Chronic cerebral hypoperfusion: A key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia

Clinical Science

Volumn 131, Issue 19, 2017, Pages 2451-2468

  Duncombe, Jessica ^a   Kitamura, Akihiro ^a   Hase, Yoshiki ^b,c   Ihara, Masafumi ^b,c   Kalaria, Raj N ^b,c   Horsburgh, Karen ^b,c  

^a UNIVERSITY OF EDINBURGH   (United Kingdom)

^b NATIONAL CEREBRAL AND CARDIOVASCULAR CENTER   (Japan)

^c NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN;

BLOOD BRAIN BARRIER; BRAIN ATROPHY; BRAIN BLOOD FLOW; BRAIN PERFUSION; COGNITIVE DEFECT; COMORBIDITY; DEMENTIA; DRUG TARGETING; GLIA CELL; HUMAN; HYPOXIA; NEUROPATHOLOGY; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; RODENT MODEL; VASCULITIS; WHITE MATTER INJURY; AMYLOID PLAQUE; ANIMAL; ANIMAL BEHAVIOR; BRAIN; BRAIN CIRCULATION; CEREBROVASCULAR DISORDERS; CHRONIC DISEASE; COGNITION; COGNITION DISORDERS; COMPLICATION; DEMENTIA, VASCULAR; DISEASE COURSE; DISEASE MODEL; DRUG EFFECTS; LEUKOENCEPHALOPATHIES; METABOLISM; PATHOLOGY; PATHOPHYSIOLOGY; PROCEDURES; PSYCHOLOGY; RISK FACTOR; SPECIES DIFFERENCE; TIME FACTOR; TRANSLATIONAL RESEARCH;

AMYLOID BETA-PEPTIDES; ANIMALS; BEHAVIOR, ANIMAL; BRAIN; CEREBROVASCULAR CIRCULATION; CEREBROVASCULAR DISORDERS; CHRONIC DISEASE; COGNITION; COGNITION DISORDERS; DEMENTIA, VASCULAR; DISEASE MODELS, ANIMAL; DISEASE PROGRESSION; HUMANS; LEUKOENCEPHALOPATHIES; PLAQUE, AMYLOID; RISK FACTORS; SPECIES SPECIFICITY; TIME FACTORS; TRANSLATIONAL MEDICAL RESEARCH;

EID: 85030555281     PISSN: 01435221     EISSN: 14708736     Source Type: Journal    
DOI: 10.1042/CS20160727     Document Type: Review

References (149)

1. Iturria-Medina, Y., Sotero, R.C., Toussaint, P.J., Mateos-Pérez, J.M., Evans, A.C. and (2016) Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis. Nat. Commun. 21, 11934
2. Pantoni, L. (2010) Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 9, 689-701
3. McCarron, M.O. and Nicoll, J.A. (2004) Cerebral amyloid angiopathy and thrombolysis-related intracerebral haemorrhage. Lancet Neurol. 3, 484-492
4. Okamoto, Y., Yamamoto, T., Kalaria, R.N., Senzaki, H., Maki, T., Hase, Y. et al. (2012) Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol. 123, 381-394
5. Arvanitakis, Z., Leurgans, S.E., Wang, Z., Wilson, R.S., Bennett, D.A. and Schneider, J.A. (2011) Cerebral amyloid angiopathy pathology and cognitive domains in older persons. Ann. Neurol. 69, 320-327
6. Toledo, J.B., Arnold, S.E., Raible, K., Brettschneider, J., Xie, S.X., Grossman, M. et al. (2013) Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre. Brain 136, 2697-2706
7. Gorelick, P.B. and Nyenhuis, D. (2013) Understanding and treating vascular cognitive impairment. Continuum (Minneap. Minn.) 19, 425-437
8. Ihara, M. and Yamamoto, Y. (2016) Emerging evidence for pathogenesis of sporadic cerebral small vessel disease. Stroke 47, 554-560
9. Wardlaw, J.M., Smith, C. and Dichgans, M. (2013) Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 12, 483-497
10. Poggesi, A., Pasi, M., Pescini, F., Pantoni, L. and Inzitari, D. (2016) Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: a review. J. Cereb. Blood Flow Metab. 36, 72-94
11. Di Marco, L.Y., Venneri, A., Farkas, E., Evans, P.C., Marzo, A. and Frangi, A.F. (2015) Vascular dysfunction in the pathogenesis of Alzheimer's disease-a review of endothelium-mediated mechanisms and ensuing vicious circles. Neurobiol. Dis. 82, 593-606
12. Alsop, D.C., Dai, W., Grossman, M. and Detre, J.A. (2010) Arterial spin labeling blood flow MRI: it's role in the early characterization of Alzheimer's disease. J. Alzheimers Dis. 20, 871-880
13. Chao, L.L., Buckley, S.T., Kornak, J., Schuff, N., Madison, C., Yaffe, K. et al. (2010) ASL perfusion MRI predicts cognitive decline and conversion from MCI to dementia. Alzheimer Dis. Assoc. Disord. 24, 19-27
14. Deary, I.J., Leaper, S.A., Murray, A.D., Staff, R.T. and Whalley, L.J. (2003) Cerebral white matter abnormalities and lifetime cognitive change: a 67-year follow-up of the Scottish Mental Survey of 1932. Psychol. Aging 18, 140-148
15. Bucur, B., Madden, D.J., Spaniol, J., Provenzale, J.M., Cabeza, R., White, L.E. et al. (2008) Age-related slowing of memory retrieval: contributions of perceptual speed and cerebral white matter integrity. Neurobiol. Aging 29, 1070-1079
16. Bastin, M.E., Clayden, J.D., Pattie, A., Gerrish, I.F., Wardlaw, J.M. and Deary, I.J. (2009) Diffusion tensor and magnetization transfer MRI measurements of periventricular white matter hyperintensities in old age. Neurobiol. Aging 30, 125-136
17. Ihara, M., Polvikoski, T.M., Hall, R., Slade, J.Y., Perry, R.H., Oakley, A.E. et al. (2010) Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer's disease, and dementia with Lewy bodies. Acta Neuropathol. 119, 579-589
18. Barker, R., Wellington, D., Esiri, M.M. and Love, S. (2013) Assessing white matter ischemic damage in dementia patients by measurement of myelin proteins. J. Cereb. Blood Flow Metab. 33, 1050-1057
19. Fernando, M.S., Simpson, J.E., Matthews, F., Brayne, C., Lewis, C.E., Barber, R. et al. (2006) White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury. Stroke 37, 1391-1398
20. Barker, R., Ashby, E.L., Wellington, D., Barrow, V.M., Palmer, J.C., Kehoe, P.G. et al. (2014) Pathophysiology of white matter perfusion in Alzheimer's disease and vascular dementia. Brain 137, 1524-1532
21. Fernando, M.S., O'Brien, J.T., Perry, R.H., English, P., Forster, G., McMeekin, W. et al. (2004) Comparison of the pathology of cerebral white matter with post-mortem magnetic resonance imaging (MRI) in the elderly brain. Neuropathol. Appl. Neurobiol. 30, 385-395
22. Chen, A., Akinyemi, R.O., Hase, Y., Firbank, M.J., Ndung'u, M.N., Foster, V. et al. (2016) Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia. Brain 139, 242-258
23. Prins, N.D. and Scheltens, P. (2015) White matter hyperintensities, cognitive impairment and dementia: an update. Nat. Rev. Neurol. 11, 157-165
24. Jucker, M. (2010) The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nat. Med. 16, 1210-1214
25. Macrae, IM. (2011) Preclinical stroke research-advantages and disadvantages of the most common rodent models of focal ischaemia. Br. J. Pharmacol. 164, 1062-1078
26. Traystman, RJ. (2003) Animal models of focal and global cerebral ischemia. ILAR J. 44, 85-95
27. Hainsworth, A.H., Allan, S.M., Boltze, J., Cunningham, C., Farris, C., Head, E. et al. (2017) Translational models for vascular cognitive impairment: a review including larger species. BMC Med. 15, 16
28. Farkas, E., Luiten, P.G. and Bari, F. (2007) Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res. Rev. 54, 162-180
29. Tomimoto, H., Ihara, M., Wakita, H., Ohtani, R., Lin, J.X., Akiguchi, I. et al. (2003) Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat. Acta Neuropathol. 106, 527-534
30. Yang, G., Kitagawa, K., Matsushita, K., Mabuchi, T., Yagita, Y., Yanagihara, T. et al. (1997) C57BL/6 strain is most susceptible to cerebral ischemia following bilateral common carotid occlusion among seven mouse strains: selective neuronal death in the murine transient forebrain ischemia. Brain Res. 752, 209-218
31. Kitagawa, K., Matsumoto, M., Yang, G., Mabuchi, T., Yagita, Y., Hori, M. et al. (1998) Cerebral ischemia after bilateral carotid artery occlusion and intraluminal suture occlusion in mice: evaluation of the patency of the posterior communicating artery. J. Cereb. Blood Flow Metab. 18, 570-579
32. Wei, G., Kibler, K.K., Koehler, R.C., Maruyama, T., Narumiya, S. and Doré, S. (2008) Prostacyclin receptor deletion aggravates hippocampal neuronal loss after bilateral common carotid artery occlusion in mouse. Neuroscience 156, 1111-1117
33. Chen, J.J., Rosas, H.D. and Salat, D.H. (2011) Age-associated reductions in cerebral blood flow are independent from regional atrophy. Neuroimage 55, 468-478
34. Chung, Y.A.J.H., Kim, J.Y., Kim, K.J. and Ahn, K.J. (2009) Hypoperfusion and ischemia in cerebral amyloid angiopathy documented by 99mTc-ECD brain perfusion SPECT. J. Nucl. Med. 50, 1969-1974
35. Beason-Held, L.L., Moghekar, A., Zonderman, A.B., Kraut, M.A. and Resnick, S.M. (2007) Longitudinal changes in cerebral blood flow in the older hypertensive brain. Stroke 38, 1766-1773
36. Shibata, M., Ohtani, R., Ihara, M. and Tomimoto, H. (2004) White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion. Stroke 35, 2598-2603
37. McQueen, J., Reimer, M.M., Holland, P.R., Manso, Y., McLaughlin, M., Fowler, J.H. et al. (2014) Restoration of oligodendrocyte pools in a mouse model of chronic cerebral hypoperfusion. PLoS ONE 9, e87227
38. Struys, T., Govaerts, K., Oosterlinck, W., Casteels, C., Bronckaers, A., Koole, M. et al. (2017) In vivo evidence for long-term vascular remodeling resulting from chronic cerebral hypoperfusion in mice. J. Cereb. Blood Flow Metab. 37, 726-739
39. Hattori, Y., Enmi, J., Iguchi, S., Saito, S., Yamamoto, Y., Nagatsuka, K. et al. (2016) Substantial reduction of parenchymal cerebral blood flow in mice with bilateral common carotid artery stenosis. Sci. Rep. 6, 32179
40. Boehm-Sturm, P., Füchtemeier, M., Foddis, M., Mueller, S., Trueman, R.C., Zille, M. et al. (2017) Neuroimaging biomarkers predict brain structural connectivity change in a mouse model of vascular cognitive impairment. Stroke 48, 468-475
41. Kitamura, A., Fujita, Y., Oishi, N., Kalaria, R.N., Washida, K., Maki, T. et al. (2012) Selective white matter abnormalities in a novel rat model of vascular dementia. Neurobiol. Aging 33, 1012.e25-e35
42. Hattori, Y., Enmi, J., Iguchi, S., Saito, S., Yamamoto, Y., Tsuji, M. et al. (2016) Gradual carotid artery stenosis in mice closely replicates hypoperfusive vascular dementia in humans. J. Am. Heart Assoc. 5, e002757
43. Hattori, Y., Enmi, J., Kitamura, A., Yamamoto, Y., Saito, S., Takahashi, Y. et al. (2015) A novel mouse model of subcortical infarcts with dementia. J. Neurosci. 35, 3915-3928
44. Coltman, R., Spain, A., Tsenkina, Y., Fowler, J.H., Smith, J., Scullion, G. et al. (2011) Selective white matter pathology induces a specific impairment in spatial working memory. Neurobiol. Aging 32, 2324.e7-e12
45. Wakita, H., Tomimoto, H., Akiguchi, I. and Kimura, J. (1994) Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study. Acta Neuropathol. 87, 484-492
46. Reimer, M.M., McQueen, J., Searcy, L., Scullion, G., Zonta, B., Desmazieres, A. et al. (2011) Rapid disruption of axon-glial integrity in response to mild cerebral hypoperfusion. J. Neurosci. 31, 18185-18194
47. Holland, P.R., Bastin, M.E., Jansen, M.A., Merrifield, G.D., Coltman, R.B., Scott, F. et al. (2011) MRI is a sensitive marker of subtle white matter pathology in hypoperfused mice. Neurobiol. Aging 32, 2325e1-2325e6
48. Holland, P.R., Searcy, J.L., Salvadores, N., Scullion, G., Chen, G., Lawson, G. et al. (2015) Gliovascular disruption and cognitive deficits in a mouse model with features of small vessel disease. J. Cereb. Blood Flow Metab. 35, 1005-1014
49. Hase, Y., Craggs, L., Hase, M., Stevenson, W., Slade, J., Lopez, D. et al. (2017) Effects of environmental enrichment on white matter glial responses in a mouse model of chronic cerebral hypoperfusion. J. Neuroinflammation 14, 81
50. Kitamura, A., Fujita, Y., Oishi, N., Kalaria, R.N., Washida, K., Maki, T. et al. (2012) Selective white matter abnormalities in a novel rat model of vascular dementia. Neurobiol. Aging 33, 1012.e25-e35
51. Ueno, M., Tomimoto, H., Akiguchi, I., Wakita, H. and Sakamoto, H. (2002) Blood-brain barrier disruption in white matter lesions in a rat model of chronic cerebral hypoperfusion. J. Cereb. Blood Flow Metab. 22, 97-104
52. Seo, J.H., Miyamoto, N., Hayakawa, K., Pham, L.D., Maki, T., Ayata, C. et al. (2013) Oligodendrocyte precursors induce early blood-brain barrier opening after white matter injury. J. Clin. Invest. 123, 782-786
53. Hattori, Y., Okamoto, Y., Maki, T., Yamamoto, Y., Oishi, N., Yamahara, K. et al. (2014) Silent information regulator 2 homolog 1 counters cerebral hypoperfusion injury by deacetylating endothelial nitric oxide synthase. Stroke 45, 3403-3411
54. Logue, M.W., Posner, H., Green, R.C., Moline, M., Cupples, L.A., Lunetta, K.L. et al. (2011) Magnetic resonance imaging-measured atrophy and its relationship to cognitive functioning in vascular dementia and Alzheimer's disease patients. Alzheimers Dement. 7, 493-500
55. Meyer, J.S., Huang, J. and Chowdhury, M.H. (2007) MRI confirms mild cognitive impairments prodromal for Alzheimer's, vascular and Parkinson-Lewy body dementias. J. Neurol. Sci. 257, 97-104
56. Jokinen, H., Lipsanen, J., Schmidt, R., Fazekas, F., Gouw, A.A., van der Flier, W.M. et al. (2012) Brain atrophy accelerates cognitive decline in cerebral small vessel disease: the LADIS study. Neurology 78, 1785-1792
57. Lambert, C., Benjamin, P., Zeestraten, E., Lawrence, A.J., Barrick, T.R. and Markus, H.S. (2016) Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease. Brain 139, 1136-1151
58. Nishio, K., Ihara, M., Yamasaki, N., Kalaria, R.N., Maki, T., Fujita, Y. et al. (2010) A mouse model characterizing features of vascular dementia with hippocampal atrophy. Stroke 41, 1278-1284
59. de la Torre, J.C. (2000) Critically attained threshold of cerebral hypoperfusion: can it cause Alzheimer's disease? Ann. N.Y. Acad. Sci. 903, 424-436
60. Sarti, C., Pantoni, L., Bartolini, L. and Inzitari, D. (2002) Cognitive impairment and chronic cerebral hypoperfusion: what can be learned from experimental models. J. Neurol. Sci. 203-204, 263-266
61. Jiwa, N.S., Garrard, P. and Hainsworth, A.H. (2010) Experimental models of vascular dementia and vascular cognitive impairment: a systematic review. J. Neurochem. 115, 814-828
62. Pappas, B.A., de la Torre, J.C., Davidson, C.M., Keyes, M.T. and Fortin, T. (1996) Chronic reduction of cerebral blood flow in the adult rat: late-emerging CA1 cell loss and memory dysfunction. Brain Res. 708, 50-58
63. Vicente, E., Degerone, D., Bohn, L., Scornavaca, F., Pimentel, A., Leite, M.C. et al. (2009) Astroglial and cognitive effects of chronic cerebral hypoperfusion in the rat. Brain Res. 1251, 204-212
64. Choi, B.R., Kim, D.H., Back, D.B., Kang, C.H., Moon, W.J., Han, J.S. et al. (2016) Characterization of white matter injury in a rat model of chronic cerebral hypoperfusion. 47, 542-547
65. Shibata, M., Yamasaki, N., Miyakawa, T., Kalaria, R.N., Fujita, Y., Ohtani, R. et al. (2007) Selective impairment of working memory in a mouse model of chronic cerebral hypoperfusion. Stroke 38, 2826-2832
66. Washida, K., Ihara, M., Nishio, K., Fujita, Y., Maki, T., Yamada, M. et al. (2010) Nonhypotensive dose of telmisartan attenuates cognitive impairment partially due to peroxisome proliferator-activated receptor-gamma activation in mice with chronic cerebral hypoperfusion. Stroke 41, 1798-1806
67. Maki, T., Ihara, M., Fujita, Y., Nambu, T., Miyashita, K., Yamada, M. et al. (2011) Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice. Stroke 42, 1122-1128
68. Kitamura, A., Manso, Y., Duncombe, J., Searcy, J., Koudelka, J., Binnie, B. et al. (2017) Long-term cilostazol treatment reduces gliovascular damage and memory in a mouse model of chronic cerebral hypoperfusion. Sci. Rep. 7, 4299
69. Hase, Y., Craggs, L., Hase, M., Stevenson, W., Slade, J., Chen, A. et al. (2017) The effects of environmental enrichment on white matter pathology in a mouse model of chronic cerebral hypoperfusion. J. Cereb. Blood Flow Metab., doi:10.1177/0271678X17694904
70. Nishio, K., Ihara, M., Yamasaki, N., Kalaria, R.N., Maki, T., Fujita, Y. et al. (2010) A mouse model characterizing features of vascular dementia with hippocampal atrophy. Stroke 41, 1278-1284
71. Ndubuizu, O. and LaManna, J.C. (2007) Brain tissue oxygen concentration measurements. Antioxid. Redox Signal. 9, 1207-1219
72. Dong, Y.F., Kataoka, K., Toyama, K., Sueta, D., Koibuchi, N., Yamamoto, E. et al. (2011) Attenuation of brain damage and cognitive impairment by direct renin inhibition in mice with chronic cerebral hypoperfusion. Hypertension 58, 635-642
73. Husain, J. and Juurlink, B. H. (1995) Oligodendroglial precursor cell susceptibility to hypoxia is related to poor ability to cope with reactive oxygen species. Brain Res. 698, 86-94
74. McTigue, D.M. and Tripathi, R.B. (2008) The life, death, and replacement of oligodendrocytes in the adult CNS. J. Neurochem. 107, 1-19
75. Hinman, J.D., Lee, M.D., Tung, S., Vinters, H.V. and Carmichael, S.T. (2015) Molecular disorganization of axons adjacent to human lacunar infarcts. Brain 138, 736-745
76. Engelhardt, S., Al-Ahmad, A.J., Gassmann, M. and Ogunshola, O.O. (2014) Hypoxia selectively disrupts brain microvascular endothelial tight junction complexes through a hypoxia-inducible factor-1 (HIF-1) dependent mechanism. J. Cell. Physiol. 229, 1096-1105
77. Seo, J.H., Maki, T., Maeda, M., Miyamoto, N., Liang, A.C., Hayakawa, K. et al. (2014) Oligodendrocyte precursor cells support blood-brain barrier integrity via TGF-β signaling. PLoS ONE 9, e103174
78. Wardlaw, J.M., Makin, S.J., Valdes Hernandez, M.C., Armitage, P.A., Heye, A.K., Chappell, F.M. et al. (2016) Blood-brain barrier failure as a core mechanism in small vessel disease and dementia: evidence from a cohort study. Alzheimers Dement., doi:10.1016/j.jalz.2016.09.006
79. Rajani, R.M. and Williams, A. (2017) Endothelial cell-oligodendrocyte interactions in small vessel disease and aging. Clin. Sci. (Lond.) 131, 369-379
80. Gomez-Nicola, D. and Hugh Perry, V. (2015) Microglial dynamics and role in the healthy and diseased brain: a paradigm of functional plasticity. Neuroscientist 21, 169-184
81. Simpson, J.E., Ince, P.G., Higham, C.E., Gelsthorpe, C.H., Fernando, M.S., Matthews, F. et al. (2007) Microglial activation in white matter lesions and nonlesional white matter of ageing brains. Neuropathol. Appl. Neurobiol. 33, 670-683
82. Simpson, J.E., Hosny, O., Wharton, S.B., Heath, P.R., Holden, H., Fernando, M.S. et al. (2009) Microarray RNA expression analysis of cerebral white matter lesions reveals changes in multiple functional pathways. Stroke 40, 369-375
83. Sloane, J.A., Hollander, W., Moss, M.B., Rosene, D.L. and Abraham, C.R. (1999) Increased microglial activation and protein nitration in white matter of the aging monkey. Neurobiol. Aging 20, 395-405
84. Manso, Y., Holland, P.R., Kitamura, A., Searcy, L., Marangoni, M., Szymkowiak, S. et al. Minocycline reduces microgliosis and improves subcortical white matter function in a model of cerebral vascular disease. Glia, doi:10.1022/glia.23190
85. Safaiyan, S., Kannaiyan, N., Snaidero, N., Brioschi, S., Biber, K., Yona, S. et al. (2016) Age-related myelin degradation burdens the clearance function of microglia during aging. Nat. Neurosci. 19, 995-998
86. Huang, Y., Zhang, W., Lin, L., Feng, J., Chen, F., Wei, W. et al. (2010) Is endothelial dysfunction of cerebral small vessel responsible for white matter lesions after chronic cerebral hypoperfusion in rats? J. Neurol. Sci. 299, 72-80
87. Wakita, H., Ruetzler, C., Illoh, K.O., Chen, Y., Takanohashi, A., Spatz, M. et al. (2008) Mucosal tolerization to E-selectin protects against memory dysfunction and white matter damage in a vascular cognitive impairment model. J. Cereb. Blood Flow Metab. 28, 341-353
88. Yata, K., Nishimura, Y., Unekawa, M., Tomita, Y., Suzuki, N., Tanaka, T. et al. (2014) In vivo imaging of the mouse neurovascular unit under chronic cerebral hypoperfusion. Stroke 45, 3698-3703
89. Füchtemeier, M., Brinckmann, M.P., Foddis, M., Kunz, A., Po, C., Curato, C. et al. (2015) Vascular change and opposing effects of the angiotensin type2 receptor in a mouse model of vascular cognitive impairment. J. Cereb. Blood Flow Metab. 35, 476-484
90. Nakaji, K., Ihara, M., Takahashi, C., Itohara, S., Noda, M., Takahashi, R. et al. (2006) Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents. Stroke 37, 2816-2823
91. Ihara, M., Tomimoto, H., Kinoshita, M., Oh, J., Noda, M., Wakita, H. et al. (2001) Chronic cerebral hypoperfusion induces MMP-2 but not MMP-9 expression in the microglia and vascular endothelium of white matter. J. Cereb. Blood Flow Metab. 21, 828-834
92. Sood, R., Yang, Y., Taheri, S., Candelario-Jalil, E., Estrada, E.Y., Walker, E.J. et al. (2009) Increased apparent diffusion coefficients on MRI linked with matrix metalloproteinases and edema in white matter after bilateral carotid artery occlusion in rats. J. Cereb. Blood Flow Metab. 29, 308-316
93. Yuan, B., Shi, H., Zheng, K., Su, Z., Su, H., Zhong, M. et al. (2017) MCP-1-mediated activation of microglia promotes white matter lesions and cognitive deficits by chronic cerebral hypoperfusion in mice. Mol. Cell. Neurosci. 78, 52-58
94. Chandler, S., Coates, R., Gearing, A., Lury, J., Wells, G. and Bone, E. (1995) Matrix metalloproteinases degrade myelin basic protein. Neurosci. Lett. 201, 223-226
95. Freeman, L.R. and Keller, J.N. (2012) Oxidative stress and cerebral endothelial cells: regulation of the blood-brain-barrier and antioxidant based interventions. Biochim. Biophys. Acta 1822, 822-829
96. Chrissobolis, S., Miller, A.A., Drummond, G.R., Kemp-Harper, B.K. and Sobey, C.G. (2011) Oxidative stress and endothelial dysfunction in cerebrovascular disease. Front. Biosci. (Landmark Ed) 16, 1733-1745
97. Rouhl, R.P., Damoiseaux, J.G., Lodder, J., Theunissen, R.O., Knottnerus, I.L., Staals, J. et al. (2012) Vascular inflammation in cerebral small vessel disease. Neurobiol. Aging 33, 1800-1806
98. Wiseman, S.J., Bastin, M.E., Jardine, C.L., Barclay, G., Hamilton, I.F., Sandeman, E. et al. (2016) Cerebral small vessel disease burden is increased in systemic lupus erythematosus. Stroke 47, 2722-2728
99. von Bernhardi, R., Eugeńin-von Bernhardi, L. and Eugeńin, J. (2015) Microglial cell dysregulation in brain aging and neurodegeneration. Front. Aging Neurosci. 7, 124
100. Wolf, G., Lotan, A., Lifschytz, T., Ben-Ari, H., Kreisel Merzel, T., Tatarskyy, P. et al. (2017) Differentially severe cognitive effects of compromised cerebral blood flow in aged mice: association with myelin degradation and microglia activation. Front. Aging Neurosci. 9, 191
101. McConnell, H.L., Kersch, C.N., Woltjer, R.L. and Neuwelt, E.A. (2017) The translational significance of the neurovascular unit. J. Biol. Chem. 292, 762-770
102. Nishino, A., Tajima, Y., Takuwa, H., Masamoto, K., Taniguchi, J., Wakizaka, H. et al. (2016) Long-term effects of cerebral hypoperfusion on neural density and function using misery perfusion animal model. Sci. Rep. 6, 25072
103. Tajima, Y., Takuwa, H., Kokuryo, D., Kawaguchi, H., Seki, C., Masamoto, K. et al. (2014) Changes in cortical microvasculature during misery perfusion measured by two-photon laser scanning microscopy. J. Cereb. Blood Flow Metab. 34, 1363-1372
104. Matin, N., Fisher, C., Jackson, W.F. and Dorrance, A.M. (2016) Bilateral common carotid artery stenosis in normotensive rats impairs endothelium-dependent dilation of parenchymal arterioles. Am. J. Physiol. Heart Circ. Physiol. 310, H1321-H1329
105. Sam, K., Crawley, A.P., Conklin, J., Poublanc, J., Sobczyk, O., Mandell, D.M. et al. (2016) Development of white matter hyperintensity is preceded by reduced cerebrovascular reactivity. Ann. Neurol. 80, 277-285
106. Bazargani, N. and Attwell, D. (2016) Astrocyte calcium signaling: the third wave. Nat. Neurosci. 19, 182-189
107. Saggu, R., Schumacher, T., Gerich, F., Rakers, C., Tai, K., Delekate, A. et al. (2016) Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia. Acta Neuropathol. Commun. 4, 76
108. Brown, W.R. and Thore, C.R. (2011) Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol. Appl. Neurobiol. 37, 56-74
109. Iliff, J.J., Wang, M., Liao, Y., Plogg, B.A., Peng, W., Gundersen, G.A. et al. (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 4, 147ra111
110. Miyamoto, N., Maki, T., Shindo, A., Liang, A.C., Maeda, M., Egawa, N. et al. (2015) Astrocytes promote oligodendrogenesis after white matter damage via brain-derived neurotrophic factor. J. Neurosci. 35, 14002-14008
111. Miyamoto, N., Pham, L.D., Hayakawa, K., Matsuzaki, T., Seo, J.H., Magnain, C. et al. (2013) Age-related decline in oligodendrogenesis retards white matter repair in mice. Stroke 44, 2573-2578
112. Yemisci, M., Gursoy-Ozdemir, Y., Vural, A., Can, A., Topalkara, K. and Dalkara, T. (2009) Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat. Med. 15, 1031-1037
113. Faraco, G., Sugiyama, Y., Lane, D., Garcia-Bonilla, L., Chang, H., Santisteban, M.M. et al. (2016) Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension. J. Clin. Invest. 126, 4674-4689
114. Joutel, A., Haddad, I., Ratelade, J. and Nelson, M.T. (2016) Perturbations of the cerebrovascular matrisome: A convergent mechanism in small vessel disease of the brain. J. Cereb. Blood Flow Metab. 36, 143-157
115. Kalaria, RN. (2012) Cerebrovascular disease and mechanisms of cognitive impairment: evidence from clinicopathological studies in humans. Stroke 43, 2526-2534
116. Weaver, J., Jalal, F.Y., Yang, Y., Thompson, J., Rosenberg, G.A. and Liu, K.J. (2014) Tissue oxygen is reduced in white matter of spontaneously hypertensive-stroke prone rats: a longitudinal study with electron paramagnetic resonance. J. Cereb. Blood Flow Metab. 34, 890-896
117. Barnes, D.E. and Yaffe, K. (2011) The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol. 10, 819-828
118. Kalaria, R.N., Akinyemi, R. and Ihara, M. (2012) Does vascular pathology contribute to Alzheimer changes. J. Neurol. Sci. 322, 141-147
119. Niwa, K., Porter, V.A., Kazama, K., Cornfield, D., Carlson, G.A. and Iadecola, C. (2001) A beta-peptides enhance vasoconstriction in cerebral circulation. Am. J. Physiol. Heart Circ. Physiol. 281, H2417-H2424
120. Okamoto, Y., Yamamoto, T., Kalaria, R.N., Senzaki, H., Maki, T., Hase, Y. et al. (2012) Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol. 123, 381-394
121. Salvadores, N., Searcy, L., Holland, P. and Horsburgh, K. (2017) Chronic cerebral hypoperfusion alters amyloid-β peptide pools leading to cerebral amyloid angiopathy, microinfarcts and hemorrhages in Tg-SwDI mice. Clin. Sci. (Lond.) 131, 2109-2123
122. Yamada, M., Ihara, M., Okamoto, Y., Maki, T., Washida, K., Kitamura, A. et al. (2011) The influence of chronic cerebral hypoperfusion on cognitive function and amyloid β metabolism in APP overexpressing mice. PLoS ONE 6, e16567
123. Weller, R.O., Subash, M., Preston, S.D., Mazanti, I. and Carare, R.O. (2008) Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathol. 18, 253-266
124. Hawkes, C.A., Hartig, W., Kacza, J., Schliebs, R., Weller, R.O., Nicoll, J.A. et al. (2011) Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol. 121, 431-443
125. Park, L., Anrather, J., Zhou, P., Frys, K., Pitstick, R., Younkin, S. et al. (2005) NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. J. Neurosci. 25, 1769-1777
126. Park, L., Zhou, P., Pitstick, R., Capone, C., Anrather, J., Norris, E.H. et al. (2008) Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc. Natl Acad. Sci. U.S.A. 105, 1347-1352
127. Shang, J., Yamashita, T., Zhai, Y., Nakano, Y., Morihara, R., Fukui, Y. et al. (2016) Strong impact of chronic cerebral hypoperfusion on neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling in Alzheimer's disease model mouse. J. Alzheimers Dis. 52, 113-126
128. Heneka, M.T., Carson, M.J., El Khoury, J., Landreth, G.E., Brosseron, F., Feinstein, D.L. et al. (2015) Neuroinflammation in Alzheimer's disease. Lancet Neurol. 14, 388-405
129. Heppner, F.L., Ransohoff, R.M. and Becher, B. (2015) Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358-372
130. Pimentel-Coelho, P.M., Michaud, J.P. and Rivest, S. (2013) Effects of mild chronic cerebral hypoperfusion and early amyloid pathology on spatial learning and the cellular innate immune response in mice. Neurobiol. Aging 34, 679-693
131. Saito, T., Matsuba, Y., Mihira, N., Takano, J., Nilsson, P., Itohara, S. et al. (2014) Single App knock-in mouse models of Alzheimer's disease. Nat. Neurosci. 17, 661-663
132. Ito, H., Hashimoto, A., Matsumoto, Y., Yao, H. and Miyakoda, G. (2010) Cilostazol, a phosphodiesterase inhibitor, attenuates photothrombotic focal ischemic brain injury in hypertensive rats. J. Cereb. Blood Flow Metab. 30, 343-351
133. Oyama, N., Yagita, Y., Kawamura, M., Sugiyama, Y., Terasaki, Y., Omura-Matsuoka, E. et al. (2011) Cilostazol, not aspirin, reduces ischemic brain injury via endothelial protection in spontaneously hypertensive rats. Stroke 42, 2571-2577
134. Hase, Y., Okamoto, Y., Fujita, Y., Kitamura, A., Nakabayashi, H., Ito, H. et al. (2012) Cilostazol, a phosphodiesterase inhibitor, prevents no-reflow and hemorrhage in mice with focal cerebral ischemia. Exp. Neurol. 233, 523-533
135. Chen, W.J., Chen, Y.H., Lin, K.H., Ting, C.H. and Yeh, Y.H. (2011) Cilostazol promotes vascular smooth muscles cell differentiation through the cAMP response element-binding protein-dependent pathway. Arterioscler. Thromb. Vasc. Biol. 31, 2106-2113
136. Watanabe, T., Zhang, N., Liu, M., Tanaka, R., Mizuno, Y. and Urabe, T. (2006) Cilostazol protects against brain white matter damage and cognitive impairment in a rat model of chronic cerebral hypoperfusion. Stroke 37, 1539-1545
137. Hiramatsu, M., Takiguchi, O., Nishiyama, A. and Mori, H. (2010) Cilostazol prevents amyloid β peptide(25-35)-induced memory impairment and oxidative stress in mice. Br. J. Pharmacol. 161, 1899-1912
138. Maki, T., Okamoto, Y., Carare, R.O., Hase, Y., Hattori, Y., Hawkes, C.A. et al. (2014) Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid. Ann. Clin. Transl. Neurol. 1, 519-533
139. Arai, H. and Takahashi, T. (2009) A combination therapy of donepezil and cilostazol for patients with moderate Alzheimer disease: pilot follow-up study. Am. J. Geriatr. Psychiatry 17, 353-354
140. Ihara, M., Nishino, M., Taguchi, A., Yamamoto, Y., Hattori, Y., Saito, S. et al. (2014) Cilostazol add-on therapy in patients with mild dementia receiving donepezil: a retrospective study. PLoS ONE 9, e89516
141. Jalal, F.Y., Yang, Y., Thompson, J.F., Roitbak, T. and Rosenberg, G.A. (2015) Hypoxia-induced neuroinflammatory white-matter injury reduced by minocycline in SHR/SP. J. Cereb. Blood Flow Metab. 35, 1145-1153
142. Yang, Y., Salayandia, V.M., Thompson, J.F., Yang, L.Y., Estrada, E.Y. and Yang, Y. (2015) Attenuation of acute stroke injury in rat brain by minocycline promotes blood-brain barrier remodeling and alternative microglia/macrophage activation during recovery. J. Neuroinflammation 12, 26
143. Ma, J., Zhang, J., Hou, W.W., Wu, X.H., Liao, R.J., Chen, Y. et al. (2015) Early treatment of minocycline alleviates white matter and cognitive impairments after chronic cerebral hypoperfusion. Sci. Rep. 5, 12079
144. Cho, K.-O., La, H.O., Cho, Y.-J., Sung, K.-W. and Kim, S.Y. (2006) Minocycline attenuate white matter damage in a rat model of chronic cerebral hypoperfusion. J. Neurosci. Res. 83, 285-291
145. Fan, R., Xu, F., Previti, M.L., Davis, J., Grande, A.M., Robinson, J.K. et al. (2007) Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J. Neurosci. 27, 3057-3063
146. Yan, P., Zhu, A., Liao, F., Xiao, Q., Kraft, A.W., Gonzales, E. et al. (2015) Minocycline reduces spontaneous hemorrhage in mouse models of cerebral amyloid angiopathy. Stroke 46, 1633-1640
147. Garcia-Alloza, M., Prada, C., Lattarulo, C., Fine, S., Borrelli, L.A., Betensky, R. et al. (2009) Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice. J. Neurochemistry 109, 1636-1647
148. Rosenberg, G.A., Sullivan, N. and Esiri, M.M. (2001) White matter damage is associated with matrix metalloproteinases in vascular dementia. Stroke 32, 1162-1168
149. Rosenberg, G.A. (2017) Extracellular matrix inflammation in vascular cognitive impairment and dementia. Clin. Sci. (Lond). 131, 425-437