APOE and cortical superficial siderosis in CAA: Meta-analysis and potential mechanisms

Andreas Charidimou, Hazel I. Zonneveld, Sara Shams, Kejal Kantarci, Ashkan Shoamanesh, Saima Hilal, Paul A. Yates, Gregoire Boulouis, Han Kyu Na, Marco Pasi, Allesandro Biffi, Yuek Ling Chai, Joyce Ruifen Chong, Lars-Olof Wahlund, Jack R. Clifford, Christopher Chen, M. Edip Gurol, Joshua N. Goldstein, Duk L. Na, Frederik Barkhof & 4 others Sang Won Seo, Jonathan Rosand, Steven M. Greenberg, Anand Viswanathan

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

OBJECTIVE: To assess potential mechanisms of cortical superficial siderosis (cSS), a central MRI biomarker in cerebral amyloid angiopathy (CAA), we performed a collaborative meta-analysis of APOE associations with cSS presence and severity. METHODS: We pooled data from published studies reporting APOE genotype and MRI assessment of cSS in 3 distinct settings: (1) stroke clinic patients with symptomatic CAA (i.e., lobar intracerebral hemorrhage, transient focal neurologic episodes) according to the Boston criteria; (2) memory clinic patients; and (3) population-based studies. We compared cSS presence and severity (focal or disseminated vs no cSS) in participants with ε2+ or ε4+ genotype vs the ε3/ε3 genotype, by calculating study-specific and random effects pooled, unadjusted odds ratios (ORs). RESULTS: Thirteen studies fulfilled inclusion criteria: 7 memory clinic cohorts (n = 2,587), 5 symptomatic CAA cohorts (n = 402), and 1 population-based study (n = 1,379). There was no significant overall association between APOE ε4+ and cSS presence or severity. When stratified by clinical setting, APOE ε4+ was associated with cSS in memory clinic (OR 2.10; 95% confidence interval [CI] 1.11-3.99) but not symptomatic CAA patients. The pooled OR showed significantly increased odds of having cSS for APOE ε2+ genotypes (OR 2.42, 95% CI 1.48-3.95) in both patient populations. This association was stronger for disseminated cSS in symptomatic CAA cohorts. In detailed subgroup analyses, APOE ε2/ε2 and APOE ε2/ε4 genotypes were most consistently and strongly associated with cSS presence and severity. CONCLUSION: CAA-related vasculopathic changes and fragility associated with APOE ε2+ allele might have a biologically meaningful role in the pathophysiology and severity of cSS.
Original languageEnglish
Pages (from-to)e358-e371
JournalNeurology
Volume93
Issue number4
Early online date26 Jun 2019
DOIs
Publication statusPublished - 2019

Cite this

Charidimou, A., Zonneveld, H. I., Shams, S., Kantarci, K., Shoamanesh, A., Hilal, S., ... Viswanathan, A. (2019). APOE and cortical superficial siderosis in CAA: Meta-analysis and potential mechanisms. Neurology, 93(4), e358-e371. https://doi.org/10.1212/WNL.0000000000007818
Charidimou, Andreas ; Zonneveld, Hazel I. ; Shams, Sara ; Kantarci, Kejal ; Shoamanesh, Ashkan ; Hilal, Saima ; Yates, Paul A. ; Boulouis, Gregoire ; Na, Han Kyu ; Pasi, Marco ; Biffi, Allesandro ; Chai, Yuek Ling ; Chong, Joyce Ruifen ; Wahlund, Lars-Olof ; Clifford, Jack R. ; Chen, Christopher ; Gurol, M. Edip ; Goldstein, Joshua N. ; Na, Duk L. ; Barkhof, Frederik ; Seo, Sang Won ; Rosand, Jonathan ; Greenberg, Steven M. ; Viswanathan, Anand. / APOE and cortical superficial siderosis in CAA : Meta-analysis and potential mechanisms. In: Neurology. 2019 ; Vol. 93, No. 4. pp. e358-e371.
@article{78d5a74f39e644459088877ad22cc6c4,
title = "APOE and cortical superficial siderosis in CAA: Meta-analysis and potential mechanisms",
abstract = "OBJECTIVE: To assess potential mechanisms of cortical superficial siderosis (cSS), a central MRI biomarker in cerebral amyloid angiopathy (CAA), we performed a collaborative meta-analysis of APOE associations with cSS presence and severity. METHODS: We pooled data from published studies reporting APOE genotype and MRI assessment of cSS in 3 distinct settings: (1) stroke clinic patients with symptomatic CAA (i.e., lobar intracerebral hemorrhage, transient focal neurologic episodes) according to the Boston criteria; (2) memory clinic patients; and (3) population-based studies. We compared cSS presence and severity (focal or disseminated vs no cSS) in participants with ε2+ or ε4+ genotype vs the ε3/ε3 genotype, by calculating study-specific and random effects pooled, unadjusted odds ratios (ORs). RESULTS: Thirteen studies fulfilled inclusion criteria: 7 memory clinic cohorts (n = 2,587), 5 symptomatic CAA cohorts (n = 402), and 1 population-based study (n = 1,379). There was no significant overall association between APOE ε4+ and cSS presence or severity. When stratified by clinical setting, APOE ε4+ was associated with cSS in memory clinic (OR 2.10; 95{\%} confidence interval [CI] 1.11-3.99) but not symptomatic CAA patients. The pooled OR showed significantly increased odds of having cSS for APOE ε2+ genotypes (OR 2.42, 95{\%} CI 1.48-3.95) in both patient populations. This association was stronger for disseminated cSS in symptomatic CAA cohorts. In detailed subgroup analyses, APOE ε2/ε2 and APOE ε2/ε4 genotypes were most consistently and strongly associated with cSS presence and severity. CONCLUSION: CAA-related vasculopathic changes and fragility associated with APOE ε2+ allele might have a biologically meaningful role in the pathophysiology and severity of cSS.",
author = "Andreas Charidimou and Zonneveld, {Hazel I.} and Sara Shams and Kejal Kantarci and Ashkan Shoamanesh and Saima Hilal and Yates, {Paul A.} and Gregoire Boulouis and Na, {Han Kyu} and Marco Pasi and Allesandro Biffi and Chai, {Yuek Ling} and Chong, {Joyce Ruifen} and Lars-Olof Wahlund and Clifford, {Jack R.} and Christopher Chen and Gurol, {M. Edip} and Goldstein, {Joshua N.} and Na, {Duk L.} and Frederik Barkhof and Seo, {Sang Won} and Jonathan Rosand and Greenberg, {Steven M.} and Anand Viswanathan",
note = "{\circledC} 2019 American Academy of Neurology.",
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Charidimou, A, Zonneveld, HI, Shams, S, Kantarci, K, Shoamanesh, A, Hilal, S, Yates, PA, Boulouis, G, Na, HK, Pasi, M, Biffi, A, Chai, YL, Chong, JR, Wahlund, L-O, Clifford, JR, Chen, C, Gurol, ME, Goldstein, JN, Na, DL, Barkhof, F, Seo, SW, Rosand, J, Greenberg, SM & Viswanathan, A 2019, 'APOE and cortical superficial siderosis in CAA: Meta-analysis and potential mechanisms' Neurology, vol. 93, no. 4, pp. e358-e371. https://doi.org/10.1212/WNL.0000000000007818

APOE and cortical superficial siderosis in CAA : Meta-analysis and potential mechanisms. / Charidimou, Andreas; Zonneveld, Hazel I.; Shams, Sara; Kantarci, Kejal; Shoamanesh, Ashkan; Hilal, Saima; Yates, Paul A.; Boulouis, Gregoire; Na, Han Kyu; Pasi, Marco; Biffi, Allesandro; Chai, Yuek Ling; Chong, Joyce Ruifen; Wahlund, Lars-Olof; Clifford, Jack R.; Chen, Christopher; Gurol, M. Edip; Goldstein, Joshua N.; Na, Duk L.; Barkhof, Frederik; Seo, Sang Won; Rosand, Jonathan; Greenberg, Steven M.; Viswanathan, Anand.

In: Neurology, Vol. 93, No. 4, 2019, p. e358-e371.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - APOE and cortical superficial siderosis in CAA

T2 - Meta-analysis and potential mechanisms

AU - Charidimou, Andreas

AU - Zonneveld, Hazel I.

AU - Shams, Sara

AU - Kantarci, Kejal

AU - Shoamanesh, Ashkan

AU - Hilal, Saima

AU - Yates, Paul A.

AU - Boulouis, Gregoire

AU - Na, Han Kyu

AU - Pasi, Marco

AU - Biffi, Allesandro

AU - Chai, Yuek Ling

AU - Chong, Joyce Ruifen

AU - Wahlund, Lars-Olof

AU - Clifford, Jack R.

AU - Chen, Christopher

AU - Gurol, M. Edip

AU - Goldstein, Joshua N.

AU - Na, Duk L.

AU - Barkhof, Frederik

AU - Seo, Sang Won

AU - Rosand, Jonathan

AU - Greenberg, Steven M.

AU - Viswanathan, Anand

N1 - © 2019 American Academy of Neurology.

PY - 2019

Y1 - 2019

N2 - OBJECTIVE: To assess potential mechanisms of cortical superficial siderosis (cSS), a central MRI biomarker in cerebral amyloid angiopathy (CAA), we performed a collaborative meta-analysis of APOE associations with cSS presence and severity. METHODS: We pooled data from published studies reporting APOE genotype and MRI assessment of cSS in 3 distinct settings: (1) stroke clinic patients with symptomatic CAA (i.e., lobar intracerebral hemorrhage, transient focal neurologic episodes) according to the Boston criteria; (2) memory clinic patients; and (3) population-based studies. We compared cSS presence and severity (focal or disseminated vs no cSS) in participants with ε2+ or ε4+ genotype vs the ε3/ε3 genotype, by calculating study-specific and random effects pooled, unadjusted odds ratios (ORs). RESULTS: Thirteen studies fulfilled inclusion criteria: 7 memory clinic cohorts (n = 2,587), 5 symptomatic CAA cohorts (n = 402), and 1 population-based study (n = 1,379). There was no significant overall association between APOE ε4+ and cSS presence or severity. When stratified by clinical setting, APOE ε4+ was associated with cSS in memory clinic (OR 2.10; 95% confidence interval [CI] 1.11-3.99) but not symptomatic CAA patients. The pooled OR showed significantly increased odds of having cSS for APOE ε2+ genotypes (OR 2.42, 95% CI 1.48-3.95) in both patient populations. This association was stronger for disseminated cSS in symptomatic CAA cohorts. In detailed subgroup analyses, APOE ε2/ε2 and APOE ε2/ε4 genotypes were most consistently and strongly associated with cSS presence and severity. CONCLUSION: CAA-related vasculopathic changes and fragility associated with APOE ε2+ allele might have a biologically meaningful role in the pathophysiology and severity of cSS.

AB - OBJECTIVE: To assess potential mechanisms of cortical superficial siderosis (cSS), a central MRI biomarker in cerebral amyloid angiopathy (CAA), we performed a collaborative meta-analysis of APOE associations with cSS presence and severity. METHODS: We pooled data from published studies reporting APOE genotype and MRI assessment of cSS in 3 distinct settings: (1) stroke clinic patients with symptomatic CAA (i.e., lobar intracerebral hemorrhage, transient focal neurologic episodes) according to the Boston criteria; (2) memory clinic patients; and (3) population-based studies. We compared cSS presence and severity (focal or disseminated vs no cSS) in participants with ε2+ or ε4+ genotype vs the ε3/ε3 genotype, by calculating study-specific and random effects pooled, unadjusted odds ratios (ORs). RESULTS: Thirteen studies fulfilled inclusion criteria: 7 memory clinic cohorts (n = 2,587), 5 symptomatic CAA cohorts (n = 402), and 1 population-based study (n = 1,379). There was no significant overall association between APOE ε4+ and cSS presence or severity. When stratified by clinical setting, APOE ε4+ was associated with cSS in memory clinic (OR 2.10; 95% confidence interval [CI] 1.11-3.99) but not symptomatic CAA patients. The pooled OR showed significantly increased odds of having cSS for APOE ε2+ genotypes (OR 2.42, 95% CI 1.48-3.95) in both patient populations. This association was stronger for disseminated cSS in symptomatic CAA cohorts. In detailed subgroup analyses, APOE ε2/ε2 and APOE ε2/ε4 genotypes were most consistently and strongly associated with cSS presence and severity. CONCLUSION: CAA-related vasculopathic changes and fragility associated with APOE ε2+ allele might have a biologically meaningful role in the pathophysiology and severity of cSS.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/31243071

U2 - 10.1212/WNL.0000000000007818

DO - 10.1212/WNL.0000000000007818

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SP - e358-e371

JO - Neurology

JF - Neurology

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