Different microvascular alterations underlie microbleeds and microinfarcts
Open accessAbstract
Objective: Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid β (Aβ) 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 Aβ‐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 Aβ (4%) and smooth muscle cells (4%) were almost never present in the vessel wall at the site of bleeding, but Aβ was frequently observed upstream or downstream (71%), as was extensive fibrin(ogen) buildup (87%). In contrast, for (n = 22) microinfarcts, vascular Aβ 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
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Inflammation does not seem to be a major component in CAA-related microhemorrhage or microinfarction, with the exception of a rare clinical subtype: CAA-related inflammation.
“Inflammation does, however, not seem to be a major component in CAA-related microhemorrhage or microinfarction [38], with the exception of a rare clinical subtype: CAA-related inflammation [6].”
From Cerebrospinal fluid levels of the neurotrophic factor neuroleukin are increased in early Alzheimer’s disease, but not in cerebral amyloid angiopathy (2021) · cites this paper as [38]
The Discussion (page unavailable) argues against local inflammatory responses as an explanation for the vessel-wall changes observed around microbleeds. It does not assess whether inflammation is a major component of CAA-related microinfarction, or rule it out generally for microhemorrhage. The rare inflammatory subtype is attached to a different citation in the citing sentence. (LLM, conf=0.83)
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References 37 · Cited by 104
Research works printed but not linked: 28
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- Authors
- van Veluw, S. J., Scherlek, A. A., Freeze, W. M., ter Telgte, A., van der Kouwe, A. J., Bacskai, B. J., Frosch, M. P., & Greenberg, S. M.
- Affiliations
- MassGeneral Institute for Neurodegenerative Disease Massachusetts General Hospital and Harvard Medical School Charlestown MA
- Harvard University (US)
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital Charlestown MA
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2019-06-14
- Volume
- 86
- Issue
- 2
- Pages
- 279-292
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC8722100
- OpenAlex
- W2947845138
- Cited by
- 104
- References
- 37
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 14 · 2023: 17 · 2022: 10 · 2021: 15 · 2020: 18 · 2019: 1
- FWCI
- 7.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Funders
- National Institutes of Health (K99 AG059893, R01 NS096730, R21 AG046657, RF1 NS110054)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (019.153LW.014, 91619021)
- Topics
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Health Sciences › Medicine › Neurology › Intracranial Aneurysms: Treatment and Complications
- Keywords
- cerebral amyloid angiopathy, cortical microbleeds, cortical microinfarcts, amyloid-beta, microvascular alterations, smooth muscle cells, fibrin deposition, ex vivo MRI, histopathology
- MeSH terms
- Aged, Aged, 80 and over, Cerebral Hemorrhage, Cerebral Infarction, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Cerebral Amyloid Angiopathy, Microvessels
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