincingly demonstrated, low physical activity level is associated with higher risk of subsequent development of MCI or AD. Larger and longer duration prospective studies that use objective measures of both physical activity and clinical outcomes are needed to understand the magnitude and mechanisms of this effect on cognitive health. The study by Buchman and colleagues furthers this work and may prompt consideration of exercise counseling or interventions such as structured activity Copyright

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programs for at-risk patient populations. Subsequent to the publication of this primary research study, a pair of systematic reviews and meta-analyses also concluded that physical activity reduces AD risk and of all the lifestyle factors considered, physical activity had the greatest magnitude of protective effect.10,11 Using meta-analytic data, Norton and colleagues estimated that the highest population attributable risk factor was physical activity in the United States (21.0%; 95% CI, 5.8-36.6), Europe (20.3%; 95% CI, 5.6-35.6), and the United Kingdom (21.8%; 95% CI, 6.1-37.7).12 REFERENCES 1. Ahlskog JE, Geda YE, Graff-Radford NR, et al. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc. 2011;86:876–884. 2. Buchman AS, Boyle PA, Yu L, et al. Total daily physical activity and the risk of AD and cognitive decline in older adults. Neurology. 2012;78:1323–1329. 3. Bennett DA, Schneider JA, Buchman AS, et al. The Rush Memory and Aging Project: study design and baseline characteristics of the study cohort. Neuroepidemiology. 2005;25:163–175. 4. Geda YE, Silber TC, Roberts RO, et al. Computer activities, physical exercise, aging, and mild cognitive impairment: a population based study. Mayo Clinic Proc. 2012;87:437–442. 5. Petersen RC, O’Brien J. Mild cognitive impairment should be considered for DSM-V. J Geriatr Psychiatry Neurol. 2006;19:147–154. 6. Rasquin SM, Lodder J, Visser PJ, et al. Predictive accuracy of MCI subtypes for Alzheimer’s disease and vascular dementia in subjects with mild cognitive impairment: a 2-year follow-up study. Dement Geriatr Cogn Disord. 2005;19:113–119. 7. Duara R, Loewenstein DA, Shen Q, et al. Amyloid positron emission tomography with (18)F-flutematamol and structural magnetic resonance imaging in the classification of mild cognitive impairment and Alzheimer’s disease. Alzheimers Dement. 2013;9: 295–301. 8. Loewenstein DA, Acevedo A, Small BJ, et al. Stability of different subtypes of mild cognitive impairment among the elderly over a 2to 3-year follow-up period. Dement Geriatr Cogn Disord. 2009;27:418–423. 9. Ganguli M, Snitz BE, Saxton JA, et al. Outcomes of mild cognitive impairment by definition: a population study. Arch Neurol. 2011;68:761–767. 10. Blondell SJ, Hammersley-Mather R, Veerman JL. Does physical activity prevent cognitive decline and dementia?: a systematic review and meta-analysis of longitudinal studies. BMC Public Health. 2014;14:510. 11. Beydoun MA, Beydoun HA, Gamaldo AA, et al. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 2014;14:643. 12. Norton S, Matthews FE, Barnes DE, et al. Potential for primary prevention of Alzheimer’s disease: an analysis of populationbased data. Lancet Neurol. 2014;13:788–794.

APPENDIX Mayo Clinic Evidence Based Clinical Practice, Research, Informatics, and Training (MERIT) Center Cofounders and Codirectors: Bart M. Demaerschalk and Dean M. Wingerchuk. Medical Library Sciences and Evidence Based Searching & Informatics Director: Kay E. Wellik. Evidence Appraisal: Gretchen Schlosser Covell, Charlene R. Hoffman-Snyder, Bart Demaerschalk, Dean M. Wingerchuk. Content Experts: Richard Caselli and Bryan Woodruff (behavioral neurology); Yonas E. Geda (neuropsychiatry). Evidence Appraisal Date: November 7, 2012 and December 15, 2014. Suggested Topic Reappraisal Date: December 15, 2016.

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Physical activity level and future risk of mild cognitive impairment or dementia: a critically appraised topic.

The relationships between physical activity, cognition, and development of neurodegenerative diseases represent an area of intense research interest. ...
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