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Clinical significance of amyloid β positivity in patients with probable cerebral amyloid angiopathy markers

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

We investigated the frequency and clinical significance of amyloid β (Aβ) positivity on PET in patients with cerebral amyloid angiopathy (CAA).

Methods

We recruited 65 patients who met the modified Boston criteria for probable CAA. All underwent amyloid PET, MRI, APOE genotyping and neuropsychological testing, and we obtained information on MRI markers of CAA and ischemic cerebral small-vessel disease (CSVD). We investigated the CAA/ischemic CSVD burden and APOE genotypes in relation to Aβ positivity and investigated the effect of Aβ positivity on longitudinal cognitive decline.

Results

Among the 65 CAA patients, 43 (66.2%) showed Aβ PET positivity (Aβ+). Patients with Aβ+ CAA had more lobar microbleeds (median 9, interquartile range 2–41, vs. 3, 2–8; P = 0.045) and a higher frequency of cortical superficial siderosis (34.9% vs. 9.1%; P = 0.025), while patients with Aβ− CAA had more lacunes (1, 0–2, vs. 0, 0–1; P = 0.029) and a higher frequency of severe white matter hyperintensities (45.5% vs. 20.9%; P = 0.040). The frequency of ε4 carriers was higher in Aβ+ patients (57.1%) than in Aβ− patients (18.2%; P = 0.003), while the frequency of ε2 carriers did not differ between the two groups. Finally, Aβ positivity was associated with faster decline in multiple cognitive domains including language (P < 0.001), visuospatial function (P < 0.001), and verbal memory (P < 0.001) in linear mixed effects models.

Conclusion

Our findings suggest that a significant proportion of patients with probable CAA in a memory clinic are Aβ− on PET. Aβ positivity in CAA patients is associated with a distinct pattern of CSVD biomarker expression, and a worse cognitive trajectory. Aβ positivity has clinical relevance in CAA and might represent either advanced CAA or additional Alzheimer’s disease neuropathological changes.

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References

  1. Knudsen KA, Rosand J, Karluk D, Greenberg SM. Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology. 2001;56:537–9.

    Article  CAS  PubMed  Google Scholar 

  2. Linn J, Halpin A, Demaerel P, Ruhland J, Giese A, Dichgans M, et al. Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology. 2010;74:1346–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Martinez-Ramirez S, Romero JR, Shoamanesh A, McKee AC, Van Etten E, Pontes-Neto O, et al. Diagnostic value of lobar microbleeds in individuals without intracerebral hemorrhage. Alzheimers Dement. 2015;11:1480–8.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Baron JC, Farid K, Dolan E, Turc G, Marrapu ST, O’Brien E, et al. Diagnostic utility of amyloid PET in cerebral amyloid angiopathy-related symptomatic intracerebral hemorrhage. J Cereb Blood Flow Metab. 2014;34:753–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gurol ME, Becker JA, Fotiadis P, Riley G, Schwab K, Johnson KA, et al. Florbetapir-PET to diagnose cerebral amyloid angiopathy: a prospective study. Neurology. 2016;87:2043–9.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ly J, Donnan GA, Villemagne VL, Zavala J, Ma H, O’Keefe G, et al. 11C-PIB binding is increased in patients with cerebral amyloid angiopathy-related hemorrhage. Neurology. 2010;74:487–93.

    Article  CAS  PubMed  Google Scholar 

  7. Bacskai BJ, Frosch MP, Freeman SH, Raymond SB, Augustinack JC, Johnson KA, et al. Molecular imaging with Pittsburgh compound B confirmed at autopsy: a case report. Arch Neurol. 2007;64:431–4.

    Article  PubMed  Google Scholar 

  8. Farid K, Charidimou A, Baron JC. Amyloid positron emission tomography in sporadic cerebral amyloid angiopathy: a systematic critical update. Neuroimage Clin. 2017;15:247–63.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Charidimou A, Farid K, Baron JC. Amyloid-PET in sporadic cerebral amyloid angiopathy: a diagnostic accuracy meta-analysis. Neurology. 2017;89:1490–8.

    Article  PubMed  Google Scholar 

  10. Ellis R, Olichney J, Thal L, Mirra S, Morris J, Beekly D, et al. Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience, Part XV. Neurology. 1996;46:1592–6.

    Article  CAS  PubMed  Google Scholar 

  11. Esiri MM, Wilcock GK. Cerebral amyloid angiopathy in dementia and old age. J Neurol Neurosurg Psychiatry. 1986;49:1221–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Thal DR, Ghebremedhin E, Orantes M, Wiestler OD. Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol. 2003;62:1287–301.

    Article  PubMed  Google Scholar 

  13. Attems J, Jellinger KA, Lintner F. Alzheimer’s disease pathology influences severity and topographical distribution of cerebral amyloid angiopathy. Acta Neuropathol. 2005;110:222–31.

    Article  PubMed  Google Scholar 

  14. Attems J. Sporadic cerebral amyloid angiopathy: pathology, clinical implications, and possible pathomechanisms. Acta Neuropathol. 2005;110:345–59.

    Article  CAS  PubMed  Google Scholar 

  15. Okello A, Koivunen J, Edison P, Archer H, Turkheimer F, Någren K, et al. Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. Neurology. 2009;73:754–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Park JH, Seo SW, Kim C, Kim SH, Kim GH, Kim ST, et al. Effects of cerebrovascular disease and amyloid beta burden on cognition in subjects with subcortical vascular cognitive impairment. Neurobiol Aging. 2014;35:254–60.

    Article  CAS  PubMed  Google Scholar 

  17. Kim HJ, Yang JJ, Kwon H, Kim C, Lee JM, Chun P, et al. Relative impact of amyloid-beta, lacunes, and downstream imaging markers on cognitive trajectories. Brain. 2016;139:2516–27.

    Article  PubMed  Google Scholar 

  18. Kim HJ, Im K, Kwon H, Lee JM, Kim C, Kim YJ, et al. Clinical effect of white matter network disruption related to amyloid and small vessel disease. Neurology. 2015;85:63–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Banerjee G, Carare R, Cordonnier C, Greenberg SM, Schneider JA, Smith EE, et al. The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice. J Neurol Neurosurg Psychiatry. 2017;88:982–94.

    Article  PubMed  Google Scholar 

  20. Greenberg SM, Charidimou A. Diagnosis of cerebral amyloid angiopathy: evolution of the Boston criteria. Stroke. 2018;49:491–7.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Park JH, Seo SW, Kim C, Kim GH, Noh HJ, Kim ST, et al. Pathogenesis of cerebral microbleeds: in vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment. Ann Neurol. 2013;73:584–93.

    Article  CAS  PubMed  Google Scholar 

  22. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:263–9.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12:822–38.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Linn J, Herms J, Dichgans M, Bruckmann H, Fesl G, Freilinger T, et al. Subarachnoid hemosiderosis and superficial cortical hemosiderosis in cerebral amyloid angiopathy. AJNR Am J Neuroradiol. 2008;29:184–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kang Y, Na DL. Seoul Neuropsychological Screening Battery (SNSB). Incheon: Human Brain Research & Consulting Co; 2003.

    Google Scholar 

  26. Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology. 1993;43:1683–9.

    Article  CAS  PubMed  Google Scholar 

  27. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage. 2002;15:273–89.

    Article  CAS  PubMed  Google Scholar 

  28. Barthel H, Gertz HJ, Dresel S, Peters O, Bartenstein P, Buerger K, et al. Cerebral amyloid-beta PET with florbetaben (18F) in patients with Alzheimer’s disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol. 2011;10:424–35.

    Article  CAS  PubMed  Google Scholar 

  29. Ahn HJ, Chin J, Park A, Lee BH, Suh MK, Seo SW, et al. Seoul Neuropsychological Screening Battery-dementia version (SNSB-D): a useful tool for assessing and monitoring cognitive impairments in dementia patients. J Korean Med Sci. 2010;25:1071–6.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Gurol ME, Viswanathan A, Gidicsin C, Hedden T, Martinez-Ramirez S, Dumas A, et al. Cerebral amyloid angiopathy burden associated with leukoaraiosis: a positron emission tomography/magnetic resonance imaging study. Ann Neurol. 2013;73:529–36.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Raposo N, Planton M, Peran P, Payoux P, Bonneville F, Lyoubi A, et al. Florbetapir imaging in cerebral amyloid angiopathy-related hemorrhages. Neurology. 2017;89:697–704.

    Article  CAS  PubMed  Google Scholar 

  32. Johnson KA, Gregas M, Becker JA, Kinnecom C, Salat DH, Moran EK, et al. Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol. 2007;62:229–34.

    Article  PubMed  Google Scholar 

  33. Charidimou A, Martinez-Ramirez S, Shoamanesh A, Oliveira-Filho J, Frosch M, Vashkevich A, et al. Cerebral amyloid angiopathy with and without hemorrhage: evidence for different disease phenotypes. Neurology. 2015;84:1206–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Seo SW, Ayakta N, Grinberg LT, Villeneuve S, Lehmann M, Reed B, et al. Regional correlations between [(11)C] PIB PET and post-mortem burden of amyloid-beta pathology in a diverse neuropathological cohort. Neuroimage Clin. 2017;13:130–7.

    Article  PubMed  Google Scholar 

  35. Jellinger KA. Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm (Vienna). 2002;109:813–36.

    Article  CAS  Google Scholar 

  36. Viswanathan A, Greenberg SM. Cerebral amyloid angiopathy in the elderly. Ann Neurol. 2011;70:871–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shoamanesh A, Martinez-Ramirez S, Oliveira-Filho J, Reijmer Y, Falcone GJ, Ayres A, et al. Interrelationship of superficial siderosis and microbleeds in cerebral amyloid angiopathy. Neurology. 2014;83:1838–43.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Na HK, Park JH, Kim JH, Kim HJ, Kim ST, Werring DJ, et al. Cortical superficial siderosis: a marker of vascular amyloid in patients with cognitive impairment. Neurology. 2015;84:849–55.

    Article  CAS  PubMed  Google Scholar 

  39. Kim YJ, Kim HJ, Park JH, Kim S, Woo SY, Kwak KC, et al. Synergistic effects of longitudinal amyloid and vascular changes on lobar microbleeds. Neurology. 2016;87:1575–82.

    Article  CAS  PubMed  Google Scholar 

  40. Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol. 2002;1:426–36.

    Article  PubMed  Google Scholar 

  41. Jang YK, Kim HJ, Lee JS, Kim YJ, Kim KW, Kim Y, et al. Distinctive clinical effects of haemorrhagic markers in cerebral amyloid angiopathy. Sci Rep. 2017;7:15984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ. Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study. Neurology. 2002;58:1629–34.

    Article  CAS  PubMed  Google Scholar 

  43. Boyle PA, Yu L, Wilson RS, Leurgans SE, Schneider JA, Bennett DA. Person-specific contribution of neuropathologies to cognitive loss in old age. Ann Neurol. 2018;83:74–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rowe CC, Doré V, Jones G, Baxendale D, Mulligan RS, Bullich S, et al. 18F-Florbetaben PET beta-amyloid binding expressed in Centiloids. Eur J Nucl Med Mol Imaging. 2017;44:2053–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

S.W.S. receives funding from the Brain Research Program through the National Research Foundation of Korea (2016M3C7A1913844), the Korea Government (MSIP) through the National Research Foundation of Korea grant (2017R1A2B2005081), and the Research of Korea Centers for Disease Control and Prevention (2018-ER6203-01).

Funding

This research was funded by the Brain Research Program through the National Research Foundation of Korea (2016M3C7A1913844), the Korea Government (MSIP) through the National Research Foundation of Korea grant (2017R1A2B2005081), and the Research of Korea Centers for Disease Control and Prevention (2018-ER6203-01).

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Correspondence to Sang Won Seo.

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Jang, H., Jang, Y.K., Kim, H.J. et al. Clinical significance of amyloid β positivity in patients with probable cerebral amyloid angiopathy markers. Eur J Nucl Med Mol Imaging 46, 1287–1298 (2019). https://doi.org/10.1007/s00259-019-04314-7

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