Living beyond our physiological means: Small vessel disease of the brain is an expression of a systemic failure in arteriolar function: A unifying hypothesis

Stroke

Volumn 40, Issue 5, 2009, Pages

  Thompson, Charlie S ^a,b,c,d   Hakim, Antoine M ^a,b,c,d  

^a UNIVERSITY OF OTTAWA   (Canada)

^b OTTAWA HOSPITAL RESEARCH INSTITUTE   (Canada)

^c UNIVERSITY OF OTTAWA   (Canada)

^d HEART AND STROKE FOUNDATION OF CANADA   (Canada)

Author keywords

Brain ischemia; Endothelium; Pathology; Vascular cognitive impairment; White matter disease

Indexed keywords

AGING; BRAIN BLOOD VESSEL; BRAIN DISEASE; CARDIOVASCULAR RISK; DISEASE ASSOCIATION; DISEASE COURSE; HISTOPATHOLOGY; HUMAN; KIDNEY DISEASE; NEUROIMAGING; PATHOPHYSIOLOGY; POPULATION RESEARCH; PREVALENCE; PRIORITY JOURNAL; RETINA DISEASE; REVIEW; STROKE; SYSTEMIC ARTERIOLAR DYSFUNCTION; VASCULAR DISEASE; ANIMAL; ARTERIOLE; CEREBROVASCULAR DISEASE; METABOLISM; NUCLEAR MAGNETIC RESONANCE IMAGING; PATHOLOGY; PHYSIOLOGY; RISK FACTOR;

AGING; ANIMALS; ARTERIOLES; CEREBROVASCULAR DISORDERS; HUMANS; KIDNEY DISEASES; MAGNETIC RESONANCE IMAGING; RETINAL DISEASES; RISK FACTORS; VASCULAR DISEASES;

EID: 65549155203     PISSN: 00392499     EISSN: None     Source Type: Journal    
DOI: 10.1161/STROKEAHA.108.542266     Document Type: Review

References (135)

1. Vermeer SE, Longstreth WT Jr, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol. 2007;6:611-619.
2. Hachinski V. World stroke day 2008: 'little strokes, big trouble.' Stroke. 2008;39:2407-2420.
3. Leary MC, Saver JL. Annual incidence of first silent stroke in the United States: a preliminary estimate. Cerebrovasc Dis. 2003;16:280-285.
4. Aguero-Torres H, Kivipelto M, von Strauss E. Rethinking the dementia diagnoses in a population-based study: what is Alzheimer's disease and what is vascular dementia? A study from the Kungsholmen Project. Dement Geriatr Cogn Disord. 2006;22:244-249.
5. Bryan RN, Wells SW, Miller TJ, Elster AD, Jungreis CA, Poirier VC, Lind BK, Manolio TA. Infarctlike lesions in the brain: prevalence and anatomic characteristics at MR imaging of the elderly-data from the Cardiovascular Health Study. Radiology. 1997;202:47-54.
6. Das RR, Seshadri S, Beiser AS, Kelly-Hayes M, Au R, Himali JJ, Kase CS, Benjamin EJ, Polak JF, O'Donnell CJ, Yoshita M, D'Agostino RB, DeCarli C, Wolf PA. Prevalence and correlates of silent cerebral infarcts in the Framington Offspring Study. Stroke. 2008;39:2929-2935.
7. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003;348:1215-1222.
8. Kertesz A, Clydesdale S. Neuropsychological deficits in vascular dementia vs Alzheimer's disease. Frontal lobe deficits prominent in vascular dementia. Arch Neurol. 1994;51:1226-1231.
9. Boyle PA, Cahn-Weiner D. Assessment and prediction of functional impairment in vascular dementia. Expert Rev Neurother. 2004;4: 109-114.
10. Mohr JP. Lacunes. Stroke. 1982;13:3-11.
11. Fisher CM. The arterial lesions underlying lacunes. Acta Neuropathol. 1968;12:1-15.
12. Bamford JM, Warlow CP. Evolution and testing of the lacunar hypothesis. Stroke. 1988;19:1074-1082.
13. Fisher CM. Lacunar infarcts-a review. Cerebrovasc Dis. 1991;1: 311-320.
14. Lammie GA. Pathology of small vessel stroke. Br Med Bull. 2000;56: 296-306.
15. Ovbiagele B, Saver JL. Cerebral white matter hyperintensities on MRI: current concepts and therapeutic implications. Cerebrovasc Dis. 2006; 22:83-90.
16. The ARIC Investigators. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. Am J Epidemiol. 1989;129: 687-702.
17. Wong TY, Klein R, Sharrett AR, Nieto FJ, Boland LL, Couper DJ, Mosley TH, Klein BE, Hubbard LD, Szklo M. Retinal microvascular abnormalities and cognitive impairment in middle-aged persons: the Atherosclerosis Risk in Communities Study. Stroke. 2002;33: 1487-1492.
18. Wong TY, Klein R, Sharrett AR, Couper DJ, Klein BE, Liao DP, Hubbard LD, Mosley TH; ARIC Investigators. Atherosclerosis Risk in Communities Study. Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA. 2002;288:67-74.
19. Wong TY, Klein R, Nieto FJ, Moraes SA, Mosley TH, Couper DJ, Klein BE, Boland LL, Hubbard LD, Sharrett AR. Is early age-related macu-lopathy related to cognitive function? The Atherosclerosis Risk in Communities Study. Am J Ophthalmol. 2002;134:828-835.
20. Cooper LS, Wong TY, Klein R, Sharrett AR, Bryan RN, Hubbard LD, Couper DJ, Heiss G, Sorlie PD. Retinal microvascular abnormalities and MRI-defined subclinical cerebral infarction: the Atherosclerosis Risk in Communities Study. Stroke. 2006;37:82-86.
21. Patton N, Pattie A, MacGillivray T, Aslam T, Dhillon B, Gow A, Starr JM, Whalley LJ, Deary IJ. The association between retinal vascular network geometry and cognitive ability in an elderly population. Invest Ophthalmol Vis Sci. 2007;48:1995-2000.
22. Baker ML, Marino Larsen EK, Kuller LH, Klein R, Klein BE, Siscovick DS, Bernick C, Manolio TA, Wong TY. Retinal microvascular signs, cognitive function, and dementia in older persons: the Cardiovascular Health Study. Stroke. 2007;38:2041-2047.
23. Ding J, Patton N, Deary IJ, Strachan MW, Fowkes FG, Mitchell RJ, Price JF. Retinal microvascular abnormalities and cognitive dysfunction: a systematic review. Br J Ophthalmol. 2008;92:1017-1025.
24. Edwards MS, Wilson DB, Craven TE, Stafford J, Fried LF, Wong TY, Klein R, Burke GL, Hansen KJ. Associations between retinal micro-vascular abnormalities and declining renal function in the elderly population: the Cardiovascular Health Study. Am J Kidney Dis. 2005;46: 214-224.
25. Martinez-Vea A, Salvado E, Bardaji A, Gutierrez C, Ramos A, Garcia C, Compte T, Peralta C, Broch M, Pastor R, Angelet P, Marcas L, Sauri A, Oliver JA. Silent cerebral white matter lesions and their relationship with vascular risk factors in middle-aged predialysis patients with CDK. Am J Kidney Dis. 2006;47:241-250.
26. Wong TY, Coresh J, Klein R, Muntner P, Couper DJ, Sharrett AR, Klein BE, Heiss G, Hubbard LD, Duncan BB. Retinal microvascular abnormalities and renal dysfunction: the Atherosclerosis Risk in Communities Study. J Am Soc Nephrol. 2004;15:2469-2476.
27. Liew G, Mitchell P, Wong TY, Iyengar SK, Wang JJ. CKD increases the risk of age-related macular degeneration. J Am Soc Nephrol. 2008;19: 806-811.
28. Khatri M, Wright CB, Nickolas TL, Yoshita M, Paik MC, Kranwinkel G, Sacco RL, DeCarli C. Chronic kidney disease is associated with white matter hyperintensity volume: the Northern Manhattan Study (NOMAS). Stroke. 2007;38:3121-3126.
29. Wada M, Nagasawa H, Iseki C, Takahashi Y, Sato H, Arawaka S, Kawanami T, Kurita K, Daimon M, Kato T. Cerebral small vessel disease and chronic kidney disease (CKD): results of a Cross-Sectional Study in Community-based Japanese Elderly. J Neurol Sci. 2008;272: 36-42.
30. Murray AM. Cognitive impairment in the aging dialysis and chronic kidney disease populations: an occult burden. Adv Chronic Kidney Dis. 2008;15:123-132.
31. Kurella M, Chertow GM, Luan J, Yaffe K. Cognitive impairment in chronic kidney disease. J Am Geriatr Soc. 2004;52:1863-1869.
32. Madan P, Kalra OP, Agarwal S, Tandon OP. Cognitive impairment in chronic kidney disease. Nephrol Dial Transplant. 2007;22:440-444.
33. Slinin Y, Paudel ML, Ishani A, Taylor BC, Yaffe K, Murray AM, Fink HA, Orwoll ES, Cummings SR, Barrett-Connor E, Jassal S, Ensrud KE. Kidney function and cognitive performance and decline in older men. J Am Geriatr Soc. 2008;56:2082-2088.
34. Kurella M, Chertow GM, Fried LF, Cummings SR, Harris T, Simonsick E, Satterfield S, Ayonayon H, Yaffe K. Chronic kidney disease and cognitive impairment in the elderly: the Health, Aging, and Body Composition Study. J Am Soc Nephrol. 2005;16:2127-2133.
35. Kurella M, Yaffe K, Shlipak MG, Wenger NK, Chertow GM. Chronic kidney disease and cognitive impairment in menopausal women. Am J Kidney Dis. 2005;45:66-76.
36. Kurella Tamura M, Wadley V, Yaffe K, McClure LA, Howard G, Go R, Allman RM, Warnock DG, McClellan W. Kidney function and cognitive impairment in us adults: the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Am J Kidney Dis. 2008;52: 227-234.
37. Chamorro A, Pujol J, Saiz A, Vila N, Vilanova JC, Alday M, Blanc R. Periventricular white matter lucencies in patients with lacunar stroke. A marker of too high or too low blood pressure? Arch Neurol. 1997;54: 1284-1288.
38. Raiha I, Tarvonen S, Kurki T, Rajala T, Sourander L. Relationship between vascular factors and white matter low attenuation of the brain. Acta Neurol Scand. 1993;87:286-289.
39. Matsushita K, Kuriyama Y, Nagatsuka K, Nakamura M, Sawada T, Omae T. Periventricular white matter lucency and cerebral blood flow autoregulation in hypertensive patients. Hypertension. 1994;23: 565-568.
40. Wong TY, Klein R, Sun C, Mitchell P, Couper DJ, Lai H, Hubbard LD, Sharrett AR. Age-related macular degeneration and risk for stroke. Ann Intern Med. 2006;145:98-106.
41. Winkler BS, Boulton ME, Gottsch JD, Sternberg P. Oxidative damage and age-related macular degeneration. Mol Vis. 1999;5:32.
42. Beatty S, Koh H, Phil M, Henson D, Boulton M. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol. 2000;45:115-134.
43. Ikram MK, De Jong FJ, Van Dijk EJ, Prins ND, Hofman A, Breteler MM, de Jong PT. Retinal vessel diameters and cerebral small vessel disease: the Rotterdam Scan Study. Brain. 2006;129:182-188.
44. Ikram MK, de Jong FJ, Bos MJ, Vingerling JR, Hofman A, Koudstaal PJ, de Jong PT, Breteler MM. Retinal vessel diameters and risk of stroke: the Rotterdam Study. Neurology. 2006;66:1339-1343.
45. de Jong FJ, Vernooij MW, Ikram MK, Ikram MA, Hofman A, Krestin GP, van der Lugt A, de Jong PT, Breteler MM. Arteriolar oxygen saturation, cerebral blood flow, and retinal vessel diameters. The Rotterdam Study. Ophthalmology. 2008;115:887-892.
46. Black S, Gao FQ, Bilbao J. Understanding white matter disease, imag-ing-pathological correlations in vascular cognitive impairment. Stroke. In press. 2008 December 8. Epub.
47. Sakata K, Funatsu H, Harino S, Noma H, Hori S. Relationship of macular microcirculation and retinal thickness with visual acuity in diabetic macular edema. Ophthalmology. 2007;114:2061-2069.
48. Kang DH, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ. Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol. 2002;13:806-816.
49. Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, Siscovick DS, Stehman-Breen C. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med. 2005;352: 2049-2060.
50. Nickolas TL, Khatri M, Boden-Albala B, Kiryluk K, Luo X, Gervasi-Franklin P, Paik M, Sacco RL. The association between kidney disease and cardiovascular risk in a multiethnic cohort: findings from the Northern Manhattan Study (NOMAS). Stroke. 2008;39:2876-2879.
51. Iadecola C, Davisson R. Hypertension and cerebrovascular dysfunction. Cell Metab. 2008;7:476-484.
52. Touyz RM. Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance? Hypertension. 2004;44:248-252.
53. Pressler SJ. Cognitive functioning and chronic heart failure: a review of the literature (2002-July 2007). J Cardiovasc Nurs. 2008;23:239-249.
54. Bokura H, Yamaguchi S, Iijima K, Nagai A, Oguro H. Metabolic syndrome is associated with silent ischemic brain lesions. Stroke. 2008; 39:1607-1609.
55. Osamichi S, Kouji K, Yoshimaro I, Tadashi U, Hiroichi T, Seiyu K, Shinji O, Noboru T. Myocardial glucose metabolism assessed by positron emission tomography and the histopathologic findings of microvessels in syndrome X. Circ J. 2004;68:220-226.
56. Pasquier F, Boulogne A, Leys D, Fontaine P. Diabetes mellitus and dementia. Diabetes Metab. 2006;32:403-414.
57. Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: a review. Stroke. 1997;28:652-659.
58. Claudio L. Ultrastructural features of the blood-brain barrier in biopsy tissue from Alzheimer's disease patients. Acta Neuropathol. 1996; 91:6-14.
59. de Jong GI, de Weerd H, Schuurman T, Traber J, Luiten PG. Micro-vascular changes in aged rat forebrain. Effects of chronic nimodipine treatment. Neurobiol Aging. 1990;11:381-389.
60. de Jong GI, Jansen AS, Horvath E, Gispen WH, Luiten PG. Nimodipine effects on cerebral microvessels and sciatic nerve in aging rats. Neu-robiol Aging. 1992;13:73-81.
61. de Jong GI, Farkas E, Stienstra CM, Plass JR, Keijser JN, de la Torre JC, Luiten PG. Cerebral hypoperfusion yields capillary damage in the hip-pocampal ca1 area that correlates with spatial memory impairment. Neuroscience. 1999;91:203-210.
62. Farkas E, de Jong GI, Apro E, De Vos RA, Steur EN, Luiten PG. Similar ultrastructural breakdown of cerebrocortical capillaries in Alzheimer's disease, Parkinson's disease, and experimental hypertension. What is the functional link? Ann NY Acad Sci. 2000;903:72-82.
63. Farkas E, de Jong GI, de Vos RA, Jansen Steur EN, Luiten PG. Pathological features of cerebral cortical capillaries are doubled in Alzheimer's disease and Parkinson's disease. Acta Neuropathol. 2000; 100:395-402.
64. Farkas E, Luiten PG. Cerebral microvascular pathology in aging and Alzheimer's disease. Progr Neurobiol. 2001;64:575-611.
65. Perlmutter LS, Chui HC. Microangiopathy, the vascular basement membrane and Alzheimer's disease: a review. Brain Res Bull. 1990;24: 677-686.
66. Szpak GM, Lewandowska E, Wierzba-Bobrowicz T, Bertrand E, Pasennik E, Mendel T, Stepien T, Leszczynska A, Rafalowska J. Small cerebral vessel disease in familial amyloid and non-amyloid angiopathies: FAD-PS-1 (P117L) mutation and CADASIL. Immunohisto-chemical and ultrastructural studies. Folia Neuropathol. 2007;45: 192-204.
67. Uspenskaia O, Liebetrau M, Herms J, Danek A, Hamann GF. Aging is associated with increased collagen type IV accumulation in the basal lamina of human cerebral microvessels. BMC Neurosci. 2004;5:37.
68. Rosenblum W. Fibrinoid necrosis of small brain arteries and arterioles and military aneurysms as causes of hypertensive hemorrhage: a critical reappraisal. Acta Neuropathol. 2008;116:361-369.
69. Kalaria RN, Kenny RA, Ballard CG, Perry R, Ince P, Polvikoski T. Towards defining the neuropathological substrates of vascular dementia. J Neurol Sci. 2004;226:75-80.
70. Wardlaw JM, Sandercock PA, Dennis MS, Starr J. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke. 2003;34:806-812.
71. Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, Hendrikse NH. Blood-brain barrier dysfunction in par-kinsonian midbrain in vivo. Ann Neurol. 2005;57:176-179.
72. Zipser BD, Johanson CE, Gonzalez L, Berzin TM, Tavares R, Hulette CM, Vitek MP, Hovanesian V, Stopa EG. Microvascular injury and blood-brain barrier leakage in Alzheimer's disease. Neurobiol Aging. 2007;28:977-986.
73. Petito CK, Cash KS. Blood-brain barrier abnormalities in the acquired immunodeficiency syndrome: immunohistochemical localization of serum proteins in postmortem brain. Ann Neurol. 1992;32:658-666.
74. Ueno M, Sakamoto H, Kanenishi K, Onodera M, Akiguchi I, Hosokawa M. Ultrastructural and permeability features of microvessels in the hippocampus, cerebellum and pons of senescence-accelerated mice (SAM). Neurobiol Aging. 2001;22:469-478.
75. Qi X, Inagaki K, Sobel RA, Mochly-Rosen D. Sustained pharmacological inhibition of deltapkc protects against hypertensive encepha-lopathy through prevention of blood-brain barrier breakdown in rats. J Clin Invest. 2008;118:173-182.
76. Ueno M, Tomimoto H, Akiguchi I, Wakita H, Sakamoto H. Blood-brain barrier disruption in white matter lesions in a rat model of chronic cerebral hypoperfusion. J Cereb Blood Flow Metab. 2002;22: 97-104.
77. Hill GS, Heudes D, Bariety J. Morphometric study of arterioles and glomeruli in the aging kidney suggests focal loss of autoregulation. Kidney Int. 2003;63:1027-1036.
78. Nangaku M, Eckardt KU. Hypoxia and the HIF system in kidney disease. J Mol Med. 2007;85:1325-1330.
79. Green WR. Histopathology of age-related macular degeneration. Mol Vis. 1999;5:27.
80. Wardlaw JM. What causes lacunar stroke? J Neurol Neurosurg Psychiatry. 2005;76:617-619.
81. Hassan A, Hunt BJ, O'Sullivan M, Bell R, D'Souza R, Jeffery S, Bamford JM, Markus HS. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain. 2004; 127:212-219.
82. Hassan A, Gormley K, O'Sullivan M, Knight J, Sham P, Vallance P, Bamford J, Markus H. Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease. Stroke. 2004;35:654-659.
83. Jun JB, Kuechle M, Harlan JM, Elkon KB. Fibroblast and endothelial apoptosis in systemic sclerosis. Curr Opin Rheumatol. 2003;15: 756-760.
84. Veyssier-Belot C, Cacoub P. Role of endothelial and smooth muscle cells in the physiopathology and treatment management of pulmonary hypertension. Cardiovasc Res. 1999;44:274-282.
85. Kuwano K, Hagimoto N, Hara N. Molecular mechanisms of pulmonary fibrosis and current treatment. Curr Mol Med. 2001;1:551-573.
86. Higgins DF, Kimura K, Iwano M, Haase VH. Hypoxia-inducible factor signaling in the development of tissue fibrosis. Cell Cycle. 2008;7: 1128-1132.
87. Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Saito Y, Johnson RS, Kretzler M, Cohen CD, Eckardt KU, Iwano M, Haase VH. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest. 2007;117:3810-3820.
88. Kimura K, Iwano M, Higgins DF, Yamaguchi Y, Nakatani K, Harada K, Kubo A, Akai Y, Rankin EB, Neilson EG, Haase VH, Saito Y. Stable expression of hif-1alpha in tubular epithelial cells promotes interstitial fibrosis. Am J Physiol Renal Physiol. 2008;295:F1023-1029.
89. Klempt ND, Sirimanne E, Gunn AJ, Klempt M, Singh K, Williams C, Gluckman PD. Hypoxia-ischemia induces transforming growth factor beta 1 mRNA in the infant rat brain. Brain Res Mol Brain Res. 1992; 13:93-101.
90. Jeong WI, Do SH, Yun HS, Song BJ, Kim SJ, Kwak WJ, Yoo SE, Park HY, Jeong KS. Hypoxia potentiates transforming growth factor-beta expression of hepatocyte during the cirrhotic condition in rat liver. Liver Int. 2004;24:658-668.
91. Dhandapani KM, Brann DW. Transforming growth factor-beta: a neu-roprotective factor in cerebral ischemia. Cell Biochem Biophys. 2003; 39:13-22.
92. Qian L, Wei SJ, Zhang D, Hu X, Xu Z, Wilson B, El-Benna J, Hong JS, Flood PM. Potent anti-inflammatory and neuroprotective effects of TGF-beta1 are mediated through the inhibition of ERK and p47phox-ser345 phosphorylation and translocation in microglia. JImmunol. 2008; 181:660-668.
93. Wyss-Coray T, Lin C, Sanan DA, Mucke L, Masliah E. Chronic overproduction of transforming growth factor-β1 by astrocytes promotes Alzheimer's disease-like microvascular degeneration in transgenic mice. Am J Pathol. 2000;156:139-150.
94. Ihn H. Pathogenesis of fibrosis: role of TGF-beta and CTGF. Curr Opin Rheumatol. 2002;14:681-685.
95. Lammie GA. Hypertensive cerebral small vessel disease and stroke. Brain Pathol. 2002;12:358-370.
96. Tomimoto H, Akiguchi I, Ohtani R, Yagi H, Kanda M, Shibasaki H, Yamamoto Y. The coagulation-fibrinolysis system in patients with leukoaraiosis and Binswanger disease. Arch Neurol. 2001;58: 1620-1625.
97. Pullicino PM. Pathogenesis of lacunar infarcts and small deep infarcts. Adv Neurol. 1993;62:125-140.
98. Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med. 1994;1:71-81.
99. Iwano M, Plieth D, DanoffTM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest. 2002;110:341-350.
100. Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest. 2003;112:1776-1784.
101. Yang J, Liu Y. Dissection of key events in tubular epithelial to myofi-broblast transition and its implications in renal interstitial fibrosis. Am J Pathol. 2001;159:1465-1475.
102. Zeisberg M, Maeshima Y, Mosterman B, Kalluri R. Renal fibrosis. Extracellular matrix microenvironment regulates migratory behavior of activated tubular epithelial cells. Am J Pathol. 2002;160:2001-2008.
103. Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, Kalluri R. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med. 2007;13:952-961.
104. Arciniegas E, Frid MG, Douglas IS, Stenmark KR. Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2007;293:L1-L8.
105. Wang K, Walz W. Unusual topographical pattern of proximal astro-gliosis around a cortical devascularizing lesion. J Neurosci Res. 2003; 73:497-506.
106. Farkas E, Luiten PG, Bari F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev. 2007;54:162-180.
107. Inflammation: a unifying theory of disease. Harv Health Lett. 2006; 31:4-5.
108. Hollyfield JG, Bonilha VL, Rayborn ME, Yang X, Shadrach KG, Lu L, Ufret RL, Salomon RG, Perez VL. Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med. 2008;14: 194-198.
109. Skeie JM, Mullins RF. Macrophages in neovascular age-related macular degeneration: friends or foes? Eye. 2008 July 4 [Epub ahead of print].
110. Schwesinger C, Yee C, Rohan RM, Joussen AM, Fernandez A, Meyer TN, Poulaki V, Ma JJ, Redmond TM, Liu S, Adamis AP, D'Amato RJ. Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium. Am J Pathol. 2001;158:1161-1172.
111. Imamura Y, Noda S, Hashizume K, Shinoda K, Yamaguchi M, Uchiyama S, Shimizu T, Mizushima Y, Shirasawa T, Tsubota K. Drusen, choroidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient mice: a model of age-related macular degeneration. Proc Natl Acad Sci U S A. 2006;103:11282-11287.
112. Hashizume K, Hirasawa M, Imamura Y, Noda S, Shimizu T, Shinoda K, Kurihara T, Noda K, Ozawa Y, Ishida S, Miyake Y, Shirasawa T, Tsubota K. Retinal dysfunction and progressive retinal cell death in SOD1-deficient mice. Am J Pathol. 2008;172:1325-1331.
113. Rektor I, Goldemund D, Sheardova K, Rektorova I, Michalkova Z, Dufek M. Vascular pathology in patients with idiopathic Parkinson's disease. Parkinsonism Relat Disord. 2009;15:24-29.
114. Erkinjuntti T. Vascular cognitive deterioration and stroke. Cerebrovasc Dis. 2007;24(suppl 1):189-194.
115. Farkas E, De Jong GI, Apro E, Keuker JI, Luiten PG. Calcium antagonists decrease capillary wall damage in aging hypertensive rat brain. Neurobiol Aging. 2001;22:299-309.
116. Cheung N, Rogers S, Couper DJ, Klein R, Sharrett AR, Wong TY. Is diabetic retinopathy an independent risk factor for ischemic stroke? Stroke. 2007;38:398-401.
117. Gordon B, Chang S, Kavanagh M, Berrocal M, Yannuzzi L, Robertson C, Drexler A. The effects of lipid lowering on diabetic retinopathy. Am J Ophthalmol. 1991;112:385-391.
118. Janknecht P, Schumann M, Hansen LL. Reduction of retinal exudates in diabetic retinopathy after heparin-induced extracorporal LDL-precipitation (HELP). A case report. Eur J Ophthalmol. 1996;6: 340-342.
119. Cusick M, Chew EY, Chan CC, Kruth HS, Murphy RP, Ferris FL III. Histopathology and regression of retinal hard exudates in diabetic reti-nopathy after reduction of elevated serum lipid levels. Ophthalmology. 2003;110:2126-2133.
120. Gupta A, Gupta V, Thapar S, Bhansali A. Lipid-lowering drug atorva-statin as an adjunct in the management of diabetic macular edema. Am J Ophthalmol. 2004;137:675-682.
121. Matsuo T. Disappearance of diabetic macular hard exudates after hemo-dialysis introduction. Acta Medica Okayama. 2006;60:201-205.
122. de Leeuw FE, de Kleine M, Frijns CJ, Fijnheer R, van Gijn J, Kappelle LJ. Endothelial cell activation is associated with cerebral white matter lesions in patients with cerebrovascular disease. Ann NY Acad Sci. 2002;977:306-314.
123. Hassan A, Hunt BJ, O'Sullivan M, Parmar K, Bamford JM, Briley D, Brown MM, Thomas DJ, Markus HS. Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis. Brain. 2003; 126:424-432.
124. van Dijk EJ, Prins ND, Vermeer SE, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM. C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation. 2005;112:900-905.
125. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J. Complement factor h polymorphism in age-related macular degeneration. Science. 2005;308:385-389.
126. Francis PJ, Zhang H, Dewan A, Hoh J, Klein ML. Joint effects of polymorphisms in the HTRA1, LOC387715/ARMS2, and CFH genes on AMD in a Caucasian population. Mol Vis. 2008;14:1395-1400.
127. Leenen FH, Dumais J, McInnis NH, Turton P, Stratychuk L, Nemeth K, Lum-Kwong MM, Fodor G. Results of the Ontario survey on the prevalence and control of hypertension. CMAJ. 2008;178:1441-1449.
128. Boutitie F, Gueyffier F, Pocock S, Fagard R, Boissel JP; INDANA Project Steering Committee. INdividual Data ANalysis of Antihyper-tensive intervention. J-shaped relationship between blood pressure and mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data [summary for patients in Ann Intern Med. 2002; 136:I49]. Ann Intern Med. 2002;136:438-448.
129. Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. JAMA. 1995;274:1846-1851.
130. Law M, Wald N, Morris J. Lowering blood pressure to prevent myo-cardial infarction and stroke: a new preventive strategy. Health Technol Assess. 2003;7:1-94.
131. Dufouil C, Chalmers J, Coskun O, Besancon V, Bousser MG, Guillon P, MacMahon S, Mazoyer B, Neal B, Woodward M, Tzourio-Mazoyer N, Tzourio C; PROGRESS MRI Substudy Investigators. Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy. Circulation. 2005;112:1644-1650.
132. Gorelick PB. William M. Feinberg Lecture: cognitive vitality and the role of stroke and cardiovascular disease risk factors. Stroke. 2005;36: 875-879.
133. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.
134. Young TK, Hachinski V. The population approach to stroke prevention: a Canadian perspective. Clin Invest Med. 2003;26:78-86.
135. Williams B. Recent hypertension trials: implications and controversies. J Am Coll Cardiol. 2005;45:813-827.