Iron deposition in the brain after aneurysmal subarachnoid haemorrhage
Iron deposition in the brain after aneurysmal subarachnoid haemorrhage
Background: After aneurysmal subarachnoid hemorrhage (SAH), thrombus forms over the cerebral cortex and releases hemoglobin. When extracellular, hemoglobin is toxic to neurones. High local hemoglobin concentration overwhelms the clearance capacity of macrophages expressing the hemoglobin-haptoglobin scavenger receptor CD163. We hypothesized that iron is deposited in the cortex after SAH and would associate with outcome. Methods: Two complementary cross-sectional studies were conducted. Postmortem brain tissue from 39 SAH (mean postictal interval of 9 days) and 22 control cases was studied with Perls' staining for iron and immunolabeling for CD163, ADAM17 (a disintegrin and metallopeptidase domain 17), CD68, and Iba1 (ionized calcium binding adaptor molecule 1). In parallel, to study the persistence of cortical iron and its relationship to clinical outcome, we conducted a susceptibility-weighted imaging study of 21 SAH patients 6 months postictus and 10 control individuals. Results: In brain tissue from patients dying soon after SAH, the distribution of iron deposition followed a gradient that diminished with distance from the brain surface. Iron was located intracellularly (mainly in macrophages, and occasionally in microglia, neurones, and glial cells) and extracellularly. Microglial activation and motility markers were increased after SAH, with a similar inward diminishing gradient. In controls, there was a positive correlation between CD163 and iron, which was lost after SAH. In SAH survivors, iron-sensitive imaging 6 months post-SAH confirmed persistence of cortical iron, related to the size and location of the blood clot immediately after SAH, and associated with cognitive outcome. Conclusions: After SAH, iron deposits in the cortical gray matter in a pattern that reflects proximity to the brain surface and thrombus and is related to cognitive outcome. These observations support therapeutic manoeuvres which prevent the permeation of hemoglobin into the cortex after SAH.
hemoglobin, inflammation, iron, ischemia, microglia, subarachnoid hemorrhage
1633–1642
Galea, Ian
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Durnford, Andrew
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Glazier, James
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Mitchell, Sophie
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Kohli, Suraj
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Foulkes, Lesley
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Norman, Jeanette
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Darekar, Angela
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Love, Seth
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Bulters, Diederik
d6f9644a-a32f-45d8-b5ed-be54486ec21d
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
1 May 2022
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
Durnford, Andrew
e915b595-7dee-40c6-901d-c9845a7e4f54
Glazier, James
6b1a50ca-5a3a-403d-bb43-bcef38302611
Mitchell, Sophie
9fdadc95-b97d-4fb3-be76-c847d1418932
Kohli, Suraj
9351e1f2-6cea-4c26-8165-6c85c46308da
Foulkes, Lesley
ca340e7e-e79a-456d-959f-17c792dd233b
Norman, Jeanette
b4fa0e8e-3b6e-458b-af1e-2f55c651639a
Darekar, Angela
3148e607-9772-4572-be87-8faa82273da7
Love, Seth
c8c00a86-ecf8-4f61-8377-254305bdbc02
Bulters, Diederik
d6f9644a-a32f-45d8-b5ed-be54486ec21d
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Galea, Ian, Durnford, Andrew, Glazier, James, Mitchell, Sophie, Kohli, Suraj, Foulkes, Lesley, Norman, Jeanette, Darekar, Angela, Love, Seth, Bulters, Diederik, Nicoll, James and Boche, Delphine
(2022)
Iron deposition in the brain after aneurysmal subarachnoid haemorrhage.
Stroke, 53 (5), .
(doi:10.1161/STROKEAHA.121.036645).
Abstract
Background: After aneurysmal subarachnoid hemorrhage (SAH), thrombus forms over the cerebral cortex and releases hemoglobin. When extracellular, hemoglobin is toxic to neurones. High local hemoglobin concentration overwhelms the clearance capacity of macrophages expressing the hemoglobin-haptoglobin scavenger receptor CD163. We hypothesized that iron is deposited in the cortex after SAH and would associate with outcome. Methods: Two complementary cross-sectional studies were conducted. Postmortem brain tissue from 39 SAH (mean postictal interval of 9 days) and 22 control cases was studied with Perls' staining for iron and immunolabeling for CD163, ADAM17 (a disintegrin and metallopeptidase domain 17), CD68, and Iba1 (ionized calcium binding adaptor molecule 1). In parallel, to study the persistence of cortical iron and its relationship to clinical outcome, we conducted a susceptibility-weighted imaging study of 21 SAH patients 6 months postictus and 10 control individuals. Results: In brain tissue from patients dying soon after SAH, the distribution of iron deposition followed a gradient that diminished with distance from the brain surface. Iron was located intracellularly (mainly in macrophages, and occasionally in microglia, neurones, and glial cells) and extracellularly. Microglial activation and motility markers were increased after SAH, with a similar inward diminishing gradient. In controls, there was a positive correlation between CD163 and iron, which was lost after SAH. In SAH survivors, iron-sensitive imaging 6 months post-SAH confirmed persistence of cortical iron, related to the size and location of the blood clot immediately after SAH, and associated with cognitive outcome. Conclusions: After SAH, iron deposits in the cortical gray matter in a pattern that reflects proximity to the brain surface and thrombus and is related to cognitive outcome. These observations support therapeutic manoeuvres which prevent the permeation of hemoglobin into the cortex after SAH.
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Galea et al 2021_postprint
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Accepted/In Press date: 16 November 2021
e-pub ahead of print date: 24 February 2022
Published date: 1 May 2022
Additional Information:
Funding Information:
Professor Galea was supported by the Medical Research Council (MR/L01453X/1). Tissue samples were obtained from the North Bristol NHS Trust as part of UK Brain Archive Information Network (BRAIN UK), which is funded by the Medical Research Council (G0701018, G1100578, MR/N004272/1) and Brain Tumour Research.
Funding Information:
Professor Galea has received research funding from Bio Products Laboratory Limited, the Engineering and Physical Sciences Research Council, and the Medical Research Council supporting work outside the remit of this article but topically related and within the past 36 months. The other authors report no conflicts.
Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.
Keywords:
hemoglobin, inflammation, iron, ischemia, microglia, subarachnoid hemorrhage
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Local EPrints ID: 453063
URI: http://eprints.soton.ac.uk/id/eprint/453063
ISSN: 0039-2499
PURE UUID: b4d15840-5453-4e86-9d6e-fa35f9c32255
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Date deposited: 07 Jan 2022 17:50
Last modified: 17 Mar 2024 06:58
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Author:
Andrew Durnford
Author:
James Glazier
Author:
Sophie Mitchell
Author:
Suraj Kohli
Author:
Lesley Foulkes
Author:
Jeanette Norman
Author:
Angela Darekar
Author:
Seth Love
Author:
Diederik Bulters
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