Damaging effects of a high-fat diet to the brain and cognition: A review of proposed mechanisms

Nutritional Neuroscience

Volumn 17, Issue 6, 2014, Pages 241-251

  Freeman, Linnea R ^a   Haley Zitlin, Vivian ^b   Rosenberger, Dorothea S ^a   Granholm, Ann Charlotte ^a  

^a MEDICAL UNIVERSITY OF SOUTH CAROLINA   (United States)

^b CLEMSON UNIVERSITY   (United States)

Author keywords

Brain Health; Cerebrovascularization; Cognition; Inflammation; Obesity

Indexed keywords

GLUTATHIONE; INTERLEUKIN 1; OMEGA 6 FATTY ACID; TRIACYLGLYCEROL; TUMOR NECROSIS FACTOR ALPHA;

BRAIN DAMAGE; CARBOHYDRATE DIET; COGNITION; DEMENTIA; HIPPOCAMPUS; HUMAN; INFLAMMATION; INSULIN RESISTANCE; LIPID DIET; METABOLIC SYNDROME X; MICROGLIA; MINI MENTAL STATE EXAMINATION; NERVOUS SYSTEM INFLAMMATION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; OXIDATIVE STRESS; PREVALENCE; RADIAL ARM MAZE TEST; REVIEW; RISK FACTOR; VASCULARIZATION; ADVERSE EFFECTS; BRAIN; COGNITION DISORDERS; COMPLICATION; PATHOPHYSIOLOGY; PHYSIOLOGY; UNITED STATES;

BRAIN; COGNITION; COGNITION DISORDERS; DEMENTIA; DIET, HIGH-FAT; HUMANS; INSULIN RESISTANCE; OBESITY; OXIDATIVE STRESS; PREVALENCE; UNITED STATES;

EID: 84919461635     PISSN: 1028415X     EISSN: 14768305     Source Type: Journal    
DOI: 10.1179/1476830513Y.0000000092     Document Type: Review

References (132)

1. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among us adults, 1999-2008. JAMA 2010;303:235-41.
2. Wang Y, Beydoun MA. The obesity epidemic in the united states-gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. Epidemiol Rev 2007;29:6-28.
3. Bray GA. Obesity: basic considerations and clinical approaches. Dis Mon 1989;35:449-537.
4. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among us adults, 1999-2010. JAMA 2012;307:491-7.
5. Runge CF. Economic consequences of the obese. Diabetes 2007;56:2668-72.
6. Malnick SD, Knobler H. The medical complications of obesity. QJM 2006;99:565-79.
7. Fung TT, Rimm EB, Spiegelman D, Rifai N, Tofler GH, Willett WC, et al. Association between dietary patterns and plasma biomarkers of obesity and cardiovascular disease risk. Am J Clin Nutr 2001;73:61-7.
8. Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, et al. Origins and evolution of the western diet: health implications for the 21st century. Am J Clin Nutr 2005;81:341-54.
9. Demigne C, Bloch-Faure M, Picard N, Sabboh H, Besson C, Remesy C, et al. Mice chronically fed a westernized experimental diet as a model of obesity, metabolic syndrome and osteoporosis. Eur J Nutr 2006;45:298-306.
10. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747-57.
11. Simopoulos AP. The importance of the ratio of omega-6/ omega-3 essential fatty acids. Biomed Pharmacother 2002;56: 365-79.
12. Subar AF, Krebs-Smith SM, Cook A, Kahle LL. Dietary sources of nutrients among us adults, 1989 to 1991. J Am Diet Assoc 1998;98:537-47.
13. Eaton SB, Konner M, Shostak M. Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Am J Med 1988;84:739-49.
14. Kalmijn S, Launer LJ, Ott A, Witteman JC, Hofman A, Breteler MM. Dietary fat intake and the risk of incident dementia in the rotterdam study. Ann Neurol 1997;42:776-82.
15. Luchsinger JA, Tang MX, Shea S, Mayeux R. Caloric intake and the risk of Alzheimer disease. Arch Neurol 2002;59: 1258-63.
16. Elias MF, Elias PK, Sullivan LM, Wolf PA, D’Agostino RB. Lower cognitive function in the presence of obesity and hypertension: the framingham heart study. Int J Obes Relat Metab Disord 2003;27:260-8.
17. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the us population: prevalence estimates using the 2000 census. Arch Neurol 2003;60:1119-22.
18. Solfrizzi V, Panza F, Capurso A. The role of diet in cognitive decline. J Neural Transm 2003;110:95-110.
19. Parrott MD, Greenwood CE. Dietary influences on cognitive function with aging: from high-fat diets to healthful eating. Ann N Y Acad Sci 2007;1114:389-97.
20. Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol 2009;66:300-5.
21. Greenwood CE, Winocur G. Learning and memory impairment in rats fed a high saturated fat diet. Behav Neural Biol 1990;53:74-87.
22. Winocur G, Greenwood CE, Piroli GG, Grillo CA, Reznikov LR, Reagan LP, et al. Memory impairment in obese zucker rats: an investigation of cognitive function in an animal model of insulin resistance and obesity. Behav Neurosci 2005; 119:1389-95.
23. Greenwood CE, Winocur G. High-fat diets, insulin resistance and declining cognitive function. Neurobiol Aging 2005;26 (Suppl 1):42-5.
24. Winocur G, Greenwood CE. Studies of the effects of high fat diets on cognitive function in a rat model. Neurobiol Aging 2005;26 (Suppl 1):46-9.
25. Kaplan RJ, Greenwood CE, Winocur G, Wolever TM. Dietary protein, carbohydrate, and fat enhance memory performance in the healthy elderly. Am J Clin Nutr 2001;74:687-93.
26. Greenwood CE, Winocur G. Glucose treatment reduces memory deficits in young adult rats fed high-fat diets. Neurobiol Learn Mem 2001;75:179-89.
27. Kaplan RJ, Greenwood CE, Winocur G, Wolever TM. Cognitive performance is associated with glucose regulation in healthy elderly persons and can be enhanced with glucose and dietary carbohydrates. Am J Clin Nutr 2000;72:825-36.
28. Winocur G, Greenwood CE. The effects of high fat diets and environmental influences on cognitive performance in rats. Behav Brain Res 1999;101:153-61.
29. Greenwood CE, Winocur G. Cognitive impairment in rats fed high-fat diets: a specific effect of saturated fatty-acid intake. Behav Neurosci 1996;110:451-9.
30. Granholm AC, Bimonte-Nelson HA, Moore AB, Nelson ME, Freeman LR, Sambamurti K. Effects of a saturated fat and high cholesterol diet on memory and hippocampal morphology in the middle-aged rat. J Alzheimers Dis 2008;14:133-45.
31. Wu A, Ying Z, Gomez-Pinilla F. The interplay between oxi-dative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition. Eur J Neurosci 2004;19:1699-707.
32. McNeilly AD, Williamson R, Sutherland C, Balfour DJ, Stewart CA. High fat feeding promotes simultaneous decline in insulin sensitivity and cognitive performance in a delayed matching and non-matching to position task. Behav Brain Res 2011;217:134-41.
33. Stranahan AM, Norman ED, Lee K, Cutler RG, Telljohann RS, Egan JM, et al. Diet-induced insulin resistance impairs hip-pocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus 2008;18:1085-8.
34. Freeman LR, Haley-Zitlin V, Stevens C, Granholm AC. Diet-induced effects on neuronal and glial elements in the middle-aged rat hippocampus. Nutr Neurosci 2011;14:32-44.
35. Morrison CD, Pistell PJ, Ingram DK, Johnson WD, Liu Y, Fernandez-Kim SO, et al. High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased nrf2 signaling. J Neurochem 2010;114: 1581-9.
36. McNeilly AD, Williamson R, Balfour DJ, Stewart CA, Sutherland C. A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with met-formin. Diabetologia 2012;55:3061-70.
37. Alzoubi KH, Khabour OF, Salah HA, Hasan Z. Vitamin e prevents high-fat high-carbohydrates diet-induced memory impairment: the role of oxidative stress. Physiol Behav 2013;119C: 72-78.
38. Freeman LR, Zhang L, Nair A, Dasuri K, Francis J, Fernandez-Kim SO, et al. Obesity increases cerebrocortical reactive oxygen species and impairs brain function. Free Radic Biol Med 2013;56:226-33.
39. Davidson TL, Monnot A, Neal AU, Martin AA, Horton JJ, Zheng W. The effects of a high-energy diet on hippocampal-dependent discrimination performance and blood-brain barrier integrity differ for diet-induced obese and diet-resistant rats. Physiol Behav 2012;107:26-33.
40. Kalmijn S, Feskens EJ, Launer LJ, Kromhout D. Polyunsaturated fatty acids, antioxidants, and cognitive function in very old men. Am J Epidemiol 1997;145:33-41.
41. Ortega RM, Requejo AM, Andres P, Lopez-Sobaler AM, Quintas ME, Redondo MR, et al. Dietary intake and cognitive function in a group of elderly people. Am J Clin Nutr 1997;66: 803-9.
42. Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS. Dietary fat intake and 6-year cognitive change in an older bira-cial community population. Neurology 2004;62:1573-9.
43. Zhang J, McKeown RE, Muldoon MF, Tang S. Cognitive performance is associated with macronutrient intake in healthy young and middle-aged adults. Nutr Neurosci 2006;9:179-87.
44. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, et al. Dietary fats and the risk of incident Alzheimer disease. Arch Neurol 2003;60:194-200.
45. Uranga RM, Bruce-Keller AJ, Morrison CD, Fernandez-Kim SO, Ebenezer PJ, Zhang L, et al. Intersection between metabolic dysfunction, high fat diet consumption, and brain aging. J Neurochem 2010;114:344-61.
46. Requejo AM, Ortega RM, Robles F, Navia B, Faci M, Aparicio A. Influence of nutrition on cognitive function in a group of elderly, independently living people. Eur J Clin Nutr 2003;57 (Suppl 1):S54-7.
47. Kalmijn S. Fatty acid intake and the risk of dementia and cognitive decline: a review of clinical and epidemiological studies. J Nutr Health Aging 2000;4:202-7.
48. Uranga RM, Keller JN. Diet and age interactions with regards to cholesterol regulation and brain pathogenesis. Curr Gerontol Geriatr Res 2010; 14 pages. 219683.
49. Schioth HB, Craft S, Brooks SJ, Frey WH, II, Benedict C. Brain insulin signaling and Alzheimer’s disease: current evidence and future directions. Mol Neurobiol 2012;46:4-10.
50. Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol 2011;68:51-7.
51. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 2012;69:29-38.
52. Nagai T, Yamada K, Kim HC, Kim YS, Noda Y, Imura A, et al. Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB J 2003;17:50-2.
53. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, et al. Gene regulation and DNA damage in the ageing human brain. Nature 2004;429:883-91.
54. Lockrow J, Prakasam A, Huang P, Bimonte-Nelson H, Sambamurti K, Granholm AC. Cholinergic degeneration and memory loss delayed by vitamin e in a down syndrome mouse model. Exp Neurol 2009;216:278-89.
55. Beltowski J, Wojcicka G, Gorny D, Marciniak A. The effect of dietary-induced obesity on lipid peroxidation, antioxidant enzymes and total plasma antioxidant capacity. J Physiol Pharmacol 2000;51:883-96.
56. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev 2011;91:461-553.
57. Merrill JE, Murphy SP. Inflammatory events at the blood brain barrier: regulation of adhesion molecules, cytokines, and che-mokines by reactive nitrogen and oxygen species. Brain Behav Immun 1997;11:245-63.
58. Parnet P, Kelley KW, Bluthe RM, Dantzer R. Expression and regulation of interleukin-1 receptors in the brain. Role in cyto-kines-induced sickness behavior. J Neuroimmunol 2002;125: 5-14.
59. Gibertini M. Il1 beta impairs relational but not procedural rodent learning in a water maze task. Adv Exp Med Biol 1996;402:207-17.
60. Gemma C, Bickford PC. Interleukin-1beta and caspase-1: players in the regulation of age-related cognitive dysfunction. Rev Neurosci 2007;18:137-48.
61. Song C, Phillips AG, Leonard BE, Horrobin DF. Ethyl-eicosa-pentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by central administration of inter-leukin-1beta in rats. Mol Psychiatry 2004;9:630-8.
62. Gemma C, Stellwagen H, Fister M, Coultrap SJ, Mesches MH, Browning MD, et al. Rosiglitazone improves contextual fear conditioning in aged rats. Neuroreport 2004;15:2255-9.
63. Palin K, Bluthe RM, Verrier D, Tridon V, Dantzer R, Lestage J. Interleukin-1beta mediates the memory impairment associated with a delayed type hypersensitivity response to bacillus calmette-guerin in the rat hippocampus. Brain Behav Immun 2004;18:223-30.
64. Neumann H, Schweigreiter R, Yamashita T, Rosenkranz K, Wekerle H, Barde YA. Tumor necrosis factor inhibits neurite outgrowth and branching of hippocampal neurons by a rho-dependent mechanism. J Neurosci 2002;22:854-62.
65. Murray CA, Lynch MA. Evidence that increased hippocampal expression of the cytokine interleukin-1 beta is a common trigger for age- and stress-induced impairments in long-term potentiation. J Neurosci 1998;18:2974-81.
66. Barrientos RM, Sprunger DB, Campeau S, Watkins LR, Rudy JW, Maier SF. Bdnf mrna expression in rat hippocampus following contextual learning is blocked by intrahippocampal il-1beta administration. J Neuroimmunol 2004;155:119-26.
67. Thirumangalakudi L, Prakasam A, Zhang R, Bimonte-Nelson H, Sambamurti K, Kindy MS, et al. High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice. J Neurochem 2008;106:475-85.
68. Pistell PJ, Morrison CD, Gupta S, Knight AG, Keller JN, Ingram DK, et al. Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol 2010;219:25-32.
69. Freeman LR, Granholm AC. Vascular changes in rat hippocampus following a high saturated fat and cholesterol diet. J Cereb Blood Flow Metab 2012;32:643-53.
70. Freeman LR, Small BJ, Bickford PC, Umphlet C, Granholm AC. A high fat/high cholesterol diet inhibits growth of fetal hip-pocampal transplants via increased inflammation. Cell Transplant 2011;20:1499-514.
71. Nakajima K, Kohsaka S, Tohyama Y, Kurihara T. Activation of microglia with lipopolysaccharide leads to the prolonged decrease of conventional protein kinase c activity. Brain Res Mol Brain Res 2003;110:92-9.
72. Matsushita Y, Nakajima K, Tohyama Y, Kurihara T, Kohsaka S. Activation of microglia by endotoxin suppresses the secretion of glial cell line-derived neurotrophic factor (gdnf) through the action of protein kinase c alpha (pkcalpha) and mitogen-acti-vated protein kinases (mapks). J Neurosci Res 2008;86: 1959-71.
73. Morgan D, Gordon MN, Tan J, Wilcock D, Rojiani AM. Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: implications for Alzheimer therapeutics. J Neuropathol Exp Neurol 2005;64: 743-53.
74. Michelucci A, Heurtaux T, Grandbarbe L, Morga E, Heuschling P. Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: effects of oligomeric and fibrillar amyloid-beta. J Neuroimmunol 2009;210:3-12.
75. Buckman LB, Hasty AH, Flaherty DK, Buckman CT, Thompson MM, Matlock BK, et al. Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system. Brain Behav Immun 2013.
76. Constantinescu E, Safciuc F, Sima AV. A hyperlipidemic diet induces structural changes in cerebral blood vessels. Curr Neurovasc Res 2011;8:131-44.
77. Franciosi S, Gama Sosa MA, English DF, Oler E, Oung T, Janssen WG, et al. Novel cerebrovascular pathology in mice fed a high cholesterol diet. Mol Neurodegener 2009;4:42.
78. Kanoski SE, Zhang Y, Zheng W, Davidson TL. The effects of a high-energy diet on hippocampal function and blood-brain barrier integrity in the rat. J Alzheimers Dis 2010;21:207-19.
79. Katsu M, Niizuma K, Yoshioka H, Okami N, Sakata H, Chan PH. Hemoglobin-induced oxidative stress contributes to matrix metalloproteinase activation and blood-brain barrier dysfunction in vivo. J Cereb Blood Flow Metab 2010;30:1939-50.
80. Sheen SH, Kim JE, Ryu HJ, Yang Y, Choi KC, Kang TC. Decrease in dystrophin expression prior to disruption of brain-blood barrier within the rat piriform cortex following status epilepticus. Brain Res 2011;1369:173-83.
81. del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab 2003;23:879-94.
82. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis 2010;37:13-25.
83. Mattson MP, Chan SL, Duan W. Modification of brain aging and neurodegenerative disorders by genes, diet, and behavior. Physiol Rev 2002;82:637-72.
84. Streit WJ. Microglia and Alzheimer’s disease pathogenesis. J Neurosci Res 2004;77:1-8.
85. Tuppo EE, Arias HR. The role of inflammation in Alzheimer’s disease. Int J Biochem Cell Biol 2005;37:289-305.
86. Ye SM, Johnson RW. An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. Neuroimmunomodulation 2001;9: 183-92.
87. Terao A, Apte-Deshpande A, Dousman L, Morairty S, Eynon BP, Kilduff TS, et al. Immune response gene expression increases in the aging murine hippocampus. J Neuroimmunol 2002;132:99-112.
88. Uz T, Pesold C, Longone P, Manev H. Aging-associated up-regulation of neuronal 5-lipoxygenase expression: putative role in neuronal vulnerability. Faseb J 1998;12:439-49.
89. Manev H, Uz T, Sugaya K, Qu T. Putative role of neuronal 5-lipoxygenase in an aging brain. Faseb J 2000;14:1464-9.
90. Giunta S. Exploring the complex relations between inflammation and aging (inflamm-aging): anti-inflamm-aging remodelling of inflamm- aging, from robustness to frailty. Inflamm Res 2008;57:558-63.
91. Giunta B, Fernandez F, Nikolic WV, Obregon D, Rrapo E, Town T, et al. Inflammaging as a prodrome to Alzheimer’s disease. J Neuroinflammation 2008;5:51.
92. Desai A, Grolleau-Julius A, Yung R. Leukocyte function in the aging immune system. J Leukoc Biol 2010;87:1001-9.
93. Perry VH, Bolton SJ, Anthony DC, Betmouni S. The contribution of inflammation to acute and chronic neurodegenera-tion. Res Immunol 1998;149:721-5.
94. Buchanan JB, Sparkman NL, Chen J, Johnson RW. Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice. Psychoneuroendocrinology 2008;33:755-65.
95. Craighead MW, Boutin H, Middlehurst KM, Allan SM, Brooks N, Kimber I, et al. Influence of corticotrophin releasing factor on neuronal cell death in vitro and in vivo. Brain Res 2000;881:139-43.
96. Allan SM, Rothwell NJ. Cytokines and acute neurodegenera-tion. Nat Rev Neurosci 2001;2:734-44.
97. McAfoose J, Baune BT. Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev 2009;33:355-66.
98. Lynch MA. Age-related impairment in long-term potentiation in hippocampus: a role for the cytokine, interleukin-1 beta Prog Neurobiol 1998;56:571-89.
99. Lynch AM, Lynch MA. The age-related increase in il-1 type i receptor in rat hippocampus is coupled with an increase in caspase-3 activation. Eur J Neurosci 2002;15:1779-88.
100. Lynch MA. Interleukin-1 beta exerts a myriad of effects in the brain and in particular in the hippocampus: analysis of some of these actions. Vitam Horm 2002;64:185-219.
101. Trompet S, de Craen AJ, Slagboom P, Shepherd J, Blauw GJ, Murphy MB, et al. Genetic variation in the interleukin-1 beta-converting enzyme associates with cognitive function. The prosper study. Brain 2008;131:1069-77.
102. Rivard A, Fabre JE, Silver M, Chen D, Murohara T, Kearney M, et al. Age-dependent impairment of angiogenesis. Circulation 1999;99:111-20.
103. Blennow K, Fredman P, Wallin A, Gottfries CG, Skoog I, Wikkelso C, et al. Protein analysis in cerebrospinal fluid. Iii. Relation to blood-cerebrospinal fluid barrier function for formulas for quantitative determination of intrathecal igg production. Eur Neurol 1993;33:134-42.
104. Toornvliet R, van Berckel BN, Luurtsema G, Lubberink M, Geldof AA, Bosch TM, et al. Effect of age on functional p-gly-coprotein in the blood-brain barrier measured by use of (r)-[(11)c]verapamil and positron emission tomography. Clin Pharmacol Ther 2006;79:540-8.
105. d’Alessio P. Aging and the endothelium. Exp Gerontol 2004;39: 165-71.
106. Schlaich MP, Parnell MM, Ahlers BA, Finch S, Marshall T, Zhang WZ, et al. Impaired l-arginine transport and endothelial function in hypertensive and genetically predisposed normoten-sive subjects. Circulation. 2004;110:3680-6.
107. Brandes RP, Fleming I, Busse R. Endothelial aging. Cardiovasc Res. 2005;66:286-94.
108. Yasui F, Ishibashi M, Matsugo S, Kojo S, Oomura Y, Sasaki K. Brain lipid hydroperoxide level increases in senescence-accelerated mice at an early age. Neurosci Lett 2003;350:66-8.
109. Baumbach GL, Dobrin PB, Hart MN, Heistad DD. Mechanics of cerebral arterioles in hypertensive rats. Circ Res 1988;62: 56-64.
110. Nag S, Takahashi JL, Kilty DW. Role of vascular endothelial growth factor in blood-brain barrier breakdown and angiogen-esis in brain trauma. J Neuropathol Exp Neurol 1997;56: 912-21.
111. Nag S, Kilty DW. Cerebrovascular changes in chronic hypertension. Protective effects of enalapril in rats. Stroke 1997;28: 1028-34.
112. Meyer JS, Kawamura J, Terayama Y. White matter lesions in the elderly. J Neurol Sci 1992;110:1-7.
113. Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, et al. Pathologic correlates of incidental mri white matter signal hyperintensities. Neurology 1993;43:1683-9.
114. Jeerakathil T, Wolf PA, Beiser A, Hald JK, Au R, Kase CS, et al. Cerebral microbleeds: prevalence and associations with cardiovascular risk factors in the Framingham study. Stroke 2004;35:1831-5.
115. Jeerakathil T, Wolf PA, Beiser A, Massaro J, Seshadri S, D’Agostino RB, et al. Stroke risk profile predicts white matter hyperintensity volume: the framingham study. Stroke 2004;35:1857-61.
116. Gouw AA, van der Flier WM, Pantoni L, Inzitari D, Erkinjuntti T, Wahlund LO, et al. On the etiology of incident brain lacunes: longitudinal observations from the ladis study. Stroke 2008;39:3083-5.
117. Gouw AA, Seewann A, Vrenken H, van der Flier WM, Rozemuller JM, Barkhof F, et al. Heterogeneity of white matter hyperintensities in Alzheimer’s disease: post-mortem quantitative MRI and neuropathology. Brain 2008;131: 3286-98.
118. de Groot JC, de Leeuw FE, Oudkerk M, Hofman A, Jolles J, Breteler MM. Cerebral white matter lesions and subjective cognitive dysfunction: the rotterdam scan study. Neurology 2001; 56:1539-45.
119. Pico F, Dufouil C, Levy C, Besancon V, de Kersaint-Gilly A, Bonithon-Kopp C, et al. Longitudinal study of carotid atherosclerosis and white matter hyperintensities: the eva-mri cohort. Cerebrovasc Dis 2002;14:109-15.
120. Moody DM, Thore CR, Anstrom JA, Challa VR, Langefeld CD, Brown WR. Quantification of afferent vessels shows reduced brain vascular density in subjects with leukoaraiosis. Radiology 2004;233:883-90.
121. Markus HS, Hunt B, Palmer K, Enzinger C, Schmidt H, Schmidt R. Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities: longitudinal results of the Austrian stroke prevention study. Stroke. 2005;36:1410-4.
122. Agrawal A, Agrawal S, Gupta S. Dendritic cells in human aging. Exp Gerontol 2007;42:421-6.
123. Sartori AC, Vance DE, Slater LZ, Crowe M. The impact of inflammation on cognitive function in older adults: implications for healthcare practice and research. J Neurosci Nurs 2012;44:206-17.
124. Chao CC, Hu S, Close K, Choi CS, Molitor TW, Novick WJ, et al. Cytokine release from microglia: differential inhibition by pentoxifylline and dexamethasone. J Infect Dis 1992;166: 847-53.
125. Giulian D, Li J, Li X, George J, Rutecki PA. The impact of microglia-derived cytokines upon gliosis in the CNS. Dev Neurosci 1994;16:128-36.
126. Giulian D, Li J, Leara B, Keenen C. Phagocytic microglia release cytokines and cytotoxins that regulate the survival of astrocytes and neurons in culture. Neurochem Int 1994;25: 227-33.
127. de Vries HE, Blom-Roosemalen MC, van Oosten M, de Boer AG, van Berkel TJ, Breimer DD, et al. The influence of cyto-kines on the integrity of the blood-brain barrier in vitro. J Neuroimmunol 1996;64:37-43.
128. Wispelwey B, Lesse AJ, Hansen EJ, Scheld WM. Haemophilus influenzae lipopolysaccharide-induced blood brain barrier permeability during experimental meningitis in the rat. J Clin Invest 1988;82:1339-46.
129. Moor AC, de Vries HE, de Boer AG, Breimer DD. The blood-brain barrier and multiple sclerosis. Biochem Pharmacol 1994; 47:1717-24.
130. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, et al. Heart disease and stroke statistics-2008 update: a report from the american heart association statistics committee and stroke statistics subcommittee. Circulation 2008;117: e25-146.
131. Ay H, Arsava EM, Rosand J, Furie KL, Singhal AB, Schaefer PW, et al. Severity of leukoaraiosis and susceptibility to infarct growth in acute stroke. Stroke 2008;39:1409-13.
132. Osmond JM, Mintz JD, Dalton B, Stepp DW. Obesity increases blood pressure, cerebral vascular remodeling, and severity of stroke in the zucker rat. Hypertension 2009;53: 381-6.