The Pathobiology of Vascular Dementia

Vascular cognitive impairment defines alterations in cognition, ranging from subtle deficits to full-blown dementia, attributable to cerebrovascular causes. Often coexisting with Alzheimer's disease, mixed vascular and neurodegenerative dementia has emerged as the leading cause of age-related cognitive impairment. Central to the disease mechanism is the crucial role that cerebral blood vessels play in brain health, not only for the delivery of oxygen and nutrients, but also for the trophic signaling that inextricably links the well-being of neurons and glia to that of cerebrovascular cells. This review will examine how vascular damage disrupts these vital homeostatic interactions, focusing on the hemispheric white matter, a region at heightened risk for vascular damage, and on the interplay between vascular factors and Alzheimer's disease. Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia.

[1]  M. van Buchem,et al.  Decline in total cerebral blood flow is linked with increase in periventricular but not deep white matter hyperintensities. , 2007, Radiology.

[2]  Sally Temple,et al.  Endothelial Cells Stimulate Self-Renewal and Expand Neurogenesis of Neural Stem Cells , 2004, Science.

[3]  K. Nakao,et al.  Angiogenic and Vasoprotective Effects of Adrenomedullin on Prevention of Cognitive Decline After Chronic Cerebral Hypoperfusion in Mice , 2011, Stroke.

[4]  H. Budka,et al.  Blood-brain barrier dysfunction in Binswanger’s disease; an immunohistochemical study , 1997, Acta Neuropathologica.

[5]  Michael Oliver Flüß,et al.  Detection of changed regional cerebral blood flow in mild cognitive impairment and early Alzheimer's dementia by perfusion-weighted magnetic resonance imaging , 2008, NeuroImage.

[6]  C. Jack,et al.  Alzheimer's Disease Neuroimaging Initiative , 2008 .

[7]  M. Cipolla Integrated Systems Physiology: From Molecule to Function , 2009 .

[8]  S. Black,et al.  Cerebral small vessel disease in aging and Alzheimer's disease: a comparative study using MRI and SPECT , 2013, European journal of neurology.

[9]  Tian Feng,et al.  Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. , 2013, The Journal of clinical investigation.

[10]  Chaeyoung Lee,et al.  Complex genetic susceptibility to vascular dementia and an evidence for its underlying genetic factors associated with memory and associative learning. , 2013, Gene.

[11]  K. Matsushita,et al.  Periventricular white matter lucency and cerebral blood flow autoregulation in hypertensive patients. , 1994, Hypertension.

[12]  W. Markesbery,et al.  Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. , 1997, JAMA.

[13]  Suzanne Craft,et al.  The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. , 2009, Archives of neurology.

[14]  D. Wilkin,et al.  Neuron , 2001, Brain Research.

[15]  W. M. van der Flier,et al.  Incident lacunes influence cognitive decline , 2011, Neurology.

[16]  J. Gallacher,et al.  Clinical and Population Studies Is Sticky Blood Bad for the Brain ? Hemostatic and Inflammatory Systems and Dementia in the Caerphilly Prospective Study , 2010 .

[17]  R. Reynolds,et al.  Molecular Changes in Normal Appearing White Matter in Multiple Sclerosis are Characteristic of Neuroprotective Mechanisms Against Hypoxic Insult , 2003, Brain pathology.

[18]  N. Secher,et al.  Dynamic cerebral autoregulatory capacity is affected early in Type 2 diabetes. , 2008, Clinical science.

[19]  J. Simpkins,et al.  Increased β-secretase activity and expression in rats following transient cerebral ischemia , 2004, Brain Research.

[20]  R. Camicioli,et al.  Circulating Endothelial Progenitor Cells and Age-Related White Matter Changes , 2009, Stroke.

[21]  D. Eidelberg,et al.  Dementia associated with bilateral carotid occlusions: neuropsychological and haemodynamic course after extracranial to intracranial bypass surgery. , 1995, Journal of neurology, neurosurgery, and psychiatry.

[22]  M. Dichgans,et al.  Prevention of vascular cognitive impairment. , 2012, Stroke.

[23]  T Suenaga,et al.  Alterations of the blood-brain barrier and glial cells in white-matter lesions in cerebrovascular and Alzheimer's disease patients. , 1996, Stroke.

[24]  A. Quyyumi,et al.  Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. , 2003, The New England journal of medicine.

[25]  Maja A. A. Binnewijzend,et al.  Specific risk factors for microbleeds and white matter hyperintensities in Alzheimer's disease , 2013, Neurobiology of Aging.

[26]  P. Scheltens,et al.  Physical Activity Prevents Progression for Cognitive Impairment and Vascular Dementia: Results From the LADIS (Leukoaraiosis and Disability) Study , 2012, Stroke.

[27]  C. DeSouza,et al.  CD31+ T cells, endothelial function and cardiovascular risk. , 2011, Heart, lung & circulation.

[28]  Ina Ruck,et al.  USA , 1969, The Lancet.

[29]  D. Leys,et al.  Treatment of vascular risk factors is associated with slower decline in Alzheimer disease , 2009, Neurology.

[30]  R. Deane,et al.  SRF and myocardin regulate LRP-mediated amyloid-β clearance in brain vascular cells , 2009, Nature Cell Biology.

[31]  Cathie Sudlow,et al.  Lacunar stroke is associated with diffuse blood–brain barrier dysfunction , 2009, Annals of neurology.

[32]  A. Hakim,et al.  Heart disease as a risk factor for dementia , 2013, Clinical epidemiology.

[33]  Chris Zarow,et al.  Cognitive impact of subcortical vascular and Alzheimer's disease pathology , 2006, Annals of neurology.

[34]  L. Launer,et al.  The Honolulu-Asia Aging Study: epidemiologic and neuropathologic research on cognitive impairment. , 2012, Current Alzheimer research.

[35]  M. Mullan,et al.  β-Amyloid-mediated vasoactivity and vascular endothelial damage , 1996, Nature.

[36]  P. Wolf,et al.  Association of Plasma ADMA Levels With MRI Markers of Vascular Brain Injury: Framingham Offspring Study , 2009, Stroke.

[37]  George A. Carlson,et al.  Alterations in Cerebral Blood Flow and Glucose Utilization in Mice Overexpressing the Amyloid Precursor Protein , 2002, Neurobiology of Disease.

[38]  Danica Stanimirovic,et al.  Engaging neuroscience to advance translational research in brain barrier biology , 2011, Nature Reviews Neuroscience.

[39]  H. Moser,et al.  X-Linked Adrenoleukodystrophy: Overview and Prognosis as a Function of Age and Brain Magnetic Resonance Imaging Abnormality. A Study Involving 372 Patients , 2000, Neuropediatrics.

[40]  T. Deerinck,et al.  Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation , 2012, Nature Communications.

[41]  R. Cohen,et al.  Vascular Oxidative Stress: The Common Link in Hypertensive and Diabetic Vascular Disease , 2010, Journal of cardiovascular pharmacology.

[42]  I. Knottnerus,et al.  Endothelial Dysfunction in Lacunar Stroke: A Systematic Review , 2009, Cerebrovascular Diseases.

[43]  Y. Dan,et al.  Spike Timing-Dependent Plasticity of Neural Circuits , 2004, Neuron.

[44]  C. Iadecola,et al.  Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-β , 2011, Proceedings of the National Academy of Sciences.

[45]  D. Borchelt,et al.  SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein , 1999, Nature Neuroscience.

[46]  B. Winblad,et al.  Perivascular deposits of serum proteins in cerebral cortex in vascular dementia , 2004, Acta Neuropathologica.

[47]  Nick C Fox,et al.  Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration , 2013, The Lancet Neurology.

[48]  F F SAVERIO,et al.  [Cerebral circulation]. , 1954, Omnia therapeutica. Supplemento.

[49]  B. Zlokovic The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders , 2008, Neuron.

[50]  J. De Keyser,et al.  Hypoperfusion of the Cerebral White Matter in Multiple Sclerosis: Possible Mechanisms and Pathophysiological Significance , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[51]  Jon Andresen,et al.  Endothelial influences on cerebrovascular tone. , 2006, Journal of applied physiology.

[52]  Wiesje M van der Flier,et al.  Brain microbleeds and Alzheimer's disease: innocent observation or key player? , 2011, Brain : a journal of neurology.

[53]  James A. Mortimer,et al.  Brain Infarction and the Clinical Expression of Alzheimer Disease-Reply , 1997 .

[54]  H. Shibasaki,et al.  Chronic Cerebral Hypoperfusion Induces MMP-2 but Not MMP-9 Expression in the Microglia and Vascular Endothelium of White Matter , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[55]  C. Iadecola,et al.  Abeta 1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[56]  R. Righart,et al.  Incident subcortical infarcts induce focal thinning in connected cortical regions , 2012, Neurology.

[57]  Gary A Rosenberg,et al.  Neurological Diseases in Relation to the Blood–Brain Barrier , 2012, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[58]  R. Mayeux,et al.  Atherosclerosis and AD , 2005, Neurology.

[59]  D. Jacobs,et al.  Cardiovascular health through young adulthood and cognitive functioning in midlife , 2013, Annals of neurology.

[60]  N. Lassen,et al.  Multi-infarct dementia. A cause of mental deterioration in the elderly. , 1974, Lancet.

[61]  R. Gons,et al.  Cerebral microbleeds are related to subjective cognitive failures: the RUN DMC study , 2013, Neurobiology of Aging.

[62]  G. Nickenig,et al.  Circulating endothelial progenitor cells and cardiovascular outcomes. , 2005, The New England journal of medicine.

[63]  G. Gao,et al.  Gypenoside attenuates white matter lesions induced by chronic cerebral hypoperfusion in rats , 2011, Pharmacology Biochemistry and Behavior.

[64]  L. Fried,et al.  Cognitive Impairment and Decline Are Associated with Carotid Artery Disease in Patients without Clinically Evident Cerebrovascular Disease , 2004, Annals of Internal Medicine.

[65]  X. Tong,et al.  Age-Dependent Rescue by Simvastatin of Alzheimer's Disease Cerebrovascular and Memory Deficits , 2012, The Journal of Neuroscience.

[66]  J. Attems,et al.  Vascular risk factors and neurodegeneration in ageing related dementias: Alzheimer's disease and vascular dementia. , 2013, Current Alzheimer research.

[67]  Y. K. Cheung,et al.  Cerebral hemodynamics and cognitive impairment , 2012, Neurology.

[68]  David Kleinfeld,et al.  A Guide to Delineate the Logic of Neurovascular Signaling in the Brain , 2010, Front. Neuroenerg..

[69]  K. Arai,et al.  An Oligovascular Niche: Cerebral Endothelial Cells Promote the Survival and Proliferation of Oligodendrocyte Precursor Cells , 2009, The Journal of Neuroscience.

[70]  Max Gassmann,et al.  Involvement of oxidative stress in hypoxia-induced blood-brain barrier breakdown. , 2012, Microvascular research.

[71]  Eric E. Smith,et al.  Cerebral microinfarcts: the invisible lesions , 2012, The Lancet Neurology.

[72]  S G Waxman,et al.  Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na(+)-Ca2+ exchanger , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[73]  R. Kalaria,et al.  Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts , 2011, Acta Neuropathologica.

[74]  V. Perry,et al.  What is immune privilege (not)? , 2007, Trends in immunology.

[75]  G. Johnson,et al.  Microvascular Abnormality in Relapsing-remitting Multiple Sclerosis: Perfusion Mr Imaging Findings in Normal-appearing White Matter , 2003 .

[76]  D. Werring,et al.  Pathogenesis of cerebral microbleeds: In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment , 2013, Annals of neurology.

[77]  Kwang-Soo Lee,et al.  Ramipril protects from free radical induced white matter damage in chronic hypoperfusion in the rat , 2008, Journal of Clinical Neuroscience.

[78]  J. Bowler Modern concept of vascular cognitive impairment. , 2007, British medical bulletin.

[79]  D. Aarsland,et al.  Hypertension is a potential risk factor for vascular dementia: systematic review , 2011, International journal of geriatric psychiatry.

[80]  R. Kauppinen,et al.  β-Amyloid precursor protein transgenic mice that harbor diffuse Aβ deposits but do not form plaques show increased ischemic vulnerability: Role of inflammation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[81]  Manjit,et al.  Neurology , 1912, NeuroImage.

[82]  K. Jellinger,et al.  Review: Sporadic cerebral amyloid angiopathy , 2011, Neuropathology and applied neurobiology.

[83]  J. Hardy,et al.  Blockage of CR1 prevents activation of rodent microglia , 2013, Neurobiology of Disease.

[84]  Bengt R. Johansson,et al.  Pericytes regulate the blood–brain barrier , 2010, Nature.

[85]  Berislav V. Zlokovic,et al.  Apolipoprotein E controls cerebrovascular integrity via cyclophilin A , 2012, Nature.

[86]  C. Ayata,et al.  Cerebrovascular lesions induce transient β-amyloid deposition. , 2011, Brain : a journal of neurology.

[87]  A. Hofman,et al.  Genome-Wide Association Study of Vascular Dementia , 2012, Stroke.

[88]  E. Wood,et al.  Rapid Disruption of Axon–Glial Integrity in Response to Mild Cerebral Hypoperfusion , 2011, The Journal of Neuroscience.

[89]  B. Mazoyer,et al.  Motor function in the elderly , 2013, Neurology.

[90]  Wilhelm Kuker,et al.  Increased Cerebral Arterial Pulsatility in Patients With Leukoaraiosis: Arterial Stiffness Enhances Transmission of Aortic Pulsatility , 2012, Stroke.

[91]  R. Weller,et al.  Drainage of Cells and Soluble Antigen from the CNS to Regional Lymph Nodes , 2013, Journal of Neuroimmune Pharmacology.

[92]  D. Bennett,et al.  Subcortical infarcts, Alzheimer's disease pathology, and memory function in older persons , 2007, Annals of neurology.

[93]  David H. Salat,et al.  The Relationship between Cortical Blood Flow and Sub-Cortical White-Matter Health across the Adult Age Span , 2013, PloS one.

[94]  S. Pendlebury,et al.  Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis , 2009, The Lancet Neurology.

[95]  C. Pusey,et al.  Pathology of Vascular Disease , 2001 .

[96]  Clifford Qualls,et al.  Blood–Brain Barrier Permeability Abnormalities in Vascular Cognitive Impairment , 2011, Stroke.

[97]  W. Mali,et al.  Total Cerebral Blood Flow, White Matter Lesions and Brain Atrophy: The SMART-MR Study , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[98]  Charles DeCarli,et al.  White matter hyperintensities and cognition: Testing the reserve hypothesis , 2011, Neurobiology of Aging.

[99]  F. Howe,et al.  Blood–brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis , 2009, Journal of Neurology, Neurosurgery & Psychiatry.

[100]  S. Black,et al.  Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association , 2011, Stroke.

[101]  K. Okamoto,et al.  Immunoglobulin G induces microglial superoxide production , 2002, Neurological research.

[102]  J. Trojanowski,et al.  Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre. , 2013, Brain : a journal of neurology.

[103]  G. Glenner,et al.  Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. , 1984, Biochemical and biophysical research communications.

[104]  J. O'Brien,et al.  White matter lesions in an unselected cohort of the elderly: astrocytic, microglial and oligodendrocyte precursor cell responses , 2007, Neuropathology and applied neurobiology.

[105]  J. Simpkins,et al.  Transient cerebral ischemia induces site-specific hyperphosphorylation of tau protein , 2004, Brain Research.

[106]  D. Kiprov,et al.  Mononeuritis and cryoglobulins , 1993, Neurology.

[107]  Paco Martorell,et al.  Monetary costs of dementia in the United States. , 2013, The New England journal of medicine.

[108]  N. Hattori,et al.  Phosphodiesterase III Inhibition Promotes Differentiation and Survival of Oligodendrocyte Progenitors and Enhances Regeneration of Ischemic White Matter Lesions in the Adult Mammalian Brain , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[109]  F. Crawford,et al.  Vasoactive effects of A beta in isolated human cerebrovessels and in a transgenic mouse model of Alzheimer's disease: role of inflammation. , 2003, Neurological research.

[110]  J. Lodder,et al.  Brain Microbleeds Are Associated With Ambulatory Blood Pressure Levels in a Hypertensive Population , 2008, Hypertension.

[111]  K. Jellinger Small concomitant cerebrovascular lesions are not important for cognitive decline in severe Alzheimer disease. , 2001, Archives of neurology.

[112]  P Pietrini,et al.  Visual cortical dysfunction in Alzheimer's disease evaluated with a temporally graded "stress test" during PET. , 1996, The American journal of psychiatry.

[113]  J. Morris,et al.  Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease , 2010, Science.

[114]  J. O'Brien,et al.  White Matter Lesions in an Unselected Cohort of the Elderly: Molecular Pathology Suggests Origin From Chronic Hypoperfusion Injury , 2006, Stroke.

[115]  D. Holtzman,et al.  Apolipoprotein E in Alzheimer's disease and other neurological disorders , 2011, The Lancet Neurology.

[116]  H. Bokura,et al.  Evaluation of asymmetric dimethylarginine and homocysteine in microangiopathy-related cerebral damage. , 2009, American journal of hypertension.

[117]  P. Tu,et al.  Impairments in Cognitive Function and Brain Connectivity in Severe Asymptomatic Carotid Stenosis , 2012, Stroke.

[118]  Frederik Barkhof,et al.  Changes in white matter as determinant of global functional decline in older independent outpatients: three year follow-up of LADIS (leukoaraiosis and disability) study cohort , 2009, BMJ : British Medical Journal.

[119]  S S Segal,et al.  Regulation of blood flow in the microcirculation: role of conducted vasodilation , 2011, Acta physiologica.

[120]  H. Zhang,et al.  Huperzine a improves chronic inflammation and cognitive decline in rats with cerebral hypoperfusion , 2009, Journal of neuroscience research.

[121]  T. Montine,et al.  White matter lesions defined by diffusion tensor imaging in older adults , 2011, Annals of neurology.

[122]  Roland Martin,et al.  Multiple sclerosis: a complicated picture of autoimmunity , 2007, Nature Immunology.

[123]  M. Silvestrini,et al.  Severe carotid stenosis and impaired cerebral hemodynamics can influence cognitive deterioration , 2013, Neurology.

[124]  Wulfram Gerstner,et al.  Spike-timing dependent plasticity , 2010, Scholarpedia.

[125]  Zsuzsanna Nagy,et al.  Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease , 1999, The Lancet.

[126]  K. Blennow,et al.  Low Cerebrospinal Fluid Sulfatide Predicts Progression of White Matter Lesions – The LADIS Study , 2012, Dementia and Geriatric Cognitive Disorders.

[127]  B T Hyman,et al.  Progression of Cerebral Amyloid Angiopathy: Accumulation of Amyloid-ß40 in Affected Vessels , 1998, Journal of neuropathology and experimental neurology.

[128]  P. Carmeliet,et al.  VEGF ligands and receptors: implications in neurodevelopment and neurodegeneration , 2013, Cellular and Molecular Life Sciences.

[129]  Wendy J Mack,et al.  Vascular risk factors and Alzheimer's disease: are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia? An evidence-based review , 2011, Alzheimer's Research & Therapy.

[130]  Shahin Rafii,et al.  Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors , 2010, Nature Reviews Cancer.

[131]  Hugh S Markus,et al.  Brain Atrophy and Cerebral Small Vessel Disease: A Prospective Follow-Up Study , 2011, Stroke.

[132]  M. Dichgans,et al.  CADASIL , 2009, The Lancet Neurology.

[133]  R. Tanzi,et al.  Depletion of GGA3 Stabilizes BACE and Enhances β-Secretase Activity , 2007, Neuron.

[134]  M. Ihara,et al.  Lessons from a Mouse Model Characterizing Features of Vascular Cognitive Impairment with White Matter Changes , 2011, Journal of aging research.

[135]  D. Bennett,et al.  LONG-TERM FETAL CELL TRANSPLANT IN HUNTINGTON DISEASE: STAYIN’ ALIVE , 2007, Neurology.

[136]  D. Kleinfeld,et al.  The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow , 2013, Nature Neuroscience.

[137]  M. Zaletel,et al.  Influence of Atorvastatin Treatment on l-Arginine Cerebrovascular Reactivity and Flow-Mediated Dilatation in Patients With Lacunar Infarctions , 2006, Stroke.

[138]  Wang Min,et al.  Leuko araiosis , 2006 .

[139]  I. Bechmann,et al.  FasL (CD95L, Apo1L) is expressed in the normal rat and human brain: Evidence for the existence of an immunological brain barrier , 1999, Glia.

[140]  Eng H. Lo,et al.  The Science of Stroke: Mechanisms in Search of Treatments , 2010, Neuron.

[141]  Robin J. M. Franklin,et al.  Remyelination in the CNS: from biology to therapy , 2008, Nature Reviews Neuroscience.

[142]  M. Esiri,et al.  White Matter Damage Is Associated With Matrix Metalloproteinases in Vascular Dementia , 2001, Stroke.

[143]  A. Parent,et al.  Vasculature Guides Migrating Neuronal Precursors in the Adult Mammalian Forebrain via Brain-Derived Neurotrophic Factor Signaling , 2009, The Journal of Neuroscience.

[144]  Koen L. Vincken,et al.  White Matter Lesions and Lacunar Infarcts Are Independently and Differently Associated with Brain Atrophy: The SMART-MR Study , 2009, Cerebrovascular Diseases.

[145]  D. Attwell,et al.  Synaptic Energy Use and Supply , 2012, Neuron.

[146]  A. Haley,et al.  Association between central elastic artery stiffness and cerebral perfusion in deep subcortical gray and white matter. , 2011, American journal of hypertension.

[147]  A. Ergul Endothelin-1 and diabetic complications: focus on the vasculature. , 2011, Pharmacological research.

[148]  C. Sudlow,et al.  Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis , 2013, Journal of Neurology Neurosurgery & Psychiatry.

[149]  J. Haxby,et al.  The effect of white matter hyperintensity volume on brain structure, cognitive performance, and cerebral metabolism of glucose in 51 healthy adults , 1995, Neurology.

[150]  M. O’Sullivan,et al.  Patterns of cerebral blood flow reduction in patients with ischemic leukoaraiosis , 2002, Neurology.

[151]  E. Niedermeyer Alzheimer Disease: Caused by Primary Deficiency of the Cerebral Blood Flow , 2006, Clinical EEG and neuroscience.

[152]  G. Johnson,et al.  Correlation of diffusion tensor and dynamic perfusion MR imaging metrics in normal-appearing corpus callosum: support for primary hypoperfusion in multiple sclerosis. , 2007, AJNR. American journal of neuroradiology.

[153]  Sandra E Black,et al.  Alzheimer's Disease, Cerebrovascular Disease, and the β-amyloid Cascade , 2012, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[154]  C. Iadecola The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia , 2010, Acta Neuropathologica.

[155]  S. Brenner REDUCED CIRCULATING ANGIOGENIC CELLS IN ALZHEIMER DISEASE , 2010, Neurology.

[156]  M. Fornage,et al.  Genome‐wide association studies of cerebral white matter lesion burden , 2011, Annals of neurology.

[157]  George A. Carlson,et al.  Exogenous Aβ1–40 Reproduces Cerebrovascular Alterations Resulting from Amyloid Precursor Protein Overexpression in Mice , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[158]  Klaus-Armin Nave,et al.  Myelination and the trophic support of long axons , 2010, Nature Reviews Neuroscience.

[159]  W. Young,et al.  Higher cerebral function and hemispheric blood flow during awake carotid artery balloon test occlusions , 1999, Journal of neurology, neurosurgery, and psychiatry.

[160]  I. Alafuzoff,et al.  β-Amyloid Aggregation in Human Brains With Cerebrovascular Lesions , 2006, Stroke.

[161]  Denise C. Park,et al.  Risk factors for β-amyloid deposition in healthy aging: vascular and genetic effects. , 2013, JAMA neurology.

[162]  D. Attwell,et al.  The neural basis of functional brain imaging signals , 2002, Trends in Neurosciences.

[163]  E Rostrup,et al.  Cerebral Perfusion and Cerebrovascular Reactivity Are Reduced in White Matter Hyperintensities , 2002, Stroke.

[164]  A. Federico,et al.  Plasma Levels of Asymmetric Dimethylarginine in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarct and Leukoencephalopathy , 2008, Cerebrovascular Diseases.

[165]  C. Thompson,et al.  Living beyond our physiological means: small vessel disease of the brain is an expression of a systemic failure in arteriolar function: a unifying hypothesis. , 2009, Stroke.

[166]  Ping Zhou,et al.  Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein , 2008, Proceedings of the National Academy of Sciences.

[167]  Ju-Young Kim,et al.  Identification of a Novel Role of T Cells in Postnatal Vasculogenesis: Characterization of Endothelial Progenitor Cell Colonies , 2007, Circulation.

[168]  E. V. van Dijk,et al.  Long-Term Cognitive Impairment After First-Ever Ischemic Stroke in Young Adults , 2013, Stroke.

[169]  P. Scheltens,et al.  Vascular Care in Patients With Alzheimer Disease With Cerebrovascular Lesions Slows Progression of White Matter Lesions on MRI: The Evaluation of Vascular Care in Alzheimer's Disease (EVA) Study , 2010, Stroke.

[170]  D. Davalos,et al.  Fibrinogen as a key regulator of inflammation in disease , 2011, Seminars in Immunopathology.

[171]  M. Ueno,et al.  Blood–Brain Barrier Disruption in White Matter Lesions in a Rat Model of Chronic Cerebral Hypoperfusion , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[172]  Hui Liu,et al.  Regional cerebral blood flow and cerebrovascular reactivity in Alzheimer's disease and vascular dementia assessed by arterial spinlabeling magnetic resonance imaging. , 2012 .

[173]  Rong Zhang,et al.  Altered cerebral hemodynamics in early Alzheimer disease: a pilot study using transcranial Doppler. , 2009, Journal of Alzheimer's disease : JAD.

[174]  T. LeCompte,et al.  Vascular Structure and Function Is Correlated to Cognitive Performance and White Matter Hyperintensities in Older Hypertensive Patients With Subjective Memory Complaints , 2009, Stroke.

[175]  C. Iadecola,et al.  Hypertension and cerebrovascular dysfunction. , 2008, Cell metabolism.

[176]  K. Arai,et al.  Astrocytes protect oligodendrocyte precursor cells via MEK/ERK and PI3K/Akt signaling , 2009, Journal of neuroscience research.

[177]  S. Lanfranconi,et al.  COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel Disease: A Systematic Review , 2010, Stroke.

[178]  R. Schmieder,et al.  Impaired Endothelial Function of the Retinal Vasculature in Hypertensive Patients , 2004, Stroke.

[179]  J. Attems,et al.  Vascular dementia: Different forms of vessel disorders contribute to the development of dementia in the elderly brain , 2012, Experimental Gerontology.

[180]  V. Henderson Alzheimer's disease and other neurological disorders , 2007, Climacteric : the journal of the International Menopause Society.

[181]  C. Iadecola,et al.  Nox2-Derived Reactive Oxygen Species Mediate Neurovascular Dysregulation in the Aging Mouse Brain , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[182]  Robert Layfield,et al.  Oligodendrocytes Promote Neuronal Survival and Axonal Length by Distinct Intracellular Mechanisms: A Novel Role for Oligodendrocyte-Derived Glial Cell Line-Derived Neurotrophic Factor , 2003, The Journal of Neuroscience.

[183]  N. Pomara,et al.  Relationship between cyclophilin a levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein e4 carriers and blood-brain barrier breakdown. , 2013, JAMA neurology.

[184]  Y. Stern Cognitive reserve in ageing and Alzheimer's disease , 2012, The Lancet Neurology.

[185]  C. Sobey,et al.  Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets , 2011, Nature Reviews Drug Discovery.

[186]  Shen Fei,et al.  Poststroke Dementia , 2005 .

[187]  Ning Zhang,et al.  Edaravone attenuates white matter lesions through endothelial protection in a rat chronic hypoperfusion model , 2009, Neuroscience.

[188]  C. Bouras,et al.  Identification of Alzheimer and vascular lesion thresholds for mixed dementia. , 2007, Brain : a journal of neurology.

[189]  J. De Reuck The human periventricular arterial blood supply and the anatomy of cerebral infarctions. , 1971, European neurology.

[190]  A. Federico,et al.  Hereditary cerebral small vessel diseases: A review , 2012, Journal of the Neurological Sciences.

[191]  Sandra Black,et al.  Understanding White Matter Disease: Imaging-Pathological Correlations in Vascular Cognitive Impairment , 2009, Stroke.

[192]  Alan J. Thomas,et al.  Long term incidence of dementia, predictors of mortality and pathological diagnosis in older stroke survivors , 2011, Brain : a journal of neurology.

[193]  S. Goldman,et al.  Glial Progenitor Cell–Based Treatment and Modeling of Neurological Disease , 2012, Science.

[194]  H. Davson Blood–brain barrier , 1977, Nature.

[195]  D. Cornfield,et al.  A beta-peptides enhance vasoconstriction in cerebral circulation. , 2001, American journal of physiology. Heart and circulatory physiology.

[196]  J. Roh,et al.  Circulating Endothelial Progenitor Cells as a New Marker of Endothelial Dysfunction or Repair in Acute Stroke , 2008, Stroke.

[197]  D. Werring,et al.  Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum , 2011, Journal of Neurology, Neurosurgery & Psychiatry.

[198]  H. Markus,et al.  Differential Effect of Three Cyclooxygenase Inhibitors on Human Cerebral Blood Flow Velocity and Carbon Dioxide Reactivity , 1994, Stroke.

[199]  Tim West,et al.  Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis , 2012, Proceedings of the National Academy of Sciences.

[200]  R. Maclennan,et al.  DIETARY FIBRE, TRANSIT-TIME, FÆCAL BACTERIA, STEROIDS, AND COLON CANCER IN TWO SCANDINAVIAN POPULATIONS Report from the International Agency for Research on Cancer Intestinal Microecology Group , 1977, The Lancet.

[201]  D. Cornfield,et al.  Aβ-peptides enhance vasoconstriction in cerebral circulation , 2001 .

[202]  S. Leurgans,et al.  The neuropathology of probable Alzheimer disease and mild cognitive impairment , 2009, Annals of neurology.

[203]  Hong Qing,et al.  Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression , 2006, Proceedings of the National Academy of Sciences.

[204]  S. Greenberg,et al.  The Pathophysiology and Clinical Presentation of Cerebral Amyloid Angiopathy , 2012, Current Atherosclerosis Reports.

[205]  K. Kataoka,et al.  Attenuation of Brain Damage and Cognitive Impairment by Direct Renin Inhibition in Mice With Chronic Cerebral Hypoperfusion , 2011, Hypertension.

[206]  A. Takanohashi,et al.  Mucosal Tolerization to E-Selectin Protects against Memory Dysfunction and White Matter Damage in a Vascular Cognitive Impairment Model , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[207]  David Attwell,et al.  The Energetics of CNS White Matter , 2012, The Journal of Neuroscience.

[208]  R. Takahashi,et al.  Chronic cerebral hypoperfusion accelerates amyloid β deposition in APPSwInd transgenic mice , 2009, Brain Research.

[209]  H. Moser,et al.  X-linked adrenoleukodystrophy: the role of contrast-enhanced MR imaging in predicting disease progression. , 2000, AJNR. American journal of neuroradiology.

[210]  Aad van der Lugt,et al.  Total Cerebral Blood Flow and Total Brain Perfusion in the General Population: The Rotterdam Scan Study , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[211]  L. Sztriha,et al.  Adrenoleukodystrophy: Cortical Hypoperfusion Demonstrated With 99mTc-HMPAO SPECT , 1994, Journal of child neurology.

[212]  北口 浩史 Chronic cerebral hypoperfusion accelerates amyloid β deposition in APPSwInd transgenic mice , 2010 .

[213]  V. Hachinski Stroke and Alzheimer disease: fellow travelers or partners in crime? , 2011, Archives of neurology.

[214]  Ping Zhou,et al.  NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. , 2005, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[215]  Kimihiko Abe,et al.  Increased Blood-Brain Barrier Permeability in White Matter Lesions of Binswanger’s Disease Evaluated by Contrast-Enhanced MRI , 2002, Dementia and Geriatric Cognitive Disorders.

[216]  R. Takahashi,et al.  Nonhypotensive Dose of Telmisartan Attenuates Cognitive Impairment Partially Due to Peroxisome Proliferator-Activated Receptor-&ggr; Activation in Mice With Chronic Cerebral Hypoperfusion , 2010, Stroke.

[217]  H S Markus,et al.  Reduced cerebral blood flow in white matter in ischaemic leukoaraiosis demonstrated using quantitative exogenous contrast based perfusion MRI , 2000, Journal of neurology, neurosurgery, and psychiatry.

[218]  C. Jack,et al.  Alzheimer's Disease Neuroimaging Initiative , 2008 .

[219]  E. Lo,et al.  Cerebrovascular degradation of TRKB by MMP9 in the diabetic brain. , 2013, The Journal of clinical investigation.

[220]  Y. Nagai,et al.  Oligodendroglial cell death with DNA fragmentation in the white matter under chronic cerebral hypoperfusion: comparison between normotensive and spontaneously hypertensive rats , 2001, Neuroscience Research.

[221]  J. Price,et al.  Reduced cerebral blood flow response and compensation among patients with untreated hypertension , 2005, Neurology.

[222]  Arshed A. Quyyumi,et al.  Circulating Endothelial Progenitor Cells, Vascular Function, and Cardiovascular Risk , 2003 .

[223]  Dixon M. Moody,et al.  Vascular dementia in leukoaraiosis may be a consequence of capillary loss not only in the lesions, but in normal-appearing white matter and cortex as well , 2007, Journal of the Neurological Sciences.

[224]  Hui Liu,et al.  Regional cerebral blood flow and cerebrovascular reactivity in Alzheimer's disease and vascular dementia assessed by arterial spinlabeling magnetic resonance imaging. , 2012, Current neurovascular research.

[225]  M. Mullan,et al.  beta-Amyloid-mediated vasoactivity and vascular endothelial damage. , 1996, Nature.

[226]  G. Rosenberg,et al.  Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. , 2011, Stroke.

[227]  W. Richardson,et al.  NG2-glia as Multipotent Neural Stem Cells: Fact or Fantasy? , 2011, Neuron.

[228]  R. Schmidt,et al.  Genetics of subcortical vascular dementia , 2012, Experimental Gerontology.

[229]  C. Cordonnier Brain microbleeds , 2010, Practical Neurology.

[230]  C. Iadecola,et al.  Increased Susceptibility to Ischemic Brain Damage in Transgenic Mice Overexpressing the Amyloid Precursor Protein , 1997, The Journal of Neuroscience.

[231]  R. Fields Change in the Brain's White Matter , 2010, Science.

[232]  F. Faraci Protecting against vascular disease in brain. , 2011, American journal of physiology. Heart and circulatory physiology.

[233]  Circulating endothelial progenitor cells and cardiovascular outcomes. , 2005 .

[234]  J. Pierce,et al.  Innate immunity receptor CD36 promotes cerebral amyloid angiopathy , 2013, Proceedings of the National Academy of Sciences.

[235]  Peter K Stys,et al.  Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis , 2009, The Lancet Neurology.

[236]  D. Holtzman,et al.  Selective Vulnerability of Late Oligodendrocyte Progenitors to Hypoxia–Ischemia , 2002, The Journal of Neuroscience.

[237]  R. Marshall Effects of altered cerebral hemodynamics on cognitive function. , 2012, Journal of Alzheimer's disease : JAD.

[238]  L. Pellerin,et al.  Endothelial Cell-Derived Nitric Oxide Enhances Aerobic Glycolysis in Astrocytes via HIF-1α-Mediated Target Gene Activation , 2012, The Journal of Neuroscience.

[239]  S. Lanfranconi,et al.  COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel Disease: A Systematic Review , 2010, Stroke.

[240]  C. Ayata,et al.  Oligodendrocyte precursors induce early blood-brain barrier opening after white matter injury. , 2013, The Journal of clinical investigation.

[241]  B. Zlokovic Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders , 2011, Nature Reviews Neuroscience.

[242]  J. Ando,et al.  Flow detection and calcium signalling in vascular endothelial cells. , 2013, Cardiovascular research.

[243]  F. Mastaglia,et al.  Prevalence of cerebral vascular amyloid-β deposition and stroke in an aging Australian population: a postmortem study , 2003, Journal of Clinical Neuroscience.

[244]  J. Meyer,et al.  Leukoaraiosis: correlation of MR and CT findings with blood flow, atrophy, and cognition. , 1990, AJNR. American journal of neuroradiology.

[245]  C. Enzinger,et al.  Markers of Endothelial and Hemostatic Activation and Progression of Cerebral White Matter Hyperintensities: Longitudinal Results of the Austrian Stroke Prevention Study , 2005, Stroke.

[246]  J. Simpkins,et al.  Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats. , 2007, Biochimica et biophysica acta.

[247]  W. Mali,et al.  White Matter Lesions and Brain Atrophy: More than Shared Risk Factors? A Systematic Review , 2009, Cerebrovascular Diseases.

[248]  T. Montine,et al.  Digestion products of the PH20 hyaluronidase inhibit remyelination , 2013, Annals of neurology.

[249]  A. Lee,et al.  Vascular Dementia , 2011, Chonnam medical journal.

[250]  Mark A Mintun,et al.  Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition. , 2012, Archives of neurology.

[251]  J. Reuck Histopathological stainings and definitions of vascular disruptions in the elderly brain , 2012, Experimental Gerontology.

[252]  R. Tanzi,et al.  Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses , 2008, Nature Reviews Neuroscience.

[253]  Rebecca A Betensky,et al.  Kinetics of Cerebral Amyloid Angiopathy Progression in a Transgenic Mouse Model of Alzheimer Disease , 2006, The Journal of Neuroscience.

[254]  K. Grzeschik,et al.  The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor , 1987, Nature.

[255]  C. DeCarli,et al.  Distinctive RNA Expression Profiles in Blood Associated With White Matter Hyperintensities in Brain , 2010, Stroke.

[256]  Jeffrey F. Thompson,et al.  Matrix Metalloproteinases Are Associated With Increased Blood–Brain Barrier Opening in Vascular Cognitive Impairment , 2011, Stroke.

[257]  R. Sahathevan,et al.  Dementia, Stroke, and Vascular Risk Factors; a Review , 2012, International journal of stroke : official journal of the International Stroke Society.

[258]  R. Kauppinen,et al.  Beta-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability: role of inflammation. , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[259]  A. Fagan,et al.  Exercise and Alzheimer's disease biomarkers in cognitively normal older adults , 2010, Annals of neurology.

[260]  C. Ayata,et al.  Genetic animal models of cerebral vasculopathies. , 2012, Progress in molecular biology and translational science.

[261]  B. Mazoyer,et al.  Large-vessel correlates of cerebral small-vessel disease , 2013, Neurology.

[262]  A. Hainsworth,et al.  Pre-clinical models of human cerebral small vessel disease: Utility for clinical application , 2012, Journal of the Neurological Sciences.

[263]  K. Nave Myelination and support of axonal integrity by glia , 2010, Nature.

[264]  C. Brayne,et al.  The neuropathology of vascular disease in the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). , 2012, Current Alzheimer research.

[265]  岩本俊彦 Leuko-araiosis と血管性痴呆 , 1996 .

[266]  Hidenao Fukuyama,et al.  Regional Cerebral Blood Flow Abnormalities in Nondemented Patients With Memory Impairment , 2002, Journal of neuroimaging : official journal of the American Society of Neuroimaging.

[267]  K. Jellinger,et al.  Alzheimer 100 – highlights in the history of Alzheimer research , 2006, Journal of Neural Transmission.

[268]  Shotai Kobayashi,et al.  Correlation of NO Metabolites and 8-Iso-Prostaglandin F2a With Periventricular Hyperintensity Severity , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[269]  Thaddeus J. Haight,et al.  Dissociable effects of Alzheimer disease and white matter hyperintensities on brain metabolism. , 2013, JAMA neurology.

[270]  Peter J. Lenting,et al.  LRP/Amyloid β-Peptide Interaction Mediates Differential Brain Efflux of Aβ Isoforms , 2004, Neuron.

[271]  Z. Khachaturian,et al.  Development of biomarkers to chart all Alzheimer’s disease stages: The royal road to cutting the therapeutic Gordian Knot , 2012, Alzheimer's & Dementia.

[272]  M. Cambron,et al.  Vascular aspects of multiple sclerosis , 2011, The Lancet Neurology.

[273]  Yan Zhou,et al.  Abnormal functional connectivity in patients with vascular cognitive impairment, no dementia: A resting-state functional magnetic resonance imaging study , 2011, Behavioural Brain Research.

[274]  M. Weiner,et al.  Cortical thinning related to periventricular and deep white matter hyperintensities , 2012, Neurobiology of Aging.

[275]  V. Gudnason,et al.  Atrial Fibrillation is Associated With Reduced Brain Volume and Cognitive Function Independent of Cerebral Infarcts , 2013, Stroke.

[276]  C. Iadecola,et al.  The immunology of stroke: from mechanisms to translation , 2011, Nature Medicine.

[277]  C. Iadecola,et al.  The role of neuronal signaling in controlling cerebral blood flow , 2007, Brain and Language.

[278]  S. Back,et al.  A ‘GAG’ reflex prevents repair of the damaged CNS , 2008, Trends in Neurosciences.

[279]  F. Abboud Special characteristics of the cerebral circulation. , 1981, Federation proceedings.

[280]  C. Garz,et al.  Blood brain barrier breakdown as the starting point of cerebral small vessel disease? - New insights from a rat model , 2013, Experimental & Translational Stroke Medicine.

[281]  M. Cambron,et al.  Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1 , 2013, Proceedings of the National Academy of Sciences.

[282]  F. LaFerla,et al.  Oligemic hypoperfusion differentially affects tau and amyloid-{beta}. , 2010, The American journal of pathology.

[283]  Nozomi Nishimura,et al.  Occlusion of cortical ascending venules causes blood flow decreases, reversals in flow direction, and vessel dilation in upstream capillaries , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[284]  S. Takeuchi,et al.  Cerebral blood flow on ECD SPECT in a patient with adult onset Alexander disease. , 2009, Clinical nuclear medicine.

[285]  Kristine Yaffe,et al.  Promising strategies for the prevention of dementia. , 2009, Archives of neurology.

[286]  K. Jellinger Clinical-neuropathologic findings in multi-infarct dementia: A report of six autopsied cases , 1997, Neurology.

[287]  S. Leurgans,et al.  APOE ε4, Alzheimer's disease pathology, cerebrovascular disease, and cognitive change over the years prior to death. , 2013, Psychology and aging.

[288]  G. C. Román,et al.  Vascular dementia , 1993, Neurology.

[289]  K. Jellinger Pathology and pathogenesis of vascular cognitive impairment—a critical update , 2013, Front. Aging Neurosci..

[290]  K. Arai,et al.  Astrocytic high-mobility group box 1 promotes endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery , 2012, Proceedings of the National Academy of Sciences.

[291]  Robert J. van Oostenbrugge,et al.  Vascular inflammation in cerebral small vessel disease , 2012, Neurobiology of Aging.

[292]  Peter M. Nilsson,et al.  Microvascular brain damage with aging and hypertension: pathophysiological consideration and clinical implications , 2011, Journal of hypertension.

[293]  A. Hofman,et al.  Cerebral hypoperfusion and clinical onset of dementia: The Rotterdam study , 2005, Annals of neurology.

[294]  C. Thompson,et al.  C-reactive protein expression in a rodent model of chronic cerebral hypoperfusion , 2011, Brain Research.

[295]  J. Bond,et al.  A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: results of the Cognitive Function and Ageing Study I and II , 2013, The Lancet.

[296]  M. Mestek,et al.  Human aging and CD31+ T-cell number, migration, apoptotic susceptibility, and telomere length. , 2010, Journal of applied physiology.

[297]  E. Huang,et al.  Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination , 2011, Nature Neuroscience.

[298]  W. Sheu,et al.  Changes of brachial flow-mediated vasodilation in different ischemic stroke subtypes , 2006, Neurology.

[299]  Carlos Matute,et al.  Roles of white matter in central nervous system pathophysiologies , 2012, ASN neuro.

[300]  J. Simpkins,et al.  Increased beta-secretase activity and expression in rats following transient cerebral ischemia. , 2004, Brain research.

[301]  B. L. Beattie,et al.  Multiple Pathologies are Common in Alzheimer Patients in Clinical Trials , 2012, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[302]  T. Tabira,et al.  Chronic cerebral hypoperfusion induced by right unilateral common carotid artery occlusion causes delayed white matter lesions and cognitive impairment in adult mice , 2008, Experimental Neurology.

[303]  W. M. van der Flier,et al.  Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[304]  S. Rivest,et al.  Innate Immunity in the CNS: Redefining the Relationship between the CNS and Its Environment , 2013, Neuron.

[305]  R. Simmons,et al.  Oxidative stress disrupts oligodendrocyte maturation , 2009, Journal of neuroscience research.

[306]  F. Eichler,et al.  Hypoperfusion predicts lesion progression in cerebral X-linked adrenoleukodystrophy. , 2012, Brain : a journal of neurology.

[307]  H. Fillit,et al.  Cardiovascular risk factors and dementia. , 2008, The American journal of geriatric pharmacotherapy.

[308]  Berislav V. Zlokovic,et al.  Pericytes Control Key Neurovascular Functions and Neuronal Phenotype in the Adult Brain and during Brain Aging , 2010, Neuron.

[309]  Farzaneh A. Sorond,et al.  Neurovascular coupling is impaired in slow walkers: The MOBILIZE Boston Study , 2011, Annals of neurology.

[310]  R. Tanzi,et al.  Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. , 2007, Neuron.

[311]  E. Lo,et al.  Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons , 2008, Proceedings of the National Academy of Sciences.

[312]  Evan Fletcher,et al.  Coevolution of white matter hyperintensities and cognition in the elderly , 2012, Neurology.

[313]  M. Dichgans,et al.  Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging , 2013, The Lancet Neurology.

[314]  J. Attems,et al.  Brain microvascular accumulation and distribution of the NOTCH3 ectodomain and granular osmiophilic material in CADASIL. , 2013, Journal of neuropathology and experimental neurology.

[315]  Thomas G. Beach,et al.  Atherosclerosis of Cerebral Arteries in Alzheimer Disease , 2004, Stroke.

[316]  R. Rouhl,et al.  Angiogenic T-Cells and Putative Endothelial Progenitor Cells in Hypertension-Related Cerebral Small Vessel Disease , 2012, Stroke.

[317]  Adrian P. Crawley,et al.  Selective Reduction of Blood Flow to White Matter During Hypercapnia Corresponds With Leukoaraiosis , 2008, Stroke.

[318]  W. Brown,et al.  Review: Cerebral microvascular pathology in ageing and neurodegeneration , 2011, Neuropathology and applied neurobiology.

[319]  Alistair Burns,et al.  Observations on the brains of demented old people. B.E. Tomlinson, G. Blessed and M. Roth, Journal of the Neurological Sciences (1970) 11, 205–242; (1968) 7, 331–356 , 1997 .

[320]  A. Convit,et al.  Impact of metabolic syndrome on cognition and brain: a selected review of the literature. , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[321]  H. Markus,et al.  Mechanisms of Cognitive Impairment in Cerebral Small Vessel Disease: Multimodal MRI Results from the St George's Cognition and Neuroimaging in Stroke (SCANS) Study , 2013, PloS one.

[322]  Y Ichiya,et al.  Leukoaraiosis and Dementia in Hypertensive Patients , 1992, Stroke.

[323]  H. C. Chui,et al.  White matter lesions impair frontal lobe function regardless of their location , 2004, Neurology.

[324]  D. Holtzman,et al.  Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. , 2000, The Journal of clinical investigation.

[325]  P. Carmeliet,et al.  Molecular mechanisms and clinical applications of angiogenesis , 2011, Nature.

[326]  D. Leys,et al.  Stroke Syndromes: Poststroke dementia , 2001 .

[327]  Nozomi Nishimura,et al.  Limitations of collateral flow after occlusion of a single cortical penetrating arteriole , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[328]  V. Hachinski,et al.  Antihypertensive treatment can prevent stroke and cognitive decline , 2012, Nature Reviews Neurology.

[329]  Yonghua Huang,et al.  Is endothelial dysfunction of cerebral small vessel responsible for white matter lesions after chronic cerebral hypoperfusion in rats? , 2010, Journal of the Neurological Sciences.

[330]  H. Nagaraja,et al.  Altered cerebral vasoregulation in hypertension and stroke , 2003, Neurology.

[331]  Jian Guo,et al.  Cerebrolysin for vascular dementia. , 2013, The Cochrane database of systematic reviews.

[332]  G C Roman,et al.  Brain infarction and the clinical expression of Alzheimer disease. , 1997, JAMA.

[333]  David A Wolk,et al.  Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias. , 2012, Brain : a journal of neurology.

[334]  David Kleinfeld,et al.  The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit , 2012, Nature Neuroscience.

[335]  H. Hendrie,et al.  Cardiovascular Risk Factors and Incident Alzheimer Disease: A Systematic Review of the Literature , 2009, Alzheimer disease and associated disorders.

[336]  H. Markus Genes, endothelial function and cerebral small vessel disease in man , 2008, Experimental physiology.

[337]  R. Westendorp,et al.  Cerebrovascular hemodynamics in Alzheimer's disease and vascular dementia: A meta-analysis of transcranial Doppler studies , 2012, Ageing Research Reviews.

[338]  R. Rouhl,et al.  Endothelial Activation in Lacunar Stroke Subtypes , 2010, Stroke.

[339]  W. Mandemakers,et al.  A Novel Purification Method for CNS Projection Neurons Leads to the Identification of Brain Vascular Cells as a Source of Trophic Support for Corticospinal Motor Neurons , 2008, The Journal of Neuroscience.

[340]  Dag Aarsland,et al.  Is physical activity a potential preventive factor for vascular dementia? A systematic review , 2010, Aging & mental health.

[341]  J. Miklossy Cerebral hypoperfusion induces cortical watershed microinfarcts which may further aggravate cognitive decline in Alzheimer's disease , 2003, Neurological research.

[342]  A. Brickman,et al.  Cerebral perfusion is associated with white matter hyperintensities in older adults with heart failure. , 2013, Congestive heart failure.

[343]  Tan Xiao-mei,et al.  CADASIL , 2005 .

[344]  R. Kraftsik,et al.  Cerebral Hypoperfusion Generates Cortical Watershed Microinfarcts in Alzheimer Disease , 2002, Stroke.

[345]  D. Rowitch,et al.  Myelin regeneration: a recapitulation of development? , 2011, Annual review of neuroscience.

[346]  C. Rowe,et al.  Subacute Ischemic Stroke Is Associated With Focal 11C PiB Positron Emission Tomography Retention But Not With Global Neocortical A&bgr; Deposition , 2012, Stroke.

[347]  W. Poewe,et al.  Ischemic stress induces deposition of amyloid beta immunoreactivity in human brain. , 1995, Acta neuropathologica.

[348]  R O Weller,et al.  Review: Cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy , 2013, Neuropathology and applied neurobiology.

[349]  J. Bevan Sites of transition between functional systemic and cerebral arteries of rabbits occur at embryological junctional sites. , 1979, Science.

[350]  B. Cauli,et al.  Revisiting the Role of Neurons in Neurovascular Coupling , 2010, Front. Neuroenerg..

[351]  N. Van Rooijen,et al.  Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice. , 1998, Journal of immunology.

[352]  H. Schmidt,et al.  NADPH Oxidase Activity and Function Are Profoundly Greater in Cerebral Versus Systemic Arteries , 2005, Circulation research.

[353]  C. Iadecola Neurovascular regulation in the normal brain and in Alzheimer's disease , 2004, Nature Reviews Neuroscience.

[354]  Paul A Armitage,et al.  Changes in Background Blood–Brain Barrier Integrity Between Lacunar and Cortical Ischemic Stroke Subtypes , 2008, Stroke.

[355]  A Hofman,et al.  Cerebral vasomotor reactivity and cerebral white matter lesions in the elderly , 1999, Neurology.

[356]  P. Carmeliet,et al.  The Neurovascular Link in Health and Disease: Molecular Mechanisms and Therapeutic Implications , 2011, Neuron.

[357]  H. Wolburg,et al.  Brain endothelial cells and the glio-vascular complex , 2008, Cell and Tissue Research.

[358]  W. Markesbery,et al.  AD brain pathology: Vascular origins? Results from the HAAS autopsy study , 2008, Neurobiology of Aging.

[359]  Claudia D. Tesche,et al.  Topological dynamics in spike-timing dependent plastic model neural networks , 2013, Front. Neural Circuits.

[360]  C. Iadecola,et al.  Angiotensin II Impairs Neurovascular Coupling in Neocortex Through NADPH Oxidase–Derived Radicals , 2004, Circulation research.

[361]  M. Dichgans,et al.  Education modifies the relation of vascular pathology to cognitive function: cognitive reserve in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy , 2013, Neurobiology of Aging.

[362]  Kirsten Shuler,et al.  A Systematic Review of Dynamic Cerebral and Peripheral Endothelial Function in Lacunar Stroke Versus Controls , 2010, Stroke.

[363]  A. Pérez-Samartín,et al.  P2X7 receptors mediate ischemic damage to oligodendrocytes , 2009, Glia.