The Aerobic and Cognitive Exercise Study (ACES) for Community-Dwelling Older Adults With or At-Risk for Mild Cognitive Impairment (MCI): Neuropsychological, Neurobiological and Neuroimaging Outcomes of a Randomized Clinical Trial

Cay Anderson-Hanley, Nicole M Barcelos, Earl A Zimmerman, Robert W Gillen, Mina Dunnam, Brian D Cohen, Vadim Yerokhin, Kenneth E Miller, David J Hayes, Paul J Arciero, Molly Maloney, Arthur F Kramer, Cay Anderson-Hanley, Nicole M Barcelos, Earl A Zimmerman, Robert W Gillen, Mina Dunnam, Brian D Cohen, Vadim Yerokhin, Kenneth E Miller, David J Hayes, Paul J Arciero, Molly Maloney, Arthur F Kramer

Abstract

Prior research has found that cognitive benefits of physical exercise and brain health in older adults may be enhanced when mental exercise is interactive simultaneously, as in exergaming. It is unclear whether the cognitive benefit can be maximized by increasing the degree of mental challenge during exercise. This randomized clinical trial (RCT), the Aerobic and Cognitive Exercise Study (ACES) sought to replicate and extend prior findings of added cognitive benefit from exergaming to those with or at risk for mild cognitive impairment (MCI). ACES compares the effects of 6 months of an exer-tour (virtual reality bike rides) with the effects of a more effortful exer-score (pedaling through a videogame to score points). Fourteen community-dwelling older adults meeting screening criteria for MCI (sMCI) were adherent to their assigned exercise for 6 months. The primary outcome was executive function, while secondary outcomes included memory and everyday cognitive function. Exer-tour and exer-score yielded significant moderate effects on executive function (Stroop A/C; d's = 0.51 and 0.47); there was no significant interaction effect. However, after 3 months the exer-tour revealed a significant and moderate effect, while exer-score showed little impact, as did a game-only condition. Both exer-tour and exer-score conditions also resulted in significant improvements in verbal memory. Effects appear to generalize to self-reported everyday cognitive function. Pilot data, including salivary biomarkers and structural MRI, were gathered at baseline and 6 months; exercise dose was associated with increased BDNF as well as increased gray matter volume in the PFC and ACC. Improvement in memory was associated with an increase in the DLPFC. Improved executive function was associated with increased expression of exosomal miRNA-9. Interactive physical and cognitive exercise (both high and low mental challenge) yielded similarly significant cognitive benefit for adherent sMCI exercisers over 6 months. A larger RCT is needed to confirm these findings. Further innovation and clinical trial data are needed to develop accessible, yet engaging and effective interventions to combat cognitive decline for the growing MCI population. ClinicalTrials.gov ID: NCT02237560.

Keywords: Alzheimer's disease; MCI; aging; cognitive; dementia; exercise; exergame; neuropsychological.

Figures

Figure 1
Figure 1
Stationary bike equipped with virtual reality display (aka “cybercycle” so named in our previous RCT; Anderson-Hanley et al., 2012). Former study participant demonstrating use of a cybercycle exergame; used with permission.
Figure 2
Figure 2
Exer-tour (relatively cognitively passive) vs. Exer-score (cognitively effortful). Exer-tour (pedaling controls speed on screen and progress along scenic bike paths; involves steering, but relatively passive compared to exer-score; for example, can't leave road or crash into anything or any rider which one can steer through; could cease steering without consequence other than tilted view, bike will follow curb). Exer-score (requires navigating in 360° radius to locate colored coins and matching colored dragons of varying speed/difficulty to steer through; the goal is to score points and strategy may be employed to avoid losing points by avoiding hazards, while also seeking out bonus points available via tagging specialized objects one can choose to explore). Former study participant demonstrating exer-tour condition; used with permission.
Figure 3
Figure 3
CONSORT flow diagram showing participant enrollment, randomization, and status in trial and analysis.
Figure 4
Figure 4
Exer-tour vs. exer-score for sMCI adherents 0–6M.
Figure 5
Figure 5
Comparison of effect sizes of components of interactive physical and cognitive exercise across four intervention conditions for 0–3M adherents. p-values represent significant change over time within-group (paired) t-tests. athe game-only condition was initially randomly assigned, but subsequently recruited separately due to challenges with enrollment and retention (see section Methods for further details). bthe pedal-only comparison data is archival/perviously reported from our lab and was obtained during the Cybercycle Study (Anderson-Hanley et al., 2012), which examined only a 3-month interval and was collected from older adults in the same region, from many of the same retirement communities, and with the same measures of executive function; this data is included here as a point of comparaitve reference, illustrating the magnitude of effect from physical exercise alone.
Figure 6
Figure 6
Neuroimaging correlates with exercise and cognition: MRI of ACC and DLPFC. Notes: Illustration of regions-of-interest (ROI): ACC (increased with exercise dose) and DLPFC (increased with improvement in verbal memory); shown here in one individual and in one hemisphere for ease of presentation. Images of ACC (green) and DLPFC (blue) in 3 sagittal (A), coronal (B), and axial (C) images aligned by crosshairs. ROI 3D model reconstructions give a sense of their structure in 3D space, as seen from the anterior (D) and left (E) sides.

References

    1. Ahlskog J. E., Geda Y. E., Graff-Radford N. R., Petersen R. C. (2011). Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin. Proc. 86, 876–884. 10.4065/mcp.2011.0252
    1. Alzheimer's Association (2014). Alzheimer's Association report: Alzheimer's disease facts and figures. Alzheimer's Demen. 10, 47–92. Available online at:
    1. Alzheimer's Association and Centers for Disease Control and Prevention (2013). The Healthy Brain Initiative: The Public Health Road Map for State and National Partnerships, 2013–2018: Chicago, IL: Alzheimer's Association.
    1. Al-Yahya E., Dawes H., Smith L., Dennis A., Howells K., Cockburn J. (2011). Cognitive motor interference while walking: a systematic review and meta-analysis. Neurosci. Biobehav. Rev. 35, 715–728. 10.1016/j.neubiorev.2010.08.008
    1. Anderson-Hanley C., Barcelos B., Maloney M., Michel M., Striegnitz S., Saulnier T. (2016). Neuropsychological effects of an Interactive Physical & Cognitive Exercise System (iPACES) for older adults: pilot comparison of in-home neuro-exergame versus neuro-game, in Presentation at the Annual Meeting of the International Neuropsychological Society (Boston, MA: ).
    1. Anderson-Hanley C., Arciero P. J., Barcelos N., Nimon J., Rocha T., Thurin M., et al. . (2014). Executive function and self-regulated exergaming adherence among older adults. Front. Hum. Neurosci. 8:989. 10.3389/fnhum.2014.00989
    1. Anderson-Hanley C., Arciero P. J., Brickman A., Nimon J., Okuma N., Westen S., et al. (2012). Exergaming improves older adult cognition: a cluster randomized clinical trial. Am. J. Prev. Med. 42, 109–119. 10.1016/j.amepre.2011.10.016
    1. Anderson-Hanley C., Maloney M., Barcelos N., Striegnitz K., Kramer A. F. (2017). Neuropsychological benefits of neuro-exergaming for older adults: a pilot study of an interactive physical and cognitive exercise system (iPACES™). J. Aging Phys. Activity 25, 73–83. 10.1123/japa.2015-0261
    1. Angevaren M., Aufdemkampe G., Verhaar H. J., Aleman A., Vanhees L. (2008). Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst. Rev. 3:CD005381 10.1002/14651858.CD005381.pub3
    1. Anguera J. A., Boccanfuso J., Rintoul J. L., Al-Hashimi O., Faraji F., Gazzaley A. (2013). Video game training enhances cognitive control in older adults. Nature 501, 97–101. 10.1038/nature12486
    1. Bahar-Fuchs A., Clare L., Woods B. (2013). Cognitive training and cognitive rehabilitation for persons with mild to moderate dementia of the Alzheimer's or vascular type: a review. Alzheimer's Res. Ther. 5:35 10.1186/alzrt189
    1. Baker L. D., Frank L. L., Foster-Schubert K., Green P. S., Wilkinson C. W., McTiernan A., et al. . (2010). Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch. Neurol. 67, 71–79. 10.1001/archneurol.2009.307
    1. Bamidis P. D., Fissler P., Papageorgiou S. G., Zilidou V., Konstantinidis E. I., Billis A. S., et al. . (2015). Gains in cognition through combined cognitive and physical training: the role of training dosage and severity of neurocognitive disorder. Front. Aging Neurosci. 7:152. 10.3389/fnagi.2015.00152
    1. Bamidis P. D., Konstantinidis E. I., Billis A., Frantzidis C., Tsolaki M., Hlauschek W., et al. (2011). A Web services-based exergaming platform for senior citizens: the Long Lasting Memories project approach to e-health care, in Conference Proceedings:…Annual International Conference Of The IEEE Engineering In Medicine And Biology Society. IEEE Engineering In Medicine And Biology Society. Annual Conference, 20112505-2509 (Boston, MA: ).
    1. Bamidis P. D., Vivas A. B., Styliadis C., Frantzidis C., Klados M., Schlee W., et al. . (2014). A review of physical and cognitive interventions in aging. Neurosci. Biobehav. Rev. 44, 206–220. 10.1016/j.neubiorev.2014.03.019
    1. Barcelos N., Shah N., Cohen K., Hogan M. J., Mulkerrin E., Arciero P. J., et al. . (2015). Aerobic and cognitive exercise (ACE) pilot study for older adults: executive function improves with cognitive challenge while exergaming. J. Int. Neuropsychol. Soc. 21, 768–779. 10.1017/S1355617715001083
    1. Barha C. K., Galea L. A., Nagamatsu L. S., Erickson K. I., Liu-Ambrose T. (2016). Personalising exercise recommendations for brain health: considerations and future directions. Brit. J. Sports Med. 51, 636–639. 10.1136/bjsports-2016-096710
    1. Barnes D. E., Santos-Modesitt W., Poelke G., Kramer A. F., Castro C., Middleton L. E., et al. . (2013). The mental activity and exercise (MAX) trial. A randomized controlled trial to enhance cognitive function in older adults. JAMA 173, 797–804. 10.1001/jamainternmed.2013.189
    1. Barry G., Galna B., Rochester L. (2014). The role of exergaming in Parkinson's disease rehabilitation: a systematic review of the evidence. J. Neuroeng. Rehabil. 11:33 10.1186/1743-0003-11-33
    1. Batistela M. S., Josviak N. D., Sulzbach C. D., de Souza R. R. (2017). An overview of circulating cell-free microRNAs as putative biomarkers in Alzheimer's and Parkinson's Diseases. Int. J. Neurosci. 127, 547–558. 10.1080/00207454.2016.1209754
    1. Beglinger L. J., Gaydos B., Tangphao-Daniels O., Duff K., Kareken D. A., Crawford J., et al. . (2005). Practice effects and the use of alternate forms in serial neuropsychological testing. Arch. Clin. Neuropsychol. 20, 517–529. 10.1016/j.acn.2004.12.003
    1. Bellar D., Glickman E. L., Juvancic-Heltzel J., Gunstad J. (2011). Serum insulin like growth factor-1 is associated with working memory, executive function, and selective attention in a sample of healthy, fit older adults. Neuroscience 178, 133–137. 10.1016/j.neuroscience.2010.12.023
    1. Bertoldi K., Cechinel L. R., Schallenberger B., Corssac G. B., Davies S., Guerreiro I. K., et al. . (2017). Circulating extracellular vesicles in the aging process: impact of aerobic exercise. Mol. Cell. Biochem. 440, 115–125. 10.1007/s11010-017-3160-4
    1. Bherer L. (2015). Cognitive plasticity in older adults: effects of cognitive training and physical exercise. Ann. N. Y. Acad. Sci. 1337, 1–6. 10.1111/nyas.12682
    1. Black J. E., Isaacs K. R., Anderson B. J., Alcantara A. A., Greenough W. T. (1990). Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. Proc. Natl. Acad. Sci. U.S.A. 87, 5568–5572. 10.1073/pnas.87.14.5568
    1. Boot W. R., Kramer A. F. (2014). The brain games conundrum: does cognitive training really sharpen the mind? Cerebrum 2014, 1–15.
    1. Boyke J., Driemeyer J., Gaser C., Büchel C., May A. (2008). Training-induced brain structure changes in the elderly. J. Neurosci. 28, 7031–7035. 10.1523/JNEUROSCI.0742-08.2008
    1. Brookmeyer R., Gray S., Kawas C. (1998). Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Amer. J. Public Health 88, 1337–1342. 10.2105/AJPH.88.9.1337
    1. Brown B. M., Peiffer J. J., Martins R. N. (2013). Multiple effects of physical activity on molecular and cognitive signs of brain aging: can exercise slow neurodegeneration and delay Alzheimer's disease? Mol. Psychiatry 18, 864–874. 10.1038/mp.2012.162
    1. Burdette J. H., Laurienti P. J., Espeland M. A., Morgan A., Telesford Q., Vechlekar C. D., et al. . (2010). Using network science to evaluate exercise-associated brain changes in older adults. Front. Aging Neurosci. 2:23. 10.3389/fnagi.2010.00023
    1. Burzynska A. Z., Jiao Y., Knecht A. M., Fanning J., Awick E. A., Chen T., et al. . (2017). White matter integrity declined over 6-months, but dance intervention improved integrity of the fornix of older adults. Front. Aging Neurosci. 9:59. 10.3389/fnagi.2017.00059
    1. Ceccarelli A., Rocca M. A., Pagani E., Falini A., Comi G., Filippi M. (2009). Cognitive learning is associated with gray matter changes in healthy human individuals: a tensor-based morphometry study. Neuroimage 48, 585–589. 10.1016/j.neuroimage.2009.07.009
    1. Chao Y., Scherer Y., Montgomery C. (2014). Effects of using nintendo wii exergames in older adults: a review of the literature. J. Aging Health 27, 379–402. 10.1177/0898264314551171
    1. Chapman S. B., Aslan S., Spence J. S., DeFina L. F., Keebler M. W., Didehbani N., et al. . (2013). Shorter term aerobic exercise improves brain, cognition, and cardiovascular fitness in aging. Front. Aging Neurosci. 5:75. 10.3389/fnagi.2013.00075
    1. Chapman S. B., Aslan S., Spence J. S., Keebler M. W., DeFina L. F., Didehbani N., et al. (2016). Distinct brain and behavioral benefits from cognitive vs. physical training: a randomized trial in aging adults. Front. Hum. Neurosci. 10:338 10.3389/fnhum.2016.00338
    1. Chodzko-Zajko W. J., Proctor D. N., Fiatarone Singh M. A., Minson C. T., Nigg C. R., Salem G. J., et al. . (2009). American College of sports medicine position stand. exercise and physical activity for older adults. Med. Sci. Sports Exerc. 41, 1510–1530. 10.1249/MSS.0b013e3181a0c95c
    1. Churchill J. D., Galvez R., Colcombe S., Swain R. A., Kramer A. F., Greenough W. T. (2002). Exercise, experience and the aging brain. Neurobiol. Aging 23, 941–955. 10.1016/S0197-4580(02)00028-3
    1. Coelho F. G., Andrade L. P., Pedroso R. V., Santos-Galduroz R. F., Gobbi S., Costa J. L., et al. . (2013b). Multimodal exercise intervention improves frontal cognitive functions and gait in Alzheimer's disease: a controlled trial. Geriatr. Gerontol. Int. 13, 198–203. 10.1111/j.1447-0594.2012.00887.x
    1. Coelho F. G., Gobbi S., Andreatto C. A. A., Corazza D. I., Pedroso R. V., Santos-Galduróz R. F. (2013a). Physical exercise modulates peripheral levels of brain-derived neurotrophic factor (BDNF): a systematic review of experimental studies in the elderly. Arch. Gerontol. Geriatr. 56, 10–15. 10.1016/j.archger.2012.06.003
    1. Colcombe S. J., Erickson K. I., Scalf P. E., Kim J. S., Prakash R., McAuley E., et al. . (2006). Aerobic exercise training increases brain volume in aging humans. J. Gerontol. 61, 1166–1170. 10.1093/gerona/61.11.1166
    1. Colcombe S., Kramer A. F. (2003). Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol. Sci. 14, 125–130. 10.1111/1467-9280.t01-1-01430
    1. Colcombe S. J., Kramer A. F., Erickson K. I., Scalf P., McAuley E., Cohen N. J., et al. . (2004). Cardiovascular fitness, cortical plasticity, and aging. Proc. Natl. Acad. Sci. U.S.A. 101, 3316–3321. 10.1073/pnas.0400266101
    1. Cotman C. W., Berchtold N. C., Christie L.-A. (2007). Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 30, 464–472. 10.1016/j.tins.2007.06.011
    1. Curlik D., Shors T. (2013). Training your brain: do mental and physical (MAP) training enhance cognition through the process of neurogenesis in the hippocampus? Neuropharmacology 64, 506–514. 10.1016/j.neuropharm.2012.07.027
    1. D'Elia L. G., Satz P., Uchiyama C. L., White T. (1996). Color Trails Test Manual. Odessa, FL: Psychological Assessment Resources.
    1. Desikan R. S., Ségonne F., Fischl B., Quinn B. T., Dickerson B. C., Blacker D., et al. . (2006). An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 31, 968–980. 10.1016/j.neuroimage.2006.01.021
    1. Desjardins-Crépeau L., Berryman N., Fraser S. A., Vu T. T. M., Kergoat M.-J., Li K. Z., et al. (2016). Effects of combined physical and cognitive training on fitness and neuropsychological outcomes in healthy older adults. Clin. Interv. Aging 11:1287 10.2147/CIA.S115711
    1. Destrieux C., Fischl B., Dale A., Halgren E. (2010). Automatic parcellation of human cortical gyri and sulci using standard anatomical nomenclature. Neuroimage 53, 1–15. 10.1016/j.neuroimage.2010.06.010
    1. Dhami P., Moreno S., DeSouza J. X. (2015). New framework for rehabilitation—Fusion of cognitive and physical rehabilitation: the hope for dancing. Front. Psychol. 5:1478. 10.3389/fpsyg.2014.01478
    1. Diamond A. (2013). Executive functions. Annu. Rev. Psychol. 64, 135–168. 10.1146/annurev-psych-113011-143750
    1. Dimitrova J., Hogan M., Khader P., O'Hora D., Kilmartin L., Walsh J. C., et al. . (2016). Comparing the effects of an acute bout of physical exercise with an acute bout of interactive mental and physical exercise on electrophysiology and executive functioning in younger and older adults. Aging Clin. Exp. Res. 29, 959–967. 10.1007/s40520-016-0683-6
    1. Dinoff A., Herrmann N., Swardfager W., Liu C. S., Sherman C., Chan S., et al. . (2016). The effect of exercise training on resting concentrations of peripheral brain-derived neurotrophic factor (BDNF): a meta-analysis. PLoS ONE 11:e0163037. 10.1371/journal.pone.0163037
    1. Domenech P., Koechlin E. (2015). Executive control and decision-making in the prefrontal cortex. Curr. Opin. Behav. Sci. 1, 101–106. 10.1016/j.cobeha.2014.10.007
    1. Edelmann E., Lessmann V., Brigadski T. (2014). Pre- and postsynaptic twists in BDNF secretion and action in synaptic plasticity. Neuropharmacology 76, 610–627. 10.1016/j.neuropharm.2013.05.043
    1. Eggenberger P., Schumacher V., Angst M., Theill N., de Bruin E. D. (2015). Does multicomponent physical exercise with simultaneous cognitive training boost cognitive performance in older adults? A 6-month randomized controlled trial with a 1-year follow-up. Clin. Interv. Aging 10, 1335–1349. 10.2147/CIA.S87732
    1. Eggenberger P., Wolf M., Schumann M., de Bruin E. D. (2016). Exergame and balance training modulate prefrontal brain activity during walking and enhance executive function in older adults. Front. Aging Neurosci. 8:66. 10.3389/fnagi.2016.00066
    1. Ehlers D. K., Daugherty A. M., Burzynska A. Z., Fanning J., Awick E. A., Chaddock-Heyman L., et al. (2017). Regional brain volumes moderate, but do not mediate, the effects of group-based exercise training on reductions in loneliness in older adults. Front. Aging Neurosci. 9:110 10.3389/fnagi.2017.00110
    1. Erickson K. I., Hillman C., Kramer A. F. (2015). Physical activity, brain, and cognition. Curr. Opin. Behav. Sci. 4, 27–32. 10.1016/j.cobeha.2015.01.005
    1. Erickson K. I., Miller D. L., Roecklein K. A. (2012). The aging hippocampus: interactions between exercise, depression, and BDNF. Neuroscientist 18, 82–97. 10.1177/1073858410397054
    1. Erickson K. I., Voss M. W., Prakash R. S., Basak C., Szabo A., Chaddock L., et al. . (2011). Exercise training increases size of hippocampus and improves memory. Proc. Natl. Acad. Sci. U.S.A. 108, 3017–3022. 10.1073/pnas.1015950108
    1. Etnier J. L., Chang Y. K. (2009). The effect of physical activity on executive function: a brief commentary on definitions, measurement issues, and the current state of the literature. J. Sport Exerc. Psychol. 31, 469–483. 10.1123/jsep.31.4.469
    1. Ettenhofer M. L., Hambrick D. Z., Abeles N. (2006). Reliability and stability of executive functioning in older adults. Neuropsychology 20, 607–613. 10.1037/0894-4105.20.5.607
    1. Fabel K., Wolf S., Ehninger D., Babu H., Galicia P., Kempermann G. (2009). Additive effects of physical exercise and environmental enrichment on adult hippocampal neurogenesis in mice. Front. Neurosci. 3:50. 10.3389/neuro.22.002.2009
    1. Fabre C., Chamari K., Mucci P., Masse-Biron J., Prefaut C. (2002). Improvement of cognitive function by mental and/or individualized aerobic training in healthy elderly subjects. Int. J. Sports Med. 23, 415–421. 10.1055/s-2002-33735
    1. Faul F., Erdfelder E., Lang A.-G., Buchner A. (2007). G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav. Res. Methods 39, 175–191. 10.3758/BF03193146
    1. Fiatarone S. M. A., Gates N., Saigal N., Wilson G. C., Meiklejohn J., Brodaty H., et al. . (2014). The Study of Mental and Resistance Training (SMART) study-resistance training and/or cognitive training in mild cognitive impairment: a randomized, double-blind, double-sham controlled trial. J. Am. Med. Dir. Assoc. 15, 873–880. 10.1016/j.jamda.2014.09.010
    1. Fischl B., Salat D. H., Busa E., Albert M., Dieterich M., Haselgrove C., et al. . (2002). Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 33, 341–355. 10.1016/S0896-6273(02)00569-X
    1. Fissler P., Kuster O., Schlee W., Kolassa I.-T. (2013). Novelty interventions to enhance broad cognitive abilities and prevent dementia: synergistic approaches for the facilitation of positive plastic change. Progress. Brain Res. 207, 403–434. 10.1016/B978-0-444-63327-9.00017-5
    1. Flöel A., Ruscheweyh R., Krüger K., Willemer C., Winter B., Völker K., et al. . (2010). Physical activity and memory functions: are neurotrophins and cerebral gray matter volume the missing link? Neuroimage 49, 2756–2763. 10.1016/j.neuroimage.2009.10.043
    1. Forbes D., Forbes S. C., Blake C. M., Thiessen E. J., Forbes S. (2015). Exercise programs for people with dementia. Cochrane Database Syst. Rev. CD006489. 10.1002/14651858.CD006489.pub4
    1. Forte R., Boreham C. G., Leite J. C., De Vito G., Brennan L., Gibney E. R., et al. . (2013). Enhancing cognitive functioning in the elderly: multicomponent vs resistance training. Clin. Interv. Aging 8, 9–27. 10.2147/CIA.S36514
    1. Foster P. P. (2013). How does dancing promote brain reconditioning in the elderly? Front. Aging Neurosci. 5:4. 10.3389/fnagi.2013.00004
    1. Frantzidis C. A., Ladas A. I., Vivas A. B., Tsolaki M., Bamidis P. D. (2014). Cognitive and physical training for the elderly: evaluating outcome efficacy by means of neurophysiological synchronization. Int. J. Psychophysiol. 93, 1–11. 10.1016/j.ijpsycho.2014.01.007
    1. Freitas S., Simões M. R., Marôco J., Alves L., Santana I. (2012). Construct validity of the Montreal Cognitive Assessment (MoCA). J. Int. Neuropsychol. Soc. 18, 242–250. 10.1017/S1355617711001573
    1. Gage F. H. (2002). Neurogenesis in the adult brain. J. Neurosci. 22, 612–613. 10.1523/JNEUROSCI.22-03-00612.2002
    1. Gallo A., Alevizos I. (2013). Isolation of circulating microRNA in saliva. Methods Mol. Biol. 1024, 183–190. 10.1007/978-1-62703-453-1_14
    1. Galvan V., Bredesen D. E. (2007). Neurogenesis in the adult brain: implications for Alzheimer's disease. CNS Neurol. Disord. Drug Targets 6, 303–310.
    1. Gates N. (2013). The effect of exercise training on cognitive function in older adults with mild cognitive impairment: a meta-analysis of randomized controlled trials. Amer. J. Geriatr. Psychiatry 21, 1086–1098. 10.1016/j.jagp.2013.02.018
    1. Geda Y. E., Roberts R. O., Knopman D. S., Christianson T. J., Pankratz V. S., Ivnik R. J., et al. . (2010). Physical exercise, aging, and mild cognitive impairment. Arch. Neurol. 67, 80–86. 10.1001/archneurol.2009.297
    1. Geerlings M. I., Sigurdsson S., Eiriksdottir G., Garcia M. E., Harris T. B., Gudnason V., et al. . (2015). Salivary cortisol, brain volumes, and cognition in community-dwelling elderly without dementia. Neurology 85, 976–983. 10.1212/WNL.0000000000001931
    1. Gerling K., Mandryk R. (2014). Custom-designed motion-based games for older adults: a review of literature in human-computer interaction. Gerontechnology 12, 68–80. 10.4017/gt.2013.12.2.001.00
    1. González-Palau F., Franco M., Bamidis P., Losada R., Parra E., Papageorgiou S. G., et al. . (2014). The effects of a computer-based cognitive and physical training program in a healthy and mildly cognitive impaired aging sample. Aging Ment. Health 18, 838–846. 10.1080/13607863.2014.899972
    1. Gordon B. A., Rykhlevskaia E. I., Brumback C. R., Lee Y., Elavsky S., Konopack J. F., et al. . (2008). Neuroanatomical correlates of aging, cardiopulmonary fitness level, and education. Psychophysiology 45, 825–838. 10.1111/j.1469-8986.2008.00676.x
    1. Grandes G., Sanchez A., Sanchez-Pinilla R. O., Torcal J., Montoya I., Lizarraga K., et al. . (2009). Effectiveness of physical activity advice and prescription by physicians in routine primary care: a cluster randomized trial. Arch. Intern. Med. 169, 694–701. 10.1001/archinternmed.2009.23
    1. Grandjean J., D'Ostilio K., Phillips C., Balteau E., Degueldre C., Luxen A., et al. . (2012). Modulation of brain activity during a Stroop inhibitory task by the kind of cognitive control required. PLoS ONE 7:e41513. 10.1371/journal.pone.0041513
    1. Greenough W. T., Cohen N. J., Juraska J. M. (1999). New neurons in old brains: learning to survive? Nat. Neurosci. 2, 203–205. 10.1038/6300
    1. Hannay J. H., Lezak M. D. (2004). The neuropsychological examination: interpretation, in Neuropsychological Assessment, 4th Edn eds Lezak M. D., Howieson D. B., Loring D. W. (New York, NY: Oxford University Press; ), 133–156.
    1. Harrison J., Minassian S. L., Jenkins L., Black R. S., Koller M., Grundman M. (2007). A neuropsychological test battery for use in Alzheimer disease clinical trials. Arch. Neurol. 64, 1323–1329. 10.1001/archneur.64.9.1323
    1. Hayes S. M., Hayes J. P., Cadden M., Verfaellie M. (2013). A review of cardiorespiratory fitness-related neuroplasticity in the aging brain. Front. Aging Neurosci. 5:31. 10.3389/fnagi.2013.00031
    1. Hess N. C. L., Dieberg G., McFarlane J. R., Smart N. A. (2014). The effect of exercise intervention on cognitive performance in persons at risk for, or with, dementia: a systematic review and meta-analysis. Healthy Aging Res. 3:3. 10.12715/har.2014.3.3
    1. Heyn P., Abreu B. C., Ottenbacher K. J. (2004). The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch. Phys. Med. Rehabil. 85, 1694–1704. 10.1016/j.apmr.2004.03.019
    1. Hillman C., Erickson K., Kramer A. (2008). Be smart, exercise your heart: exercise effects on brain and cognition. Nat. Rev. Neurosci. 9, 58–65. 10.1038/nrn2298
    1. Hiyamizu M., Morioka S., Shomoto K., Shimada T. (2012). Effects of dual task balance training on dual task performance in elderly people: a randomized controlled trial. Clin. Rehabil. 26, 58–67. 10.1177/0269215510394222
    1. Hosseini S. H., Bruno J. L., Baker J. M., Gundran A., Harbott L. K., Gerdes J. C., et al. . (2017). Neural, physiological, and behavioral correlates of visuomotor cognitive load. Sci. Rep. 7:8866. 10.1038/s41598-017-07897-z
    1. Hotting K., Roder B. (2013). Effects of physical exercise on neuroplasticity and cognition. Neurosci. Biobehav. Rev. 37, 2243–2257. 10.1016/j.neubiorev.2013.04.005
    1. Houx P. J., Shepherd J., Blauw G.-J., Murphy M. B., Ford I., Bollen E. L., et al. . (2002). Testing cognitive function in elderly populations: The PROSPER study. J. Neurol. Neurosurg. Psychiatr. 73, 385–389. 10.1136/jnnp.73.4.385
    1. Huang E. J., Reichardt L. F. (2001). Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736. 10.1146/annurev.neuro.24.1.677
    1. Huntley J. D., Gould R. L., Liu K., Smith M., Howard R. J. (2015). Do cognitive interventions improve general cognition in dementia? A meta-analysis and meta-regression. BMJ Open 5:e005247. 10.1136/bmjopen-2014-005247
    1. Jak A. J., Bondi M. W., Delano-Wood L., Wierenga C., Corey-Bloom J., Salmon D. P., et al. . (2009). Quantification of five neuropsychological approaches to defining mild cognitive impairment. Am. J. Geriatr. Psychiatry 17, 368–375. 10.1097/JGP.0b013e31819431d5
    1. Jak A. J., Preis S. R., Beiser A. S., Seshadri S., Wolf P. A., Bondi M. W., et al. . (2016). Neuropsychological criteria for mild cognitive impairment and dementia risk in the Framingham Heart Study. J. Int. Neuropsychol. Soc. 22, 937–943. 10.1017/S1355617716000199
    1. Jessberger S., Gage F. H. (2014). Adult neurogenesis: bridging the gap between mice and humans. Trends Cell Biol. 24, 558–563. 10.1016/j.tcb.2014.07.003
    1. Jonasson L. S., Nyberg L., Kramer A. F., Lundquist A., Riklund K., Boraxbekk C. J. (2017). Aerobic exercise intervention, cognitive performance, and brain structure: Results from the Physical Influences on Brain in Aging (PHIBRA) Study. Front. Aging Neurosci. 8:336. 10.3389/fnagi.2016.00336
    1. Julayanont P., Brousseau M., Chertkow H., Phillips N., Nasreddine Z. S. (2014). Montreal Cognitive Assessment Memory Index Score (MoCA-MIS) as a predictor of conversion from mild cognitive impairment to Alzheimer's disease. J. Am. Geriatr. Soc. 62, 679–684. 10.1111/jgs.12742
    1. Karlawish J. (2008). Measuring decision-making capacity in cognitively impaired individuals. Neurosignals 16, 91–98. 10.1159/000109763
    1. Karr J. E., Areshenkoff C. N., Rast P., Garcia-Barrera M. A. (2014). An empirical comparison of the therapeutic benefits of physical exercise and cognitive training on the executive functions of older adults: a meta-analysis of controlled trials. Neuropsychology 28, 829–845. 10.1037/neu0000101
    1. Karssemeijer E. A., Aaronson J. A., Bossers W. J., Smits T., Olde Rikkert M. M., Kessels R. C. (2017). Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: a meta-analysis. Ageing Res. Rev. 40, 75–83. 10.1016/j.arr.2017.09.003
    1. Kattenstroth J., Kalisch T., Holt S., Tegenthoff M., Dinse H. R. (2013). Six months of dance intervention enhances postural, sensorimotor, and cognitive performance in elderly without affecting cardio-respiratory functions. Front. Aging Neurosci. 5:5. 10.3389/fnagi.2013.00005
    1. Kleemeyer M. M., Polk T. A., Schaefer S., Bodammer N. C., Brechtel L., Lindenberger U. (2017). Exercise-induced fitness changes correlate with changes in neural specificity in older adults. Front. Hum. Neurosci. 11:123 10.3389/fnhum.2017.00123
    1. Klusmann V., Evers A., Schwarzer R., Schlattmann P., Reischies F. M., Heuser I., et al. . (2010). Complex mental and physical activity in older women and cognitive performance: a 6-month randomized controlled trial. J. Gerontol. 65, 680–688. 10.1093/gerona/glq053
    1. Knaepen K., Goekint M., Heyman E. M., Meeusen R. (2010). Neuroplasticity – exercise-induced response of peripheral brain-derived neurotrophic factor: a systematic review of experimental studies in human subjects. Sports Med. 40, 765–801. 10.2165/11534530-000000000-00000
    1. Konstantinidis E. I., Bamparopoulos G., Bamidis P. D. (2017). Moving real exergaming engines on the web: the webfitforall case study in an active and healthy ageing living lab environment. IEEE J. Biomed. Health Inform. 21, 859–866. 10.1109/JBHI.2016.2559787
    1. Kraft E. (2012). Cognitive function, physical activity, and aging: possible biological links and implications for multimodal interventions. Aging Neuropsychol. C 19, 248–263. 10.1080/13825585.2011.645010
    1. Kramer A. F., Hahn S., Cohen N. J., Banich M. T., McAuley E., Harrison C. R., et al. . (1999). Ageing, fitness and neurocognitive function. Nature 400, 418–419. 10.1038/22682
    1. Kramer A., Erickson K. (2007). Capitalizing on cortical plasticity: Influence of physical activity on cognition and brain function. Trends Cogn. Sci. 11, 342–348. 10.1016/j.tics.2007.06.009
    1. Kramer A., Wickens C., Donchin E. (1985). Processing of stimulus properties: evidence for dual-task integrality. J. Exp. Psychol. 11, 393–408. 10.1037/0096-1523.11.4.393
    1. Kumar S., Reddy P. H. (2016). Are circulating microRNAs peripheral biomarkers for Alzheimer's disease? Biochim. Biophys. Acta 1862, 1617–1627. 10.1016/j.bbadis.2016.06.001
    1. Lam M., Eng G. K., Rapisarda A., Subramanium M., Kraus M., Keefe R. E., et al. . (2013). Formulation of the age–education index: measuring age and education effects in neuropsychological performance. Psychol. Assess. 25, 61–70. 10.1037/a0030548
    1. Lansbergen M. M., Kenemans J. L., van Engeland H. (2007). Stroop interference and attention-deficit/hyperactivity disorder: a review and meta-analysis. Neuropsychology 21, 251–262. 10.1037/0894-4105.21.2.251
    1. Lara J., Cooper R., Nissan J., Ginty A. T., Khaw K.-T., Deary I. J., et al. (2015). A proposed panel of biomarkers of healthy ageing. BMC Med. 13:222 10.1186/s12916-015-0470-9
    1. Larson E. (2010). Prospects for delaying the rising tide of worldwide, late-life dementias. Int. Psychogeriatr. 22, 1196–1202. 10.1017/S1041610210001080
    1. Lauenroth A., Ioannidis A. E., Teichmann B. (2016). Influence of combined physical and cognitive training on cognition: a systematic review. BMC Geriatr. 16:141 10.1186/s12877-016-0315-1
    1. Law L. L., Barnett F., Yau M. K., Gray M. A. (2014). Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: a systematic review. Ageing Res. Rev. 15, 61–75. 10.1016/j.arr.2014.02.008
    1. Leckie R. L., Oberlin L. E., Voss M. W., Prakash R. S., Szabo-Reed A., Chaddock-Heyman L., et al. . (2014). BDNF mediates improvements in executive function following a 1-year exercise intervention. Front. Hum. Neurosci. 8:985. 10.3389/fnhum.2014.00985
    1. Lee Y. Y., Wu C. Y., Teng C. H., Hsu W. C., Chang K. C., Chen P. (2016). Evolving methods to combine cognitive and physical training for individuals with mild cognitive impairment: study protocol for a randomized controlled study. Trials 17:526 10.1186/s13063-016-1650-4
    1. Legault C., Jennings J. M., Katula J. A., Dagenbach D., Gaussoin S. A., Sink K. M., et al. (2011). Designing clinical trials for assessing the effects of cognitive training and physical activity interventions on cognitive outcomes: The Seniors Health and Activity Research Program Pilot (SHARP-P) study, a randomized controlled trial. BMC Geriatr. 11:27 10.1186/1471-2318-11-27
    1. Leßmann V., Brigadski T. (2009). Mechanisms, locations, and kinetics of synaptic BDNF secretion: an update. Neurosci. Res. 65, 11–22. 10.1016/j.neures.2009.06.004
    1. Li M., Huang M., Li S., Tao J., Zheng G., Chen L. (2017). The effects of aerobic exercise on the structure and function of DMN-related brain regions: a systematic review. Int. J. Neurosci. 127, 634–649. 10.1080/00207454.2016.1212855
    1. Li S., Yan Y., Jiao Y., Gao Z., Xia Y., Kong L., et al. . (2016). Neuroprotective effect of osthole on neuron synapses in an alzheimer's disease cell model via upregulation of MicroRNA-9. J. Mol. Neurosci. 60, 71–81. 10.1007/s12031-016-0793-9
    1. Lieberman D. A. (2009). Designing serious games for learning and health in informal and formal settings, in Serious Games: Mechanisms and Effects, eds Ritterfeld U., Cody M., Vorderer P. (New York, NY: Routledge; ), 117–130.
    1. Lipardo D. S., Aseron A. C., Kwan M. M., Tsang W. W. (2017). Effect of exercise and cognitive training on falls and fall-related factors in older adults with mild cognitive impairment: a systematic review. Arch. Phys. Med. Rehabil. 98, 2079–2096. 10.1016/j.apmr.2017.04.021
    1. Lommatzsch M., Zingler D., Schuhbaeck K., Schloetcke K., Zingler C., Schuff-Werner P., et al. . (2005). The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol. Aging 26, 115–123. 10.1016/j.neurobiolaging.2004.03.002
    1. Lorens-Martín M., Torres-Alemán I., Trejo J. L. (2009). Reviews: mechanisms mediating brain plasticity: IGF-1 and adult hippocampal neurogenesis. Neuroscientist 15, 134–148. 10.1177/1073858408331371
    1. Maass A., Duzel S., Brigads T., Goerke M., Becke A., Sobieray U., et al. . (2016). Relationships of peripheral IGF-1, VEGF and BDNF levels to exercise-related changes in memory, hippocampal perfusion and volumes in older adults. Neuroimage 131, 142–154. 10.1016/j.neuroimage.2015.10.084
    1. Maillot P., Perrot A., Hartley A. (2012). Effects of interactive physical-activity video- game training on physical and cognitive function in older adults. Psychol. Aging 3, 589–600. 10.1037/a0026268
    1. Mandel A., Ozdener H., Utermohlen V. (2011). Brain-derived neurotrophic factor in human saliva: ELISA optimization and biological correlates. J. Immunoassay Immunochem. 32, 18–30. 10.1080/15321819.2011.538625
    1. Marquez D. X., Wilson R., Aguiñaga S., Vásquez P., Fogg L., Yang Z., et al. . (2017). Regular latin dancing and health education may improve cognition of late middle-aged and older latinos. J. Aging Phys. Act. 25, 482–489. 10.1123/japa.2016-0049
    1. Marshall G. A., Rentz D. M., Frey M. T., Locascio J. J., Johnson K. A., Sperling R. A. (2011). Executive function and instrumental activities of daily living in mild cognitive impairment and Alzheimer's disease. Alzheimer's Dementia 7, 300–308. 10.1016/j.jalz.2010.04.005
    1. Martin M., Clare L., Altgassen A. M., Cameron M. H., Zehnder F. (2011). Cognition-based interventions for healthy older people and people with mild cognitive impairment. Cochrane Database Syst. Rev. 1:CD006220 10.1002/14651858.CD006220.pub2
    1. McAuley E., Mullen S. P., Szabo A. N., White S. M., Wojcicki T. R., Mailey E. L., et al. . (2011). Self-regulatory processes and exercise adherence in older adults: Executive function and self-efficacy effects. Am. J. Prev. Med. 41, 284–290. 10.1016/j.amepre.2011.04.014
    1. Mills K. L., Tamnes C. K. (2014). Methods and considerations for longitudinal structural brain imaging analysis across development. Dev. Cogn. Neurosci. 9, 172–190. 10.1016/j.dcn.2014.04.004
    1. Monteiro-Junior R. S., de Tarso Maciel-Pinheiro P., da Matta Mello Portugal E., da Silva Figueiredo L. F., Terra R., Carneiro L. F., et al. . (2017). Effect of exercise on inflammatory profile of older persons: systematic review and meta-analyses. J. Phys. Act. Health 15, 64–71. 10.1123/jpah.2016-0735
    1. Morrison-Bogorad M., Cahan V., Wagster M. (2007). Brain health interventions: the need for further research. Alzheimers Dem. 3, S80–S85. 10.1016/j.jalz.2007.01.015
    1. Muijden J. V., Band G. P. H., Hommel B. (2012). Online games training aging brains: limited transfer to cognitive control functions. Front. Hum. Neurosci. 6:221. 10.3389/fnhum.2012.00221
    1. Müller P., Rehfeld K., Schmicker M., Hökelmann A., Dordevic M., Lessmann V., et al. . (2017). Evolution of neuroplasticity in response to physical activity in old age: the case for dancing. Front. Aging Neurosci. 9:56. 10.3389/fnagi.2017.00056
    1. Nasreddine Z. S., Phillips N. A., Bédirian V., Charbonneau S., Whitehead V., Collin I., et al. . (2005). The montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J. Am. Geriatr. Soc. 53, 695–699. 10.1111/j.1532-5415.2005.53221.x
    1. National Alzheimer's Project Act (2011). National Alzheimer's Project Act of 2011. Public Law. No. 111–375.
    1. Nishiguchi S., Yamada M., Tanigawa T., Sekiyama K., Kawagoe T., Suzuki M., et al. . (2015). A 12-week physical and cognitive exercise program can improve cognitive function and neural efficiency in community-dwelling older adults: a randomized controlled trial. J. Am. Geriatr. Soc. 63, 1355–1363. 10.1111/jgs.13481
    1. Ogawa E. F., You T., Leveille S. G. (2016). Potential benefits of exergaming for cognition and dual-task function in older adults: a systematic review. J. Aging Phys. Activ. 24:332336 10.1123/japa.2014-0267
    1. Olson A. K., Eadie B. D., Ernst C., Christie B. R. (2006). Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus 16, 250–260. 10.1002/hipo.20157
    1. Oswald W. D., Gunzelmann T., Rupprecht R., Hagen B. (2006). Differential effects of single versus combined cognitive and physical training with older adults: the SimA study in a 5- year perspective. Eur. J. Aging 3, 179–192. 10.1007/s10433-006-0035-z
    1. Owen A., Hampshire A., Grahn J. A., Stenton R., Dajani S., Burns A. S., et al. . (2010). Putting brain training to the test. Nature 465, 775–778. 10.1038/nature09042
    1. Park H., Poo M. (2013). Neurotrophin regulation of neural circuit development and function. Nat. Rev. Neurosci. 14, 7–23. 10.1038/nrn3379
    1. Párrizas M., Brugnara L., Esteban Y., González-Franquesa A., Canivell S., Murillo S., et al. . (2015). Circulating miR-192 and miR-193b are markers of prediabetes and are modulated by an exercise intervention. J. Clin. Endocrinol. Metab. 100, E407–E415. 10.1210/jc.2014-2574
    1. Payne B. R., Jackson J. J., Noh S. R., Stine-Morrow E. L. (2011). In the zone: Flow state and cognition in older adults. Psychol. Aging 26, 738–743. 10.1037/a0022359
    1. Pereira F. S., Yassuda M. S., Oliveira A. M., Forlenza O. V. (2008). Executive dysfunction correlates with impaired functional status in older adults with varying degrees of cognitive impairment. Int. Psychogeriatr. 20, 1104–1115. 10.1017/S1041610208007631
    1. Pfaffl M. W., Horgan G. W., Dempfle L. (2002). Relative expression software tool (REST (c)) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 30:e36 10.1093/nar/30.9.e36
    1. Phillips C., Baktir M. A., Das D., Lin B., Salehi A. (2015). The link between physical activity and cognitive dysfunction in Alzheimer disease. Phys. Ther. 95, 1046–1060. 10.2522/ptj.20140212
    1. Phillips C., Baktir M. A., Srivatsan M., Salehi A. (2014). Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling. Front. Cell. Neurosci. 8:170. 10.3389/fncel.2014.00170
    1. Podhorna J., Krahnke T., Shear M., Harrison J. E. (2016). Alzheimer's Disease Assessment Scale-Cognitive subscale variants in mild cognitive impairment and mild Alzheimer's disease: change over time and the effect of enrichment strategies. Alzheimer's Res. Ther. 8:8. 10.1186/s13195-016-0170-5
    1. Podsiadlo D., Richardson S. (1991). The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J. Am. Geriatr. Soc. 39, 142–148. 10.1111/j.1532-5415.1991.tb01616.x
    1. Pusic K. M., Pusic A. D., Kraig R. P. (2016). Environmental enrichment stimulates immune cell secretion of exosomes that promote CNS myelination and may regulate inflammation. Cell. Mol. Neurobiol. 36, 313–325. 10.1007/s10571-015-0269-4
    1. Rahe J., Becker J., Fink G. R., Kessler J., Kukolja J., Rahn A., et al. . (2015). Cognitive training with and without additional physical activity in healthy older adults: cognitive effects, neurobiological mechanisms, and prediction of training success. Front. Aging Neurosci. 7:187. 10.3389/fnagi.2015.00187
    1. Raichlen D. A., Alexander G. E. (2014). Exercise, APOE genotype, and the evolution of the human lifespan. Trends Neurosci. 37, 247–255. 10.1016/j.tins.2014.03.001
    1. Read J. L., Shortell S. M. (2011). Interactive games to promote behavior change in prevention and treatment. JAMA 305, 1704–1705. 10.1001/jama.2011.408
    1. Redick T. S., Shipstead Z., Harrison T. L., Hicks K. L., Fried D. E., Hambrick D. Z., et al. . (2013). No evidence of intelligence improvement after working memory training: a randomized, placebo-controlled study. J. Exp. Psychol. Gen. 142, 359–379. 10.1037/a0029082
    1. Rehfeld K., Müller P., Aye N., Schmicker M., Dordevic M., Kaufmann J., et al. . (2017). Dancing or fitness sport? The effects of two training programs on hippocampal plasticity and balance abilities in healthy seniors. Front. Hum. Neurosci. 11:305. 10.3389/fnhum.2017.00305
    1. Reuter M., Schmansky N. J., Rosas H. D., Fischl B. (2012). Within-subject template estimation for unbiased longitudinal image analysis. Neuroimage 62, 1402–1418. 10.1016/j.neuroimage.2012.02.084
    1. Riancho J., Vázquez-Higuera J. L., Pozueta A., Lage C., Kazimierczak M., Bravo M., et al. . (2017). MicroRNA profile in patients with Alzheimer's disease: analysis of miR-9-5p and miR-598 in raw and exosome enriched cerebrospinal fluid samples. J. Alzheimer's Dis. 57, 483–491. 10.3233/JAD-161179
    1. Roberts R., Knopman D. S. (2013). Classification and epidemiology of MCI. Clin. Geriatr. Med. 29, 753–772. 10.1016/j.cger.2013.07.003
    1. Ruigrok A. V., Salimi-Khorshidi G., Lai M., Baron-Cohen S., Lombardo M. V., Tait R. J., et al. . (2014). A meta-analysis of sex differences in human brain structure. Neurosci. Biobehav. Rev. 39, 34–50. 10.1016/j.neubiorev.2013.12.004
    1. Ruijter J. M., Thygesen H. H., Schoneveld O. J., Das A T., Berkhout B., Lamers W. H. (2006). Factor correction as a tool to eliminate between-session variation in replicate experiments: application to molecular biology and retrovirology. Retrovirology 3:2. 10.1186/1742-4690-3-2
    1. Ruijter J. M., Ramakers C., Hoogaars W. M., Karlen Y., Bakker O., van den Hoff M. J., et al. . (2009). Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data. Nucleic Acids Res. 37:e45. 10.1093/nar/gkp045
    1. Russell A. P., Lamon S., Boon H., Wada S., Güller I., Brown E. L., et al. . (2013). Regulation of miRNAs in human skeletal muscle following acute endurance exercise and short-term endurance training. J. Physiol. 591, 4637–4653. 10.1113/jphysiol.2013.255695
    1. Sano M., Ernesto C., Thomas R. G., Klauber M. R., Schafer K., Grundman M., et al. (1997). A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N. Engl. J. Med. 336, 1216–1222. 10.1056/NEJM199704243361704
    1. Satoh M., Ogawa J., Tokita T., Nakaguchi N., Nakao K., Kida H., et al. . (2014). The effects of physical exercise with music on cognitive function of elderly people: Mihama-Kiho Project. PLoS ONE 9:e95230. 10.1371/journal.pone.0095230
    1. Schaefer S., Schumacher V. (2011). The interplay between cognitive and motor functioning in healthy older adults: findings from dual-task studies and suggestions for intervention. Gerontology 57, 239–246. 10.1159/000322197
    1. Schoene D., Lord S. R., Delbaere K., Severino C., Davies T. A., Smith S. T. (2013). A randomized controlled pilot study of home-based step training in older people using videogame technology. PLoS ONE 8:e57734. 10.1371/journal.pone.0057734
    1. Schoene D., Valenzuela T., Lord S. R., de Bruin E. D. (2014). The effect of interactive cognitive-motor training in reducing fall risk in older people: a systematic review. BMC Geriatr. 14:107 10.1186/1471-2318-14-107
    1. Schoene D., Valenzuela T., Toson B., Delbaere K., Severino C., Garcia J., et al. . (2015). Interactive cognitive-motor step training improves cognitive risk factors of falling in older adults - a randomized controlled trial. PLoS ONE 10:e0145161. 10.1371/journal.pone.0145161
    1. Sexton C. E., Betts J. F., Demnitz N., Dawes H., Ebmeier K. P., Johansen-Berg H. (2016). A systematic review of MRI studies examining the relationship between physical fitness and activity and the white matter of the ageing brain. Neuroimage 131, 81–90. 10.1016/j.neuroimage.2015.09.071
    1. Shah T., Verdile G., Sohrabi H., Campbell A., Putland E., Cheetham C., et al. . (2014). A combination of physical activity and computerized brain training improves verbal memory and increases cerebral glucose metabolism in the elderly. Transl. Psychiatry 4:e487. 10.1038/tp.2014.122
    1. Shatil E. (2013). Does combined cognitive training and physical activity training enhance cognitive abilities more than either alone? A four-condition randomized controlled trial among healthy older adults. Front. Aging Neurosci. 5:8. 10.3389/fnagi.2013.00008
    1. Simons D. J., Boot W. R., Charness N., Gathercole S. E., Chabris C. F., Hambrick D. Z., et al. . (2016). Do ‘brain-training’ programs work? Psychol. Sci. Public Interest 17, 103–186. 10.1177/1529100616661983
    1. Smith P. J., Blumenthal J. A., Hoffman B. M., Cooper H., Strauman T. A., et al. (2010). Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized control trials. Psychosom. Med. 72, 239–252. 10.1097/PSY.0b013e3181d14633
    1. Snyder A., Anderson-Hanley C., Arciero P. J. (2012). Virtual and live social facilitation while exergaming: competitiveness moderates effort. J. Sport Exerc. Psychol. 34, 252–259. 10.1123/jsep.34.2.252
    1. Stanmore E., Stubbs B., Vancampfort D., de Bruin E. D., Firth J. (2017). The effect of active video games on cognitive functioning in clinical and non-clinical populations: a meta-analysis of randomized controlled trials. Neurosci. Biobehav. Rev. 78, 34–43. 10.1016/j.neubiorev.2017.04.011
    1. Strauss E., Sherman E. M. S., Spreen O. (2006). A Compendium of Neuropsychological Tests, 3rd Edn New York, NY: Oxford University Press.
    1. Studenski S., Carlson M. C., Fillit H., Greenough W. T., Kramer A., Rebok G. W. (2006). From bedside to bench: does mental and physical activity promote cognitive vitality in late life? Sci. Aging Knowledge Environ. 10:pe21 10.1126/sageke.2006.10.pe21
    1. Styliadis C., Kartsidis P., Paraskevopoulos E., Ioannides A. A., Bamidis P. D. (2015). Neuroplastic effects of combined computerized physical and cognitive training in elderly individuals at risk for dementia: an eLORETA controlled study on resting states. Neural Plast. 2015, 172–192. 10.1155/2015/172192
    1. Suo C., Singh M. F., Gates N., Wen W., Sachdev P., Brodaty H., et al. (2016). Therapeutically relevant structural and functional mechanisms triggered by physical and cognitive exercise. Mol. Psychiatry 21, 1633–1642. 10.1038/mp.2016.19
    1. Suzuki T., Shimada H., Makizako H., Doi T., Yoshida D., Tsutsumimoto K., et al. (2012). Effects of multicomponent exercise on cognitive function in older adults with amnestic mild cognitive impairment: a randomized controlled trial. BMC Neurol. 12:128 10.1186/1471-2377-12-128
    1. Szuhany K. L., Bugatti M., Otto M. W. (2014). A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor. J. Psychiatr. Res. 60, 56–64. 10.1016/j.jpsychires.2014.10.003
    1. Teixeira C. L., Rezende T. J., Weiler M., Nogueira M. H., Campos B. M., Pegoraro L. F., et al. (2016). Relation between aerobic fitness and brain structures in amnestic mild cognitive impairment elderly. Age 38:51 10.1007/s11357-016-9912-3
    1. ten Brinke L. F., Bolandzadeh N., Nagamatsu L. S., Hsu C. L., Davis J. C., Miran-Khan K., et al. . (2015). Aerobic exercise increases hippocampal volume in older women with probable mild cognitive impairment: a 6-month randomised controlled trial. Br. J. Sports Med. 49, 248–254. 10.1136/bjsports-2013-093184
    1. Terry P. C., Lane A. M., Fogarty G. J. (2003). Construct validity of the Profile of Mood States-Adolescents for use with adults. Psychol. Sport Exerc. 4, 125–139. 10.1016/S1469-0292(01)00035-8
    1. Theill N., Schumacher V., Adelsberger R., Martin M., Jäncke L. (2013). Effects of simultaneously performed cognitive and physical training in older adults. BMC Neurosci. 14:103 10.1186/1471-2202-14-103
    1. Thery C., Amigorena S., Raposo G., Clayton A. (2006). Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr. Protoc. Cell. Biol. Chapter 3:Unit 3 22. 10.1002/0471143030.cb0322s30
    1. Thielen J., Kärgel C., Müller B. W., Rasche I., Genius J., Bus B., et al. . (2016). Aerobic activity in the healthy elderly is associated with larger plasticity in memory related brain structures and lower systemic inflammation. Front. Aging Neurosci. 8:319. 10.3389/fnagi.2016.00319
    1. Thomas A. G., Dennis A., Bandettini P. A., Johansen-Berg H. (2012). The effects of aerobic activity on brain structure. Front. Psychol. 3:86. 10.3389/fpsyg.2012.00086
    1. Toril P., Reales J. M., Ballesteros S. (2014). Video game training enhances cognition of older adults: a meta-analytic study. Psychol. Aging 29, 706–716. 10.1037/a0037507
    1. Trachtenberg J. T., Chen B. E., Knott G. W., Feng G., Sanes J. R., Welker E., et al. (2002). Longterm in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420, 788–794. 10.1038/nature01273
    1. Train the Brain Consortium (2017). Randomized trial on the effects of a combined physical/cognitive training in aged MCI subjects: the Train the Brain study. Sci. Rep. 7:39471 10.1038/srep39471
    1. Tsai S., Chen P., Calkins M. J., Wu S., Kuo Y. (2016). Exercise counteracts aging-related memory impairment: a potential role for the astrocytic metabolic shuttle. Front. Aging Neurosci. 8:57. 10.3389/fnagi.2016.00057
    1. Van der Elst W., Van Boxtel M. J., Van Breukelen G. P., Jolles J. (2006). The stroop color-word test: influence of age, sex, and education; and normative data for a large sample across the adult age range. Assessment 13, 62–79. 10.1177/1073191105283427
    1. van Praag H. (2008). Neurogenesis and exercise: past and future directions. Neuromol. Med. 10, 128–140. 10.1007/s12017-008-8028-z
    1. Van Praag H., Shubert T., Zhao C., Gage F. H. (2005). Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. 25, 8680–8685. 10.1523/JNEUROSCI.1731-05.2005
    1. Van Schaik P., Blake J., Pernet F., Spears I., Fencott C. (2008). Virtual augmented exercise gaming for older adults. CyberPsychol. Behav. 11, 103–106. 10.1089/cpb.2007.9925
    1. Vaughan S., Wallis M., Polit D., Steele M., Shum D., Morris N. (2014). The effects of multimodal exercise on cognitive and physical functioning and brain-derived neurotrophic factor in older women: a randomised controlled trial. Age Ageing 43, 623–629. 10.1093/ageing/afu010
    1. Vellas B., Carrie I., Gillette-Guyonnet S., Touchon J., Dantoine T., Dartigues J. F., et al. . (2014). MAPT Study: a multidomain approach for preventing Alzheimer's disease: design and baseline data. J. Prevent. Alzheimer's Dis. 1, 13–22.
    1. Veterans Administration Medical Center (VAMC). (2007). Impaired Decision Making Capacity Screening Assessment Form. Unpublished document. Syracuse, NY: VAMC. Available online at:
    1. Vickers A. J. (2005). Parametric versus non-parametric statistics in the analysis of randomized trials with non-normally distributed data. BMC Med. Res. Methodol. 5:35. 10.1186/1471-2288-5-35
    1. Vidoni E. D., Johnson D. K., Morris J. K., Van Sciver A., Greer C. S., Billinger S. A., et al. . (2015). Dose-response of aerobic exercise on cognition: a community-based, pilot randomized controlled trial. PLoS ONE 10:e0131647. 10.1371/journal.pone.0131647
    1. Vijayakumar N., Whittle S., Yücel M., Dennison M., Simmons J., Allen N. B. (2014). Thinning of the lateral prefrontal cortex during adolescence predicts emotion regulation in females. Soc. Cogn. Affect. Neurosci. 9, 1845–1854. 10.1093/scan/nst183
    1. Vital T. M., Stein A. M., de Melo Coelho F. G., Arantes F. J., Teodorov E., Santos-Galduróz R. F. (2014). Physical exercise and vascular endothelial growth factor (VEGF) in elderly: a systematic review. Arch. Gerontol. Geriatr. 59, 234–239. 10.1016/j.archger.2014.04.011
    1. Voss M. W., Prakash R. S., Erickson K. I., Basak C., Chaddock L., Kim J. S., et al. . (2010). Plasticity of brain networks in a randomized intervention trial of exercise training in older adults. Front. Aging Neurosci. 2:32. 10.3389/fnagi.2010.00032
    1. Voss M., Vivar C., Kramer A. F., van Praag H. (2013). Bridging animal and human models of exercise-induced brain plasticity. Trends Cogn. Sci. 17, 525–544. 10.1016/j.tics.2013.08.001
    1. Wang C., Yu J., Wang H., Tan C., Meng X., Tan L. (2014). Non-pharmacological interventions for patients with mild cognitive impairment: a meta-analysis of randomized controlled trials of cognition-based and exercise interventions. J. Alzheimer's Dis. 42, 663–678. 10.3233/JAD-140660
    1. Wang P., Liu H., Zhu X., Meng T., Li H., Zuo X. (2016). Action video game training for healthy adults: a meta-analytic study. Front. Psychol. 7:907. 10.3389/fpsyg.2016.00907
    1. Wang X., Goh D. H. (2017). Video game acceptance: a meta-analysis of the extended technology acceptance model. Cyberpsychol. Behav. Soc. Netw. 20, 662–671. 10.1089/cyber.2017.0086
    1. Wecker N. S., Kramer J. H., Wisniewski A., Delis D. C., Kaplan E. (2000). Age effects on executive ability. Neuropsychology 14, 409–414. 10.1037/0894-4105.14.3.409
    1. Weinstein A. M., Voss M. W., Prakash R. S., Chaddock L., Szabo A., White S. M., et al. . (2012). The association between aerobic fitness and executive function is mediated by prefrontal cortex volume. Brain Behav. Immun. 26, 811–819. 10.1016/j.bbi.2011.11.008
    1. Willis S. L., Tennstedt S. L., Marsiske M., Ball K., Elias J., Koepke K. M., et al. . (2006). Long-term effects of cognitive training on everyday functional outcomes in older adults. JAMA 296, 2805–2814. 10.1001/jama.296.23.2805
    1. Witwer K. W., Buzás E. I., Bemis L. T., Bora A., Lässer C., Lötvall J., et al. . (2013). Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracell. Vesicles 2. 10.3402/jev.v2i0.20360
    1. Wong C. N., Chaddock-Heyman L., Voss M. W., Burzynska A. Z., Basak C., Erickson K. I., et al. . (2015). Brain activation during dual-task processing is associated with cardiorespiratory fitness and performance in older adults. Front. Aging Neurosci. 7:154. 10.3389/fnagi.2015.00154
    1. Yokoyama H., Okazaki K., Imai D., Yamashina Y., Takeda R., Naghavi N., et al. (2015). The effect of cognitive-motor dual-task training on cognitive function and plasma amyloid beta peptide 42/40 ratio in healthy elderly persons: a randomized controlled trial. BMC Geriatr. 15:60 10.1186/s12877-015-0058-4
    1. Young J., Angevaren M., Rusted J., Tabet N. (2015). Aerobic exercise to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst. Rev. CD005381. 10.1002/14651858.CD005381.pub4
    1. Zatorre R. J., Douglas Fields R., Johansen-Berg H. (2012). Plasticity in gray and white: Neuroimaging changes in brain structure during learning. Nat. Neurosci. 15, 528–536. 10.1038/nn.3045
    1. Zhang R., Zhang Q., Niu J., Lu K., Xie B., Cui D., et al. . (2014). Screening of microRNAs associated with Alzheimer's disease using oxidative stress cell model and different strains of senescence accelerated mice. J. Neurol. Sci. 338, 57–64. 10.1016/j.jns.2013.12.017
    1. Zheng G., Xia R., Zhou W., Tao J., Chen L. (2016). Aerobic exercise ameliorates cognitive function in older adults with mild cognitive impairment: a systematic review and meta-analysis of randomised controlled trials. Brit. J. Sports Med. 10.1136/bjsports-2015-095699 [Epub ahead of print].
    1. Zhu X., Yin S., Lang M., He R., Li J. (2016). The more the better? A meta-analysis on effects of combined cognitive and physical intervention on cognition in healthy older adults. Ageing Res. Rev. 31, 67–79. 10.1016/j.arr.2016.07.003
    1. Zilidou V. I., Konstantinidis E. I., Romanopoulou E. D., Karagianni M., Kartsidis P., Bamidis P. D. (2016). Investigating the effectiveness of physical training through exergames: focus on balance and aerobic protocols, in International Conference on, Technology and Innovation in Sports, Health and Wellbeing (TISHW) (Vila Real: IEEE: ), 1–6.
    1. Zokaei N., MacKellar C., Cepukaityte G., Patai E. Z., Nobre A. C. (2016). Cognitive training in the elderly: bottlenecks and new avenues. J. Cogn. Neurosci. 29, 1473–1482. 10.1162/jocn_a_01080

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