Pathogenesis of cerebral microbleeds: In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment

Jae Hyun Park, Sang Won Seo, Changsoo Kim, Geon Ha Kim, Hyun Jin Noh, Sung Tae Kim, Ki Chang Kwak, Uicheul Yoon, Jong Min Lee, Jong Weon Lee, Ji Soo Shin, Chi Hun Kim, Young Noh, Hanna Cho, Hee Jin Kim, Cindy W. Yoon, Seung Jun Oh, Jae Seung Kim, Yearn Seong Choe, Kyung Han LeeJae Hong Lee, Michael Ewers, Michael W. Weiner, David J. Werring, Duk L. Na

Research output: Contribution to journalArticle

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Abstract

Objective Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment. Methods We included 226 patients: 89 with Alzheimer disease-related cognitive impairment (ADCI) and 137 with subcortical vascular cognitive impairment (SVCI). All subjects underwent amyloid imaging with [11C] Pittsburgh compound B (PiB) positron emission tomography, and MRI to detect CMBs and markers of subcortical SVD, including the volume of white matter hyperintensities (WMH) and the number of lacunes. Results Parietal and occipital lobar CMBs counts were higher in PiB+ ADCI with moderate WMH than PiB+ ADCI with minimal WMH, whereas PiB- patients with SVCI (ie, "pure" SVCI) showed both lobar and deep CMBs. In multivariate analyses of the whole cohort, WMH volume and lacuna counts were positively associated with both lobar and deep CMBs, whereas amyloid burden (PiB) was only associated with lobar CMBs. There was an interaction between lacuna burden and PiB retention on lobar (but not deep) CMBs (p<0.001). Interpretation Our findings suggest that although deep CMBs are mainly linked to subcortical SVD, both subcortical SVD and amyloid-related pathologies (eg, CAA) contribute to the pathogenesis of lobar CMBs, at least in subjects with mixed lobar and deep CMBs. Furthermore, subcortical SVD and amyloid-related pathologies interact to increase the risk of lobar CMBs. Ann Neurol 2013;73:584-593

Original languageEnglish
Pages (from-to)584-593
Number of pages10
JournalAnnals of Neurology
Volume73
Issue number5
DOIs
Publication statusPublished - 2013 May 1

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Amyloid
Cerebral Amyloid Angiopathy
Blood Vessels
Alzheimer Disease
Magnetic Resonance Imaging
Pathology
Cerebrovascular Disorders
Cognitive Dysfunction
Neuroimaging
Positron-Emission Tomography
2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
Multivariate Analysis
White Matter

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Park, Jae Hyun ; Seo, Sang Won ; Kim, Changsoo ; Kim, Geon Ha ; Noh, Hyun Jin ; Kim, Sung Tae ; Kwak, Ki Chang ; Yoon, Uicheul ; Lee, Jong Min ; Lee, Jong Weon ; Shin, Ji Soo ; Kim, Chi Hun ; Noh, Young ; Cho, Hanna ; Kim, Hee Jin ; Yoon, Cindy W. ; Oh, Seung Jun ; Kim, Jae Seung ; Choe, Yearn Seong ; Lee, Kyung Han ; Lee, Jae Hong ; Ewers, Michael ; Weiner, Michael W. ; Werring, David J. ; Na, Duk L. / Pathogenesis of cerebral microbleeds : In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment. In: Annals of Neurology. 2013 ; Vol. 73, No. 5. pp. 584-593.
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abstract = "Objective Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment. Methods We included 226 patients: 89 with Alzheimer disease-related cognitive impairment (ADCI) and 137 with subcortical vascular cognitive impairment (SVCI). All subjects underwent amyloid imaging with [11C] Pittsburgh compound B (PiB) positron emission tomography, and MRI to detect CMBs and markers of subcortical SVD, including the volume of white matter hyperintensities (WMH) and the number of lacunes. Results Parietal and occipital lobar CMBs counts were higher in PiB+ ADCI with moderate WMH than PiB+ ADCI with minimal WMH, whereas PiB- patients with SVCI (ie, {"}pure{"} SVCI) showed both lobar and deep CMBs. In multivariate analyses of the whole cohort, WMH volume and lacuna counts were positively associated with both lobar and deep CMBs, whereas amyloid burden (PiB) was only associated with lobar CMBs. There was an interaction between lacuna burden and PiB retention on lobar (but not deep) CMBs (p<0.001). Interpretation Our findings suggest that although deep CMBs are mainly linked to subcortical SVD, both subcortical SVD and amyloid-related pathologies (eg, CAA) contribute to the pathogenesis of lobar CMBs, at least in subjects with mixed lobar and deep CMBs. Furthermore, subcortical SVD and amyloid-related pathologies interact to increase the risk of lobar CMBs. Ann Neurol 2013;73:584-593",
author = "Park, {Jae Hyun} and Seo, {Sang Won} and Changsoo Kim and Kim, {Geon Ha} and Noh, {Hyun Jin} and Kim, {Sung Tae} and Kwak, {Ki Chang} and Uicheul Yoon and Lee, {Jong Min} and Lee, {Jong Weon} and Shin, {Ji Soo} and Kim, {Chi Hun} and Young Noh and Hanna Cho and Kim, {Hee Jin} and Yoon, {Cindy W.} and Oh, {Seung Jun} and Kim, {Jae Seung} and Choe, {Yearn Seong} and Lee, {Kyung Han} and Lee, {Jae Hong} and Michael Ewers and Weiner, {Michael W.} and Werring, {David J.} and Na, {Duk L.}",
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Park, JH, Seo, SW, Kim, C, Kim, GH, Noh, HJ, Kim, ST, Kwak, KC, Yoon, U, Lee, JM, Lee, JW, Shin, JS, Kim, CH, Noh, Y, Cho, H, Kim, HJ, Yoon, CW, Oh, SJ, Kim, JS, Choe, YS, Lee, KH, Lee, JH, Ewers, M, Weiner, MW, Werring, DJ & Na, DL 2013, 'Pathogenesis of cerebral microbleeds: In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment', Annals of Neurology, vol. 73, no. 5, pp. 584-593. https://doi.org/10.1002/ana.23845

Pathogenesis of cerebral microbleeds : In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment. / Park, Jae Hyun; Seo, Sang Won; Kim, Changsoo; Kim, Geon Ha; Noh, Hyun Jin; Kim, Sung Tae; Kwak, Ki Chang; Yoon, Uicheul; Lee, Jong Min; Lee, Jong Weon; Shin, Ji Soo; Kim, Chi Hun; Noh, Young; Cho, Hanna; Kim, Hee Jin; Yoon, Cindy W.; Oh, Seung Jun; Kim, Jae Seung; Choe, Yearn Seong; Lee, Kyung Han; Lee, Jae Hong; Ewers, Michael; Weiner, Michael W.; Werring, David J.; Na, Duk L.

In: Annals of Neurology, Vol. 73, No. 5, 01.05.2013, p. 584-593.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pathogenesis of cerebral microbleeds

T2 - In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment

AU - Park, Jae Hyun

AU - Seo, Sang Won

AU - Kim, Changsoo

AU - Kim, Geon Ha

AU - Noh, Hyun Jin

AU - Kim, Sung Tae

AU - Kwak, Ki Chang

AU - Yoon, Uicheul

AU - Lee, Jong Min

AU - Lee, Jong Weon

AU - Shin, Ji Soo

AU - Kim, Chi Hun

AU - Noh, Young

AU - Cho, Hanna

AU - Kim, Hee Jin

AU - Yoon, Cindy W.

AU - Oh, Seung Jun

AU - Kim, Jae Seung

AU - Choe, Yearn Seong

AU - Lee, Kyung Han

AU - Lee, Jae Hong

AU - Ewers, Michael

AU - Weiner, Michael W.

AU - Werring, David J.

AU - Na, Duk L.

PY - 2013/5/1

Y1 - 2013/5/1

N2 - Objective Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment. Methods We included 226 patients: 89 with Alzheimer disease-related cognitive impairment (ADCI) and 137 with subcortical vascular cognitive impairment (SVCI). All subjects underwent amyloid imaging with [11C] Pittsburgh compound B (PiB) positron emission tomography, and MRI to detect CMBs and markers of subcortical SVD, including the volume of white matter hyperintensities (WMH) and the number of lacunes. Results Parietal and occipital lobar CMBs counts were higher in PiB+ ADCI with moderate WMH than PiB+ ADCI with minimal WMH, whereas PiB- patients with SVCI (ie, "pure" SVCI) showed both lobar and deep CMBs. In multivariate analyses of the whole cohort, WMH volume and lacuna counts were positively associated with both lobar and deep CMBs, whereas amyloid burden (PiB) was only associated with lobar CMBs. There was an interaction between lacuna burden and PiB retention on lobar (but not deep) CMBs (p<0.001). Interpretation Our findings suggest that although deep CMBs are mainly linked to subcortical SVD, both subcortical SVD and amyloid-related pathologies (eg, CAA) contribute to the pathogenesis of lobar CMBs, at least in subjects with mixed lobar and deep CMBs. Furthermore, subcortical SVD and amyloid-related pathologies interact to increase the risk of lobar CMBs. Ann Neurol 2013;73:584-593

AB - Objective Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment. Methods We included 226 patients: 89 with Alzheimer disease-related cognitive impairment (ADCI) and 137 with subcortical vascular cognitive impairment (SVCI). All subjects underwent amyloid imaging with [11C] Pittsburgh compound B (PiB) positron emission tomography, and MRI to detect CMBs and markers of subcortical SVD, including the volume of white matter hyperintensities (WMH) and the number of lacunes. Results Parietal and occipital lobar CMBs counts were higher in PiB+ ADCI with moderate WMH than PiB+ ADCI with minimal WMH, whereas PiB- patients with SVCI (ie, "pure" SVCI) showed both lobar and deep CMBs. In multivariate analyses of the whole cohort, WMH volume and lacuna counts were positively associated with both lobar and deep CMBs, whereas amyloid burden (PiB) was only associated with lobar CMBs. There was an interaction between lacuna burden and PiB retention on lobar (but not deep) CMBs (p<0.001). Interpretation Our findings suggest that although deep CMBs are mainly linked to subcortical SVD, both subcortical SVD and amyloid-related pathologies (eg, CAA) contribute to the pathogenesis of lobar CMBs, at least in subjects with mixed lobar and deep CMBs. Furthermore, subcortical SVD and amyloid-related pathologies interact to increase the risk of lobar CMBs. Ann Neurol 2013;73:584-593

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