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The prevention and treatment of Alzheimer’s disease (AD) is a pressing public health issue. Epidemiologic and experimental evidence suggests that exercise has a beneficial effect on cognitive health (Physical Activity Guidelines Advisory Committee, 2008). At the brain level, this association may be explained, in part, by cognitive reserve theory. Cognitive reserve theory suggests that the physically fit brain may be more

efficient, flexible, and/or capable of recruiting neural resources than the unfit brain (Stern, 2009). A brain functioning in this manner is more difficult to disrupt, and therefore fit individuals should be better able to maintain their cognitive abilities despite, for example, advancing AD pathology. Researchers at Columbia University have devised a systematic approach to testing these plausible mechanisms using functional magnetic resonance imaging (fMRI) (Stern, 2009). Although there is a growing body of neuroimaging research demonstrating that the fit brain functions differently than the unfit brain, the current study was the first to study the role of exercise in building CR using this methodology.

Manuscript 1 reports, more specifically, our investigation of 1) whether

participation in a 16-week walking program increased brain efficiency, and 2) whether increased brain efficiency correlated with change in fitness and cognitive performance. Twelve participants underwent fMRI scanning before and after exercise training. During fMRI scanning, participants completed the Sternberg delayed-match-to-sample letter task. Brain activation during the low-demand task condition was subtracted from brain

activation during the high-demand condition. We expected this difference to become lesser with exercise training. Within our sample (mean age 63), the difference became greater in the following brain regions with exercise training: left inferior frontal gyrus, left cuneus, right rolandic operculum, left middle temporal gyrus, left postcentral gyrus, left superior med frontal, left superior frontal gyrus, right caudate, right inferior temporal gyrus (ps < 0.001). No task-related brain regions were utilized more efficiently after exercise training (ps > 0.001). These findings suggest that exercise training may lead to greater recruitment of task-related neural resources (not greater network efficiency, as hypothesized) in this sample. As there were no observable relationships between change in task-related brain activation and change in cognitive performance (measured as

reaction time slope), these findings should be interpreted with caution.

Manuscript 2 reports our investigation of the cognitive effects of a 16-week walking program. Intervention participants (n=17; mean age 64) completed a battery of cognitive tasks (CANTAB©) before beginning and after completing exercise training; control group participants (n=18; mean age 66) completed the battery on dates

approximately 16-weeks apart. There were no significant differences between the groups on any cognitive performance measures based on ANOVA analyses (ps > 0.24). Due to the small sample size, we also calculated effect sizes. Effects of the exercise intervention were small for the total trial and total error outcomes on the paired associate learning task (d=0.20 and d=0.39, respectively), as well as for the spatial span task (d=0.38). For the control group, effect sizes were small for the verbal free recall task (d=0.23), medium for the rapid visual processing (d=0.62) and paired associate learning task (d=0.71 and

d=0.52 for the total trial and total error outcomes, respectively), and large for the spatial span task (d=1.02).

Much can be learned from the unexpected findings in both manuscripts. In Study 1, contrary to our a priori hypothesis, task-related brain activation increased with exercise training. This finding may suggest that exercise-induced cognitive reserve presents as increased neural capacity, rather than efficiency, in our sample. It is possible that our sample was not comparable to average older adults, and thus the women in our study did not employ the efficiency mechanism we expected based on previous research (Scarmeas et al., 2003). The average IQ of women undergoing fMRI was 119, which falls within the 90th percentile. These women also had been very socially and mentally active throughout life, according to their Lifetime Experience Questionnaire responses. High levels of ‘mental activity’-induced cognitive reserve at baseline may have affected how exercise-induced reserve manifested in these participants. It is also possible that exercise-induced cognitive reserve has completely different mechanisms than cognitive reserve ‘built’ through mental or social activity, and therefore our original hypothesis may have been misguided and this project fully exploratory. Alternatively, the findings do not fully support cognitive reserve theory because we found no evidence linking increased task-related brain activation with improved cognitive performance. The lack of a control group makes it even more difficult to determine whether the increased task- related brain activation was a true demonstration of beneficial, exercise-induced

adaptations in the brain, or normal brain changes associated with aging or other factors. In Study 2, we observed improvements on multiple cognitive tasks in control group participants. These unexpected effects may have resulted from a number of factors.

Less time between cognitive testing sessions in control compared to intervention

participants may have meant that control participants felt more familiar with the cognitive battery at follow-up and may have been able to strategize more effectively. Additionally, control group participants were recruited to be part of a memory and thinking study (as opposed to an exercise study), and therefore may have been worried about memory. These participants may have been more motivated to improve their performance at their follow-up visit, and may have been more likely to engage in ‘brain training’ activities between sessions. Lastly, an experimenter bias may have negatively affected the performance of intervention participants at follow-up, as these participants became very familiar with the primary investigator over the course of the 16-week intervention and may have felt added pressure to improve their performance at follow-up.

Overall, Study 1 provides a stepping-stone for future cognitive reserve studies in the field of exercise science. Randomized, controlled investigations with more diverse samples should test our tentative conclusion that exercise-induced cognitive reserve presents as greater neural network capacity in healthy older women. Study 2 should also be replicated with a larger, randomized sample, and a careful eye toward avoiding practice effects, as investigations of the cognitive benefits of walking are timely and could make an important public health impact.

References

Alzheimer's Association. (2014). 2014 Alzheimer's Disease Facts and Figures. Chicago, IL.

American College of Sport Medicine. ( 2010). ACSM's guidelines for exercise testing and prescription (8th ed.). Baltimore, MD: Lippincott Williams & Wilkins.

Anderson-Hanley, C., Arciero, P. J., Brickman, A. M., Nimon, J. P., Okuma, N., Westen, S. C., . . . Zimmerman, E. A. (2012). Exergaming and older adult cognition: a cluster randomized clinical trial. American Journal of Preventive Medicine, 42(2), 109-119. doi: 10.1016/j.amepre.2011.10.016

Arab, L., & Sabbagh, M. N. (2010). Are certain lifestyle habits associated with lower Alzheimer's disease risk? Journal of Alzheimer's Disease, 20(3), 785-794. doi: 10.3233/jad-2010-091573

Attwell, D., & Iadecola, C. (2002). The neural basis of functional brain imaging signals.

Trends in Neurosciences, 25(12), 621-625.

Baker, L. D., Frank, L. L., Foster-Schubert, K., Green, P. S., Wilkinson, C. W., McTiernan, A., . . . Craft, S. (2010a). Aerobic exercise improves cognition for older adults with glucose intolerance, a risk factor for Alzheimer's disease.

Journal of Alzheimer's Disease, 22(2), 569-579. doi: 10.3233/JAD-2010-100768 Baker, L. D., Frank, L. L., Foster-Schubert, K., Green, P. S., Wilkinson, C. W.,

cognitive impairment: a controlled trial. Archives of Neurology, 67(1), 71-79. doi: 10.1001/archneurol.2009.307

Barnes, D. E., Santos-Modesitt, W., Poelke, G., Kramer, A. F., Castro, C., Middleton, L. E., & Yaffe, K. (2013). The Mental Activity and eXercise (MAX) Trial: A Randomized Controlled Trial to Enhance Cognitive Function in Older Adults.

JAMA Internal Medicine, 1-8. doi: 10.1001/jamainternmed.2013.189

Barnhart, J. M., Wright, N. D., Freeman, K., Silagy, F., Correa, N., & Walker, E. A. (2009). Risk perception and its association with cardiac risk and health behaviors among urban minority adults: the Bronx Coronary Risk Perception study.

American Journal of Health Promotion, 23(5), 339-342. doi: 10.4278/ajhp.07072574

Bird, C. M., Papadopoulou, K., Ricciardelli, P., Rossor, M. N., & Cipolotti, L. (2004). Monitoring cognitive changes: psychometric properties of six cognitive tests.

British Journal of Clinical Psychology, 43(Pt 2), 197-210. doi: 10.1348/014466504323088051

Blacker, D., Lee, H., Muzikansky, A., Martin, E. C., Tanzi, R., McArdle, J. J., . . . Albert, M. (2007). Neuropsychological measures in normal individuals that predict subsequent cognitive decline. Archives of Neurology, 64(6), 862-871. doi: 10.1001/archneur.64.6.862

Boecker, H. (2011). On the emerging role of neuroimaging in determining functional and structural brain integrity induced by physical exercise: impact for predictive, preventive, and personalized medicine. The EPMA Journal, 2(3), 277-285. doi: 10.1007/s13167-011-0093-y

Bowen, M. E. (2012). A prospective examination of the relationship between physical activity and dementia risk in later life. American Journal of Health Promotion, 26(6), 333-340. doi: 10.4278/ajhp.110311-QUAN-115

Braak, H. B., E. (1991). Neuropathological staging of Alzheimer-related changes. Acta Neuropathologica, 82(239-259).

Buchman, A. S., Boyle, P. A., Yu, L., Shah, R. C., Wilson, R. S., & Bennett, D. A. (2012). Total daily physical activity and the risk of AD and cognitive decline in older adults. Neurology, 78(17), 1323-1329. doi:

10.1212/WNL.0b013e3182535d35

Buckner, R. L. (2004). Memory and executive function in aging and AD: multiple factors that cause decline and reserve factors that compensate. Neuron, 44(1), 195-208. doi: 10.1016/j.neuron.2004.09.006

Cabeza, R. (2002). Hemispheric asymmetry reduction in older adults: the HAROLD model. Psychology and Aging, 17(1), 85-100.

Carlson, M. C., Saczynski, J. S., Rebok, G. W., Seeman, T., Glass, T. A., McGill, S., . . . Fried, L. P. (2008). Exploring the effects of an "everyday" activity program on executive function and memory in older adults: Experience Corps. Gerontologist, 48(6), 793-801.

Cassilhas, R. C., Viana, V.A.R., Grassmann, V., Santos, R.T., Santos, R.F., Tufik, S. & Mellow, M.T. (2007). The Impact of Resistance Exercise on the Cognitive Function of the Elderly. Medicine & Science in Sport & Exercise, 1401-1407.

Chang, Y. K., Nien, Y. H., Tsai, C. L., & Etnier, J. L. (2010). Physical activity and cognition in older adults: the potential of Tai Chi Chuan. Journal of Aging and Physical Activity, 18(4), 451-472.

Colcombe, S. J., Erickson, K. I., Raz, N., Webb, A. G., Cohen, N. J., McAuley, E., & Kramer, A. F. (2003). Aerobic fitness reduces brain tissue loss in aging humans.

Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 58(2), 176-180.

Colcombe, S. J., Erickson, K. I., Scalf, P. E., Kim, J. S., Prakash, R., McAuley, E., . . . Kramer, A. F. (2006). Aerobic exercise training increases brain volume in aging humans. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 61(11), 1166-1170.

Colcombe, S. J., & Kramer, A. F. (2003). Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychological Science, 14(2), 125-130. Colcombe, S. J., Kramer, A. F., Erickson, K. I., Scalf, P., McAuley, E., Cohen, N. J., . . .

Elavsky, S. (2004). Cardiovascular fitness, cortical plasticity, and aging.

Proceedings of the National Academy of Sciences of the United States of America, 101(9), 3316-3321. doi: 10.1073/pnas.0400266101

Collie, A., Maruff, P., & Currie, J. (2002). Behavioral characterization of mild cognitive impairment. Journal of Clinical and Experimental Neuropsychology, 24(6), 720- 733. doi: 10.1076/jcen.24.6.720.8397

Cotman, C. W., Berchtold, N. C., & Christie, L. A. (2007). Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends in Neurosciences, 30(9), 464-472. doi: 10.1016/j.tins.2007.06.011

Daviglus, M. L., Plassman, B. L., Pirzada, A., Bell, C. C., Bowen, P. E., Burke, J. R., . . . Williams, J. W., Jr. (2011). Risk factors and preventive interventions for

Alzheimer disease: state of the science. Archives of Neurology, 68(9), 1185-1190. doi: 10.1001/archneurol.2011.100

De Jager, C., Blackwell, A. D., Budge, M. M., & Sahakian, B. J. (2005). Predicting cognitive decline in healthy older adults. American Journal of Geriatric Psychiatry, 13(8), 735-740. doi: 10.1176/appi.ajgp.13.8.735

De Jager, C. A., & Budge, M. M. (2005). Stability and predictability of the classification of mild cognitive impairment as assessed by episodic memory test performance over time. Neurocase, 11(1), 72-79. doi: 10.1080/13554790490896820

Department of Health and Human Services. (2011). National Alzheimer's Project Act. Department of Health and Human Services. (2012). National Plan to Address Alzheimer's

Disease.

Erickson, K. I., Colcombe, S. J., Elavsky, S., McAuley, E., Korol, D. L., Scalf, P. E., & Kramer, A. F. (2007). Interactive effects of fitness and hormone treatment on brain health in postmenopausal women. Neurobiology of Aging, 28(2), 179-185. doi: 10.1016/j.neurobiolaging.2005.11.016

Erickson, K. I., Prakash, R. S., Voss, M. W., Chaddock, L., Hu, L., Morris, K. S., . . . Kramer, A. F. (2009). Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus, 19(10), 1030-1039. doi: 10.1002/hipo.20547 Erickson, K. I., Voss, M. W., Prakash, R. S., Basak, C., Szabo, A., Chaddock, L., . . .

improves memory. Proceedings of the National Academy of Sciences of the United States of America, 108(7), 3017-3022. doi: 10.1073/pnas.1015950108 Etnier, J. L., Caselli, R. J., Reiman, E. M., Alexander, G. E., Sibley, B. A., Tessier, D., &

McLemore, E. C. (2007). Cognitive performance in older women relative to ApoE-epsilon4 genotype and aerobic fitness. Medicine and Science in Sports and Exercise, 39(1), 199-207. doi: 10.1249/01.mss.0000239399.85955.5e

Etnier, J. L., Nowell, P. M., Landers, D. M., & Sibley, B. A. (2006). A meta-regression to examine the relationship between aerobic fitness and cognitive performance.

Brain Research Reviews, 52, 119-130.

Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12(3), 189-198.

Habeck, C., Hilton, H. J., Zarahn, E., Flynn, J., Moeller, J., & Stern, Y. (2003). Relation of cognitive reserve and task performance to expression of regional covariance networks in an event-related fMRI study of nonverbal memory. Neuroimage, 20(3), 1723-1733.

Habeck, C., Rakitin, B. C., Moeller, J., Scarmeas, N., Zarahn, E., Brown, T., & Stern, Y. (2005). An event-related fMRI study of the neural networks underlying the encoding, maintenance, and retrieval phase in a delayed-match-to-sample task.

Brain Research. Cognitive Brain Research, 23(2-3), 207-220. doi: 10.1016/j.cogbrainres.2004.10.010

Hamer, M., & Chida, Y. (2009). Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence. Psychological Medicine, 39(1), 3-11. doi: 10.1017/s0033291708003681

Hawkins, M. N., Raven, P. B., Snell, P. G., Stray-Gundersen, J., & Levine, B. D. (2007). Maximal oxygen uptake as a parametric measure of cardiorespiratory capacity.

Medicine and Science in Sports and Exercise, 39(1), 103-107. doi: 10.1249/01.mss.0000241641.75101.64

Hedden, T., & Gabrieli, J. D. (2004). Insights into the ageing mind: a view from cognitive neuroscience. Nature Reviews Neuroscience, 5(2), 87-96. doi: 10.1038/nrn1323

Hollmann, W., Struder, H. K., Tagarakis, C. V., & King, G. (2007). Physical activity and the elderly. European Journal of Cardiovascular Prevention & Rehabilitation, 14(6), 730-739. doi: 10.1097/HJR.0b013e32828622f9

Holtzer, R., Rakitin, B. C., Steffener, J., Flynn, J., Kumar, A., & Stern, Y. (2009). Age effects on load-dependent brain activations in working memory for novel material.

Brain Research, 1249, 148-161. doi: 10.1016/j.brainres.2008.10.009

Holzschneider, K., Wolbers, T., Roder, B., & Hotting, K. (2012). Cardiovascular fitness modulates brain activation associated with spatial learning. Neuroimage, 59(3), 3003-3014. doi: 10.1016/j.neuroimage.2011.10.021

Jack, C. R., Jr. (2012). Alzheimer disease: new concepts on its neurobiology and the clinical role imaging will play. Radiology, 263(2), 344-361. doi:

Jack, C. R., Jr., Petersen, R. C., Xu, Y., O'Brien, P. C., Smith, G. E., Ivnik, R. J., . . . Kokmen, E. (1998). Rate of medial temporal lobe atrophy in typical aging and Alzheimer's disease. Neurology, 51(4), 993-999.

James, B. D., Leurgans, S. E., Hebert, L. E., Scherr, P. A., Yaffe, K., & Bennett, D. A. (2014). Contribution of Alzheimer disease to mortality in the United States.

Neurology. doi: 10.1212/wnl.0000000000000240

James, B. D., Wilson, R. S., Barnes, L. L., & Bennett, D. A. (2011). Late-life social activity and cognitive decline in old age. Journal of the International

Neuropsychological Society, 17(6), 998-1005. doi: 10.1017/s1355617711000531 Johnson, K. A., Minoshima, S., Bohnen, N. I., Donohoe, K. J., Foster, N. L., Herscovitch,

P., . . . Thies, W. H. (2013). Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association. Alzheimer's & Dementia, 9(1), e-1-16. doi: 10.1016/j.jalz.2013.01.002

Kramer, A. F., Erickson, K. I., & Colcombe, S. J. (2006). Exercise, cognition, and the aging brain. Journal of Applied Physiology, 101, 1237-1242.

Kramer, A. F., Hahn, S., Cohen, N. J., Banich, M. T., McAuley, E., Harrison, C. R., . . . Colcombe, A. (1999). Ageing, fitness and neurocognitive function. Nature, 400(6743), 418-419. doi: 10.1038/22682

Lange-Asschenfeldt, C., & Kojda, G. (2008). Alzheimer's disease, cerebrovascular dysfunction and the benefits of exercise: from vessels to neurons. Experimental Gerontology, 43(6), 499-504. doi: 10.1016/j.exger.2008.04.002

Lautenschlager, N. T., Cox, K. L., Flicker, L., Foster, J.K., van Bockxmeer, F.M., Xiao, J., Greenop, K.R. and Almeida, O.P. (2008). Effect of physical activity on cognitive function in older adults at risk for Alzheimer's disease: A randomized trial. JAMA, 300(9), 1027-1037.

Lee, I. M., & Buchner, D. M. (2008). The importance of walking to public health.

Medicine and Science in Sports and Exercise, 40(7 Suppl), S512-518. doi: 10.1249/MSS.0b013e31817c65d0

Levine, B. D., & Stray-Gundersen, J. (1997). "Living high-training low": effect of moderate-altitude acclimatization with low-altitude training on performance.

Journal of Applied Physiology, 83(1), 102-112.

Liu-Ambrose, T., & Donaldson, M. G. (2008). Exercise and cognition in older adults: Is there a role for resistance training programmes? British Journal of Sports

Medicine, 43, 25-27.

Liu-Ambrose, T., Nagamatsu, L. S., Voss, M. W., Khan, K. M., & Handy, T. C. (2012). Resistance training and functional plasticity of the aging brain: a 12-month randomized controlled trial. Neurobiology of Aging, 33(8), 1690-1698. doi: 10.1016/j.neurobiolaging.2011.05.010

Lowe, C., & Rabbitt, P. (1998). Test/re-test reliability of the CANTAB and ISPOCD neuropsychological batteries: theoretical and practical issues. Cambridge Neuropsychological Test Automated Battery. International Study of Post- Operative Cognitive Dysfunction. Neuropsychologia, 36(9), 915-923.

Marchant, N. L., Reed, B. R., Sanossian, N., Madison, C. M., Kriger, S., Dhada, R., . . . Jagust, W. J. (2013). The aging brain and cognition: contribution of vascular

injury and abeta to mild cognitive dysfunction. JAMA Neurology, 70(4), 488-495. doi: 10.1001/2013.jamaneurol.405

McNair, D. M., Lorr, M., & Droppleman, L. F. (1992). POMS Manual: Profile of Mood States. San Diego, CA: Educational and Industrial Testing Service.

Middleton, L. E., Manini, T. M., Simonsick, E. M., Harris, T. B., Barnes, D. E., Tylavsky, F., . . . Yaffe, K. (2011). Activity energy expenditure and incident cognitive

impairment in older adults. Archives of Internal Medicine, 171(14), 1251-1257. doi: 10.1001/archinternmed.2011.277

Murphy, M. H., Nevill, A. M., Murtagh, E. M., & Holder, R. L. (2007). The effect of walking on fitness, fatness and resting blood pressure: a meta-analysis of randomised, controlled trials. Preventive Medicine, 44(5), 377-385. doi: 10.1016/j.ypmed.2006.12.008

Nagamatsu, L. S., Handy, T. C., Hsu, C. L., Voss, M., & Liu-Ambrose, T. (2012). Resistance training promotes cognitive and functional brain plasticity in seniors with probable mild cognitive impairment. Archives of Internal Medicine, 172(8), 666-668. doi: 10.1001/archinternmed.2012.379

Norton, M. C., Dew, J., Smith, H., Fauth, E., Piercy, K. W., Breitner, J. C., . . . Welsh- Bohmer, K. (2012). Lifestyle behavior pattern is associated with different levels of risk for incident dementia and Alzheimer's disease: the Cache County study.

Journal of the American Geriatrics Society, 60(3), 405-412. doi: 10.1111/j.1532- 5415.2011.03860.x

Oldfield, R. C. (1971). The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia, 9(1), 97-113.

Paillard-Borg, S., Fratiglioni, L., Xu, W., Winblad, B., & Wang, H. X. (2012). An active