Iron Deposition in the Brain After Aneurysmal Subarachnoid Hemorrhage

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.

CAU-Net: A Deep Learning Method for Deep Gray Matter Nuclei Segmentation

“…The quantitative measurement of brain iron content using QSM has brought into focus the role of iron in the brain development, physical function modulation, and aging (Salami et al, 2018;Peterson et al, 2019), as well as in various neurological diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, metabolic diseases (hepatic encephalopathy and renal encephalopathy), sleep disorders, hematological system diseases, and cerebrovascular diseases (Chai et al, 2015a;Xia et al, 2015;Miao et al, 2018;Chai et al, 2019;Valdés Hernández et al, 2019;Pudlac et al, 2020;Cogswell et al, 2021;Thomas et al, 2021;Zhang et al, 2021;Galea et al, 2022). As iron has been proned to accumulate in the gray matter nuclei in normal people and all these neurological diseases have abnormal iron deposition in the gray matter nuclei, the gray matter nuclei are the critical target structures to explore the abnormal iron deposition.…”

Microglial heterogeneity after subarachnoid haemorrhage

“… 5 This microglial reaction was highest in the outer cortex closest to the brain surface, with a gradient that diminished inwards in the deeper cortex, in keeping with effects of substances diffusing into the cortex from the subarachnoid space. 5 The most abundant substance released by the blood clot is haemoglobin, which is toxic to neurones and pro-inflammatory. 8 Hence efforts to keep haemoglobin out of the parenchyma, by cerebrospinal fluid diversion or by therapeutic strategies that increase subarachnoid haptoglobin concentration, or both, are likely to be of clinical benefit.…”

“…Second, there is a temporal variation in microglial activation relative to the SAH event, with evidence of a wave of response spreading centrifugally from the base to the cortex of both hemispheres 3 and a shift from M1 to M2 with time 4 . Third the microglial reaction is most intense close to the blood clot 5 or aneurysmal rupture 3,4 in both human 3,5 and experimental 4 studies. In summary, microglia after SAH are likely to exhibit functional heterogeneity, with at least three factors determining the functional state of individual microglial cells: time post‐SAH, location (distance away from aneurysm or blood clot) and pathology (ischaemia, mechanical tissue stretch, inflammation and haemoglobin exposure).…”

“…Hence the presence of a parenchymal microglial reaction suggests one of two possibilities: (1) either the occurrence of events within the parenchyma secondary to the SAH (such as ischaemia from vasospasm) or else (2) an intraparenchymal reaction to factors outside the parenchyma. With respect to the latter, a recent post‐mortem study of brain tissue from 39 patients dying after SAH and 22 controls showed that microglia within the parenchyma upregulated markers of phagocytosis and motility after SAH 5 . This microglial reaction was highest in the outer cortex closest to the brain surface, with a gradient that diminished inwards in the deeper cortex, in keeping with effects of substances diffusing into the cortex from the subarachnoid space 5 .…”

Rethinking the initial changes in subarachnoid haemorrhage: Focusing on real-time metabolism during early brain injury

“… 16 In addition, free iron (Fe 3+ ) released from haemolytic red blood cells is also involved in arteriolar and capillary microvasospasms after SAH in mice, 17 while iron deposits in the cortex have been reported to be associated with cognitive outcomes in SAH patients. 18 …”