Advertisement

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

  • Hyemin Jang
  • Young Kyoung Jang
  • Hee Jin Kim
  • David John Werring
  • Jin San Lee
  • Yeong Sim Choe
  • Seongbeom Park
  • Juyeon Lee
  • Ko Woon Kim
  • Yeshin Kim
  • Soo Hyun Cho
  • Si Eun Kim
  • Seung Joo Kim
  • Andreas Charidimou
  • Duk L. Na
  • Sang Won SeoEmail author
Original Article

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.

Keywords

Cerebral amyloid angiopathy Amyloid β Amyloid β PET 

Notes

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).

Compliance with ethical standards

Conflicts of interest

None.

Role of the funder

The funders had no role in the design or conduct of the study; in the collection, management, analysis or interpretation of the data; in the preparation, review or approval of the manuscript; or in the decision to submit the manuscript for publication.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

259_2019_4314_MOESM1_ESM.docx (30 kb)
ESM 1 (DOCX 30 kb)

References

  1. 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.CrossRefGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 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.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. 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.CrossRefGoogle Scholar
  7. 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.CrossRefGoogle Scholar
  8. 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.CrossRefGoogle Scholar
  9. 9.
    Charidimou A, Farid K, Baron JC. Amyloid-PET in sporadic cerebral amyloid angiopathy: a diagnostic accuracy meta-analysis. Neurology. 2017;89:1490–8.CrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 11.
    Esiri MM, Wilcock GK. Cerebral amyloid angiopathy in dementia and old age. J Neurol Neurosurg Psychiatry. 1986;49:1221–6.CrossRefGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. 14.
    Attems J. Sporadic cerebral amyloid angiopathy: pathology, clinical implications, and possible pathomechanisms. Acta Neuropathol. 2005;110:345–59.CrossRefGoogle Scholar
  15. 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.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 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.CrossRefGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 20.
    Greenberg SM, Charidimou A. Diagnosis of cerebral amyloid angiopathy: evolution of the Boston criteria. Stroke. 2018;49:491–7.CrossRefGoogle Scholar
  21. 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.CrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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.CrossRefGoogle Scholar
  25. 25.
    Kang Y, Na DL. Seoul Neuropsychological Screening Battery (SNSB). Incheon: Human Brain Research & Consulting Co; 2003.Google Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.CrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.CrossRefGoogle Scholar
  35. 35.
    Jellinger KA. Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm (Vienna). 2002;109:813–36.CrossRefGoogle Scholar
  36. 36.
    Viswanathan A, Greenberg SM. Cerebral amyloid angiopathy in the elderly. Ann Neurol. 2011;70:871–80.CrossRefGoogle Scholar
  37. 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.CrossRefGoogle Scholar
  38. 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.CrossRefGoogle Scholar
  39. 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.CrossRefGoogle Scholar
  40. 40.
    Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol. 2002;1:426–36.CrossRefGoogle Scholar
  41. 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.CrossRefGoogle Scholar
  42. 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.CrossRefGoogle Scholar
  43. 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.CrossRefGoogle Scholar
  44. 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.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Hyemin Jang
    • 1
    • 2
  • Young Kyoung Jang
    • 1
    • 2
  • Hee Jin Kim
    • 1
    • 2
  • David John Werring
    • 3
  • Jin San Lee
    • 4
  • Yeong Sim Choe
    • 1
  • Seongbeom Park
    • 1
  • Juyeon Lee
    • 5
  • Ko Woon Kim
    • 6
  • Yeshin Kim
    • 7
  • Soo Hyun Cho
    • 1
    • 2
  • Si Eun Kim
    • 8
  • Seung Joo Kim
    • 1
    • 2
  • Andreas Charidimou
    • 9
  • Duk L. Na
    • 1
    • 2
    • 10
  • Sang Won Seo
    • 1
    • 2
    • 10
    Email author
  1. 1.Department of Neurology, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulRepublic of Korea
  2. 2.Neuroscience CenterSamsung Medical CenterSeoulKorea
  3. 3.UCL Stroke Research Centre, Department of Brain Repair and RehabilitationUCL Institute of Neurology and the National Hospital for Neurology and NeurosurgeryLondonUK
  4. 4.Department of NeurologyKyung Hee University School of MedicineSeoulKorea
  5. 5.Department of NeurologyChungnam National University School of MedicineDaejeonKorea
  6. 6.Department of Neurology, Chonbuk National University HospitalChonbuk National University Medical SchoolJeonjuKorea
  7. 7.Department of NeurologyKangwon National University Hospital, Kangwon National University College of MedicineChuncheonKorea
  8. 8.Department of NeurologyInje University College of Medicine, Haeundae Paik HospitalBusanKorea
  9. 9.Department of NeurologyMassachusetts General Hospital Stroke Research Center, Harvard Medical SchoolBostonUSA
  10. 10.Department of Health Sciences and TechnologySAIHST, Sungkyunkwan UniversityGangnam-guRepublic of Korea

Personalised recommendations