Home > News > Advances in our Understanding of the Pathophysiology, Detection and Management of Cerebral Amyloid Angiopathy
Stroke
Read Time: 2 mins

Advances in our Understanding of the Pathophysiology, Detection and Management of Cerebral Amyloid Angiopathy

Published Online: May 15th 2012 European Neurological Review, 2012;7(2):134-9 DOI: http://doi.org/10.17925/ENR.2012.07.02.134
Authors: Octavio M Pontes-Neto, Eitan Auriel, Steven M Greenberg
Quick Links:
Abstract
Article
Article Information
Abstract:
Overview

Cerebral amyloid angiopathy (CAA) is pathologically defined as the deposition of amyloid protein, most commonly the amyloid β peptide (Aβ), primarily within the media and adventitia of small and medium-sized arteries of the leptomeninges, cerebral and cerebellar cortex. This deposition likely reflects an imbalance between Aβ production and clearance within the brain and leads to weakening of the overall structure of brain small vessels, predisposing patients tolobar intracerebral haemorrhage (ICH), brain ischaemia and cognitive decline. CAA is associated with markers of small vessel disease, like lobar microbleeds and white matter hyperintensities on magnetic resonance imaging. Therefore, it can be now be diagnosed during life with reasonable accuracy by clinical and neuroimaging criteria. Despite the lack of a specific treatment for this condition, the detection of CAA may help in the management of patients, regarding the prevention of major haemorrhagic complications and genetic counselling. This review discusses recent advances in our understanding of the pathophysiology, detection and management of CAA.

Keywords

Amyloid angiopathy, intracerebral haemorrhage, cognitive decline, stroke, amyloid

Article:

Cerebral amyloid angiopathy (CAA) is a disorder of the central nervous system characterised by the deposition of amyloid proteins in the wall of small- to medium-sized vessels, most frequently arteries, within the leptomeninges and cortex of the brain.1 In vessels affected by CAA, local muscle and elastic elements of the arterial wall are lost and replaced by amyloid fibrils, primarily the amyloid-β (Aβ) peptide. Since the first description of neurovascular amyloid deposition in 1909 by Gustav Oppenheim, sound scientific evidence has supported the concept that the associated disruption of the overall structure of those small vessels predisposes to both ischaemic small vesseldisease and cerebral haemorrhage.2–4

Sporadic CAA is a major cause of lobar intracerebral haemorrhage (ICH) and cognitive decline in the elderly, including the normotensive population.5,6 Hereditary forms of CAA are generally rare, usually more severe and earlier in onset. Rare non-Aβ familial CAAs can also present clinically with lobar ICH.7 Regarding sporadic CAA, two major challenges persist:

  • a definitive diagnosis requires a neuropathological exam; and8
  • no treatment or preventive strategy for CAA or CAA-ICH has been firmly established.

Nevertheless, in the last decades of research, there has been remarkable progress in our understanding of this condition. CAA pathology has been associated with markers of small vessel disease, including lobar cerebral microbleeds (CMB) and white matter hyperintensities on magnetic resonance imaging (MRI).9–11 The availability of MRI sequences that are particularly sensitive to susceptibility effects like the T2* gradient-recalled echo (GRE) and susceptibility weighted imaging (SWI) now allow reliable assessment of an individual’s haemorrhagic burden over time and reasonable accuracy by clinical and neuroimaging diagnostic criteria.10–13 As our understanding of CAA pathophysiology evolves, specific targets have been identified as candidates for the prevention and treatment of this condition.14 As newresearch tools such as the Pittsburgh Compound B (PiB) or other amyloid-imaging agents for positron emission tomography (PET) scan become incorporated into clinical practice, it may also be possible to detect vascular amyloid deposition in the brain noninvasively in living patients, perhaps before an ICH or significant cognitive decline.15

To view the full article in PDF or eBook formats, please click on the icons above.

Article Information:
Disclosure

The authors have no conflicts of interest to declare.

Correspondence

Steven M Greenberg, J Philip Kistler Stroke Research Center, Massachusetts General Hospital, 175 Cambridge Street, Suite 300, Boston, MA 02114, US. E: sgreenberg@partners.org

Support

The authors would like to thank Matthew P Frosch, Andrew Dumas, Edip Gurol and Alison Ayres for their help with the pictures of this manuscript. Octavio M Pontes-Neto receives research support from the Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP).

Received

2012-06-16T00:00:00

References

  1. Okazaki H, Reagan TJ, Campbell RJ, Clinicopathologic studies of primary cerebral amyloid angiopathy, Mayo Clin Proc, 1979;54:22–31.
  2. Oppenheim G, Über “drusige Nekrosen” in der Grosshirnrinde, Neurol Centralbl, 1909;28:410–3.
  3. Vinters HV, Cerebral amyloid angiopathy, A critical review, Stroke, 1987;18:311–24.
  4. Greenberg SM, Vonsattel JP, Stakes JW, et al., The clinical spectrum of cerebral amyloid angiopathy: presentations without lobar hemorrhage, Neurology, 1993;43(10):2073–9.
  5. Neuropathology Group, Medical Research Council Cognitive Function and Aging Study. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS), Lancet, 2001;357(9251):169–75.
  6. Pfeifer LA, White LR, Ross GW, et al., Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study, Neurology, 2002;58(11):1629–34.
  7. Palsdottir A, Snorradottir AO, Thorsteinsson L, Hereditary cystatin C amyloid angiopathy: genetic, clinical, and pathological aspects, Brain Pathol, 2006;16(1):55–9.
  8. Greenberg SM, Vonsattel JP, Diagnosis of cerebral amyloid angiopathy, sensitivity and specificity of cortical biopsy, Stroke, 1997;28:1418–22.
  9. Scharf J, Brauherr E, Forsting M, Sartor K, Significance of haemorrhagic lacunes on MRI in patients with hypertensive cerebrovascular disease and intracerebral haemorrhage, Neuroradiology, 1994;36:504–8.
  10. Offenbacher H, Fazekas F, Schmidt R, et al., MR of cerebral abnormalities concomitant with primary intracerebral hematomas, Am J Neuroradiol, 1996;17:573–8.
  11. Fazekas F, Kleinert R, Roob G, et al., Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds, Am J Neuroradiol, 1999;20:637–42.
  12. Greenberg SM, Vernooij MW, Cordonnier C, et al., Cerebral microbleeds: a guide to detection and interpretation, Lancet Neurol, 2009;8(2):165–74.
  13. Knudsen KA, Rosand J, Karluk D, Greenberg SM, Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria, Neurology, 2001;56:537–9.
  14. Auriel E, Greenberg SM, The pathophysiology and clinical presentation of cerebral amyloid angiopathy, Curr Atheroscler Rep, 2012;14(4):343–50.
  15. Johnson KA, Gregas M, Becker JA, et al., Imaging of amyloid burden and distribution in cerebral amyloid angiopathy, Ann Neurol, 2007;62(3):229–34.
  16. Goldgaber D, Lerman MI, McBride OW, et al., Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease, Science, 1987;235:877–80.
  17. Haass C, Schlossmacher MG, Hung AY, et al., Amyloid beta-peptide is produced by cultured cells during normal metabolism, Nature, 1992;359:322–5.
  18. Robakis NK, Ramakrishna N, Wolfe G, Wisniewski HM, Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides, Proc Natl Acad Sci U S A, 1987;84:4190–4.
  19. Busciglio J, Gabuzda DH, Matsudaira P, Yankner BA, Generation of beta- amyloid in the secretory pathway in neuronal and nonneuronal cells, Proc Natl Acad Sci U S A, 1993;90:2092–6.
  20. Rostagno A, Lal R, Ghiso J, Protein misfolding, aggregation, and fibril formation: common features of cerebral and non-cerebral amyloid diseases. In: Dawbarn D, Allen S (eds), The Neurobiology of Alzheimer’s Disease, Oxford: Oxford University Press, 2007;133–60.
  21. Hartz AM, Bauer B, Soldner EL, et al., Amyloid-β contributes to blood–brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy, Stroke, 2012;43:514–23.
  22. Herzig MC, Van Nostrand WE, Jucker M, Mechanism of cerebral beta-amyloid angiopathy: murine and cellular models, Brain Pathol, 2006;16(1):40–54.
  23. Fukuchi K, Ho L, Younkin SG, et al., High levels of circulating beta-amyloid peptide do not cause cerebral beta-amyloidosis in transgenic mice, Am J Pathol, 1996;149(1):219–27.
  24. Burgermeister P, Calhoun ME, Winkler DT, Jucker M, Mechanisms of cerebrovascular amyloid deposition. Lessons from mouse models, Ann N Y Acad Sci, 2000;903:307–16.
  25. Eisele YS, Obermüller U, Heilbronner G, et al., Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis, Science, 2010;330:980–2.
  26. Garcia-Alloza M, Gregory J, Kuchibhotla KV, et al., Cerebrovascular lesions induce transient β-amyloid deposition, Brain, 2011;134:3697–707.
  27. Vinters HV, Wang ZZ, Secor DL, Brain parenchymal and microvascular amyloid in Alzheimer’s disease, Brain Pathol, 1996;6:179–95.
  28. Winkler DT, Bondolfi L, Herzig MC, et al., Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy, J Neurosci, 2001;21:1619–27.
  29. Greenberg SM, Nandigam RN, Delgado P, et al., Microbleeds versus macrobleeds: evidence for distinct entities, Stroke, 2009;40(7):2382–6.
  30. Mandybur TI, Cerebral amyloid angiopathy: the vascular pathology and complications, J Neuropathol Exp Neurol, 1986;45(1):79–90.
  31. Vonsattel JP, Myers RH, Hedley-Whyte ET, et al., Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study, Ann Neurol, 1991;30:637–49.
  32. Revesz T, Ghiso J, Lashley T, et al., Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view, J Neuropathol Exp Neurol, 2003;62:885–98.
  33. Fisher CM, Pathological observations in hypertensive cerebral hemorrhage, J Neuropathol Exp Neurol, 1971;30:536–50.
  34. Neuropathology Group. Medical Research Council Cognitive Function and Aging Study (MRC CFAS), Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales, Lancet, 2001;357:169–75.
  35. Jellinger KA, Alzheimer disease and cerebrovascular pathology: an update, J Neural Transm, 2002;109:813–36.
  36. Ellis RJ, Olichney JM, Thal LJ, et al., Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience, Part XV, Neurology, 1996;46:1592–6.
  37. Sudlow C, Martínez González NA, Kim J, Clark C, Does apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage? Systematic review and metaanalyses of 31 studies among 5961 cases and 17,965 controls, Stroke, 2006;37:364–70.
  38. Nicoll JA, Burnett C, Love S, et al., High frequency of apolipoprotein E epsilon 2 allele in hemorrhage due to cerebral amyloid angiopathy, Ann Neurol, 1997;41:716–21.
  39. Farrer LA, Cupples LA, Haines JL, et al., Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis, APOE and Alzheimer Disease Meta Analysis Consortium, JAMA, 1997;278:1349–56.
  40. Holtzman DM, Role of apoe/Abeta interactions in the pathogenesis of Alzheimer’s disease and cerebral amyloid angiopathy, J Mol Neurosci, 2001;17:147–55.

Further Resources

Share this Article
Related Content In Stroke
  • Copied to clipboard!
    accredited arrow-down-editablearrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-red tick-whiteticktimetranscriptup-arrowwebinar Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72