Acta Neuropathologica

, Volume 120, Issue 3, pp 287–296 | Cite as

The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia



There is increasing evidence that cerebrovascular dysfunction plays a role not only in vascular causes of cognitive impairment but also in Alzheimer’s disease (AD). Vascular risk factors and AD impair the structure and function of cerebral blood vessels and associated cells (neurovascular unit), effects mediated by vascular oxidative stress and inflammation. Injury to the neurovascular unit alters cerebral blood flow regulation, depletes vascular reserves, disrupts the blood–brain barrier, and reduces the brain’s repair potential, effects that amplify the brain dysfunction and damage exerted by incident ischemia and coexisting neurodegeneration. Clinical-pathological studies support the notion that vascular lesions aggravate the deleterious effects of AD pathology by reducing the threshold for cognitive impairment and accelerating the pace of the dementia. In the absence of mechanism-based approaches to counteract cognitive dysfunction, targeting vascular risk factors and improving cerebrovascular health offers the opportunity to mitigate the impact of one of the most disabling human afflictions.



Supported by NIH grants NS37806 and HL96571.


  1. 1.
    Abbott NJ, Patabendige AAK, Dolman DEM, Yusof SR, Begley DJ (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37:13–25PubMedCrossRefGoogle Scholar
  2. 2.
    Aho L, Jolkkonen J, Alafuzoff I (2006) Beta-amyloid aggregation in human brains with cerebrovascular lesions. Stroke 37:2940–2945PubMedCrossRefGoogle Scholar
  3. 3.
    Andresen J, Shafi NI, Bryan RM Jr (2006) Endothelial influences on cerebrovascular tone. J Appl Physiol 100:318–327PubMedCrossRefGoogle Scholar
  4. 4.
    Arai K, Lo EH (2009) An oligovascular niche: cerebral endothelial cells promote the survival and proliferation of oligodendrocyte precursor cells. J Neurosci 29:4351–4355PubMedCrossRefGoogle Scholar
  5. 5.
    Arai K, Lo EH (2010) Astrocytes protect oligodendrocyte precursor cells via MEK/ERK and PI3K/Akt signaling. J Neurosci Res 88:758–763PubMedGoogle Scholar
  6. 6.
    Bateman GA, Levi CR, Schofield P, Wang Y, Lovett EC (2006) Quantitative measurement of cerebral haemodynamics in early vascular dementia and Alzheimer’s disease. J Clin Neurosci 13:563–568PubMedCrossRefGoogle Scholar
  7. 7.
    Beach TG, Wilson JR, Sue LI et al (2007) Circle of Willis atherosclerosis: association with Alzheimer’s disease, neuritic plaques and neurofibrillary tangles. Acta Neuropathol 113:13–21PubMedCrossRefGoogle Scholar
  8. 8.
    Bell RD, Deane R, Chow N et al (2009) SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. Nat Cell Biol 11:143–153PubMedCrossRefGoogle Scholar
  9. 9.
    Bell RD, Zlokovic BV (2009) Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 118:103–113PubMedCrossRefGoogle Scholar
  10. 10.
    Breteler MM (2000) Vascular risk factors for Alzheimer’s disease: an epidemiologic perspective. Neurobiol Aging 21:153–160PubMedCrossRefGoogle Scholar
  11. 11.
    Brown WR, Moody DM, Thore CR, Challa VR, Anstrom JA (2007) 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. J Neurol Sci 257:62–66PubMedCrossRefGoogle Scholar
  12. 12.
    Chow N, Bell RD, Deane R et al (2007) Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer’s phenotype. Proc Natl Acad Sci USA 104:823–828PubMedCrossRefGoogle Scholar
  13. 13.
    Chui HC, Victoroff JI, Margolin D et al (1992) Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer’s Disease Diagnostic and Treatment Centers. Neurology 42:473–480PubMedGoogle Scholar
  14. 14.
    Cirrito JR, Deane R, Fagan AM et al (2005) P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest 115:3285–3290PubMedCrossRefGoogle Scholar
  15. 15.
    Cirrito JR, Yamada KA, Finn MB et al (2005) Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48:913–922PubMedCrossRefGoogle Scholar
  16. 16.
    Cotman CW, Berchtold NC, Christie L-A (2007) Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 30:464–472PubMedCrossRefGoogle Scholar
  17. 17.
    de la Torre JC, Mussivand T (1993) Can disturbed brain microcirculation cause Alzheimer’s disease? Neurol Res 15:146–153Google Scholar
  18. 18.
    Deane R, Du Yan S, Submamaryan RK et al (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 9:907–913PubMedCrossRefGoogle Scholar
  19. 19.
    Deane R, Wu Z, Sagare A et al (2004) LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron 43:333–344PubMedCrossRefGoogle Scholar
  20. 20.
    Dede DS, Yavuz B, Yavuz BB et al (2007) Assessment of endothelial function in Alzheimer’s disease: is Alzheimer’s disease a vascular disease? J Am Geriatr Soc 55:1613–1617PubMedCrossRefGoogle Scholar
  21. 21.
    Deininger MH, Fimmen BA, Thal DR, Schluesener HJ, Meyermann R (2002) Aberrant neuronal and paracellular deposition of endostatin in brains of patients with Alzheimer’s disease. J Neurosci 22:10621–10626PubMedGoogle Scholar
  22. 22.
    Deschaintre Y, Richard F, Leys D, Pasquier F (2009) Treatment of vascular risk factors is associated with slower decline in Alzheimer disease. Neurology 73:674–680PubMedCrossRefGoogle Scholar
  23. 23.
    Erkinjuntti T, Gauthier S (2009) The concept of vascular cognitive impairment. Front Neurol Neurosci 24:79–85PubMedCrossRefGoogle Scholar
  24. 24.
    Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD (1999) Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer’s disease. Lancet 354:919–920PubMedCrossRefGoogle Scholar
  25. 25.
    Faraci FM (2006) Reactive oxygen species: influence on cerebral vascular tone. J Appl Physiol 100:739–743PubMedCrossRefGoogle Scholar
  26. 26.
    Farrall AJ, Wardlaw JM (2009) Blood-brain barrier: ageing and microvascular disease–systematic review and meta-analysis. Neurobiol Aging 30:337–352PubMedCrossRefGoogle Scholar
  27. 27.
    Fernando MS, Simpson JE, Matthews F et al (2006) White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury. Stroke 37:1391–1398PubMedCrossRefGoogle Scholar
  28. 28.
    Fotuhi M, Hachinski V, Whitehouse PJ (2009) Changing perspectives regarding late-life dementia. Nat Rev Neurol 5:649–658PubMedCrossRefGoogle Scholar
  29. 29.
    Furie B, Furie BC (2008) Mechanisms of thrombus formation. N Engl J Med 359:938–949PubMedCrossRefGoogle Scholar
  30. 30.
    Gill R, Tsung A, Billiar T (2010) Linking oxidative stress to inflammation: Toll-like receptors. Free Radic Biol Med 48:1121–1132PubMedCrossRefGoogle Scholar
  31. 31.
    Gomis M, Sobrino T, Ois A et al (2009) Plasma beta-amyloid 1–40 is associated with the diffuse small vessel disease subtype. Stroke 40:3197–3201PubMedCrossRefGoogle Scholar
  32. 32.
    Goulding JM, Signorini DF, Chatterjee S et al (1999) Inverse relation between Braak stage and cerebrovascular pathology in Alzheimer predominant dementia. J Neurol Neurosurg Psychiatry 67:654–657PubMedCrossRefGoogle Scholar
  33. 33.
    Gurol ME, Irizarry MC, Smith EE et al (2006) Plasma beta-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy. Neurology 66:23–29PubMedCrossRefGoogle Scholar
  34. 34.
    Hachinski V, Iadecola C, Petersen RC et al (2006) National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 37:2220–2241PubMedCrossRefGoogle Scholar
  35. 35.
    Hachinski VC, Bowler JV (1993) Vascular dementia. Neurology 43:2159–2160 author reply 2160–2161PubMedGoogle Scholar
  36. 36.
    Hachinski VC, Lassen NA, Marshall J (1974) Multi-infarct dementia. A cause of mental deterioration in the elderly. Lancet 2:207–210PubMedCrossRefGoogle Scholar
  37. 37.
    Hayashi S, Sato N, Yamamoto A et al (2009) Alzheimer disease-associated peptide, amyloid beta40, inhibits vascular regeneration with induction of endothelial autophagy. Arterioscler Thromb Vasc Biol 29:1909–1915PubMedCrossRefGoogle Scholar
  38. 38.
    Helzner EP, Luchsinger JA, Scarmeas N et al (2009) Contribution of vascular risk factors to the progression in Alzheimer disease. Arch Neurol 66:343–348PubMedCrossRefGoogle Scholar
  39. 39.
    Heyman A, Fillenbaum GG, Welsh-Bohmer KA et al (1998) Cerebral infarcts in patients with autopsy-proven Alzheimer’s disease: CERAD, part XVIII. Consortium to Establish a Registry for Alzheimer’s Disease. Neurology 51:159–162PubMedGoogle Scholar
  40. 40.
    Honig LS, Kukull W, Mayeux R (2005) Atherosclerosis and AD: analysis of data from the US National Alzheimer’s Coordinating Center. Neurology 64:494–500PubMedGoogle Scholar
  41. 41.
    Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5:347–360PubMedCrossRefGoogle Scholar
  42. 42.
    Iadecola C, Davisson RL (2008) Hypertension and cerebrovascular dysfunction. Cell Metab 7:476–484PubMedCrossRefGoogle Scholar
  43. 43.
    Iadecola C, Gorelick PB (2003) Converging pathogenic mechanisms in vascular and neurodegenerative dementia. Stroke 34:335–337PubMedCrossRefGoogle Scholar
  44. 44.
    Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369–1376PubMedCrossRefGoogle Scholar
  45. 45.
    Iadecola C, Zhang F, Niwa K et al (1999) SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat Neurosci 2:157–161PubMedCrossRefGoogle Scholar
  46. 46.
    Ihara M, Polvikoski TM, Hall R 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 119:579–589PubMedCrossRefGoogle Scholar
  47. 47.
    Jagust WJ, Haan MN, Reed BR, Eberling JL (1998) Brain perfusion imaging predicts survival in Alzheimer’s disease. Neurology 51:1009–1013PubMedGoogle Scholar
  48. 48.
    Jellinger KA (2007) The enigma of mixed dementia. Alzheimers Dement 3:40–53PubMedCrossRefGoogle Scholar
  49. 49.
    Jellinger KA (2008) Morphologic diagnosis of “vascular dementia”—a critical update. J Neurol Sci 270:1–12PubMedCrossRefGoogle Scholar
  50. 50.
    Jellinger KA, Attems J (2010) Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol 119:421–433PubMedCrossRefGoogle Scholar
  51. 51.
    Jellinger KA, Mitter-Ferstl E (2003) The impact of cerebrovascular lesions in Alzheimer disease—a comparative autopsy study. J Neurol 250:1050–1055PubMedCrossRefGoogle Scholar
  52. 52.
    Jendroska K, Poewe W, Daniel SE et al (1995) Ischemic stress induces deposition of amyloid beta immunoreactivity in human brain. Acta Neuropathol 90:461–466PubMedCrossRefGoogle Scholar
  53. 53.
    Jennings JR, Muldoon MF, Ryan C et al (2005) Reduced cerebral blood flow response and compensation among patients with untreated hypertension. Neurology 64:1358–1365PubMedGoogle Scholar
  54. 54.
    Johnson KA, Albert MS (2000) Perfusion abnormalities in prodromal AD. Neurobiol Aging 21:289–292PubMedCrossRefGoogle Scholar
  55. 55.
    Kalaria RN (1992) The blood-brain barrier and cerebral microcirculation in Alzheimer disease. Cerebrovasc Brain Metab Rev 4:226–260PubMedGoogle Scholar
  56. 56.
    Kalaria RN (2000) The role of cerebral ischemia in Alzheimer’s disease. Neurobiol Aging 21:321–330PubMedCrossRefGoogle Scholar
  57. 57.
    Kalaria RN (2009) Linking cerebrovascular defense mechanisms in brain ageing and Alzheimer’s disease. Neurobiol Aging 30:1512–1514PubMedCrossRefGoogle Scholar
  58. 58.
    Kalaria RN (2009) Neurodegenerative disease: diabetes, microvascular pathology and Alzheimer disease. Nat Rev Neurol 5:305–306PubMedCrossRefGoogle Scholar
  59. 59.
    Kazama K, Anrather J, Zhou P et al (2004) Angiotensin II impairs neurovascular coupling in neocortex through NADPH-oxidase-derived radicals. Circ Res 95:1019–1026PubMedCrossRefGoogle Scholar
  60. 60.
    Kim YS, Immink RV, Stok WJ et al (2008) Dynamic cerebral autoregulatory capacity is affected early in Type 2 diabetes. Clin Sci 115:255–262PubMedCrossRefGoogle Scholar
  61. 61.
    Kitayama J, Faraci FM, Lentz SR, Heistad DD (2007) Cerebral vascular dysfunction during hypercholesterolemia. Stroke 38:2136–2141PubMedCrossRefGoogle Scholar
  62. 62.
    Koike MA, Green KN, Blurton-Jones M, LaFerla FM (2010) Oligemic hypoperfusion differentially affects tau and amyloid-{beta}. Am J Pathol. doi:10.2353/ajpath.2010.090750
  63. 63.
    Koistinaho M, Kettunen MI, Goldsteins G et al (2002) Beta-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability: role of inflammation. Proc Natl Acad Sci USA 99:1610–1615PubMedCrossRefGoogle Scholar
  64. 64.
    Konsman JP, Drukarch B, Van Dam A-M (2007) (Peri)vascular production and action of pro-inflammatory cytokines in brain pathology. Clin Sci 112:1–25PubMedCrossRefGoogle Scholar
  65. 65.
    Lam CK, Yoo T, Hiner B, Liu Z, Grutzendler J (2010) Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization. Nature 465:478–482PubMedCrossRefGoogle Scholar
  66. 66.
    Last D, Alsop DC, Abduljalil AM et al (2007) Global and regional effects of type 2 diabetes on brain tissue volumes and cerebral vasoreactivity. Diabetes Care 30:1193–1199PubMedCrossRefGoogle Scholar
  67. 67.
    Lee JH, Olichney JM, Hansen LA, Hofstetter CR, Thal LJ (2000) Small concomitant vascular lesions do not influence rates of cognitive decline in patients with Alzheimer disease. Arch Neurol 57:1474–1479PubMedCrossRefGoogle Scholar
  68. 68.
    Lewis H, Beher D, Cookson N et al (2006) Quantification of Alzheimer pathology in ageing and dementia: age-related accumulation of amyloid-beta(42) peptide in vascular dementia. Neuropathol Appl Neurobiol 32:103–118PubMedCrossRefGoogle Scholar
  69. 69.
    Li L, Zhang X, Yang D et al (2009) Hypoxia increases Abeta generation by altering beta- and gamma-cleavage of APP. Neurobiol Aging 30:1091–1098PubMedCrossRefGoogle Scholar
  70. 70.
    Libon DJ, Price CC, Heilman KM, Grossman M (2006) Alzheimer’s “other dementia”. Cogn Behav Neurol 19:112–116PubMedCrossRefGoogle Scholar
  71. 71.
    Marchesi C, Paradis P, Schiffrin EL (2008) Role of the renin-angiotensin system in vascular inflammation. Trends Pharmacol Sci 29:367–374PubMedCrossRefGoogle Scholar
  72. 72.
    Mentis MJ, Alexander GE, Krasuski J et al (1998) Increasing required neural response to expose abnormal brain function in mild versus moderate or severe Alzheimer’s disease: PET study using parametric visual stimulation. Am J Psychiatry 155:785–794PubMedGoogle Scholar
  73. 73.
    Modrick ML, Didion SP, Sigmund CD, Faraci FM (2009) Role of oxidative stress and AT1 receptors in cerebral vascular dysfunction with aging. Am J Physiol Heart Circ Physiol 296:H1914–H1919PubMedCrossRefGoogle Scholar
  74. 74.
    Moskowitz MA, Lo EH, Iadecola C (2010) The science of stroke: mechanisms in search of treatments. Neuron. doi:10.1016/j.neuron.2010.07.002
  75. 75.
    Nagy Z, Esiri MM, Jobst KA et al (1997) The effects of additional pathology on the cognitive deficit in Alzheimer disease. J Neuropathol Exp Neurol 56:165–170PubMedCrossRefGoogle Scholar
  76. 76.
    Niwa K, Kazama K, Younkin L et al (2002) Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein. Am J Physiol Heart Circ Physiol 283:H315–H323PubMedGoogle Scholar
  77. 77.
    Niwa K, Younkin L, Ebeling C et al (2000) Abeta 1–40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc Natl Acad Sci USA 97:9735–9740PubMedCrossRefGoogle Scholar
  78. 78.
    Ohab J, Fleming S, Blesch A, Carmichael S (2006) A neurovascular niche for neurogenesis after stroke. J Neurosci 26:13007–13016PubMedCrossRefGoogle Scholar
  79. 79.
    Pang Y, Campbell L, Zheng B et al (2010) Lipopolysaccharide-activated microglia induce death of oligodendrocyte progenitor cells and impede their development. Neuroscience 166:464–475PubMedCrossRefGoogle Scholar
  80. 80.
    Park L, Anrather J, Girouard H, Zhou P, Iadecola C (2007) Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. J Cereb Blood Flow Metab 27:1908–1918PubMedCrossRefGoogle Scholar
  81. 81.
    Park L, Zhou P, Pitstick R et al (2008) Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci USA 105:1347–1352PubMedCrossRefGoogle Scholar
  82. 82.
    Patel NS, Mathura VS, Bachmeier C et al (2010) Alzheimer’s beta-amyloid peptide blocks vascular endothelial growth factor mediated signaling via direct interaction with VEGFR-2. J Neurochem 112:66–76PubMedCrossRefGoogle Scholar
  83. 83.
    Paulson OB, Hasselbalch SG, Rostrup E, Knudsen GM, Pelligrino D (2010) Cerebral blood flow response to functional activation. J Cereb Blood Flow Metab 30:2–14PubMedCrossRefGoogle Scholar
  84. 84.
    Prohovnik I, Mayeux R, Sackeim HA et al (1988) Cerebral perfusion as a diagnostic marker of early Alzheimer’s disease. Neurology 38:931–937PubMedGoogle Scholar
  85. 85.
    Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344PubMedCrossRefGoogle Scholar
  86. 86.
    Roman GC, Takemici TK, Erkinjuntti T et al (1993) Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN international workshop. Neurology 43:250–260PubMedGoogle Scholar
  87. 87.
    Ruitenberg A, den Heijer T, Bakker SL et al (2005) Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ann Neurol 57:789–794PubMedCrossRefGoogle Scholar
  88. 88.
    Savva GM, Wharton SB, Ince PG et al (2009) Age, neuropathology, and dementia. N Engl J Med 360:2302–2309PubMedCrossRefGoogle Scholar
  89. 89.
    Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA (2009) The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol 66:200–208PubMedCrossRefGoogle Scholar
  90. 90.
    Schneider JA, Wilson RS, Bienias JL, Evans DA, Bennett DA (2004) Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology 62:1148–1155PubMedGoogle Scholar
  91. 91.
    Schroeter ML, Cutini S, Wahl MM, Scheid R, Yves von Cramon D (2007) Neurovascular coupling is impaired in cerebral microangiopathy—an event-related Stroop study. Neuroimage 34:26–34PubMedCrossRefGoogle Scholar
  92. 92.
    Selnes OA, Vinters HV (2006) Vascular cognitive impairment. Nat Clin Pract Neurol 2:538–547PubMedCrossRefGoogle Scholar
  93. 93.
    Shibata M, Yamada S, Kumar SR et al (2000) Clearance of Alzheimer’s amyloid-beta (1–40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 106:1489–1499PubMedCrossRefGoogle Scholar
  94. 94.
    Siegel GJ, Chauhan NB (2000) Neurotrophic factors in Alzheimer’s and Parkinson’s disease brain. Brain Res Brain Res Rev 33:199–227PubMedCrossRefGoogle Scholar
  95. 95.
    Silvestrini M, Pasqualetti P, Baruffaldi R et al (2006) Cerebrovascular reactivity and cognitive decline in patients with Alzheimer disease. Stroke 37:1010–1015PubMedCrossRefGoogle Scholar
  96. 96.
    Sim FJ, Zhao C, Penderis J, Franklin RJ (2002) The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation. J Neurosci 22:2451–2459PubMedGoogle Scholar
  97. 97.
    Simpson JE, Fernando MS, Clark L et al (2007) White matter lesions in an unselected cohort of the elderly: astrocytic, microglial and oligodendrocyte precursor cell responses. Neuropathol Appl Neurobiol 33:410–419PubMedCrossRefGoogle Scholar
  98. 98.
    Simpson JE, Ince PG, Haynes LJ et al (2010) Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer-type pathology in the ageing brain. Neuropathol Appl Neurobiol 36:25–40PubMedCrossRefGoogle Scholar
  99. 99.
    Simpson JE, Ince PG, Higham CE et al (2007) Microglial activation in white matter lesions and nonlesional white matter of ageing brains. Neuropathol Appl Neurobiol 33:670–683PubMedCrossRefGoogle Scholar
  100. 100.
    Smith PJ, Blumenthal JA, Babyak MA et al (2010) Effects of the dietary approaches to stop hypertension diet, exercise, and caloric restriction on neurocognition in overweight adults with high blood pressure. Hypertension 55:1331–1338PubMedCrossRefGoogle Scholar
  101. 101.
    Snapyan M, Lemasson M, Brill MS et al (2009) Vasculature guides migrating neuronal precursors in the adult mammalian forebrain via brain-derived neurotrophic factor signaling. J Neurosci 29:4172–4188PubMedCrossRefGoogle Scholar
  102. 102.
    Snowdon DA, Greiner LH, Mortimer JA et al (1997) Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 277:813–817PubMedCrossRefGoogle Scholar
  103. 103.
    Song IU, Kim JS, Kim YI, Eah KY, Lee KS (2007) Clinical significance of silent cerebral infarctions in patients with Alzheimer disease. Cogn Behav Neurol 20:93–98PubMedCrossRefGoogle Scholar
  104. 104.
    Sonnen JA, Larson EB, Brickell K et al (2009) Different patterns of cerebral injury in dementia with or without diabetes. Arch Neurol 66:315–322PubMedCrossRefGoogle Scholar
  105. 105.
    Sparks DL, Scheff SW, Liu H et al (1995) Increased incidence of neurofibrillary tangles (NFT) in non-demented individuals with hypertension. J Neurol Sci 131:162–169PubMedCrossRefGoogle Scholar
  106. 106.
    Staekenborg SS, Koedam ELGE, Henneman WJP et al (2009) Progression of mild cognitive impairment to dementia: contribution of cerebrovascular disease compared with medial temporal lobe atrophy. Stroke 40:1269–1274PubMedCrossRefGoogle Scholar
  107. 107.
    Sun X, He G, Qing H et al (2006) Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci USA 103:18727–18732PubMedCrossRefGoogle Scholar
  108. 108.
    Tanaka M, Fukuyama H, Yamauchi H et al (2002) Regional cerebral blood flow abnormalities in nondemented patients with memory impairment. J Neuroimaging 12:112–118PubMedCrossRefGoogle Scholar
  109. 109.
    Tarkowski E, Issa R, Sjögren M et al (2002) Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer’s disease and vascular dementia. Neurobiol Aging 23:237–243PubMedCrossRefGoogle Scholar
  110. 110.
    Tesco G, Koh YH, Kang EL et al (2007) Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron 54:721–737PubMedCrossRefGoogle Scholar
  111. 111.
    Thomas T, Thomas G, McLendon C, Sutton T, Mullan M (1996) β-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380:168–171PubMedCrossRefGoogle Scholar
  112. 112.
    Tong L, Balazs R, Soiampornkul R, Thangnipon W, Cotman CW (2008) Interleukin-1 beta impairs brain derived neurotrophic factor-induced signal transduction. Neurobiol Aging 29:1380–1393PubMedCrossRefGoogle Scholar
  113. 113.
    Trapp BD, Stys PK (2009) Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 8:280–291PubMedCrossRefGoogle Scholar
  114. 114.
    van Beek AH, Claassen JA, Rikkert MG, Jansen RW (2008) Cerebral autoregulation: an overview of current concepts and methodology with special focus on the elderly. J Cereb Blood Flow Metab 28:1071–1085PubMedCrossRefGoogle Scholar
  115. 115.
    Venters HD, Dantzer R, Kelley KW (2000) A new concept in neurodegeneration: TNFalpha is a silencer of survival signals. Trends Neurosci 23:175–180PubMedCrossRefGoogle Scholar
  116. 116.
    Vermeer SE, Prins ND, den Heijer T et al (2003) Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 348:1215–1222PubMedCrossRefGoogle Scholar
  117. 117.
    Warkentin S, Passant U (1997) Functional imaging of the frontal lobes in organic dementia. Regional cerebral blood flow findings in normals, in patients with frontotemporal dementia and in patients with Alzheimer’s disease, performing a word fluency test. Dement Geriatr Cogn Disord 8:105–109PubMedCrossRefGoogle Scholar
  118. 118.
    Weber C, Fraemohs L, Dejana E (2007) The role of junctional adhesion molecules in vascular inflammation. Nat Rev Immunol 7:467–477PubMedCrossRefGoogle Scholar
  119. 119.
    Weinstein BM (2005) Vessels and nerves: marching to the same tune. Cell 120:299–302PubMedCrossRefGoogle Scholar
  120. 120.
    Weller RO, Boche D, Nicoll JA (2009) Microvasculature changes and cerebral amyloid angiopathy in Alzheimer’s disease and their potential impact on therapy. Acta Neuropathol 118:87–102PubMedCrossRefGoogle Scholar
  121. 121.
    Wen Y, Onyewuchi O, Yang S, Liu R, Simpkins JW (2004) Increased beta-secretase activity and expression in rats following transient cerebral ischemia. Brain Res 1009:1–8PubMedCrossRefGoogle Scholar
  122. 122.
    Wen Y, Yang S-H, Liu R et al (2007) Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats. Biochim Biophys Acta 1772:473–483PubMedGoogle Scholar
  123. 123.
    White L (2009) Brain lesions at autopsy in older Japanese-American men as related to cognitive impairment and dementia in the final years of life: a summary report from the Honolulu-Asia aging study. J Alzheimers Dis 18:713–725PubMedGoogle Scholar
  124. 124.
    Wolburg H, Noell S, Mack A, Wolburg-Buchholz K, Fallier-Becker P (2009) Brain endothelial cells and the glio-vascular complex. Cell Tissue Res 335:75–96PubMedCrossRefGoogle Scholar
  125. 125.
    Wu Z, Guo H, Chow N et al (2005) Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nat Med 11:959–965PubMedGoogle Scholar
  126. 126.
    Yang S-P, Bae D-G, Kang HJ et al (2004) Co-accumulation of vascular endothelial growth factor with beta-amyloid in the brain of patients with Alzheimer’s disease. Neurobiol Aging 25:283–290PubMedCrossRefGoogle Scholar
  127. 127.
    Yoshiura T, Hiwatashi A, Yamashita K et al (2009) Simultaneous measurement of arterial transit time, arterial blood volume, and cerebral blood flow using arterial spin-labeling in patients with Alzheimer disease. Am J Neuroradiol 30:1388–1393PubMedCrossRefGoogle Scholar
  128. 128.
    Zacchigna S, Lambrechts D, Carmeliet P (2008) Neurovascular signalling defects in neurodegeneration. Nat Rev Neurosci 9:169–181PubMedCrossRefGoogle Scholar
  129. 129.
    Zekry D, Duyckaerts C, Moulias R et al (2002) Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly. Acta Neuropathol 103:481–487PubMedCrossRefGoogle Scholar
  130. 130.
    Zhang F, Eckman C, Younkin S, Hsiao KK, Iadecola C (1997) Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein. J Neurosci 17:7655–7661PubMedGoogle Scholar
  131. 131.
    Zhiyou C, Yong Y, Shanquan S et al (2009) Upregulation of BACE1 and beta-amyloid protein mediated by chronic cerebral hypoperfusion contributes to cognitive impairment and pathogenesis of Alzheimer’s disease. Neurochem Res 34:1226–1235PubMedCrossRefGoogle Scholar
  132. 132.
    Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201PubMedCrossRefGoogle Scholar

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© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Division of NeurobiologyWeill Cornell Medical CollegeNew YorkUSA

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