TY - JOUR
T1 - Different microvascular alterations underlie microbleeds and microinfarcts
AU - van Veluw, Susanne J.
AU - Scherlek, Ashley A.
AU - Freeze, Whitney M.
AU - ter Telgte, Annemieke
AU - van der Kouwe, Andre J.
AU - Bacskai, Brian J.
AU - Frosch, Matthew P.
AU - Greenberg, Steven M.
N1 - Funding Information:
The work described in this study was supported by the NIH (NINDS R01 NS096730, NIA K99 AG059893, NINDS RF1 NS110054, and NIA R21 AG046657) and the Netherlands Organization for Scientific Research (Rubicon fellowship 019.153LW.014 and Veni 91619021).
Funding Information:
The work described in this study was supported by the NIH (NINDS R01 NS096730, NIA K99 AG059893, NINDS RF1 NS110054, and NIA R21 AG046657) and the Netherlands Organization for Scientific Research (Rubicon fellowship 019.153LW.014 and Veni 91619021). We thank the families of the patients who generously donated their brains to our research studies, and N. Clement for his excellent assistance in the autopsy procedures.
Publisher Copyright:
© 2019 American Neurological Association
PY - 2019/8
Y1 - 2019/8
N2 - Objective Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid beta (A beta) in the walls of cortical vessels and the accrual of microbleeds and microinfarcts over time. The relationship between CAA severity and microbleeds and microinfarcts as well as the sequence of events that lead to lesion formation remain poorly understood. Methods We scanned intact formalin-fixed hemispheres of 12 CAA cases with magnetic resonance imaging (MRI), followed by histopathological examination in predefined areas and serial sectioning in targeted areas with multiple lesions. Results In total, 1,168 cortical microbleeds and 472 cortical microinfarcts were observed on ex vivo MRI. Increasing CAA severity at the whole-brain or regional level was not associated with the number of microbleeds or microinfarcts. However, locally, the density of A beta-positive cortical vessels was lower surrounding a microbleed compared to a simulated control lesion, and higher surrounding microinfarcts. Serial sectioning revealed that for (n = 28) microbleeds, both A beta (4%) and smooth muscle cells (4%) were almost never present in the vessel wall at the site of bleeding, but A beta was frequently observed upstream or downstream (71%), as was extensive fibrin(ogen) buildup (87%). In contrast, for (n = 22) microinfarcts, vascular A beta was almost always observed at the core of the lesion (91%, p <0.001) as well as upstream or downstream (82%), but few vessels associated with microinfarcts had intact smooth muscle cells (9%). Interpretation These observations provide a model for how a single neuropathologic process such as CAA may result in hemorrhagic or ischemic brain lesions potentially through 2 different mechanistic pathways. ANN NEUROL 2019;86:279-292
AB - Objective Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid beta (A beta) in the walls of cortical vessels and the accrual of microbleeds and microinfarcts over time. The relationship between CAA severity and microbleeds and microinfarcts as well as the sequence of events that lead to lesion formation remain poorly understood. Methods We scanned intact formalin-fixed hemispheres of 12 CAA cases with magnetic resonance imaging (MRI), followed by histopathological examination in predefined areas and serial sectioning in targeted areas with multiple lesions. Results In total, 1,168 cortical microbleeds and 472 cortical microinfarcts were observed on ex vivo MRI. Increasing CAA severity at the whole-brain or regional level was not associated with the number of microbleeds or microinfarcts. However, locally, the density of A beta-positive cortical vessels was lower surrounding a microbleed compared to a simulated control lesion, and higher surrounding microinfarcts. Serial sectioning revealed that for (n = 28) microbleeds, both A beta (4%) and smooth muscle cells (4%) were almost never present in the vessel wall at the site of bleeding, but A beta was frequently observed upstream or downstream (71%), as was extensive fibrin(ogen) buildup (87%). In contrast, for (n = 22) microinfarcts, vascular A beta was almost always observed at the core of the lesion (91%, p <0.001) as well as upstream or downstream (82%), but few vessels associated with microinfarcts had intact smooth muscle cells (9%). Interpretation These observations provide a model for how a single neuropathologic process such as CAA may result in hemorrhagic or ischemic brain lesions potentially through 2 different mechanistic pathways. ANN NEUROL 2019;86:279-292
KW - CEREBRAL AMYLOID ANGIOPATHY
KW - CORTICAL MICROINFARCTS
KW - BURDEN
KW - SITES
U2 - 10.1002/ana.25512
DO - 10.1002/ana.25512
M3 - Article
C2 - 31152566
SN - 0364-5134
VL - 86
SP - 279
EP - 292
JO - Annals of Neurology
JF - Annals of Neurology
IS - 2
ER -