Skip to main content

Vascular Dysfunction and Neurodegenerative Disease

  • Chapter
  • First Online:
Vessel Based Imaging Techniques

Abstract

The brain is the most metabolically active and complex organ in the human body, consisting of nearly 100 billion neurons and with over 100 trillion intricate connections. In order to maintain its intensive metabolic demands, the brain is highly vascularized, with nearly every neuron possessing its own capillary and total capillary length of nearly 400 miles. The integrity of the cerebral vascular system is accomplished through a vast vascular network of arteries, arterioles, capillaries, and veins which assure the continuous supply of oxygen and nutrients as well as provide a pathway for washing out metabolic waste products. Structural and functional integrity of blood vessels for adequate blood supply delivery is essential to maintain normal neurological function. A healthy neuronal-vascular relationship is critical for proper neurological processing, and vascular insults can consequentially initiate a cascade of molecular events which ultimately may result in neurodegeneration. Deterioration of brain functionality occurs progressively with advancing age, and an aged brain is consequently highly prone to neurodegenerative disorders. With increasing awareness of the importance of the neurovascular contribution to neurodegenerative disease, a better understanding of the contributory pathophysiological mechanisms is necessary. This chapter will cover the link between neurovascular dysfunction and neurodegeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Snyder HM, Corriveau RA, Craft S, et al. Vascular contributions to cognitive impairment and dementia including Alzheimer's disease. Alzheimers Dement. 2015;11(6):710–7.

    Article  PubMed  Google Scholar 

  3. Korczyn AD. Vascular parkinsonism--characteristics, pathogenesis and treatment. Nat Rev Neurol. 2015;11(6):319–26.

    Article  PubMed  Google Scholar 

  4. Winkler EA, Sengillo JD, Sullivan JS, Henkel JS, Appel SH, Zlokovic BV. Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol. 2013;125(1):111–20.

    Article  CAS  PubMed  Google Scholar 

  5. Kalaria RN, Maestre GE, Arizaga R, et al. Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol. 2008;7(9):812–26.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet. 2001;357(9251):169–75.

    Google Scholar 

  7. Bailey TL, Rivara CB, Rocher AB, Hof PR. The nature and effects of cortical microvascular pathology in aging and Alzheimer's disease. Neurol Res. 2004;26(5):573–8.

    Article  PubMed  Google Scholar 

  8. Begley DJ, Brightman MW. Structural and functional aspects of the blood-brain barrier. Prog Drug Res Fortschritte der Arzneimittelforschung Progres des recherches pharmaceutiques. 2003;61:39–78.

    CAS  PubMed  Google Scholar 

  9. Zlokovic BV. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 2005;28(4):202–8.

    Article  CAS  PubMed  Google Scholar 

  10. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010;37(1):13–25.

    Article  CAS  PubMed  Google Scholar 

  11. Daneman R, Engelhardt B. Brain barriers in health and disease. Neurobiol Dis. 2017;107:1–3.

    Article  PubMed  Google Scholar 

  12. Golding EM, Marrelli SP, You J, Bryan RM Jr. Endothelium-derived hyperpolarizing factor in the brain: a new regulator of cerebral blood flow? Stroke. 2002;33(3):661–3.

    Article  PubMed  Google Scholar 

  13. Wolburg H, Noell S, Mack A, Wolburg-Buchholz K, Fallier-Becker P. Brain endothelial cells and the glio-vascular complex. Cell Tissue Res. 2009;335(1):75–96.

    Article  PubMed  Google Scholar 

  14. Oberheim NA, Takano T, Han X, et al. Uniquely hominid features of adult human astrocytes. J Neurosci. 2009;29(10):3276–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7(1):41–53.

    Article  CAS  PubMed  Google Scholar 

  16. Iadecola C, Nedergaard M. Glial regulation of the cerebral microvasculature. Nat Neurosci. 2007;10(11):1369–76.

    Article  CAS  PubMed  Google Scholar 

  17. Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science. 2009;323(5918):1211–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bonkowski D, Katyshev V, Balabanov RD, Borisov A, Dore-Duffy P. The CNS microvascular pericyte: pericyte-astrocyte crosstalk in the regulation of tissue survival. Fluids Barriers CNS. 2011;8(1):8.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Winkler EA, Bell RD, Zlokovic BV. Central nervous system pericytes in health and disease. Nat Neurosci. 2011;14(11):1398–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cheslow L, Alvarez JI. Glial-endothelial crosstalk regulates blood-brain barrier function. Curr Opin Pharmacol. 2016;26:39–46.

    Article  CAS  PubMed  Google Scholar 

  21. Yousif LF, Di Russo J, Sorokin L. Laminin isoforms in endothelial and perivascular basement membranes. Cell Adhes Migr. 2013;7(1):101–10.

    Article  Google Scholar 

  22. Morris AW, Carare RO, Schreiber S, Hawkes CA. The cerebrovascular basement membrane: role in the clearance of beta-amyloid and cerebral amyloid angiopathy. Front Aging Neurosci. 2014;6:251.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Owens T, Bechmann I, Engelhardt B. Perivascular spaces and the two steps to neuroinflammation. J Neuropathol Exp Neurol. 2008;67(12):1113–21.

    Article  PubMed  Google Scholar 

  24. Baeten KM, Akassoglou K. Extracellular matrix and matrix receptors in blood-brain barrier formation and stroke. Dev Neurobiol. 2011;71(11):1018–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Daneman R, Prat A. The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015;7(1):a020412.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Erickson MA, Banks WA. Blood-brain barrier dysfunction as a cause and consequence of Alzheimer's disease. J Cereb Blood Flow Metab. 2013;33(10):1500–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zenaro E, Piacentino G, Constantin G. The blood-brain barrier in Alzheimer's disease. Neurobiol Dis. 2017;107:41–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67(2):181–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Enager P, Piilgaard H, Offenhauser N, et al. Pathway-specific variations in neurovascular and neurometabolic coupling in rat primary somatosensory cortex. J Cereb Blood Flow Metab. 2009;29(5):976–86.

    Article  CAS  PubMed  Google Scholar 

  30. Wells JA, Christie IN, Hosford PS, et al. A critical role for purinergic signalling in the mechanisms underlying generation of BOLD fMRI responses. J Neurosci. 2015;35(13):5284–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zacchigna S, Lambrechts D, Carmeliet P. Neurovascular signalling defects in neurodegeneration. Nat Rev Neurosci. 2008;9(3):169–81.

    Article  CAS  PubMed  Google Scholar 

  32. Sorond FA, Hurwitz S, Salat DH, Greve DN, Fisher ND. Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people. Neurology. 2013;81(10):904–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sorond FA, Kiely DK, Galica A, et al. Neurovascular coupling is impaired in slow walkers: the MOBILIZE Boston study. Ann Neurol. 2011;70(2):213–20.

    Article  PubMed  PubMed Central  Google Scholar 

  34. van Beek AH, Claassen JA, Rikkert MG, Jansen RW. Cerebral autoregulation: an overview of current concepts and methodology with special focus on the elderly. J Cereb Blood Flow Metab. 2008;28(6):1071–85.

    Article  PubMed  Google Scholar 

  35. Jessen SB, Mathiesen C, Lind BL, Lauritzen M. Interneuron deficit associates attenuated network synchronization to mismatch of energy supply and demand in aging mouse brains. Cereb Cortex. 2017;27(1):646–59.

    Article  PubMed  Google Scholar 

  36. Wei YH, Lu CY, Wei CY, Ma YS, Lee HC. Oxidative stress in human aging and mitochondrial disease-consequences of defective mitochondrial respiration and impaired antioxidant enzyme system. Chin J Physiol. 2001;44(1):1–11.

    CAS  PubMed  Google Scholar 

  37. Sheng ZH. Mitochondrial trafficking and anchoring in neurons: new insight and implications. J Cell Biol. 2014;204(7):1087–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Toth P, Tarantini S, Tucsek Z, et al. Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and downregulation of NADPH oxidase. Am J Physiol Heart Circ Physiol. 2014;306(3):H299–308.

    Article  CAS  PubMed  Google Scholar 

  39. Deane R, Du Yan S, Submamaryan RK, et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003;9(7):907–13.

    Article  CAS  PubMed  Google Scholar 

  40. Kalaria RN, Akinyemi R, Ihara M. Does vascular pathology contribute to Alzheimer changes? J Neurol Sci. 2012;322(1–2):141–7.

    Article  CAS  PubMed  Google Scholar 

  41. Bell RD, Deane R, Chow N, et al. SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. Nat Cell Biol. 2009;11(2):143–53.

    Article  CAS  PubMed  Google Scholar 

  42. Cirrito JR, Deane R, Fagan AM, et al. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest. 2005;115(11):3285–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Toledo JB, Arnold SE, Raible K, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's coordinating Centre. Brain. 2013;136(Pt 9):2697–706.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Weller RO, Boche D, Nicoll JA. Microvasculature changes and cerebral amyloid angiopathy in Alzheimer's disease and their potential impact on therapy. Acta Neuropathol. 2009;118(1):87–102.

    Article  CAS  PubMed  Google Scholar 

  45. Montagne A, Zhao Z, Zlokovic BV. Alzheimer's disease: a matter of blood-brain barrier dysfunction? J Exp Med. 2017;214(11):3151–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hirao K, Ohnishi T, Hirata Y, et al. The prediction of rapid conversion to Alzheimer’s disease in mild cognitive impairment using regional cerebral blood flow SPECT. NeuroImage. 2005;28(4):1014–21.

    Article  PubMed  Google Scholar 

  47. Johnson NA, Jahng GH, Weiner MW, et al. Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology. 2005;234(3):851–9.

    Article  PubMed  Google Scholar 

  48. Ledo A, Lourenco CF, Laranjinha J, Brett CM, Gerhardt GA, Barbosa RM. Ceramic-based multisite platinum microelectrode arrays: morphological characteristics and electrochemical performance for extracellular oxygen measurements in brain tissue. Anal Chem. 2017;89(3):1674–83.

    Article  CAS  PubMed  Google Scholar 

  49. Lourenco CF, Ledo A, Barbosa RM, Laranjinha J. Neurovascular uncoupling in the triple transgenic model of Alzheimer's disease: impaired cerebral blood flow response to neuronal-derived nitric oxide signaling. Exp Neurol. 2017;291:36–43.

    Article  CAS  PubMed  Google Scholar 

  50. Li L, Zhang X, Yang D, Luo G, Chen S, Le W. Hypoxia increases Abeta generation by altering beta- and gamma-cleavage of APP. Neurobiol Aging. 2009;30(7):1091–8.

    Article  CAS  PubMed  Google Scholar 

  51. Thomas T, Thomas G, McLendon C, Sutton T, Mullan M. beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature. 1996;380(6570):168–71.

    Article  CAS  PubMed  Google Scholar 

  52. Sutton ET, Hellermann GR, Thomas T. beta-amyloid-induced endothelial necrosis and inhibition of nitric oxide production. Exp Cell Res. 1997;230(2):368–76.

    Article  CAS  PubMed  Google Scholar 

  53. Launer LJ, Andersen K, Dewey ME, et al. Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups. European Studies of Dementia. Neurology. 1999;52(1):78–84.

    Article  CAS  PubMed  Google Scholar 

  54. Petrovitch H, White LR, Izmirilian G, et al. Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia aging Study. Neurobiol Aging. 2000;21(1):57–62.

    Article  CAS  PubMed  Google Scholar 

  55. Becker C, Jick SS, Meier CR. Risk of stroke in patients with idiopathic Parkinson disease. Parkinsonism Relat Disord. 2010;16(1):31–5.

    Article  PubMed  Google Scholar 

  56. Huang TL, Zandi PP, Tucker KL, et al. Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4. Neurology. 2005;65(9):1409–14.

    Article  CAS  PubMed  Google Scholar 

  57. de Laat KF, van Norden AG, Gons RA, et al. Cerebral white matter lesions and lacunar infarcts contribute to the presence of mild parkinsonian signs. Stroke. 2012;43(10):2574–9.

    Article  PubMed  Google Scholar 

  58. Hatate J, Miwa K, Matsumoto M, et al. Association between cerebral small vessel diseases and mild parkinsonian signs in the elderly with vascular risk factors. Parkinsonism Relat Disord. 2016;26:29–34.

    Article  PubMed  Google Scholar 

  59. Schwartz RS, Halliday GM, Cordato DJ, Kril JJ. Small-vessel disease in patients with Parkinson's disease: a clinicopathological study. Mov Disord. 2012;27(12):1506–12.

    Article  PubMed  Google Scholar 

  60. Jellinger KA. Prevalence of cerebrovascular lesions in Parkinson's disease. A postmortem study. Acta Neuropathol. 2003;105(5):415–9.

    PubMed  Google Scholar 

  61. Hong CT, Hu HH, Chan L, Bai CH. Prevalent cerebrovascular and cardiovascular disease in people with Parkinson's disease: a meta-analysis. Clin Epidemiol. 2018;10:1147–54.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Liang CL, Wang TT, Luby-Phelps K, German DC. Mitochondria mass is low in mouse substantia nigra dopamine neurons: implications for Parkinson's disease. Exp Neurol. 2007;203(2):370–80.

    Article  CAS  PubMed  Google Scholar 

  63. Palikaras K, Tavernarakis N. Mitophagy in neurodegeneration and aging. Front Genet. 2012;3:297.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Gredilla R, Bohr VA, Stevnsner T. Mitochondrial DNA repair and association with aging--an update. Exp Gerontol. 2010;45(7–8):478–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Takahashi M, Ko LW, Kulathingal J, Jiang P, Sevlever D, Yen SH. Oxidative stress-induced phosphorylation, degradation and aggregation of alpha-synuclein are linked to upregulated CK2 and cathepsin D. Eur J Neurosci. 2007;26(4):863–74.

    Article  PubMed  Google Scholar 

  66. Wei X, Yan R, Chen Z, et al. Combined diffusion tensor imaging and arterial spin labeling as markers of early Parkinson's disease. Sci Rep. 2016;6:33762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Al-Bachari S, Parkes LM, Vidyasagar R, et al. Arterial spin labelling reveals prolonged arterial arrival time in idiopathic Parkinson's disease. Neuroimage Clin. 2014;6:1–8.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Vokatch N, Grotzsch H, Mermillod B, Burkhard PR, Sztajzel R. Is cerebral autoregulation impaired in Parkinson's disease? A transcranial Doppler study. J Neurol Sci. 2007;254(1–2):49–53.

    Article  CAS  PubMed  Google Scholar 

  69. Rodriguez M, Morales I, Rodriguez-Sabate C, et al. The degeneration and replacement of dopamine cells in Parkinson's disease: the role of aging. Front Neuroanat. 2014;8:80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Rappold PM, Tieu K. Astrocytes and therapeutics for Parkinson's disease. Neurotherapeutics. 2010;7(4):413–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Drinkut A, Tereshchenko Y, Schulz JB, Bahr M, Kugler S. Efficient gene therapy for Parkinson's disease using astrocytes as hosts for localized neurotrophic factor delivery. Mol Ther. 2012;20(3):534–43.

    Article  CAS  PubMed  Google Scholar 

  72. Baltazar MT, Dinis-Oliveira RJ, de Lourdes BM, Tsatsakis AM, Duarte JA, Carvalho F. Pesticides exposure as etiological factors of Parkinson's disease and other neurodegenerative diseases--a mechanistic approach. Toxicol Lett. 2014;230(2):85–103.

    Article  CAS  PubMed  Google Scholar 

  73. Leonardi A, Abbruzzese G, Arata L, Cocito L, Vische M. Cerebrospinal fluid (CSF) findings in amyotrophic lateral sclerosis. J Neurol. 1984;231(2):75–8.

    Article  CAS  PubMed  Google Scholar 

  74. Annunziata P, Volpi N. High levels of C3c in the cerebrospinal fluid from amyotrophic lateral sclerosis patients. Acta Neurol Scand. 1985;72(1):61–4.

    Article  CAS  PubMed  Google Scholar 

  75. Donnenfeld H, Kascsak RJ, Bartfeld H. Deposits of IgG and C3 in the spinal cord and motor cortex of ALS patients. J Neuroimmunol. 1984;6(1):51–7.

    Article  CAS  PubMed  Google Scholar 

  76. Miyazaki K, Ohta Y, Nagai M, et al. Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis. J Neurosci Res. 2011;89(5):718–28.

    Article  CAS  PubMed  Google Scholar 

  77. Garbuzova-Davis S, Saporta S, Sanberg PR. Implications of blood-brain barrier disruption in ALS. Amyotroph Lateral Scler. 2008;9(6):375–6.

    Article  PubMed  Google Scholar 

  78. Blann AD, Woywodt A, Bertolini F, et al. Circulating endothelial cells. Biomarker of vascular disease. Thromb Haemost. 2005;93(2):228–35.

    Article  CAS  PubMed  Google Scholar 

  79. Garbuzova-Davis S, Woods RL 3rd, Louis MK, et al. Reduction of circulating endothelial cells in peripheral blood of ALS patients. PLoS One. 2010;5(5):e10614.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Robberecht W. Oxidative stress in amyotrophic lateral sclerosis. J Neurol. 2000;247(Suppl 1):I1–6.

    Article  PubMed  Google Scholar 

  81. Pun PB, Lu J, Moochhala S. Involvement of ROS in BBB dysfunction. Free Radic Res. 2009;43(4):348–64.

    Article  CAS  PubMed  Google Scholar 

  82. Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS. Vitamin E and cognitive decline in older persons. Arch Neurol. 2002;59(7):1125–32.

    Article  PubMed  Google Scholar 

  83. Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS. Fish consumption and cognitive decline with age in a large community study. Arch Neurol. 2005;62(12):1849–53.

    Article  PubMed  Google Scholar 

  84. Kidd PM. Alzheimer's disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention. Altern Med Rev. 2008;13(2):85–115.

    PubMed  Google Scholar 

  85. Joseph JA, Shukitt-Hale B, Willis LM. Grape juice, berries, and walnuts affect brain aging and behavior. J Nutr. 2009;139(9):1813S–7S.

    Article  CAS  PubMed  Google Scholar 

  86. Rovio S, Spulber G, Nieminen LJ, et al. The effect of midlife physical activity on structural brain changes in the elderly. Neurobiol Aging. 2010;31(11):1927–36.

    Article  PubMed  Google Scholar 

  87. Podewils LJ, Guallar E, Kuller LH, et al. Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. Am J Epidemiol. 2005;161(7):639–51.

    Article  PubMed  Google Scholar 

  88. Scarmeas N, Luchsinger JA, Schupf N, et al. Physical activity, diet, and risk of Alzheimer disease. JAMA. 2009;302(6):627–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jing Zhang .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gao, Z., Cilento, E.M., Stewart, T., Zhang, J. (2020). Vascular Dysfunction and Neurodegenerative Disease. In: Yuan, C., Hatsukami, T., Mossa-Basha, M. (eds) Vessel Based Imaging Techniques . Springer, Cham. https://doi.org/10.1007/978-3-030-25249-6_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-25249-6_1

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-25248-9

  • Online ISBN: 978-3-030-25249-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics