Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The role of brain vasculature in neurodegenerative disorders

Nature Neuroscience volume 21, pages 1318–1331 (2018)Cite this article

Subjects

Abstract

Adequate supply of blood and structural and functional integrity of blood vessels are key to normal brain functioning. On the other hand, cerebral blood flow shortfalls and blood–brain barrier dysfunction are early findings in neurodegenerative disorders in humans and animal models. Here we first examine molecular definition of cerebral blood vessels, as well as pathways regulating cerebral blood flow and blood–brain barrier integrity. Then we examine the role of cerebral blood flow and blood–brain barrier in the pathogenesis of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. We focus on Alzheimer’s disease as a platform of our analysis because more is known about neurovascular dysfunction in this disease than in other neurodegenerative disorders. Finally, we propose a hypothetical model of Alzheimer’s disease biomarkers to include brain vasculature as a factor contributing to the disease onset and progression, and we suggest a common pathway linking brain vascular contributions to neurodegeneration in multiple neurodegenerative disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Molecular definition of the BBB and cerebral blood vessels.
Fig. 2: Key cellular and molecular pathways regulating CBF.
Fig. 3: Key cellular and molecular pathways regulating BBB integrity.
Fig. 4: Hypothetical updated Jack model of AD biomarkers to include the role of brain vasculature.
Fig. 5: Commonality of an early involvement of brain vasculature in different neurodegenerative disorders.

Similar content being viewed by others

References

  1. Iadecola, C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96, 17–42 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kisler, K., Nelson, A. R., Montagne, A. & Zlokovic, B. V. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 18, 419–434 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Zhao, Z., Nelson, A. R., Betsholtz, C. & Zlokovic, B. V. Establishment and dysfunction of the blood-brain barrier. Cell 163, 1064–1078 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sweeney, M. D., Ayyadurai, S. & Zlokovic, B. V. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat. Neurosci. 19, 771–783 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Montagne, A., Zhao, Z. & Zlokovic, B. V. Alzheimer’s disease: a matter of blood-brain barrier dysfunction? J. Exp. Med. 214, 3151–3169 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Vanlandewijck, M. et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature 554, 475–480 (2018). This is the first study to examine molecular landmarks and heterogeneity of cerebrovascular cells in the adult mouse brain and investigate the concept of zonation along the arterio–capillary–venous axis.

    Article  CAS  PubMed  Google Scholar 

  8. Jack, C. R. Jr. et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207–216 (2013). This study proposed and recognized hypothetical model of biomarker changes during Alzheimer’s disease pathophysiological progression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nguyen, L. N. et al. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 509, 503–506 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Ben-Zvi, A. et al. Mfsd2a is critical for the formation and function of the blood-brain barrier. Nature 509, 507–511 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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).

    Article  CAS  PubMed  Google Scholar 

  12. Alarcon-Martinez, L. et al. Capillary pericytes express α-smooth muscle actin, which requires prevention of filamentous-actin depolymerization for detection. eLife 7, e34861 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kisler, K. et al. Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat. Neurosci. 20, 406–416 (2017). This was the first study to demonstrate that pericyte degeneration in a pericyte loss-of-function model leads to a loss of neurovascular coupling and diminished oxygen delivery to brain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Peppiatt, C. M., Howarth, C., Mobbs, P. & Attwell, D. Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700–704 (2006). This important work in brain slices and retina demonstrated pericyte contractility and control of capillary diameter.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hall, C. N. et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508, 55–60 (2014). This was the first study to show that pericytes have an active role in cerebral blood flow regulation in vivo and that capillaries can dilate ahead of arterioles. In ischemic conditions, pericytes rapidly constrict capillaries and die, consistent with the no-reflow phenomenon observed in stroke.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mishra, A. et al. Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nat. Neurosci. 19, 1619–1627 (2016). This was the first study to show that astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles in brain, which involves a rise of calcium in astrocytes caused by entry through adenosine triphosphate-gated channels.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Biesecker, K. R. et al. Glial cell calcium signaling mediates capillary regulation of blood flow in the retina. J. Neurosci. 36, 9435–9445 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Shih, A. & Hartmann, D. In vivo optical imaging and manipulation of pericytes in the mouse brain. in Optics and the Brain BrW3B–1 (2017).

  20. Mapelli, L. et al. Granular layer neurons control cerebellar neurovascular coupling through an NMDA receptor/NO-dependent system. J. Neurosci. 37, 1340–1351 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wei, H. S. et al. Erythrocytes are oxygen-sensing regulators of the cerebral microcirculation. Neuron 91, 851–862 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hillman, E. M. C. Coupling mechanism and significance of the BOLD signal: a status report. Annu. Rev. Neurosci. 37, 161–181 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Longden, T. A. et al. Capillary K+-sensing initiates retrograde hyperpolarization to increase local cerebral blood flow. Nat. Neurosci. 20, 717–726 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Blinder, P. et al. The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow. Nat. Neurosci. 16, 889–897 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kur, J. & Newman, E. A. Purinergic control of vascular tone in the retina. J. Physiol. (Lond.) 592, 491–504 (2014).

    Article  CAS  Google Scholar 

  27. Uhlirova, H. et al. Cell type specificity of neurovascular coupling in cerebral cortex. eLife 5, e14315 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Gebremedhin, D. et al. Production of 20-HETE and its role in autoregulation of cerebral blood flow. Circ. Res. 87, 60–65 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Nippert, A. R., Biesecker, K. R. & Newman, E. A. Mechanisms mediating functional hyperemia in the brain. Neuroscientist 24, 73–83 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Bény, J.-L., Nguyen, M. N., Marino, M. & Matsui, M. Muscarinic receptor knockout mice confirm involvement of M3 receptor in endothelium-dependent vasodilatation in mouse arteries. J. Cardiovasc. Pharmacol. 51, 505–512 (2008).

    Article  PubMed  CAS  Google Scholar 

  31. Yamada, M. et al. Cholinergic dilation of cerebral blood vessels is abolished in M(5) muscarinic acetylcholine receptor knockout mice. Proc. Natl. Acad. Sci. USA 98, 14096–14101 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Daneman, R., Zhou, L., Kebede, A. A. & Barres, B. A. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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). This study not only describes the role of pericytes in maintaining in vivo blood–brain barrier integrity, microvascular density, and functional hyperemia during adulthood and brain aging but also shows that a primary loss of pericytes may lead to two parallel pathways of neurodegeneration, blood–brain barrier breakdown, and hypoperfusion, which lead to secondary neurodegenerative changes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Armulik, A. et al. Pericytes regulate the blood-brain barrier. Nature 468, 557–561 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Winkler, E. A., Bell, R. D. & Zlokovic, B. V. Central nervous system pericytes in health and disease. Nat. Neurosci. 14, 1398–1405 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nikolakopoulou, A. M., Zhao, Z., Montagne, A. & Zlokovic, B. V. Regional early and progressive loss of brain pericytes but not vascular smooth muscle cells in adult mice with disrupted platelet-derived growth factor receptor-β signaling. PLoS One 12, e0176225 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Foo, S. S. et al. Ephrin-B2 controls cell motility and adhesion during blood-vessel-wall assembly. Cell 124, 161–173 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Yao, Y., Chen, Z.-L., Norris, E. H. & Strickland, S. Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity. Nat. Commun. 5, 3413 (2014).

    Article  PubMed  CAS  Google Scholar 

  39. Bell, R. D. et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512–516 (2012). This important study demonstrates APOE4-dependent activation of a pro-inflammatory signaling pathway in pericytes involving cyclophilin A–nuclear factor-kappa B–matrix metalloproteinase-9-mediated degradation of blood–brain barrier basement membrane and tight junction proteins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang, Y., Chang, H., Rattner, A. & Nathans, J. Frizzled receptors in development and disease. Curr. Top. Dev. Biol. 117, 113–139 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Liebner, S. et al. Wnt/beta-catenin signaling controls development of the blood-brain barrier. J. Cell Biol. 183, 409–417 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Iturria-Medina, Y., Sotero, R. C., Toussaint, P. J., Mateos-Pérez, J. M. & Evans, A. C. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat. Commun. 7, 11934 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Montagne, A. et al. Brain imaging of neurovascular dysfunction in Alzheimer’s disease. Acta Neuropathol. 131, 687–707 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Montagne, A. et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85, 296–302 (2015). This study was the first to demonstrate age-associated blood–brain barrier breakdown in the hippocampus in the living human brain and accelerated breakdown in humans with mild cognitive impairment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sweeney, M. D., Sagare, A. P. & Zlokovic, B. V. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 14, 133–150 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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). This large cross-sectional neuropathological study showed that cerebral vessel disease plays a part in dementia that is typically attributed to Alzheimer’s disease during life.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Toledo, J. B. et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain 136, 2697–2706 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Iadecola, C. The pathobiology of vascular dementia. Neuron 80, 844–866 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Rabin, J.S. et al. Interactive associations of vascular risk and β-amyloid burden with cognitive decline in clinically normal elderly individuals: findings from the Harvard Aging Brain Study. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2018.1123 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  50. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ruitenberg, A. et al. Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ann. Neurol. 57, 789–794 (2005). This large population-based study showed that diminished cerebral blood flow precedes cognitive decline and hippocampal atrophy.

    Article  PubMed  Google Scholar 

  52. Chen, Y. et al. Voxel-level comparison of arterial spin-labeled perfusion MRI and FDG-PET in Alzheimer disease. Neurology 77, 1977–1985 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hays, C. C., Zlatar, Z. Z. & Wierenga, C. E. The utility of cerebral blood flow as a biomarker of preclinical Alzheimer’s disease. Cell. Mol. Neurobiol. 36, 167–179 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wierenga, C. E. et al. Effect of mild cognitive impairment and APOE genotype on resting cerebral blood flow and its association with cognition. J. Cereb. Blood Flow Metab. 32, 1589–1599 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Alexopoulos, P. et al. Perfusion abnormalities in mild cognitive impairment and mild dementia in Alzheimer’s disease measured by pulsed arterial spin labeling MRI. Eur. Arch. Psychiatry Clin. Neurosci. 262, 69–77 (2012).

    Article  PubMed  Google Scholar 

  56. Dai, W. et al. Mild cognitive impairment and Alzheimer disease: patterns of altered cerebral blood flow at MR imaging. Radiology 250, 856–866 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Hu, W. T. et al. Distinct cerebral perfusion patterns in FTLD and AD. Neurology 75, 881–888 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nation, D. A. et al. Cortical and subcortical cerebrovascular resistance index in mild cognitive impairment and Alzheimer’s disease. J. Alzheimers Dis. 36, 689–698 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  59. van de Haar, H. J. et al. Neurovascular unit impairment in early Alzheimer’s disease measured with magnetic resonance imaging. Neurobiol. Aging 45, 190–196 (2016).

    Article  PubMed  Google Scholar 

  60. Yoshiura, T. et al. Simultaneous measurement of arterial transit time, arterial blood volume, and cerebral blood flow using arterial spin-labeling in patients with Alzheimer disease. AJNR Am. J. Neuroradiol. 30, 1388–1393 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Leeuwis, A. E. et al. Lower cerebral blood flow is associated with impairment in multiple cognitive domains in Alzheimer’s disease. Alzheimers Dement. 13, 531–540 (2017).

    Article  PubMed  Google Scholar 

  62. Ma, H. R. et al. Aberrant pattern of regional cerebral blood flow in Alzheimer’s disease: a voxel-wise meta-analysis of arterial spin labeling MR imaging studies. Oncotarget 8, 93196–93208 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  63. de Eulate, R. G. et al. Reduced cerebral blood flow in mild cognitive impairment assessed using phase-contrast MRI. J. Alzheimers Dis. 58, 585–595 (2017).

    Article  PubMed  CAS  Google Scholar 

  64. Leijenaar, J. F. et al. Lower cerebral blood flow in subjects with Alzheimer’s dementia, mild cognitive impairment, and subjective cognitive decline using two-dimensional phase-contrast magnetic resonance imaging. Alzheimers Dement. 9, 76–83 (2017).

    Google Scholar 

  65. Wirth, M. et al. Divergent regional patterns of cerebral hypoperfusion and gray matter atrophy in mild cognitive impairment patients. J. Cereb. Blood Flow Metab. https://doi.org/10.1177/2F0271678X16641128 (2016).

  66. 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).

    Article  CAS  PubMed  Google Scholar 

  67. Thambisetty, M., Beason-Held, L., An, Y., Kraut, M. A. & Resnick, S. M. APOE epsilon4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch. Neurol. 67, 93–98 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  68. den Abeelen, A. S. S. M., Lagro, J., van Beek, A. H. E. A. & Claassen, J. A. H. R. Impaired cerebral autoregulation and vasomotor reactivity in sporadic Alzheimer’s disease. Curr. Alzheimer Res. 11, 11–17 (2014).

    Article  CAS  Google Scholar 

  69. Yezhuvath, U. S. et al. Forebrain-dominant deficit in cerebrovascular reactivity in Alzheimer’s disease. Neurobiol. Aging 33, 75–82 (2012).

    Article  PubMed  Google Scholar 

  70. Hecht, M., Krämer, L. M., von Arnim, C. A. F., Otto, M. & Thal, D. R. Capillary cerebral amyloid angiopathy in Alzheimer’s disease: association with allocortical/hippocampal microinfarcts and cognitive decline. Acta Neuropathol. 135, 681–694 (2018).

    Article  CAS  PubMed  Google Scholar 

  71. Suri, S. et al. Reduced cerebrovascular reactivity in young adults carrying the APOE ε4 allele. Alzheimers Dement. 11, 648–57.e1 (2015).

    Article  PubMed  Google Scholar 

  72. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  73. 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).

    Article  CAS  PubMed  Google Scholar 

  74. Rombouts, S. A. et al. Functional MR imaging in Alzheimer’s disease during memory encoding. AJNR Am. J. Neuroradiol. 21, 1869–1875 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Dumas, A. et al. Functional magnetic resonance imaging detection of vascular reactivity in cerebral amyloid angiopathy. Ann. Neurol. 72, 76–81 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Iadecola, C. et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat. Neurosci. 2, 157–161 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Niwa, K. et al. Abeta 1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc. Natl. Acad. Sci. USA 97, 9735–9740 (2000). This paper was the first to demonstrate altered neurovascular coupling by amyloid-β.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Park, L. et al. Age-dependent neurovascular dysfunction and damage in a mouse model of cerebral amyloid angiopathy. Stroke 45, 1815–1821 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Montagne, A. et al. Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat. Med. 24, 326–337 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Alata, W., Ye, Y., St-Amour, I., Vandal, M. & Calon, F. Human apolipoprotein E ɛ4 expression impairs cerebral vascularization and blood-brain barrier function in mice. J. Cereb. Blood Flow Metab. 35, 86–94 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. van de Haar, H. J. et al. Blood-brain barrier leakage in patients with Early Alzheimer disease. Radiology 281, 527–535 (2016).

    Article  PubMed  Google Scholar 

  82. van de Haar, H. J. et al. Subtle blood-brain barrier leakage rate and spatial extent: Considerations for dynamic contrast-enhanced MRI. Med. Phys. 44, 4112–4125 (2017).

    Article  PubMed  Google Scholar 

  83. Heringa, S. M. et al. Multiple microbleeds are related to cerebral network disruptions in patients with early Alzheimer’s disease. J. Alzheimers Dis. 38, 211–221 (2014).

    Article  PubMed  Google Scholar 

  84. Poliakova, T., Levin, O., Arablinskiy, A., Vasenina, E. & Zerr, I. Cerebral microbleeds in early Alzheimer’s disease. J. Neurol. 263, 1961–1968 (2016).

    Article  CAS  PubMed  Google Scholar 

  85. Shams, S. et al. Cerebral microbleeds: different prevalence, topography, and risk factors depending on dementia diagnosis—the Karolinska Imaging Dementia Study. AJNR Am. J. Neuroradiol. 36, 661–666 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Shams, S. & Wahlund, L.-O. Cerebral microbleeds as a biomarker in Alzheimer’s disease? A review in the field. Biomark. Med. 10, 9–18 (2016).

    Article  CAS  PubMed  Google Scholar 

  87. Vernooij, M. W. et al. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology 70, 1208–1214 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Yates, P. A. et al. Incidence of cerebral microbleeds in preclinical Alzheimer disease. Neurology 82, 1266–1273 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Brundel, M. et al. High prevalence of cerebral microbleeds at 7Tesla MRI in patients with early Alzheimer’s disease. J. Alzheimers Dis. 31, 259–263 (2012). A high prevalence of cerebral microbleeds is detected in mild cognitive impairment and early Alzheimer’s disease brains (78% of subjects) using state-of-the-art 7-Tesla magnetic resonance imaging.

    Article  CAS  PubMed  Google Scholar 

  90. Uetani, H. et al. Prevalence and topography of small hypointense foci suggesting microbleeds on 3T susceptibility-weighted imaging in various types of dementia. AJNR Am. J. Neuroradiol. 34, 984–989 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wardlaw, J. M. et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 12, 822–838 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Saito, S. & Ihara, M. Interaction between cerebrovascular disease and Alzheimer pathology. Curr. Opin. Psychiatry 29, 168–173 (2016).

    Article  PubMed  Google Scholar 

  93. Iaccarino, L. et al. A cross-validation of FDG- and amyloid-PET biomarkers in mild cognitive impairment for the risk prediction to dementia due to Alzheimer’s disease in a clinical setting. J. Alzheimers Dis. 59, 603–614 (2017).

    Article  CAS  PubMed  Google Scholar 

  94. Mosconi, L. et al. Amyloid and metabolic positron emission tomography imaging of cognitively normal adults with Alzheimer’s parents. Neurobiol. Aging 34, 22–34 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Mosconi, L. et al. Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer’s disease, and other dementias. J. Nucl. Med. 49, 390–398 (2008).

    Article  PubMed  Google Scholar 

  96. Protas, H. D. et al. Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for Alzheimer disease. JAMA Neurol. 70, 320–325 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Mosconi, L. Brain glucose metabolism in the early and specific diagnosis of Alzheimer’s disease. FDG-PET studies in MCI and AD. Eur. J. Nucl. Med. Mol. Imaging 32, 486–510 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Bailly, M. et al. Precuneus and cingulate cortex atrophy and hypometabolism in patients with Alzheimer’s disease and mild cognitive impairment: MRI and (18)F-FDG PET quantitative analysis using FreeSurfer. BioMed Res. Int. 2015, 583931 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367, 795–804 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Mosconi, L. et al. Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer’s disease. J. Nucl. Med. 47, 1778–1786 (2006).

    CAS  PubMed  Google Scholar 

  101. Landau, S. M. et al. Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI. Neurobiol. Aging 32, 1207–1218 (2011).

    Article  PubMed  Google Scholar 

  102. Landau, S. M. et al. Comparing predictors of conversion and decline in mild cognitive impairment. Neurology 75, 230–238 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Mosconi, L. et al. FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer’s disease. Eur. J. Nucl. Med. Mol. Imaging 36, 811–822 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Jack, C. R. Jr. et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 14, 535–562 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Winkler, E. A. et al. GLUT1 reductions exacerbate Alzheimer’s disease vasculo-neuronal dysfunction and degeneration. Nat. Neurosci. 18, 521–530 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Gejl, M. et al. Blood-brain glucose transfer in Alzheimer’s disease: effect of GLP-1 analog treatment. Sci. Rep. 7, 17490 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Jagust, W. J. et al. Diminished glucose transport in Alzheimer’s disease: dynamic PET studies. J. Cereb. Blood Flow Metab. 11, 323–330 (1991).

    Article  CAS  PubMed  Google Scholar 

  108. Piert, M., Koeppe, R. A., Giordani, B., Berent, S. & Kuhl, D. E. Diminished glucose transport and phosphorylation in Alzheimer’s disease determined by dynamic FDG-PET. J. Nucl. Med. 37, 201–208 (1996).

    CAS  PubMed  Google Scholar 

  109. Mooradian, A. D., Chung, H. C. & Shah, G. N. GLUT-1 expression in the cerebra of patients with Alzheimer’s disease. Neurobiol. Aging 18, 469–474 (1997).

    Article  CAS  PubMed  Google Scholar 

  110. Kalaria, R. N. & Harik, S. I. Reduced glucose transporter at the blood-brain barrier and in cerebral cortex in Alzheimer disease. J. Neurochem. 53, 1083–1088 (1989).

    Article  CAS  PubMed  Google Scholar 

  111. Simpson, I. A., Chundu, K. R., Davies-Hill, T., Honer, W. G. & Davies, P. Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer’s disease. Ann. Neurol. 35, 546–551 (1994).

    Article  CAS  PubMed  Google Scholar 

  112. Horwood, N. & Davies, D. C. Immunolabelling of hippocampal microvessel glucose transporter protein is reduced in Alzheimer’s disease. Virchows Arch. 425, 69–72 (1994).

    Article  CAS  PubMed  Google Scholar 

  113. Kilbourn, M. R. Small molecule PET tracers for transporter imaging. Semin. Nucl. Med. 47, 536–552 (2017).

    Article  PubMed  Google Scholar 

  114. Cirrito, J. R. et al. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J. Clin. Invest. 115, 3285–3290 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Deo, A. K. et al. Activity of P-glycoprotein, a β-amyloid transporter at the blood-brain barrier, is compromised in patients with mild Alzheimer disease. J. Nucl. Med. 55, 1106–1111 (2014).

    Article  CAS  PubMed  Google Scholar 

  116. van Assema, D. M. E. et al. Blood-brain barrier P-glycoprotein function in Alzheimer’s disease. Brain 135, 181–189 (2012).

    Article  PubMed  Google Scholar 

  117. Sagare, A. P. et al. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat. Commun. 4, 2932 (2013).

    Article  PubMed  CAS  Google Scholar 

  118. Paul, J., Strickland, S. & Melchor, J. P. Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer’s disease. J. Exp. Med. 204, 1999–2008 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Deane, R. et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat. Med. 9, 907–913 (2003).

    Article  CAS  PubMed  Google Scholar 

  120. Deane, R. et al. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron 43, 333–344 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Gama Sosa, M. A. et al. Age-related vascular pathology in transgenic mice expressing presenilin 1-associated familial Alzheimer’s disease mutations. Am. J. Pathol. 176, 353–368 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Wen, P. H. et al. Selective expression of presenilin 1 in neural progenitor cells rescues the cerebral hemorrhages and cortical lamination defects in presenilin 1-null mutant mice. Development 132, 3873–3883 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Blair, L. J. et al. Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy. Acta Neuropathol. Commun. 3, 8 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Cacciottolo, M. et al. The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer’s disease of humans and mice. Neurobiol. Aging 37, 47–57 (2016).

    Article  CAS  PubMed  Google Scholar 

  126. Melzer, T. R. et al. Arterial spin labelling reveals an abnormal cerebral perfusion pattern in Parkinson’s disease. Brain 134, 845–855 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Syrimi, Z. J. et al. Arterial spin labelling detects posterior cortical hypoperfusion in non-demented patients with Parkinson’s disease. J. Neural Transm. (Vienna) 124, 551–557 (2017).

    Article  CAS  Google Scholar 

  128. Chen, J. J., Salat, D. H. & Rosas, H. D. Complex relationships between cerebral blood flow and brain atrophy in early Huntington’s disease. Neuroimage 59, 1043–1051 (2012).

    Article  PubMed  Google Scholar 

  129. Ingrisch, M. et al. Quantification of perfusion and permeability in multiple sclerosis: dynamic contrast-enhanced MRI in 3D at 3T. Invest. Radiol. 47, 252–258 (2012).

    Article  PubMed  Google Scholar 

  130. Hojjat, S.-P. et al. Cortical perfusion alteration in normal-appearing gray matter is most sensitive to disease progression in relapsing-remitting multiple sclerosis. AJNR Am. J. Neuroradiol. 37, 1454–1461 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Murphy, M. J. et al. Widespread cerebral haemodynamics disturbances occur early in amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 13, 202–209 (2012).

    Article  PubMed  Google Scholar 

  132. Rule, R. R., Schuff, N., Miller, R. G. & Weiner, M. W. Gray matter perfusion correlates with disease severity in ALS. Neurology 74, 821–827 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Camargo, C. H. F. et al. Abnormal cerebrovascular reactivity in patients with Parkinson’s disease. Parkinsons Dis. 2015, 523041 (2015).

    PubMed  PubMed Central  Google Scholar 

  134. Al-Bachari, S., Vidyasagar, R., Emsley, H. C. & Parkes, L. M. Structural and physiological neurovascular changes in idiopathic Parkinson’s disease and its clinical phenotypes. J. Cereb. Blood Flow Metab. 37, 3409–3421 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Marshall, O., Chawla, S., Lu, H., Pape, L. & Ge, Y. Cerebral blood flow modulation insufficiency in brain networks in multiple sclerosis: A hypercapnia MRI study. J. Cereb. Blood Flow Metab. 36, 2087–2095 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Al-Bachari, S. MRI assessment of neurovascular changes in idiopathic Parkinson’s disease. Doctoral thesis, University of Manchester (2016).

  137. Drouin-Ouellet, J. et al. Cerebrovascular and blood-brain barrier impairments in Huntington’s disease: Potential implications for its pathophysiology. Ann. Neurol. 78, 160–177 (2015). Blood–brain barrier leakage and cerebrovascular dysfunction in Huntington’s disease investigated by neuroimaging and postmortem tissue analysis in human subjects and further corroborated in a mouse model of Huntington’s disease.

    Article  PubMed  Google Scholar 

  138. Taheri, S., Gasparovic, C., Shah, N. J. & Rosenberg, G. A. Quantitative measurement of blood-brain barrier permeability in human using dynamic contrast-enhanced MRI with fast T1 mapping. Magn. Reson. Med. 65, 1036–1042 (2011).

    Article  PubMed  Google Scholar 

  139. Cramer, S. P., Simonsen, H., Frederiksen, J. L., Rostrup, E. & Larsson, H. B. W. Abnormal blood-brain barrier permeability in normal appearing white matter in multiple sclerosis investigated by MRI. Neuroimage Clin. 4, 182–189 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Gaitán, M. I. et al. Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions. Ann. Neurol. 70, 22–29 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Ham, J. H. et al. Cerebral microbleeds in patients with Parkinson’s disease. J. Neurol. 261, 1628–1635 (2014).

    Article  PubMed  Google Scholar 

  142. Kim, J.-H., Park, J., Kim, Y.-H., Ma, H.-I. & Kim, Y. J. Characterization of cerebral microbleeds in idiopathic Parkinson’s disease. Eur. J. Neurol. 22, 377–383 (2015).

    Article  PubMed  Google Scholar 

  143. Yamashiro, K. et al. The prevalence and risk factors of cerebral microbleeds in patients with Parkinson’s disease. Parkinsonism Relat. Disord. 21, 1076–1081 (2015).

    Article  PubMed  Google Scholar 

  144. Kwan, J. Y. et al. Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: correlating 7 tesla MRI and pathology. PLoS One 7, e35241 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kortekaas, R. et al. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann. Neurol. 57, 176–179 (2005).

    Article  CAS  PubMed  Google Scholar 

  146. Gerwien, H. et al. Imaging matrix metalloproteinase activity in multiple sclerosis as a specific marker of leukocyte penetration of the blood-brain barrier. Sci. Transl. Med. 8, 364ra152 (2016). The authors developed an important, novel approach to image initial leukocyte penetration of the blood–brain barrier in multiple sclerosis patients and animal models.

    Article  PubMed  CAS  Google Scholar 

  147. Zlokovic, B. V. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat. Rev. Neurosci. 12, 723–738 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. 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).

    Article  CAS  PubMed  Google Scholar 

  149. Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat. Rev. Neurosci. 5, 347–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  150. Montagne, A. et al. Ultra-sensitive molecular MRI of cerebrovascular cell activation enables early detection of chronic central nervous system disorders. Neuroimage 63, 760–770 (2012).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The work of B.V.Z. is supported by the National Institutes of Health grants R01AG023084, R01NS090904, R01NS034467, R01AG039452, 1R01NS100459, 5P01AG052350, and 5P50AG005142, in addition to the Alzheimer’s Association, Cure Alzheimer’s Fund, and the Foundation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease reference no. 16 CVD 05. We apologize to those authors whose excellent original papers we were not able to cite due to space limitations; instead, we sometimes cited recent reviews by leading authorities so that the reader can access all key primary papers in the field of our review.

Author information

Author notes

  1. These authors contributed equally: Melanie D. Sweeney, Kassandra Kisler, Axel Montagne.

Authors and Affiliations

  1. Department of Physiology and Neuroscience and the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Melanie D. Sweeney, Kassandra Kisler, Axel Montagne & Berislav V. Zlokovic

  2. Laboratory of Neuro Imaging, Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Arthur W. Toga

Authors
  1. Melanie D. Sweeney
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kassandra Kisler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Axel Montagne
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arthur W. Toga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Berislav V. Zlokovic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Berislav V. Zlokovic.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sweeney, M.D., Kisler, K., Montagne, A. et al. The role of brain vasculature in neurodegenerative disorders. Nat Neurosci 21, 1318–1331 (2018). https://doi.org/10.1038/s41593-018-0234-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41593-018-0234-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing