title: Exercise-induced cognitive plasticity, implications for mild cognitive impairment and Alzheimer's disease.
abstract: Lifestyle factors such as intellectual stimulation, cognitive and social engagement, nutrition, and various types of exercise appear to reduce the risk for common age-associated disorders such as Alzheimer's disease (AD) and vascular dementia. In fact, many studies have suggested that promoting physical activity can have a protective effect against cognitive deterioration later in life. Slowing or a deterioration of walking speed is associated with a poor performance in tests assessing psychomotor speed and verbal fluency in elderly individuals. Fitness training influences a wide range of cognitive processes, and the largest positive impact observed is for executive (a.k.a. frontal lobe) functions. Studies show that exercise improves additional cognitive functions such as tasks mediated by the hippocampus, and result in major changes in plasticity in the hippocampus. Interestingly, this exercise-induced plasticity is also pronounced in APOE ε4 carriers who express a risk factor for late-onset AD that may modulate the effect of treatments. Based on AD staging by Braak and Braak (1991) and Braak et al. (1993) we propose that the effects of exercise occur in two temporo-spatial continua of events. The "inward" continuum from isocortex (neocortex) to entorhinal cortex/hippocampus for amyloidosis and a reciprocal "outward" continuum for neurofibrillary alterations. The exercise-induced hypertrophy of the hippocampus at the core of these continua is evaluated in terms of potential for prevention to stave off neuronal degeneration. Exercise-induced production of growth factors such as the brain-derived neurotrophic factor (BDNF) has been shown to enhance neurogenesis and to play a key role in positive cognitive effects. Insulin-like growth factor (IGF-1) may mediate the exercise-induced response to exercise on BDNF, neurogenesis, and cognitive performance. It is also postulated to regulate brain amyloid β (Aβ) levels by increased clearance via the choroid plexus. Growth factors, specifically fibroblast growth factor and IGF-1 receptors and/or their downstream signaling pathways may interact with the Klotho gene which functions as an aging suppressor gene. Neurons may not be the only cells affected by exercise. Glia (astrocytes and microglia), neurovascular units and the Fourth Element may also be affected in a differential fashion by the AD process. Analyses of these factors, as suggested by the multi-dimensional matrix approach, are needed to improve our understanding of this complex multi-factorial process, which is increasingly relevant to conquering the escalating and intersecting world-wide epidemics of dementia, diabetes, and sarcopenia that threaten the global healthcare system. Physical activity and interventions aimed at enhancing and/or mimicking the effects of exercise are likely to play a significant role in mitigating these epidemics, together with the embryonic efforts to develop cognitive rehabilitation for neurodegenerative disorders.
authors: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Medical Branch Galveston, TX, USA.
authors: Philip P
authors: PP
authors: Foster
authors: Kevin P
authors: KP
authors: Rosenblatt
authors: Rodrigo O
authors: RO
authors: Kuljiš
references: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3316-21
references: 14978288
references: Nature. 2010 Mar 25;464(7288):504-12
references: 20336132
references: N Engl J Med. 1980 Jun 12;302(24):1333-43
references: 6990257
references: Neuroscience. 2004;124(1):71-9
references: 14960340
references: J Mol Med (Berl). 2004 Mar;82(3):156-62
references: 14647921
references: Neuropharmacology. 2010 Mar;58(3):561-8
references: 19951717
references: FASEB J. 2010 Jul;24(7):2533-45
references: 20228251
references: J Health Psychol. 2010 Jan;15(1):21-32
references: 20064881
references: Ann Neurol. 1999 Mar;45(3):358-68
references: 10072051
references: Brain Res. 2010 Jun 23;1341:41-51
references: 19560443
references: Brain Res. 2010 Oct 28;1358:172-83
references: 20735996
references: Front Neurol. 2010 Jun 28;1:4
references: 21188250
references: J Alzheimers Dis. 2008 Jul;14(3):329-33
references: 18599959
references: Front Neurol. 2010 Nov 23;1:144
references: 21188267
references: J Neurochem. 1995 Oct;65(4):1740-51
references: 7561872
references: Neurology. 2011 Feb 8;76(6):518-25
references: 21288982
references: Nature. 2008 Jul 24;454(7203):463-9
references: 18650917
references: Exp Neurol. 2003 Nov;184(1):31-9
references: 14637076
references: N Engl J Med. 1980 Jun 5;302(23):1283-92
references: 6154243
references: Ann Neurol. 2010 Sep;68(3):311-8
references: 20818789
references: J Gerontol A Biol Sci Med Sci. 2003 Feb;58(2):176-80
references: 12586857
references: J Neuroinflammation. 2007 Sep 04;4:21
references: 17784957
references: Acta Neuropathol. 1991;82(4):239-59
references: 1759558
references: Nat Neurosci. 1999 Mar;2(3):266-70
references: 10195220
references: Lancet. 1998 Sep 5;352(9130):759-62
references: 9737279
references: N Engl J Med. 1985 Aug 8;313(6):388-9
references: 4010760
references: Eur J Cardiovasc Prev Rehabil. 2007 Dec;14(6):730-9
references: 18043292
references: Proc Natl Acad Sci U S A. 1986 May;83(9):3012-6
references: 3458259
references: J Intern Med. 2004 Sep;256(3):183-94
references: 15324362
references: Nat Rev Neurol. 2010 Dec;6(12):650-1
references: 21131912
references: Nature. 2010 Feb 4;463(7281):657-61
references: 20090680
references: Neuroepidemiology. 2007;28(4):224-34
references: 17878737
references: Neurology. 2010 Oct 12;75(15):1381-7
references: 20938031
references: Nat Med. 2002 Dec;8(12):1390-7
references: 12415260
references: Clin Anat. 1995;8(6):429-31
references: 8713166
references: J Physiol. 2008 Apr 1;586(7):1951-62
references: 18258658
references: Neuroscience. 2010 Dec 29;171(4):1228-40
references: 20875841
references: J Appl Physiol (1985). 2006 Apr;100(4):1124-33
references: 16357073
references: Aging Cell. 2011 Jun;10(3):403-17
references: 21272192
references: Brain Res. 1996 Jul 8;726(1-2):49-56
references: 8836544
references: Lancet Neurol. 2007 Aug;6(8):734-46
references: 17616482
references: Proc Natl Acad Sci U S A. 1985 Oct;82(19):6507-11
references: 3863109
references: Nature. 1995 Jan 12;373(6510):109
references: 7816089
references: Brain Behav Immun. 2011 Feb;25(2):181-213
references: 20970492
references: J Appl Physiol (1985). 2007 Sep;103(3):1093-8
references: 17347387
references: Stroke. 2009 Mar;40(3):983-6
references: 19118241
references: N Engl J Med. 2004 Dec 23;351(26):2694-703
references: 15616204
references: J Neurochem. 2010 Jun;113(5):1221-9
references: 20345761
references: Proc Natl Acad Sci U S A. 1986 Oct;83(19):7297-301
references: 2429303
references: J Cereb Blood Flow Metab. 1993 May;13(3):378-88
references: 8478396
references: J Neurosci. 2005 Apr 27;25(17):4217-21
references: 15858047
references: J Alzheimers Dis. 2011;25(1):29-41
references: 21335659
references: Science. 2007 Jun 15;316(5831):1615-8
references: 17569864
references: FASEB J. 2008 Jul;22(7):2253-62
references: 18263701
references: Nat Rev Neurosci. 2004 May;5(5):347-60
references: 15100718
references: Nature. 2006 Oct 19;443(7113):774-9
references: 17051203
references: J Alzheimers Dis. 2011;25(2):373-81
references: 21460439
references: J Alzheimers Dis. 2010;20(3):699-709
references: 20182020
references: Front Aging Neurosci. 2010 Aug 26;2:
references: 20890449
references: J Neurosci. 2010 Dec 15;30(50):16755-62
references: 21159946
references: Lancet. 2004 Apr 3;363(9415):1139-46
references: 15064035
references: Ann Intern Med. 2006 Jan 17;144(2):73-81
references: 16418406
references: J Biol Chem. 2005 Nov 11;280(45):38029-34
references: 16186101
references: J Gerontol A Biol Sci Med Sci. 2006 Nov;61(11):1166-70
references: 17167157
references: Brain Res. 2010 Feb 22;1315:119-27
references: 20026320
references: J Clin Invest. 2000 Dec;106(12):1489-99
references: 11120756
references: Nature. 2005 Aug 11;436(7052):801-6
references: 15965463
references: Nat Rev Neurosci. 2009 Jan;10(1):9-22
references: 19096367
references: Nature. 1996 May 30;381(6581):425-8
references: 8632799
references: J Neurol Sci. 2007 Sep 15;260(1-2):175-82
references: 17553526
references: J Neuropathol Exp Neurol. 2008 Sep;67(9):842-56
references: 18716559
references: Brain Res. 1997 May 9;756(1-2):205-14
references: 9187334
references: Acta Neuropathol. 2007 Jan;113(1):1-12
references: 17036244
references: Lancet Neurol. 2008 Feb;7(2):161-72
references: 18207114
references: Biol Chem. 2008 Mar;389(3):233-41
references: 18177265
references: Nat Rev Neurol. 2011 Jan;7(1):10-2
references: 21135883
references: J Appl Physiol (1985). 2007 Aug;103(2):693-9
references: 17303714
references: Am J Physiol Heart Circ Physiol. 2002 Jul;283(1):H315-23
references: 12063304
references: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13427-31
references: 10557337
references: Neurochem Res. 2005 Jun-Jul;30(6-7):791-6
references: 16187214
references: Nat Med. 2005 Sep;11(9):959-65
references: 16116430
references: Neurosci Lett. 2004 Jan 23;355(1-2):152-4
references: 14729257
references: Lancet Neurol. 2010 Nov;9(11):1118-27
references: 20934914
references: Glia. 1994 May;11(1):73-80
references: 7520887
references: Front Aging Neurosci. 2010 Jul 21;2:
references: 20725635
references: Brain. 1991 Oct;114 ( Pt 5):2283-301
references: 1933245
references: J Neurochem. 2001 Oct;79(2):311-8
references: 11677259
references: Proc Natl Acad Sci U S A. 1981 Nov;78(11):7205-9
references: 6458820
references: Acta Neuropathol. 1994;87(6):554-67
references: 7522386
references: Neuron. 1991 Dec;7(6):1031-41
references: 1662517
references: Neurosci Lett. 2004 Aug 5;366(1):80-5
references: 15265595
references: Front Aging Neurosci. 2010 Jul 21;2:
references: 20725636
references: PLoS One. 2010 Aug 16;5(8):e12188
references: 20808440
references: Psychol Sci. 2003 Mar;14(2):125-30
references: 12661673
references: Arch Neurol. 2009 Mar;66(3):382-9
references: 19273758
references: Mol Neurobiol. 2003 Apr;27(2):153-62
references: 12777685
references: J Appl Physiol (1985). 2002 Jul;93(1):3-30
references: 12070181
references: Am J Physiol Endocrinol Metab. 2006 Dec;291(6):E1258-63
references: 16835397
references: Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):961-5
references: 1992488
references: Alzheimers Dement. 2009 Jul;5(4):287-94
references: 19560099
references: Exp Gerontol. 2009 Sep;44(9):579-85
references: 19539742
references: Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9444-8
references: 1409655
references: Hippocampus. 2010 Jun;20(6):706-12
references: 19603528
references: J Neurochem. 2007 Dec;103(6):2471-81
references: 17953674
references: J Appl Physiol (1985). 2007 Jul;103(1):376-7
references: 17446409
references: Proc Natl Acad Sci U S A. 1990 Jul;87(14):5568-72
references: 1695380
references: Neurology. 2005 Feb 8;64(3):494-500
references: 15699381
references: J Biol Chem. 2006 Mar 10;281(10):6120-3
references: 16436388
references: Neurobiol Aging. 2006 Sep;27(9):1250-7
references: 16183170
references: Science. 1972 Jun 30;176(4042):1445-7
references: 5033647
references: Nature. 2000 May 11;405(6783):187-91
references: 10821275
references: J Appl Physiol (1985). 2006 Oct;101(4):1237-42
references: 16778001
references: Lancet. 1979 Jan;1(8107):72-5
references: 84129
references: J Neuroinflammation. 2006 Mar 16;3:5
references: 16542445
references: Science. 1997 Oct 17;278(5337):419-24
references: 9334293
references: Pflugers Arch. 2009 Mar;457(5):963-77
references: 18704490
references: J Alzheimers Dis. 2011;23(2):281-91
references: 21178286
references: J Neurosci. 2010 Apr 14;30(15):5368-75
references: 20392958
references: Front Aging Neurosci. 2010 Aug 13;2:
references: 20802804
references: Am J Epidemiol. 2005 Apr 1;161(7):639-51
references: 15781953
references: Science. 2003 Apr 18;300(5618):486-9
references: 12702875
references: J Gerontol A Biol Sci Med Sci. 2009 Oct;64(10):1058-65
references: 19561146
references: J Neurocytol. 1986 Feb;15(1):53-61
references: 3711940
references: J Neurosci. 2001 Aug 1;21(15):5678-84
references: 11466439
references: J Alzheimers Dis. 2010;22(1):17-36
references: 20847414
references: Aging (Albany NY). 2010 Sep;2(9):597-611
references: 20844314
references: J Neurosci. 2001 Mar 1;21(5):1628-34
references: 11222653
references: Circ Res. 2002 Jun 14;90(11):1197-204
references: 12065323
references: Endocrinology. 1985 Dec;117(6):2383-91
references: 4065037
references: Stroke. 2004 Nov;35(11 Suppl 1):2616-9
references: 15459438
references: Eur Neurol. 1993;33(6):403-8
references: 8307060
references: Lancet Neurol. 2010 Jan;9(1):119-28
references: 20083042
references: Curr Sports Med Rep. 2003 Oct;2(5):239-42
references: 12959703
references: Proc Natl Acad Sci U S A. 1986 Oct;83(19):7537-41
references: 3463983
references: Nat Rev Neurol. 2009 Jun;5(6):305-6
references: 19498432
references: Behav Brain Res. 2011 Jan 1;216(1):270-4
references: 20709113
references: Lancet. 1996 Feb 10;347(8998):405
references: 8598736
references: Arch Neurol. 2006 May;63(5):665-72
references: 16682536
references: Trends Neurosci. 2002 Jun;25(6):295-301
references: 12086747
references: Neurology. 2009 Sep 15;73(11):847-53
references: 19752451
references: Neurobiol Aging. 2006 Nov;27(11):1618-31
references: 16274856
references: Am J Physiol Regul Integr Comp Physiol. 2010 Apr;298(4):R912-7
references: 20106991
references: Med Hypotheses. 2009 Sep;73(3):315-8
references: 19394151
references: Lancet Neurol. 2004 Mar;3(3):184-90
references: 14980533
references: Mol Cell Neurosci. 2010 Jun;44(2):109-17
references: 20206269
references: Exp Gerontol. 2011 Jan;46(1):53-9
references: 20951791
references: Arch Intern Med. 2008 Feb 11;168(3):284-90
references: 18268169
references: PLoS One. 2009 Nov 20;4(11):e7934
references: 19936205
references: Neurochem Int. 2010 Nov;57(4):440-5
references: 20193723
references: Ann N Y Acad Sci. 2000;924:53-61
references: 11193802
references: Brain Res. 2011 Jan 31;1371:161-70
references: 21112317
references: Neuroimage. 2007 Feb 1;34(3):1238-44
references: 17134916
references: Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):3017-22
references: 21282661
references: Science. 2010 Dec 24;330(6012):1774
references: 21148344
references: Endocrinology. 1986 Jan;118(1):82-90
references: 3940857
references: Med Sci Sports Exerc. 2010 Dec;42(12):2173-9
references: 20404768
references: Lancet Neurol. 2010 Apr;9(4):363-72
references: 20189881
references: J Neurocytol. 1982 Dec;11(6):967-83
references: 7153792
references: Neurology. 2003 Nov 11;61(9):1185-90
references: 14610118
references: Front Neurol. 2010 Aug 26;1:15
references: 21188254
references: Scand J Med Sci Sports. 2012 Apr;22(2):240-8
references: 21204993
references: Ann N Y Acad Sci. 2009 Feb;1153:240-6
references: 19236346
references: J Intern Med. 2004 Sep;256(3):240-6
references: 15324367
references: Stroke. 2004 Nov;35(11 Suppl 1):2620-2
references: 15375299
references: Neurology. 2007 Apr 10;68(15):1223-6
references: 17420407
references: Nature. 1997 Nov 6;390(6655):45-51
references: 9363890
references: Stroke. 2008 Mar;39(3):814-21
references: 18258839
references: Neuroscience. 2003;117(4):1037-46
references: 12654355
references: Arch Neurol. 2010 Aug;67(8):949-56
references: 20697045
references: Neuroscience. 2010 May 19;167(3):588-97
references: 20219647
references: Neuroimage. 2011 Mar 15;55(2):522-31
references: 21195775
references: J Alzheimers Dis. 2011;23(2):307-18
references: 21098985
references: Nature. 1988 Mar 24;332(6162):360-1
references: 3352734
references: Am J Physiol Endocrinol Metab. 2010 Aug;299(2):E145-61
references: 20371735
references: Nature. 2006 Oct 19;443(7113):768-73
references: 17051202
references: Science. 2005 Sep 16;309(5742):1829-33
references: 16123266
references: Physiol Rev. 2000 Jul;80(3):1055-81
references: 10893431
references: Nature. 2000 Jul 13;406(6792):195-9
references: 10910361
references: Am J Physiol Endocrinol Metab. 2005 Apr;288(4):E782-8
references: 15585585
references: J Appl Physiol (1985). 1994 Oct;77(4):1913-8
references: 7836218
references: Brain. 1990 Dec;113 ( Pt 6):1823-42
references: 2276046
references: J Neurosci. 1989 Nov;9(11):3728-40
references: 2585052
references: Stroke. 2004 Nov;35(11 Suppl 1):2623-7
references: 15375298
references: Brain Res. 2011 Jan 19;1369:21-35
references: 21040713