Increased physical activity and higher adherence to a Mediterranean-type diet (MeDi) have been independently associated with reduced risk of Alzheimer’s disease (AD). Their association has not been investigated with the use of biomarkers. This study examines whether, among cognitively normal (NL) individuals, those who are less physically active and show lower MeDi adherence have brain biomarker abnormalities consistent with AD. Methods: Forty-five NL individuals (age 54 ± 11, 71% women) with complete leisure time physical activity (LTA), dietary information, and cross-sectional 3D T1-weigthed MRI, 11C-Pittsburgh Compound B (PiB) and 18F-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) scans were examined. Voxel-wise multivariate partial least square (PLS) regression was used to examine the effects of LTA, MeDi and their interaction on brain biomarkers. Age, gender, ethnicity, education, caloric intake, BMI, family history of AD, Apolipoprotein E (APOE) genotype, presence of hypertension and insulin resistance were examined as confounds. Subjects were dichotomized into more and less physically active (LTA+ vs. LTA-; n = 21 vs. 24), and into higher vs. lower MeDi adherence groups (n = 18 vs. 27) using published scoring methods. Spatial patterns of brain biomarkers that represented the optimal association between the images and the groups were generated for all modalities using voxel-wise multivariate Partial Least Squares (PLS) regression. Results: Groups were comparable for clinical and neuropsychological measures. Independent effects of LTA and MeDi factors were observed in AD-vulnerable brain regions for all modalities (p < 0.001). Increased AD-burden (in particular higher Aβ load and lower glucose metabolism) were observed in LTA- compared to LTA+ subjects, and in MeDi- as compared to MeDi+ subjects. A gradient effect was observed for all modalities so that LTA+/MeDi+ subjects had the highest and LTA+/MeDi+ subjects had the lowest AD-burden (p < 0.001), although the LTA × MeDi interaction was significant only for FDG measures (p < 0.03). Adjusting for covariates did not attenuate these relationships. Conclusion: Lower physical activity and MeDi adherence were associated with increased brain AD-burden among NL individuals, in-dicating that lifestyle factors may modulate AD risk. Studies with larger samples and longitudinal evaluations are needed to determine the predictive power of
References
[1]
Barnes, D.E. and Yaffe, K. (2011) The Projected Effect of Risk Factor Reduction on Alzheimer’s Disease Prevalence. The Lancet Neurology, 10, 819-828. http://dx.doi.org/10.1016/S1474-4422(11)70072-2
[2]
Sperling, R.A., Karlawish, J. and Johnson, K.A. (2013) Preclinical Alzheimer Disease—The Challenges Ahead. Nature Reviews Neurology, 9, 54-58. http://dx.doi.org/10.1038/nrneurol.2012.241
[3]
Jack Jr., C.R., Knopman, D.S., Jagust, W.J., et al. (2010) Hypothetical Model of Dynamic Biomarkers of the Alzheimer’s Pathological Cascade. The Lancet Neurology, 9, 119-128. http://dx.doi.org/10.1016/S1474-4422(09)70299-6
[4]
Gu, Y. and Scarmeas, N. (2011) Dietary Patterns in Alzheimer’s Disease and Cognitive Aging. Current Alzheimer Research, 8, 510-519. http://dx.doi.org/10.2174/156720511796391836
[5]
Scarmeas, N., Stern, Y., Mayeux, R., Manly, J.J., Schupf, N. and Luchsinger, J.A. (2009) Mediterranean Diet and Mild Cognitive Impairment. Archives of Neurology, 66, 216-225. http://dx.doi.org/10.1001/archneurol.2008.536
[6]
Scarmeas, N., Stern, Y., Tang, M.X., Mayeux, R. and Luchsinger, J.A. (2006) Mediterranean Diet and Risk for Alzheimer’s Disease. Annals of Neurology, 59, 912-921. http://dx.doi.org/10.1002/ana.20854
[7]
Trichopoulou, A., Costacou, T., Bamia, C. and Trichopoulos, D. (2003) Adherence to a Mediterranean Diet and Survival in a Greek Population. New England Journal of Medicine, 348, 2599-2608. http://dx.doi.org/10.1056/NEJMoa025039
[8]
Feart, C., Samieri, C., Rondeau, V., et al. (2009) Adherence to a Mediterranean Diet, Cognitive Decline, and Risk of Dementia. JAMA, 302, 638-648. http://dx.doi.org/10.1001/jama.2009.1793
[9]
Mosconi, L., Murray, J., Tsui, W.H., et al. (2014) Mediterranean Diet and Magnetic Resonance Imaging-Assessed Brain Atrophy in Cognitively Normal Individuals at Risk for Alzheimer’s Disease. Journal of Prevention of Alzheimer’s Disease, 1, 1-11.
[10]
Scarmeas, N., Luchsinger, J.A., Stern, Y., et al. (2011) Mediterranean Diet and Magnetic Resonance Imaging-Assessed Cerebrovascular Disease. Annals of Neurology, 69, 257-268. http://dx.doi.org/10.1002/ana.22317
[11]
Gardener, H., Scarmeas, N., Gu, Y., Boden-Albala, B., Elkind, M.S.V., Sacco, R.L., et al. (2012) Mediterranean Diet and White Matter Hyperintensity Volume in the Northern Manhattan Study. Archives of Neurology, 69, 251-256. http://dx.doi.org/10.1001/archneurol.2011.548
[12]
Hillman, C.H., Erickson, K.I. and Kramer, A.F. (2008) Be Smart, Exercise Your Heart: Exercise Effects on Brain and Cognition. Nature Reviews Neuroscience, 9, 58-65. http://dx.doi.org/10.1038/nrn2298
[13]
Hayes, S.M., Hayes, J.P., Cadden, M. and Verfaellie, M. (2013) A Review of Cardiorespiratory Fitness-Related Neuroplasticity in the Aging Brain. Frontiers in Aging Neuroscience, 5, 31. http://dx.doi.org/10.3389/fnagi.2013.00031
[14]
Scarmeas, N., Luchsinger, J.A., Schupf, N., Brickman, A.M., Cosentino, S., Tang, M.X. and Stern, Y. (2009) Physical Activity, Diet, and Risk of Alzheimer Disease. JAMA, 302, 627-637. http://dx.doi.org/10.1001/jama.2009.1144
[15]
Burns, J.M., Cronk, B.B., Anderson, H.S., Donnelly, J.E., Thomas, G.P., Harsha, A., et al. (2008) Cardiorespiratory Fitness and Brain Atrophy in Early Alzheimer Disease. Neurology, 71, 210-216. http://dx.doi.org/10.1212/01.wnl.0000317094.86209.cb
[16]
Head, D., Bugg, J.M., Goate, A.M., Fagan, A.M., Mintun, M.A., Benzinger, T., et al. (2012) Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition. Archives of Neurology, 69, 636-643. http://dx.doi.org/10.1001/archneurol.2011.845
[17]
Honea, R.A., Thomas, G.P., Harsha, A., Anderson, H.S., Donnelly, J.E., Brooks, W.M., et al. (2009) Cardiorespiratory Fitness and Preserved Medial Temporal Lobe Volume in Alzheimer Disease. Alzheimer Disease & Associated Disorders, 23, 188-197. http://dx.doi.org/10.1097/WAD.0b013e31819cb8a2
[18]
Liang, K.Y., Mintun, M.A., Fagan, A.M., Goate, A.M., Bugg, J.M., Holtzman, D.M., et al. (2010) Exercise and Alzheimer’s Disease Biomarkers in Cognitively Normal Older Adults. Annals of Neurology, 68, 311-318. http://dx.doi.org/10.1002/ana.22096
[19]
De Santi, S., Pirraglia, E., Barr, W., Babb, J., Williams, S., Rogers, K., et al. (2008) Robust and Conventional Neuropsychological Norms: Diagnosis and Prediction of Age-Related Cognitive Decline. Neuropsychology, 22, 469-484. http://dx.doi.org/10.1037/0894-4105.22.4.469
[20]
Lann, D. and LeRoith, D. (2007) Insulin Resistance as the Underlying Cause for the Metabolic Syndrome. Medical Clinics of North America, 91, 1063-1077. http://dx.doi.org/10.1016/j.mcna.2007.06.012
[21]
Glodzik, L., Mosconi, L., Tsui, W., de Santi, S., Zinkowski, R., Pirraglia, E., et al. (2012) Alzheimer’s Disease Markers, Hypertension, and Gray Matter Damage in Normal Elderly. Neurobiology of Aging, 33, 1215-1227. http://dx.doi.org/10.1016/j.neurobiolaging.2011.02.012
[22]
Mosconi, L., Brys, M., Switalski, R., Mistur, R., Glodzik, L., Pirraglia, E., et al. (2007) Maternal Family History of Alzheimer’s Disease Predisposes to Reduced Brain Glucose Metabolism. Proceedings of the National Academy of Sciences of the United States of America, 104, 19067-19072. http://dx.doi.org/10.1073/pnas.0705036104
[23]
Hixson, J.E. and Powers, P.K. (1991) Restriction Isotyping of Human Apolipoprotein A-IV: Rapid Typing of Known Isoforms and Detection of a New Isoform That Deletes a Conserved Repeat. Journal of Lipid Research, 32, 1529-1535.
[24]
Taylor, H.L., Jacobs Jr., D.R., Schucker, B., Knudsen, J., Leon, A.S. and Debacker, G. (1978) A Questionnaire for the Assessment of Leisure Time Physical Activities. Journal of Chronic Diseases, 31, 741-755. http://dx.doi.org/10.1016/0021-9681(78)90058-9
[25]
Thompson, P.D., Buchner, D., Pina, I.L., Balady, G.J., Williams, M.A., Marcus, B.H., et al. (2003) Exercise and Physical Activity in the Prevention and Treatment of Atherosclerotic Cardiovascular Disease: A Statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation, 107, 3109-3116. http://dx.doi.org/10.1161/01.CIR.0000075572.40158.77
[26]
Strath, S.J., Kaminsky, L.A., Ainsworth, B.E., Ekelund, U., Freedson, P.S., Gary, R.A., et al. (2013) Guide to the Assessment of Physical Activity: Clinical and Research Applications: A Scientific Statement from the American Heart Association. Circulation, 128, 2259-2279. http://dx.doi.org/10.1161/01.cir.0000435708.67487.da
[27]
Willett, W.C., Sampson, L., Stampfer, M.J., Rosner, B., Bain, C., Witschi, J., et al. (1985) Reproducibility and Validity of a Semiquantitative Food Frequency Questionnaire. American Journal of Epidemiology, 122, 51-65.
[28]
Mosconi, L., Murray, J., Tsui, W., Spector, N., Goldowsky, A., Williams, S., et al. (2014) Brain Imaging of Cognitively Normal Individuals with 2 Parents Affected by Late-Onset AD. Neurology, In Press. http://dx.doi.org/10.1212/WNL.0000000000000181
[29]
Mosconi, L., Andrews, R.D. and Matthews, D.C., the Alzheimer’s Disease Neuroimaging Initiative (2013) Comparing Brain Amyloid Deposition, Glucose Metabolism, and Atrophy in Mild Cognitive Impairment with and without a Family History of Dementia. Journal of Alzheimer’s Disease, 35, 509-524.
[30]
Joshi, A., Koeppe, R.A. and Fessler, J.A. (2009) Reducing between Scanner Differences in Multi-Center PET Studies. Neuroimage, 46, 154-159. http://dx.doi.org/10.1016/j.neuroimage.2009.01.057
[31]
Ashburner, J. and Friston, K.J. (2000) Voxel-Based Morphometry—The Methods. Neuroimage, 11, 805-821. http://dx.doi.org/10.1006/nimg.2000.0582
[32]
Ashburner, J. (2007) A Fast Diffeomorphic Image Registration Algorithm. Neuroimage, 38, 95-113. http://dx.doi.org/10.1016/j.neuroimage.2007.07.007
[33]
Krishnan, A., Williams, L.J., McIntosh, A.R. and Abdi, H. (2011) Partial Least Squares (PLS) Methods for Neuroimaging: A Tutorial and Review. Neuroimage, 56, 455-475. http://dx.doi.org/10.1016/j.neuroimage.2010.07.034
[34]
McIntosh, A.R. and Lobaugh, N.J. (2004) Partial Least Squares Analysis of Neuroimaging Data: Applications and Advances. Neuroimage, 23, S250-S263. http://dx.doi.org/10.1016/j.neuroimage.2004.07.020
[35]
Churchill, N., Spring, R., Abdi, H., Kovacevic, N., McIntosh, A.R. and Strother, S. (2013) The Stability of Behavioral PLS Results in Ill-Posed Neuroimaging Problems. In: Abdi, H., Chin, W., Vinzi, E., Russolillo, G. and Trinchera, L., Eds., New Perspectives in Partial Least Squares and Related Methods, Springer Varlag, New York, 173-185. http://dx.doi.org/10.1007/978-1-4614-8283-3_11
[36]
Scarmeas, N., Stern, Y., Mayeux, R. and Luchsinger, J.A. (2006) Mediterranean Diet, Alzheimer Disease, and Vascular Mediation. Archives of Neurology, 63, 1709-1717. http://dx.doi.org/10.1001/archneur.63.12.noc60109
[37]
Vemuri, P., Lesnick, T.G., Przybelski, S.A., Knopman, D.S., Roberts, R.O., Lowe, V.J., et al. (2012) Effect of Lifestyle Activities on Alzheimer Disease Biomarkers and Cognition. Annals of Neurology, 72, 730-738. http://dx.doi.org/10.1002/ana.23665
[38]
Wirth, M., Haase, C.M., Villeneuve, S., Vogel, J. and Jagust, W.J. (2014) Neuroprotective Pathways: Lifestyle Activity, Brain Pathology, and Cognition in Cognitively Normal Older Adults. Neurobiology of Aging, 35, 1873-1882. http://dx.doi.org/10.1016/j.neurobiolaging.2014.02.015
[39]
Mosconi, L., Tsui, W.H., De Santi, S., Li, J., Rusinek, H., Convit, A., et al. (2005) Reduced Hippocampal Metabolism in MCI and AD: Automated FDG-PET Image Analysis. Neurology, 64, 1860-1867. http://dx.doi.org/10.1212/01.WNL.0000163856.13524.08
[40]
Mosconi, L. (2013) Glucose Metabolism in Normal Aging and Alzheimer’s Disease: Methodological and Physiological Considerations for PET Studies. Clinical and Translational Imaging, 1, 217-233.
[41]
Adlard, P.A., Perreau, V.M., Pop, V. and Cotman, C.W. (2005) Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer’s Disease. The Journal of Neuroscience, 25, 4217-4221. http://dx.doi.org/10.1523/JNEUROSCI.0496-05.2005
[42]
Cotman, C.W., Berchtold, N.C. and Christie, L.A. (2007) Exercise Builds Brain Health: Key Roles of Growth Factor Cascades and Inflammation. Trends in Neurosciences, 30, 464-472. http://dx.doi.org/10.1016/j.tins.2007.06.011
[43]
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. Proceedings of the National Academy of Sciences of the United States of America, 108, 3017-3022. http://dx.doi.org/10.1073/pnas.1015950108
[44]
Swerdlow, R.H. (2012) Mitochondria and Cell Bioenergetics: Increasingly Recognized Components and a Possible Etiologic Cause of Alzheimer’s Disease. Antioxidants & Redox Signaling, 16, 1434-1455. http://dx.doi.org/10.1089/ars.2011.4149
[45]
Tikhonova, L.A., Kaminsky, Y.G., Reddy, V.P., Li, Y., Solomadin, I.N., Kosenko, E.A., et al. (2014) Impact of Amyloid β25-35 on Membrane Stability, Energy Metabolism, and Antioxidant Enzymes in Erythrocytes. American Journal of Alzheimer’s Disease and Other Dementias, Published Online. http://dx.doi.org/10.1177/1533317514534757
[46]
Kaminsky, Y.G., Reddy, V.P., Ashraf, G.M., Ahmad, A., Benberin, V.V., Kosenko, E.A., et al. (2013) Age-Related Defects in Erythrocyte 2,3-Diphosphoglycerate Metabolism in Dementia. Aging and Disease, 4, 244-255. http://dx.doi.org/10.14336/AD.2013.0400244
[47]
Bragin, V., Chemodanova, M., Dzhafarova, N., Bragin, I., Czerniawski, J.L. and Aliev, G. (2005) Integrated Treatment Approach Improves Cognitive Function in Demented and Clinically Depressed Patients. American Journal of Alzheimer’s Disease and Other Dementias, 20, 21-26. http://dx.doi.org/10.1177/153331750502000103
[48]
Aliev, G., Ashraf, G.M., Kaminsky, Y.G., Sheikh, I.A., Sudakov, S.K., Yakhno, N.N., et al. (2013) Implication of the Nutritional and Nonnutritional Factors in the Context of Preservation of Cognitive Performance in Patients with Dementia/Depression and Alzheimer Disease. American Journal of Alzheimer’s Disease and Other Dementias, 28, 660- 670. http://dx.doi.org/10.1177/1533317513504614
