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Correlation of hypointensities in susceptibility-weighted images to tissue histology in dementia patients with cerebral amyloid angiopathy: a postmortem MRI study

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Abstract

Neuroimaging with iron-sensitive MR sequences [gradient echo T2* and susceptibility-weighted imaging (SWI)] identifies small signal voids that are suspected brain microbleeds. Though the clinical significance of these lesions remains uncertain, their distribution and prevalence correlates with cerebral amyloid angiopathy (CAA), hypertension, smoking, and cognitive deficits. Investigation of the pathologies that produce signal voids is necessary to properly interpret these imaging findings. We conducted a systematic correlation of SWI-identified hypointensities to tissue pathology in postmortem brains with Alzheimer’s disease (AD) and varying degrees of CAA. Autopsied brains from eight AD patients, six of which showed advanced CAA, were imaged at 3T; foci corresponding to hypointensities were identified and studied histologically. A variety of lesions was detected; the most common lesions were acute microhemorrhage, hemosiderin residua of old hemorrhages, and small lacunes ringed by hemosiderin. In lesions where the bleeding vessel could be identified, β-amyloid immunohistochemistry confirmed the presence of β-amyloid in the vessel wall. Significant cellular apoptosis was noted in the perifocal region of recent bleeds along with heme oxygenase 1 activity and late complement activation. Acutely extravasated blood and hemosiderin were noted to migrate through enlarged Virchow–Robin spaces propagating an inflammatory reaction along the local microvasculature; a mechanism that may contribute to the formation of lacunar infarcts. Correlation of imaging findings to tissue pathology in our cases indicates that a variety of CAA-related pathologies produce MR-identified signal voids and further supports the use of SWI as a biomarker for this disease.

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Abbreviations

GRE-T2*:

Gradient echo T2*

SWI:

Susceptibility-weighted imaging

MR:

Magnetic resonance

BMB:

Brain microbleed

CAA:

Cerebral amyloid angiopathy

AD:

Alzheimer’s disease

HO-1:

Heme oxygenase 1

References

  1. Aliev G, Smith MA, Seyidov D et al (2002) The role of oxidative stress in the pathophysiology of cerebrovascular lesions in Alzheimer’s disease. Brain Pathol 12:21–35

    Article  PubMed  CAS  Google Scholar 

  2. Anders K, Wang Z, Kornfeld M et al (1997) Giant cell arteritis in association with cerebral amyloid angiopathy: immunohistochemical and molecular studies. Hum Pathol 89:1237–1246

    Article  Google Scholar 

  3. Atlas SW, Mark AS, Grossman RI, Gomori JM (1988) Intracranial hemorrhage: gradient-echo MR imaging at 1.5 T. Comparison with spin-echo imaging and clinical applications. Radiology 168:803–807

    PubMed  CAS  Google Scholar 

  4. Blamire A, Rowe J, Styles P, McDonald B (1999) Optimising imaging parameters for post mortem MR imaging of the human brain. Acta Radiol 40:593–597

    Article  PubMed  CAS  Google Scholar 

  5. Bush V, Moyer T, Batts K, Parisi J (1995) Essential and toxic element concentrations in fresh and formalin-fixed human autopsy tissues. Clin Chem 41(2):284–294

    PubMed  CAS  Google Scholar 

  6. Cadmen E, Puttfarcken P (1997) Beta-amyloid peptides initiate the complement cascade without producing a comparable effect on the terminal pathway in vitro. Exp Neurol 146:388–394

    Article  Google Scholar 

  7. Carvlin M, Asato R, Hackney D, Kassab E, Joseph P (1989) High-resolution MR of the spinal cord in humans and rats. Am J Neuroradiol 10:13–17

    PubMed  CAS  Google Scholar 

  8. Cordonnier C, Al-Shahi Salman R, Wardlaw J (2007) Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 130:1988–2003

    Article  PubMed  Google Scholar 

  9. Cordonnier C, Potter G, Jackson C, Doubal F, Sodlow C, Wardlaw J, Al-Shahi Salman R (2008) Improving interrater agreement about brain microbleeds: development of the Brain Observer MicroBleed Scale. Stroke 40:94–99

    Article  PubMed  Google Scholar 

  10. Cordonnier C, van der Flier WM, Sluimer JD, Leys D, Barkhof F, Scheltens P (2006) Prevalence and severity of microbleeds in a memory clinic setting. Neurology 66:1356–1360

    Article  PubMed  CAS  Google Scholar 

  11. Cullen KM, Kocsi Z, Stone J (2005) Pericapillary haem-rich deposits: evidence for microhaemorrhages in aging human cerebral cortex. J Cereb Blood Flow Metab 25:1656–1667

    Article  PubMed  CAS  Google Scholar 

  12. Davis J, Cribbs DH, Cotman CW, Van Nostrand WE (1999) Pathogenic amyloid-beta protein induces apoptosis in cultured human cerebrovascular smooth muscle cells. Amyloid 6:157–164

    PubMed  CAS  Google Scholar 

  13. Ellis R, Olichney J, Thal L et al (1996) Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience, Part XV. Neurology 46:1592–1596

    PubMed  CAS  Google Scholar 

  14. Fazekas F, Kleinert R, Roob G et al (1999) 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. AJNR Am J Neuroradiol 20:637–642

    PubMed  CAS  Google Scholar 

  15. Fisher C (1991) Lacunar infarcts—a review. Cerebrovasc Dis 1:311–320

    Article  Google Scholar 

  16. Greenberg S, Nandigam R, Delgado P et al (2009) Microbleeds versus macrobleeds: evidence for distinct entities. Stroke 40:2382–2386

    Article  PubMed  Google Scholar 

  17. Greenberg S, Vonsattel JP (1997) Diagnosis of cerebral amyloid angiopathy. Stroke 28:1418–1422

    PubMed  CAS  Google Scholar 

  18. Haacke EM, Cheng NY, House MJ et al (2005) Imaging iron stores in the brain using magnetic resonance imaging. Magn Reson Imaging 23:1–25

    Article  PubMed  CAS  Google Scholar 

  19. Haacke EM, DelProposto ZS, Chaturvedi S et al (2007) Imaging cerebral amyloid angiopathy with susceptibility-weighted imaging. AJNR Am J Neuroradiol 28:316–317

    PubMed  CAS  Google Scholar 

  20. Haacke EM, Xu Y, Cheng YC, Reichenbach JR (2004) Susceptibility weighted imaging (SWI). Magn Reson Med 52:612–618

    Article  PubMed  Google Scholar 

  21. Igase M, Tabara Y, Igase K et al (2009) Asymptomatic cerebral microbleeds seen in healthy subjects have a strong association with asymptomatic lacunar infarction. Circ J 73:530–533

    Article  PubMed  Google Scholar 

  22. Jellinger KA, Lauda F, Attems J (2007) Sporadic cerebral amyloid angiopathy is not a frequent cause of spontaneous brain hemorrhage. Eur J Neurol 14:923–928

    Article  PubMed  CAS  Google Scholar 

  23. Kirsch W, McAuley G, Holshouser B et al (2009) Serial susceptibility weighted MRI measures brain iron and microbleeds in dementia. J Alzheimer’s Dis 17:599–609

    CAS  Google Scholar 

  24. Knudsen KA, Rosand J, Karluk D, Greenberg SM (2001) Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology 56:537–539

    PubMed  CAS  Google Scholar 

  25. Koennecke HC (2006) Cerebral microbleeds on MRI: prevalence, associations, and potential clinical implications. Neurology 66:165–171

    Article  PubMed  Google Scholar 

  26. Nicholl R, Balasubramanian V, Urguhart D, Sellathurai N, Rutherford M (2007) Postmortem brain MRI with selective tissue biopsy as an adjunct to autopsy following neonatal encephalopathy. Eur J Paediatr Neurol 11:167–174

    Article  PubMed  CAS  Google Scholar 

  27. Rosand J, Muzikansky A, Kumar A et al (2005) Spatial clustering of hemorrhages in probable cerebral amyloid angiopathy. Ann Neurol 58:459–462

    Article  PubMed  Google Scholar 

  28. Pfefferbaum A, Sullivan E, Adalsteinssom E, Garrick T, Harper C (2004) Postmortem MR imaging of formalin-fixed human brain. Neuroimage 21:1585–1595

    Article  PubMed  Google Scholar 

  29. Pollock H, Hutchings M, Weller RO, Zhang ET (1997) Perivascular spaces in the basal ganglia of the human brain: their relationship to lacunes. J Anat 191:337–347

    Article  PubMed  Google Scholar 

  30. Roher A, Kuo Y, Esh C et al (2003) Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer’s disease. Mol Med 9:112–122

    PubMed  Google Scholar 

  31. Schley D, Carare-Nnadi R, Please C, Perry V, Weller R (2006) Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theor Biol 238:962–974

    Article  PubMed  CAS  Google Scholar 

  32. Schmierer K, Wheeler-Kingshott C, Boulby P et al (2007) Diffusion tensor imaging of post mortem multiple sclerosis brain. Neuroimage 35:467–477

    Article  PubMed  Google Scholar 

  33. Sehgal V, Delproposto Z, Haacke EM et al (2005) Clinical applications of neuroimaging with susceptibility-weighted imaging. J Magn Reson Imaging 22:439–450

    Article  PubMed  Google Scholar 

  34. Soontornniyomkij V, Lynch M, Mermash S et al (2009) Cerebral microinfarcts associated with severe cerebral beta-amyloid angiopathy. Brain Path (in press)

  35. Sveinbjornsdottir S, Sigurdsson S, Aspelund T et al (2008) Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location. J Neurol Neurosurg Psychiatry 79:1002–1006

    Article  PubMed  CAS  Google Scholar 

  36. Tanaka A, Ueno Y, Nakayama Y, Takano K, Takebayashi S (1999) Small chronic microhemorrhages and ischemic lesion in association with spontaneous intracerebral hematomas. Stroke 30:1637–1642

    PubMed  CAS  Google Scholar 

  37. Tatsumi S, Shinohara M, Yamamoto T (2008) Direct comparison of histology of microbleed with postmortem MR images: a case report. Cerebrovasc Dis 26:142–146

    Article  PubMed  Google Scholar 

  38. Terai K, Walker D, McGeer E, McGeer P (1997) Neurons express proteins of the classical complement pathway in Alzheimer disease. Brain Res 769:385–390

    Article  PubMed  CAS  Google Scholar 

  39. Tong KA, Ashwal S, Holshouser BA et al (2003) Hemorrhagic shearing lesions in children and adolescents with posttraumatic diffuse axonal injury: improved detection and initial results. Radiology 227:332–339

    Article  PubMed  Google Scholar 

  40. Tong KA, Ashwal S, Holshouser BA et al (2004) Diffuse axonal injury in children: clinical correlation with hemorrhagic lesions. Ann Neurol 56:36–50

    Article  PubMed  Google Scholar 

  41. Viswanathan A, Chabriat H (2006) Cerebral microhemorrhage. Stroke 37:550–555

    Article  PubMed  Google Scholar 

  42. Walker DA, Broderick DF, Kotsenas AL, Rubino FA (2004) Routine use of gradient-echo MRI to screen for cerebral amyloid angiopathy in elderly patients. AJR Am J Roentgenol 182:1547–1550

    PubMed  CAS  Google Scholar 

  43. Walker D, Dalsing-Hernandez J, Lue L (2008) Human postmortem brain-derived cerebrovascular smooth muscle cells express all genes of the classical complement pathway: a potential mechanism for vascular damage in cerebral amyloid angiopathy and Alzheimer’s disease. Microvasc Res 75:411–419

    Article  PubMed  CAS  Google Scholar 

  44. Wardlaw J, Dennis M, Warlow, Sandercock P (2001) Imaging appearance of the symptomatic perforating artery in patients with lacunar infarction: 1 occlusion or other vascular pathology. Ann Neurol 50:208–15

  45. Yakushiji Y, Nishiyama M, Yakushiji S et al (2008) Brain microbleeds and global cognitive function in adults without neurological disorder. Stroke 39:3323–3328

    Article  PubMed  Google Scholar 

  46. Yasojima K, Schwab C, McGeer E, McGeer P (1999) Up-regulated production and activation of the complement system in Alzheimer’s disease brain. Am J Pathol 154:927–936

    PubMed  CAS  Google Scholar 

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Acknowledgments

This research was funded by the National Institutes of Health (AG20948). Harry V. Vinters is supported in part by P01 AG12435, P50 AG16570 and the Daljit S. and Elaine Sarkaria Chair in Diagnostic Medicine. E. Mark Haacke is a consultant to Siemens Corporation. None of the other authors have real or potential conflicts of interest related to this work. We thank Zachary Taylor who was an undergraduate summer researcher in our lab, as well as Cindy Dickson, April Dickson and Jackie Knecht for administrative assistance and for editing the manuscript.

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Authors and Affiliations

  1. Neurosurgery Center for Research, Training and Education, Loma Linda University, Coleman Pavilion, Suite 11113, 11175 Campus St, Loma Linda, CA, 92350, USA

    Matthew Schrag, Grant McAuley, Arshad Jiffry, Claudius Mueller & Wolff M. Kirsch

  2. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Justine Pomakian, Spencer Tung & Harry V. Vinters

  3. Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Justine Pomakian, Spencer Tung & Harry V. Vinters

  4. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA

    Claudius Mueller

  5. The Magnetic Resonance Imaging Institute for Biomedical Research, Detroit, MI, USA

    E. Mark Haacke, Barbara Holshouser & Daniel Kido

  6. Department of Radiology, Loma Linda University School of Medicine, Loma Linda, CA, USA

    E. Mark Haacke

  7. Department of Radiology, Wayne State University, Detroit, MI, USA

    E. Mark Haacke

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  1. Matthew Schrag
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  2. Grant McAuley
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Correspondence to Wolff M. Kirsch.

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Schrag, M., McAuley, G., Pomakian, J. et al. Correlation of hypointensities in susceptibility-weighted images to tissue histology in dementia patients with cerebral amyloid angiopathy: a postmortem MRI study. Acta Neuropathol 119, 291–302 (2010). https://doi.org/10.1007/s00401-009-0615-z

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  • DOI: https://doi.org/10.1007/s00401-009-0615-z

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