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Introduction Vasospasm is a major cause of morbidity after subarachnoid hemorrhage (SAH), and current screening techniques (angiography, transcranial Doppler [TCD], and clinical examination) have serious limitations. Brain oximetry is a promising noninvasive tool to detect reduced brain oxygenation from vasospasm. Methods Consecutive SAH patients at high risk for vasospasm were monitored with the INVOS (Somanetics, IL, USA) 5100C cerebral oximeter. We prospectively collected oximeter readings (rO2) with concurrent values for vital signs, intracerebral pressure (ICP), arterial blood gas measurement, and hemoglobin (HGB). Data were prospectively collected every 12 h and at clinical events (angiography, transfusion, etc.). We prospectively recorded clinical history, clinical events, radiology results, and outcomes. Results Six patients were measured 123 times. rO2 values were correlated with the contralateral side, HGB, blood pressure, and PaO2, but not with ICP or perfusion pressure. There were no measured effects of angiography or transfusion. Patterns relating rO2 readings to clinical, angiographic, or TCD evidence of vasospasm were unclear, and there were no associations with the outcome (cerebral infarction, NIH Stroke Scale, or modified Rankin Scale). Conclusion INVOS rO2 readings are associated with other factors that relate to cerebral oxygen delivery but seem to be of limited use as a screening tool for vasospasm or cerebral infarction after SAH.

Saccular intracranial aneurysms (sIA) are pouch-like pathological dilatations of intracranial arteries that develop when the cerebral artery wall becomes too weak to resist hemodynamic pressure and distends. Some sIAs remain stable over time, but in others mural cells die, the matrix degenerates, and eventually the wall ruptures, causing life-threatening hemorrhage. The wall of unruptured sIAs is characterized by myointimal hyperplasia and organizing thrombus, whereas that of ruptured sIAs is characterized by a decellularized, degenerated matrix and a poorly organized luminal thrombus. Cell-mediated and humoral inflammatory reaction is seen in both, but inflammation is clearly associated with degenerated and ruptured walls. Inflammation, however, seems to be a reaction to the ongoing degenerative processes, rather than the cause. Current data suggest that the loss of mural cells and wall degeneration are related to impaired endothelial function and high oxidative stress, caused in part by luminal thrombosis. The aberrant flow conditions caused by sIA geometry are the likely cause of the endothelial dysfunction, which results in accumulation of cytotoxic and pro-inflammatory substances into the sIA wall, as well as thrombus formation. This may start the processes that eventually can lead to the decellularized and degenerated sIA wall that is prone to rupture.

Abstract BACKGROUND Estrogen deficiency is associated with cerebral aneurysm rupture, but the precise mechanism is unknown. OBJECTIVE To test the hypothesis that IL-6 is required for the increase in aneurysm rupture rate observed in estrogen-deficient mice. METHODS We analyzed IL-6 expression in human cerebral aneurysms. We induced cerebral aneurysms in estrogen-deficient female C57BL/6 mice that had undergone 4-vinylcyclohexene diepoxide (VCD) treatment or bilateral ovariectomy (OVE). Mice were blindly randomized to selective IL-6 inhibition (IL-6 receptor [IL-6R] neutralizing antibody, n = 25) or control (isotype-matched IgG, n = 28). Murine cerebral arteries at the circle of Willis were assessed for aneurysm rupture and macrophage infiltration. RESULTS IL-6 is expressed in human cerebral aneurysms, but not in control arteries. Serum IL-6 is elevated in ovariectomized female mice compared to sham control (14.3 ± 1.7 pg/mL vs 7.4 ± 1.5 pg/mL, P = .008). Selective IL-6R inhibition suppressed cerebral aneurysm rupture in estrogen-deficient mice compared with control (VCD: 31.6% vs 70.0%, P = .026; OVE: 28.6% vs 65.2%, P = .019). IL-6R inhibition had no effect on formation or rupture rate in wild-type mice. IL-6R neutralizing antibody significantly reduced macrophage infiltration at the circle of Willis (1.9 ± 0.2 vs 5.7 ± 0.6 cells/2500 μm2; n = 8 vs n = 15; P < .001). CONCLUSION IL-6 is increased in the serum of estrogen-deficient mice and appears to play a role in promoting murine estrogen deficiency-associated cerebral aneurysm rupture via enhanced macrophage infiltration at the circle of Willis. Inhibition of IL-6 signaling via IL-6 receptor neutralizing antibody inhibits aneurysm rupture in estrogen-deficient mice. IL-6 receptor inhibition had no effect on aneurysm formation or rupture in wild-type animals.

Intracranial aneurysm (IA) is a common cerebrovascular disease in which sacral aneurysms occurring in the Wills ring region can lead to devastating subarachnoid hemorrhage. Despite advances in research, the underlying mechanisms of IA formation and rupture remain incompletely understood, hindering early diagnosis and effective treatment. This review comprehensively summarizes the current landscape of IA biomarkers, encompassing genetic markers, DNA, RNA, inflammatory molecules, oxidative stress proteins, and extracellular matrix (ECM) components. Accumulating evidence suggests that various biomarkers are associated with different stages of IA pathogenesis, including initiation, progression, and rupture. Aberrant ECM composition and remodeling have been observed in IA patients, and extracellular matrix-degrading enzymes are implicated in IA growth and rupture. Biomarker research in IA holds great potential for improving clinical outcomes. Future studies should focus on validating the existing biomarkers, identifying novel ones, and investigating their underlying mechanisms to facilitate the development of personalized preventive and therapeutic strategies for IA.

Abstract Saccular intracranial aneurysm (sIA) rupture leads to a disabling subarachnoid hemorrhage. Chronic inflammation and lipid accumulation in the sIA wall contribute to wall degenerative remodeling that precedes its rupture. A better understanding of the pathobiological process is essential for improved future treatment of patients carrying sIAs. Serum amyloid A (SAA) is an acute-phase protein produced in response to acute and chronic inflammation and tissue damage. Here, we studied the presence and the potential role of SAA in 36 intraoperatively resected sIAs (16 unruptured and 20 ruptured), that had previously been studied by histology and immunohistochemistry. SAA was present in all sIAs, but the extent of immunopositivity varied greatly. SAA immunopositivity correlated with wall degeneration (p = 0.028) and rupture (p = 0.004), with numbers of CD163-positive and CD68-positive macrophages and CD3-positive T lymphocytes (all p < 0.001), and with the expression of myeloperoxidase, matrix metalloproteinase-9, prostaglandin E-2 receptor, and cyclo-oxygenase 2 in the sIA wall. Moreover, SAA positivity correlated with the accumulation of apolipoproteins A-1 and B-100. In conclusion, SAA occurs in the sIA wall and, as an inflammation-related factor, may contribute to the development of a rupture-prone sIA.

The prevalence of intracranial aneurysm (IA) is increasing, and the consequences of its rupture are severe. This study aimed to reveal specific, sensitive, and non‐invasive biomarkers for diagnosis and classification of ruptured and unruptured IA, to benefit the development of novel treatment strategies and therapeutics altering the course of the disease. We first assembled an extensive candidate biomarker bank of IA, comprising up to 717 proteins, based on altered proteins discovered in the current tissue and serum proteomic analysis, as well as from previous studies. Mass spectrometry assays for hundreds of biomarkers were efficiently designed using our proposed deep learning‐based method, termed DeepPRM. A total of 113 potential markers were further quantitated in serum cohort I ( n  = 212) & II ( n  = 32). Combined with a machine‐learning‐based pipeline, we built two sets of biomarker combinations (P6 & P8) to accurately distinguish IA from healthy controls (accuracy: 87.50%) or classify IA rupture patients (accuracy: 91.67%) upon evaluation in the external validation set ( n  = 32). This extensive circulating biomarker development study provides valuable knowledge about IA biomarkers. Synopsis This study constructed a comprehensive mass spectrometry‐based proteomics strategy for serum protein biomarker discovery for intracranial aneurysm (IA). The presented workflow integrates the results of current proteome research and previously reported studies, yielding a comprehensive serum protein biomarker bank of IA. A highly efficient and timesaving PRM assay approach (DeepPRM) is proposed to facilitate targeted quantification of large‐scale candidate proteins. Machine learning on the serum proteome distinguishes IA from healthy controls with an accuracy of 87.50%, and ruptured from unruptured IA with an accuracy of 91.67%. Graphical Abstract This study constructed a comprehensive mass spectrometry‐based proteomics strategy for serum protein biomarker discovery for intracranial aneurysm (IA).

Subarachnoid hemorrhage due to rupture of an intracranial aneurysm has a quite poor prognosis after the onset of symptoms, despite the modern technical advances. Thus, the mechanisms underlying the rupture of lesions should be clarified. To this end, we obtained gene expression profile data and identified the neutrophil-related enriched terms in rupture-prone lesions using Gene Ontology analysis. Next, to validate the role of neutrophils in the rupture of lesions, granulocyte-colony stimulating factor (G-CSF) was administered to a rat model, in which more than half of induced lesions spontaneously ruptured, leading to subarachnoid hemorrhage. As a result, G-CSF treatment not only increased the number of infiltrating neutrophils, but also significantly facilitated the rupture of lesions. To clarify the mechanisms of how neutrophils facilitate this rupture, we used HL-60 cell line and found an enhanced collagenolytic activity, corresponding to matrix metalloproteinase 9 (MMP9), upon inflammatory stimuli. The immunohistochemical analyses revealed the accumulation of neutrophils around the site of rupture and the production of MMP9 from these cells in situ. Consistently, the collagenolytic activity of MMP9 could be detected in the lysate of ruptured lesions. These results suggest the crucial role of neutrophils to the rupture of intracranial aneurysms; implying neutrophils as a therapeutic or diagnostic target candidate.

Intracranial aneurysms are pathological dilatations of cerebral arteries that may rupture and cause subarachnoid hemorrhage. Extracellular matrix remodeling, particularly of Collagen and Elastin, is central to aneurysm progression, but detailed molecular insights remain limited. In this proof-of-concept study, we applied confocal Raman microspectroscopy to matched aneurysmal and healthy basilar artery tissue from the same patient, complemented by an additional control from a second patient. Raman imaging was performed on cryo-sectioned samples using a 532 nm excitation laser. Data were processed using a non-negative matrix factorization–based component analysis with reference spectra of Collagen Types I, III, IV and Elastin. Spectral differences were analyzed by Amide I peak deconvolution and Principal Component Analysis. Aneurysmal tissue showed reduced Collagen and Elastin signals and altered spatial organization. Amide I deconvolution indicated a shift from β-sheet–dominated to α-helical and disordered protein structures. Principal Component Analysis revealed consistent spectral markers separating healthy from diseased tissue. These results demonstrate the potential of confocal Raman microspectroscopy to detect extracellular matrix remodeling and protein conformational changes in intracranial aneurysms, supporting the development of spectroscopic markers for aneurysm wall integrity and rupture risk.

Intracranial aneurysms (IAs) affect 1%-5% of the public and are a major cause of subarachnoid hemorrhage. Currently, there is no medical treatment to prevent the progression or rupture of IAs. Recent studies have defined IA as a chronic inflammatory disease in which macrophages infiltrate intracranial arteries via the CCL2-CCR2 axis. The chemokine signal regulator FROUNT mediates this axis, and it can be inhibited by the anti-alcoholism drug disulfiram. Therefore, inhibition of macrophage infiltration by interfering with FROUNT using disulfiram may represent a strategy to prevent exacerbation of IAs. Here, effects of disulfiram were investigated in vitro and in an animal model of IAs. FROUNT expression was observed on infiltrated macrophages both in human IAs and in the rat IA model by immunohistochemistry. In vitro treatment with disulfiram suppressed CCL2-mediated migration of cultured rat macrophages in a transwell system. Disulfiram administered in a rat model of IAs inhibited both the initiation and the enlargement of IAs in a dose-dependent manner; this was accompanied by suppression of macrophage infiltration. These results suggest that pharmacological inhibition of the CCL2-CCR2-FROUNT signaling cascade could be a treatment of patients with IAs.

Intracranial aneurysms (IAs) are a common cerebrovascular pathology with deadly potential. Neurointerventionalists commonly treat IAs with endovascular coiling, minimizing procedural risk at the cost of an increased recurrence rate. New therapies for reducing the rate of coiled and uncoiled IA growth and rupture would help reduce the morbidity and mortality patients experience when IAs rupture. Hemodynamic shear stress drives IA formation through molecular mechanisms, generating damage-associated molecular proteins (DAMPs), which lead to inflammation and extracellular matrix remodeling. Nuclear factor κB (NF-κB) and interleukin-6 (IL-6) maintain an inflammatory environment in IA walls, generating immune-cell chemotactic proteins, such as monocyte chemoattractant protein-1 (MCP-1) and IL-8. These molecules play a complex role in IAs, being important for IA formation and IA healing. Vascular smooth muscle cells and infiltrated immune cells secrete matrix metalloproteinases (MMPs), which initiate extracellular matrix remodeling. Tissue inhibitors of matrix metalloproteinases (TIMPs) balance this remodeling. The increased MMP to TIMP ratio is characteristic of IA progression, making these molecules important targets for IA therapies. Endothelial dysfunction generates nitric oxide and other reactive oxygen species, which exacerbate inflammation and cell death in IA walls. A better understanding of molecular mechanisms underlying IA formation, progression, and rupture will allow researchers to develop molecular IA therapies.