Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease

Nature Reviews Neuroscience

Volumn 18, Issue 7, 2017, Pages 419-434

  Kisler, Kassandra ^a   Nelson, Amy R ^a   Montagne, Axel ^a   Zlokovic, Berislav V ^a  

^a UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE; APOLIPOPROTEIN E4; CARBON DIOXIDE; FLUORODEOXYGLUCOSE F 18; NEUROTRANSMITTER; NOTCH3 RECEPTOR;

ALZHEIMER DISEASE; ANIMAL MODEL; ARTERIOLE; ASTROCYTE; AUTOSOMAL DOMINANT INHERITANCE; BOLD SIGNAL; BRAIN ARTERY; BRAIN BLOOD FLOW; BRAIN BLOOD VESSEL; BRAIN MICROCIRCULATION; BRAIN PERICYTE; CAPILLARY FLOW; ENDOTHELIAL DYSFUNCTION; ENDOTHELIUM; ENDOTHELIUM CELL; FUNCTIONAL CONNECTIVITY; FUNCTIONAL MAGNETIC RESONANCE IMAGING; HEMODYNAMICS; HUMAN; HYPERTENSION; INTRACELLULAR SIGNALING; MEDIAL PREFRONTAL CORTEX; NERVE DEGENERATION; NEUROVASCULAR COUPLING; NONHUMAN; PATHOGENESIS; POSTERIOR CINGULATE; PRECUNEUS; PRIORITY JOURNAL; REVIEW; SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY; VASCULAR SMOOTH MUSCLE CELL; VASOCONSTRICTION; BIOLOGICAL MODEL; BRAIN; BRAIN CIRCULATION; CEREBROVASCULAR DISEASE; COMPLICATION; PATHOPHYSIOLOGY; PHYSIOLOGY; VASCULARIZATION;

ALZHEIMER DISEASE; BRAIN; CEREBROVASCULAR CIRCULATION; CEREBROVASCULAR DISORDERS; HUMANS; MODELS, NEUROLOGICAL; NEUROVASCULAR COUPLING;

EID: 85021150580     PISSN: 1471003X     EISSN: 14710048     Source Type: Journal    
DOI: 10.1038/nrn.2017.48     Document Type: Review

References (184)

1. Zlokovic, B. V. Neurovascular pathways to neurodegeneration in Alzheimer?s disease and other disorders. Nat. Rev. Neurosci. 12, 723-738 (2011
2. Attwell, D., et al. Glial and neuronal control of brain blood flow. Nature 468, 232-243 (2010
3. Iadecola, C. The pathobiology of vascular dementia. Neuron 80, 844-866 (2013
4. Moskowitz, M. A., Lo, E. H., & Iadecola, C. The science of stroke: mechanisms in search of treatments. Neuron 67, 181-198 (2010
5. Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer?s disease. Nat. Rev. Neurosci. 5, 347-360 (2004
6. Buxton, R. B. Interpreting oxygenation-based neuroimaging signals: the importance and the challenge of understanding brain oxygen metabolism. Front. Neuroenergetics 2, 8 (2010
7. Lin, A. L., Fox, P. T., Hardies, J., Duong, T. Q., & Gao, J. H. Nonlinear coupling between cerebral blood flow, oxygen consumption, and ATP production in human visual cortex. Proc. Natl Acad. Sci. USA 107, 8446-8451 (2010
8. Greicius, M. D., Krasnow, B., Reiss, A. L., & Menon, V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc. Natl Acad. Sci. USA 100, 253-258 (2003
9. Snyder, A. Z., & Raichle, M. E. A brief history of the resting state: the Washington University perspective. Neuroimage 62, 902-910 (2012
10. Attwell, D., & Iadecola, C. The neural basis of functional brain imaging signals. Trends Neurosci. 25, 621-625 (2002
11. Lauritzen, M., Mathiesen, C., Schaefer, K., & Thomsen, K. J. Neuronal inhibition and excitation, and the dichotomic control of brain hemodynamic and oxygen responses. Neuroimage 62, 1040-1050 (2012
12. Hillman, E. M. C. Coupling mechanism and significance of the BOLD signal: a status report. Annu. Rev. Neurosci. 37, 161-181 (2014
13. Cauli, B., & Hamel, E. Revisiting the role of neurons in neurovascular coupling. Front. Neuroenergetics 2, 9 (2010
14. Iadecola, C., & Nedergaard, M. Glial regulation of the cerebral microvasculature. Nat. Neurosci. 10, 1369-1376 (2007
15. Zhao, Z., Nelson, A. R., Betsholtz, C., & Zlokovic, B. V. Establishment and dysfunction of the blood-brain barrier. Cell 163, 1064-1078 (2015
16. Chen, B. R., Bouchard, M. B., McCaslin, A. F. H., Burgess, S. A., & Hillman, E. M. C. High-speed vascular dynamics of the hemodynamic response. Neuroimage 54, 1021-1030 (2011
17. Chen, B. R., Kozberg, M. G., Bouchard, M. B., Shaik, M. A., & Hillman, E. M. C. A. Critical role for the vascular endothelium in functional neurovascular coupling in the brain. J. Am. Heart Assoc. 3, e000787 (2014
18. Iadecola, C., Yang, G., Ebner, T. J., & Chen, G. Local and propagated vascular responses evoked by focal synaptic activity in cerebellar cortex. J. Neurophysiol. 78, 651-659 (1997
19. Tian, P., et al. Cortical depth-specific microvascular dilation underlies laminar differences in blood oxygenation level-dependent functional MRI signal. Proc. Natl Acad. Sci. USA 107, 15246-15251 (2010
20. Devor, A., et al. ?Overshoot? of O2 is required to maintain baseline tissue oxygenation at locations distal to blood vessels. J. Neurosci. 31, 13676-13681 (2011
21. Kasischke, K. A., et al. Two-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions. J. Cereb. Blood Flow Metab. 31, 68-81 (2011
22. Sakadžić, S., et al. Large arteriolar component of oxygen delivery implies a safe margin of oxygen supply to cerebral tissue. Nat. Commun. 5, 5734 (2014
23. Kisler, K., et al. Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat. Neurosci. 20, 406-416 (2017
24. Hall, C. N., et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508, 55-60 (2014
25. Hill, R. A., et al. Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron 87, 95-110 (2015
26. Mishra, A., et al. Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nat. Neurosci. 19, 1619-1627 (2016
27. Biesecker, K. R., et al. Glial cell calcium signaling mediates capillary regulation of blood flow in the retina. J. Neurosci. 36, 9435-9445 (2016
28. Khakh, B. S., & Sofroniew, M. V. Diversity of astrocyte functions and phenotypes in neural circuits. Nat. Neurosci. 18, 942-952 (2015
29. Tsai, H. H., et al. Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337, 358-362 (2012
30. Gundersen, V., Storm-Mathisen, J., & Bergersen, L. H. Neuroglial transmission. Physiol. Rev. 95, 695-726 (2015
31. Lee, H. S., et al. Astrocytes contribute to gamma oscillations and recognition memory. Proc. Natl Acad. Sci. USA 111, E3343-E3352 (2014
32. Sofroniew, M. V. Astrocyte barriers to neurotoxic inflammation. Nat. Rev. Neurosci. 16, 249-263 (2015
33. Mulligan, S. J., & MacVicar, B. A. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431, 195-199 (2004
34. Zonta, M., et al. Neuron-To astrocyte signaling is central to the dynamic control of brain microcirculation. Nat. Neurosci. 6, 43-50 (2003
35. Takano, T., et al. Astrocyte-mediated control of cerebral blood flow. Nat. Neurosci. 9, 260-267 (2006
36. MacVicar, B. A., & Newman, E. A. Astrocyte regulation of blood flow in the brain. Cold Spring Harb. Perspect. Biol. 7, a020388 (2015
37. Otsu, Y., et al. Calcium dynamics in astrocyte processes during neurovascular coupling. Nat. Neurosci. 18, 210-218 (2015
38. Agulhon, C., et al. What is the role of astrocyte calcium in neurophysiology? Neuron 59, 932-946 (2008
39. Nizar, K., et al. In vivo stimulus-induced vasodilation occurs without IP3 receptor activation and may precede astrocytic calcium increase. J. Neurosci. 33, 8411-8422 (2013
40. Bonder, D. E., & McCarthy, K. D. Astrocytic Gq GPCR-linked IP3R dependent Ca2+ signaling does not mediate neurovascular coupling in mouse visual cortex in vivo. J. Neurosci. 34, 13139-13150 (2014
41. Sun, W., et al. Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science 339, 197-200 (2013
42. Piet, R., & Jahr, C. E. Glutamatergic and purinergic receptor-mediated calcium transients in Bergmann glial cells. J. Neurosci. 27, 4027-4035 (2007
43. Kim, K. J., et al. Astrocyte contributions to flow/ pressure-evoked parenchymal arteriole vasoconstriction. J. Neurosci. 35, 8245-8257 (2015
44. Dunn, K. M., Hill-Eubanks, D. C., Liedtke, W. B., & Nelson, M. T. TRPV4 channels stimulate Ca2+-induced Ca2+ release in astrocytic endfeet and amplify neurovascular coupling responses. Proc. Natl Acad. Sci. USA 110, 6157-6162 (2013
45. Longden, T. A., & Nelson, M. T. Vascular inward rectifier K+ channels as external K+ sensors in the control of cerebral blood flow. Microcirculation 22, 183-196 (2015
46. Girouard, H., et al. Astrocytic endfoot Ca2+ and BK channels determine both arteriolar dilation and constriction. Proc. Natl Acad. Sci. USA 107, 3811-3816 (2010
47. Gordon, G. R. J., Choi, H. B., Rungta, R. L., Ellis-Davies, G. C. R., & MacVicar, B. A. Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456, 745-749 (2008
48. Mishra, A., Hamid, A., & Newman, E. A. Oxygen modulation of neurovascular coupling in the retina. Proc. Natl Acad. Sci. USA 108, 17827-17831 (2011
49. Brazitikos, P. D., Pournaras, C. J., Munoz, J. L., & Tsacopoulos, M. Microinjection of L lactate in the preretinal vitreous induces segmental vasodilation in the inner retina of miniature pigs. Invest. Ophthalmol. Vis. Sci. 34, 1744-1752 (1993
50. Dai, M., Yang, Y., & Shi, X. Lactate dilates cochlear capillaries via type V fibrocyte-vessel coupling signaled by nNOS. Am. J. Physiol. Heart Circ. Physiol. 301, H1248-H1254 (2011
51. Faraci, F. M., & Breese, K. R. Nitric oxide mediates vasodilatation in response to activation of N methyl- D aspartate receptors in brain. Circ. Res. 72, 476-480 (1993
52. Bhardwaj, A., et al. P-450 epoxygenase and NO synthase inhibitors reduce cerebral blood flow response to N methyl-D aspartate. Am. J. Physiol. Heart Circ. Physiol. 279, H1616-H1624 (2000
53. Buerk, D. G., Ances, B. M., Greenberg, J. H., & Detre, J. A. Temporal dynamics of brain tissue nitric oxide during functional forepaw stimulation in rats. Neuroimage 18, 1-9 (2003
54. Kur, J., & Newman, E. A. Purinergic control of vascular tone in the retina. J. Physiol. 592, 491-504 (2014
55. Horiuchi, T., Dietrich, H. H., Tsugane, S., & Dacey, R. G. Analysis of purine- And pyrimidine-induced vascular responses in the isolated rat cerebral arteriole. Am. J. Physiol. Heart Circ. Physiol. 280, H767-H776 (2001
56. Fields, R. D., & Burnstock, G. Purinergic signalling in neuron-glia interactions. Nat. Rev. Neurosci. 7, 423-436 (2006
57. Pascual, O., et al. Astrocytic purinergic signaling coordinates synaptic networks. Science 310, 113-116 (2005
58. Lovatt, D., et al. Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity. Proc. Natl Acad. Sci. USA 109, 6265-6270 (2012
59. Bekar, L. K., Wei, H. S., & Nedergaard, M. The locus coeruleus-norepinephrine network optimizes coupling of cerebral blood volume with oxygen demand. J. Cereb. Blood Flow Metab. 32, 2135-2145 (2012
60. Kozberg, M. G., Chen, B. R., DeLeo, S. E., Bouchard, M. B., & Hillman, E. M. C. Resolving the transition from negative to positive blood oxygen level-dependent responses in the developing brain. Proc. Natl Acad. Sci. USA 110, 4380-4385 (2013
61. Uhlirova, H., et al. Cell type specificity of neurovascular coupling in cerebral cortex. eLife 5, e14315 (2016
62. Wölfle, S. E., et al. Non-linear relationship between hyperpolarisation and relaxation enables long distance propagation of vasodilatation. J. Physiol. 589, 2607-2623 (2011
63. Ralevic, V., & Dunn, W. R. Purinergic transmission in blood vessels. Auton. Neurosci. 191, 48-66 (2015
64. Zlokovic, B. V., Deane, R., Sagare, A. P., Bell, R. D., & Winkler, E. A. Low-density lipoprotein receptor-related protein 1: a serial clearance homeostatic mechanism controlling Alzheimer?s amyloid β peptide elimination from the brain. J. Neurochem. 115, 1077-1089 (2010
65. Attwell, D., Mishra, A., Hall, C. N., O?Farrell, F. M., & Dalkara, T. What is a pericyte? J. Cereb. Blood Flow Metab. 36, 451-455 (2016
66. Fernández-Klett, F., & Priller, J. Diverse functions of pericytes in cerebral blood flow regulation and ischemia. J. Cereb. Blood Flow Metab. 35, 883-887 (2015
67. Hartmann, D. A., et al. Pericyte structure and distribution in the cerebral cortex revealed by high-resolution imaging of transgenic mice. Neurophotonics 2, 041402 (2015
68. Cuevas, P., et al. Pericyte endothelial gap junctions in human cerebral capillaries. Anat. Embryol. (Berl.) 170, 155-159 (1984
69. Armulik, A., Genové, G., & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193-215 (2011
70. Gerhardt, H., Wolburg, H., & Redies, C. N Cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken. Dev. Dyn. 218, 472-479 (2000
71. Winkler, E. A., Bell, R. D., & Zlokovic, B. V. Central nervous system pericytes in health and disease. Nat. Neurosci. 14, 1398-1405 (2011
72. Zeisel, A., et al. Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 347, 1138-1142 (2015
73. Sweeney, M. D., Ayyadurai, S., & Zlokovic, B. V. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat. Neurosci. 19, 771-783 (2016
74. Dai, M., Nuttall, A., Yang, Y., & Shi, X. Visualization and contractile activity of cochlear pericytes in the capillaries of the spiral ligament. Hear. Res. 254, 100-107 (2009
75. Fernández-Klett, F., Offenhauser, N., Dirnagl, U., Priller, J., & Lindauer, U. Pericytes in capillaries are contractile in vivo, but arterioles mediate functional hyperemia in the mouse brain. Proc. Natl Acad. Sci. USA 107, 22290-22295 (2010
76. Neuhaus, A. A., Couch, Y., Sutherland, B. A., & Buchan, A. M. Novel method to study pericyte contractility and responses to ischaemia in vitro using electrical impedance. J. Cereb. Blood Flow Metab. http://dx.doi.org/10.1177/0271678X16659495 (2016
77. Peppiatt, C. M., Howarth, C., Mobbs, P., & Attwell, D. Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700-704 (2006
78. Yamanishi, S., Katsumura, K., Kobayashi, T., & Puro, D. G. Extracellular lactate as a dynamic vasoactive signal in the rat retinal microvasculature. Am. J. Physiol. Heart Circ. Physiol. 290, H925-H934 (2006
79. Wei, H. S., et al. Erythrocytes are oxygen-sensing regulators of the cerebral microcirculation. Neuron 91, 851-862 (2016
80. Kawamura, H., et al. Effects of angiotensin II on the pericyte-containing microvasculature of the rat retina. J. Physiol. 561, 671-683 (2004
81. Bandopadhyay, R., et al. Contractile proteins in pericytes at the blood-brain and blood-retinal barriers. J. Neurocytol. 30, 35-44 (2001
82. Chaigneau, E., Oheim, M., Audinat, E., & Charpak, S. Two-photon imaging of capillary blood flow in olfactory bulb glomeruli. Proc. Natl Acad. Sci. USA 100, 13081-13086 (2003
83. Stefanovic, B., et al. Functional reactivity of cerebral capillaries. J. Cereb. Blood Flow Metab. 28, 961-972 (2008
84. Hutchinson, E. B., Stefanovic, B., Koretsky, A. P., & Silva, A. C. Spatial flow-volume dissociation of the cerebral microcirculatory response to mild hypercapnia. Neuroimage 32, 520-530 (2006
85. Fernández-Klett, F., et al. Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke. J. Cereb. Blood Flow Metab. 33, 428-439 (2013
86. Yemisci, M., et al. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat. Med. 15, 1031-1037 (2009
87. Kawamura, H., et al. ATP: a vasoactive signal in the pericyte-containing microvasculature of the rat retina. J. Physiol. 551, 787-799 (2003
88. Lacar, B., Herman, P., Hartman, N. W., Hyder, F., & Bordey, A. S phase entry of neural progenitor cells correlates with increased blood flow in the young subventricular zone. PLoS ONE 7, e31960 (2012
89. Hamilton, N. B., Attwell, D., & Hall, C. N. Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front. Neuroenergetics 2, 5 (2010
90. Toledo, J. B., et al. Clinical and multimodal biomarker correlates of ADNI neuropathological findings. Acta Neuropathol. Commun. 1, 65 (2013
91. Montagne, A., et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85, 296-302 (2015
92. Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. Cerebrospinal fluid biomarkers of neurovascular dysfunction in mild dementia and Alzheimer?s disease. J. Cereb. Blood Flow Metab. 35, 1055-1068 (2015
93. Arvanitakis, Z., Capuano, A. W., Leurgans, S. E., Bennett, D. A., & Schneider, J. A. Relation of cerebral vessel disease to Alzheimer?s disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol. 15, 934-943 (2016
94. Iturria-Medina, Y., Sotero, R. C., Toussaint, P. J., Mateos-Pérez, J. M., & Evans, A. C. Alzheimer?s Disease Neuroimaging Initiative. Early role of vascular dysregulation on late-onset Alzheimer?s disease based on multifactorial data-driven analysis. Nat. Commun. 7, 11934 (2016
95. Nelson, A. R., Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer?s disease. Biochim. Biophys. Acta 1862, 887-900 (2016
96. Wardlaw, J. M., et al. STandards for ReportIng Vascular changes on nEuroimaging (STRIVE v1). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 12, 822-838 (2013
97. Montine, T. J., et al. ADRD 2013 Conference Organizing Committee. Recommendations of the Alzheimer?s disease-related dementias conference. Neurology 83, 851-860 (2014
98. Snyder, H. M., et al. Vascular contributions to cognitive impairment and dementia including Alzheimer?s disease. Alzheimers Dement. 11, 710-717 (2015
99. Hachinski, V. World Stroke Organization. Stroke and potentially preventable dementias proclamation: updated World Stroke Day proclamation. Stroke 46, 3039-3040 (2015
100. Iadecola, C. Cerebrovascular effects of amyloid-β peptides: mechanisms and implications for Alzheimer?s dementia. Cell. Mol. Neurobiol. 23, 681-689 (2003
101. Zlokovic, B. V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178-201 (2008
102. Bell, R. D., et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409-427 (2010
103. Sengillo, J. D., et al. Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer?s disease. Brain Pathol. 23, 303-310 (2013
104. Halliday, M. R., et al. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer?s disease. J. Cereb. Blood Flow Metab. 36, 216-227 (2015
105. Park, L., et al. Age-dependent neurovascular dysfunction and damage in a mouse model of cerebral amyloid angiopathy. Stroke 45, 1815-1821 (2014
106. Sagare, A. P., et al. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat. Commun. 4, 2932 (2013
107. Farkas, E., & Luiten, P. G. Cerebral microvascular pathology in aging and Alzheimer?s disease. Prog. Neurobiol. 64, 575-611 (2001
108. Baloyannis, S. J., & Baloyannis, I. S. The vascular factor in Alzheimer?s disease: a study in Golgi technique and electron microscopy. J. Neurol. Sci. 322, 117-121 (2012
109. Winkler, E. A., et al. Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol. 125, 111-120 (2013
110. Winkler, E. A., Sengillo, J. D., Bell, R. D., Wang, J., & Zlokovic, B. V. Blood-spinal cord barrier pericyte reductions contribute to increased capillary permeability. J. Cereb. Blood Flow Metab. 32, 1841-1852 (2012
111. Underly, R. G., et al. Pericytes as inducers of rapid, matrix metalloproteinase 9 dependent capillary damage during ischemia. J. Neurosci. 37, 129-140 (2017
112. Wilhelmus, M. M. M., et al. Lipoprotein receptor-related protein 1 mediates amyloid-β-mediated cell death of cerebrovascular cells. Am. J. Pathol. 171, 1989-1999 (2007
113. Faraco, G., & Iadecola, C. Hypertension: a harbinger of stroke and dementia. Hypertension 62, 810-817 (2013
114. Capone, C., et al. Central cardiovascular circuits contribute to the neurovascular dysfunction in angiotensin II hypertension. J. Neurosci. 32, 4878-4886 (2012
115. Faraco, G., et al. Hypertension enhances Aβ induced neurovascular dysfunction, promotes β secretase activity, and leads to amyloidogenic processing of APP. J. Cereb. Blood Flow Metab. 36, 241-252 (2016
116. Capone, C., et al. The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension. Am. J. Physiol. Heart Circ. Physiol. 300, H397-H407 (2011
117. Kazama, K. Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ. Res. 95, 1019-1026 (2004
118. Girouard, H. Angiotensin II attenuates endothelium-dependent responses in the cerebral microcirculation through Nox 2 derived radicals. Arterioscler. Thromb. Vasc. Biol. 26, 826-832 (2006
119. Didion, S. P., Sigmund, C. D., Faraci, F. M., & Katusic, Z. S. Impaired endothelial function in transgenic mice expressing both human renin and human angiotensinogen. Stroke 31, 760-765 (2000
120. Toth, P., et al. Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II induced hypertension. J. Cereb. Blood Flow Metab. 33, 1732-1742 (2013
121. Ghosh, M., et al. Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Ann. Neurol. 78, 887-900 (2015
122. Joutel, A., et al. Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease. J. Clin. Invest. 120, 433-445 (2010
123. Dziewulska, D., & Lewandowska, E. Pericytes as a new target for pathological processes in CADASIL. Neuropathology 32, 515-521 (2012
124. Lacombe, P., Oligo, C., Domenga, V., Tournier- Lasserve, E., & Joutel, A. Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy. Stroke 36, 1053-1058 (2005
125. Bell, R. D., et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512-516 (2012
126. Wiesmann, M., et al. A dietary treatment improves cerebral blood flow and brain connectivity in aging apoE4 mice. Neural Plast. 2016, 6846721 (2016
127. Alata, W., Ye, Y., St Amour, I., Vandal, M., & Calon, F. Human apolipoprotein E e4 expression impairs cerebral vascularization and blood-brain barrier function in mice. J. Cereb. Blood Flow Metab. 35, 86-94 (2015
128. Thomas, T., Thomas, G., McLendon, C., Sutton, T., & Mullan, M. β-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380, 168-171 (1996
129. Zhang, F., Eckman, C., Younkin, S., Hsiao, K. K., & Iadecola, C. Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein. J. Neurosci. 17, 7655-7661 (1997
130. Iadecola, C., et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat. Neurosci. 2, 157-161 (1999
131. Niwa, K., et al. Aβ1 40 related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc. Natl Acad. Sci. USA 97, 9735-9740 (2000
132. Deane, R., et al. RAGE mediates amyloid-í peptide transport across the blood-brain barrier and accumulation in brain. Nat. Med. 9, 907-913 (2003
133. Deane, R., et al. A multimodal RAGE-specific inhibitor reduces amyloid β mediated brain disorder in a mouse model of Alzheimer disease. J. Clin. Invest. 122, 1377-1392 (2012
134. Park, L., et al. NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid í peptide. J. Neurosci. 25, 1769-1777 (2005
135. Park, L., et al. The key role of transient receptor potential melastatin 2 channels in amyloid-β induced neurovascular dysfunction. Nat. Commun. 5, 5318 (2014
136. Park, L., et al. Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-í. Proc. Natl Acad. Sci. USA 108, 5063-5068 (2011
137. Bell, R. D., et al. SRF and myocardin regulate LRP-mediated amyloid-í clearance in brain vascular cells. Nat. Cell Biol. 11, 143-153 (2009
138. Kimbrough, I. F., Robel, S., Roberson, E. D., & Sontheimer, H. Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer?s disease. Brain 138, 3716-3733 (2015
139. Chow, N., et al. Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer?s phenotype. Proc. Natl Acad. Sci. USA 104, 823-828 (2007
140. Wiesmann, M., et al. Angiotensin II, hypertension, and angiotensin II receptor antagonism: roles in the behavioural and brain pathology of a mouse model of Alzheimer?s disease. J. Cereb. Blood Flow Metab. http:// dx.doi.org/10.1177/0271678X16667364 (2016
141. Okamoto, Y., et al. Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol. 123, 381-394 (2012
142. Milner, E., et al. Cerebral amyloid angiopathy increases susceptibility to infarction after focal cerebral ischemia in Tg2576 mice. Stroke 45, 3064-3069 (2014
143. Toda, N., & Okamura, T. Hyperhomocysteinemia impairs regional blood flow: involvements of endothelial and neuronal nitric oxide. Pflugers Arch. 468, 1517-1525 (2016
144. Sudduth, T. L., Powell, D. K., Smith, C. D., Greenstein, A., & Wilcock, D. M. Induction of hyperhomocysteinemia models vascular dementia by induction of cerebral microhemorrhages and neuroinflammation. J. Cereb. Blood Flow Metab. 33, 708-715 (2013
145. Sudduth, T. L., Weekman, E. M., Brothers, H. M., Braun, K., & Wilcock, D. M. β Amyloid deposition is shifted to the vasculature and memory impairment is exacerbated when hyperhomocysteinemia is induced in APP/PS1 transgenic mice. Alzheimers Res. Ther. 6, 32 (2014
146. Den Abeelen, A. S., Lagro, J., van Beek, A. H., & Claassen, J. A. Impaired cerebral autoregulation and vasomotor reactivity in sporadic Alzheimer?s disease. Curr. Alzheimer Res. 11, 11-17 (2014
147. Suri, S., et al. Reduced cerebrovascular reactivity in young adults carrying the APOE e4 allele. Alzheimers Dement. 11, 648-657.e1 (2015
148. Hajjar, I., Sorond, F., & Lipsitz, L. A. Apolipoprotein E, carbon dioxide vasoreactivity, and cognition in older adults: effect of hypertension. J. Am. Geriatr. Soc. 63, 276-281 (2015
149. Yezhuvath, U. S., et al. Forebrain-dominant deficit in cerebrovascular reactivity in Alzheimer?s disease. Neurobiol. Aging 33, 75-82 (2012
150. Ruitenberg, A., et al. Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ann. Neurol. 57, 789-794 (2005
151. Kogure, D., et al. Longitudinal evaluation of early Alzheimer?s disease using brain perfusion SPECT. J. Nucl. Med. 41, 1155-1162 (2000
152. Minoshima, S., et al. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer?s disease. Ann. Neurol. 42, 85-94 (1997
153. Hirao, K., et al. Functional interactions between entorhinal cortex and posterior cingulate cortex at the very early stage of Alzheimer?s disease using brain perfusion single-photon emission computed tomography. Nucl. Med. Commun. 27, 151-156 (2006).
154. Yuan, B., et al. Differential effects of APOE genotypes on the anterior and posterior subnetworks of default mode network in amnestic mild cognitive impairment. J. Alzheimers Dis. 54, 1409-1423 (2016
155. Matsuda, H., et al. Longitudinal evaluation of both morphologic and functional changes in the same individuals with Alzheimer?s disease. J. Nucl. Med. 43, 304-311 (2002
156. Daulatzai, M. A. Cerebral hypoperfusion and glucose hypometabolism: key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer?s disease. J. Neurosci. Res. 95, 943-972 (2016
157. Mosconi, L., et al. Functional interactions of the entorhinal cortex: an 18F FDG PET study on normal aging and Alzheimer?s disease. J. Nucl. Med. 45, 382-392 (2004
158. Hirao, K., et al. The prediction of rapid conversion to Alzheimer?s disease in mild cognitive impairment using regional cerebral blood flow SPECT. Neuroimage 28, 1014-1021 (2005
159. Borroni, B., et al. Combined 99mTc ECD SPECT and neuropsychological studies in MCI for the assessment of conversion to AD. Neurobiol. Aging 27, 24-31 (2006
160. Thambisetty, M., Beason-Held, L., An, Y., Kraut, M. A., & Resnick, S. M. APOE 4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch. Neurol. 67, 93-98 (2010
161. Reiman, E. M., et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer?s dementia. Proc. Natl Acad. Sci. USA 101, 284-289 (2004
162. Chen, Y., et al. Voxel-level comparison of arterial spin-labeled perfusion MRI and FDG-PET in Alzheimer disease. Neurology 77, 1977-1985 (2011
163. Michels, L., et al. Arterial spin labeling imaging reveals widespread and Aβ independent reductions in cerebral blood flow in elderly apolipoprotein epsilon 4 carriers. J. Cereb. Blood Flow Metab. 36, 581-595 (2016
164. Wirth, M., et al. Divergent regional patterns of cerebral hypoperfusion and gray matter atrophy in mild cognitive impairment patients. J. Cereb. Blood Flow Metab. 37, 814-824 (2016
165. Small, S. A., Perera, G. M., DeLaPaz, R., Mayeux, R., & Stern, Y. Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer?s disease. Ann. Neurol. 45, 466-472 (1999
166. Sperling, R. A., et al. fMRI studies of associative encoding in young and elderly controls and mild Alzheimer?s disease. J. Neurol. Neurosurg. Psychiatry 74, 44-50 (2003
167. Smith, C. D., et al. Altered brain activation in cognitively intact individuals at high risk for Alzheimer?s disease. Neurology 53, 1391-1396 (1999
168. Dumas, A., et al. Functional magnetic resonance imaging detection of vascular reactivity in cerebral amyloid angiopathy. Ann. Neurol. 72, 76-81 (2012
169. Kim, S. G., & Ogawa, S. Biophysical and physiological origins of blood oxygenation level-dependent fMRI signals. J. Cereb. Blood Flow Metab. 32, 1188-1206 (2012
170. Dennis, E. L., & Thompson, P. M. Functional brain connectivity using fMRI in aging and Alzheimer?s disease. Neuropsychol. Rev. 24, 49-62 (2014
171. Raichle, M. E., et al. A default mode of brain function. Proc. Natl Acad. Sci. USA 98, 676-682 (2001
172. Greicius, M. D., Srivastava, G., Reiss, A. L., & Menon, V. Default-mode network activity distinguishes Alzheimer?s disease from healthy aging: evidence from functional MRI. Proc. Natl Acad. Sci. USA 101, 4637-4642 (2004
173. Wang, L., et al. Changes in hippocampal connectivity in the early stages of Alzheimer?s disease: evidence from resting state fMRI. Neuroimage 31, 496-504 (2006
174. Chhatwal, J. P., et al. Impaired default network functional connectivity in autosomal dominant Alzheimer disease. Neurology 81, 736-744 (2013
175. Thomas, J. B., et al. Functional connectivity in autosomal dominant and late-onset Alzheimer disease. JAMA Neurol. 71, 1111-1122 (2014
176. Sheline, Y. I., et al. APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42. J. Neurosci. 30, 17035-17040 (2010
177. Zimmerman, K. W. Der feinere Bau der Blutkapillaren [German]. Z. Anat. Entwicklungsgesch. 68, 29-110 (1923
178. Winkler, E. A., Sagare, A. P., & Zlokovic, B. V. The pericyte: a forgotten cell type with important implications for Alzheimer?s disease? Brain Pathol. 24, 371-386 (2014
179. Nehls, V., & Drenckhahn, D. Heterogeneity of microvascular pericytes for smooth muscle type alpha-Actin. J. Cell Biol. 113, 147-154 (1991
180. Montagne, A., et al. Brain imaging of neurovascular dysfunction in Alzheimer?s disease. Acta Neuropathol. 131, 687-707 (2016
181. Starr, J. M., Farrall, A. J., Armitage, P., McGurn, B., & Wardlaw, J. Blood-brain barrier permeability in Alzheimer?s disease: a case-control MRI study. Psychiatry Res. 171, 232-241 (2009
182. Van de Haar, H. J., et al. Blood-brain barrier leakage in patients with early Alzheimer disease. Radiology 281, 527-535 (2016
183. Taheri, S., et al. Blood-brain barrier permeability abnormalities in vascular cognitive impairment. Stroke 42, 2158-2163 (2011
184. Nir, T. M., et al. Effectiveness of regional DTI measures in distinguishing Alzheimer?s disease, MCI, and normal aging. Neuroimage Clin. 3, 180-195 (2013