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      Usefulness of TNFR1 as biomarker of intracranial aneurysm in patients with spontaneous subarachnoid hemorrhage

      1 , 2 , 3 , 4 , 5 , 6 , * , 1 , 3
      Future Science OA
      Future Science Ltd
      aneurysm, biomarker, spontaneous subarachnoid hemorrhage, stroke, TNFR1

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          To determine the utility of TNF-α receptor (TNFR1) as a biomarker for the presence of aneurysms in patients with acute subarachnoid hemorrhage (SAH).

          Patient & methods:

          This is a prospective study in patients with acute spontaneous SAH. Arterial blood from catheter near aneurysm and peripheral venous blood samples are collected. TNFR1 levels were analyzed in patients with and without aneurysm.


          80 patients were included, 58 were analyzed. 41 patients (70.7%) had an aneurysm. Venous TNFR1 levels >1658 pg/ml had 46.3% sensitivity and 94.1% specificity for aneurysms presence. TNFR1 >1658 pg/ml was also an independent predictor for its presence (odds ratio = 12.03 [1.13–128.16]; p = 0.039).


          High levels of TNFR1 in peripheral venous blood are associated with the presence of aneurysm in patients with acute SAH.

          Lay abstract

          Subarachnoid hemorrhage (SAH) is a neurological emergency, in many cases caused by the rupture of a cerebral aneurysm. Usually aneurysms are detected in imaging tests, but sometimes they can be very small and go unnoticed. TNF-α is an inflammatory biomarker related to the presence and rupture of intracranial aneurysms and its receptor, TNFR1, could be detected in peripheral blood. This study demonstrates that elevated peripheral blood TNFR1 values are related to the presence of intracranial aneurysms in patients with acute subarachnoid hemorrhage. Following further research, it could become a useful tool for detecting small aneurysms in addition to conventional imaging tests.

          Most cited references14

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          Increased plasma levels of BDNF and inflammatory markers in Alzheimer's disease.

          Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Neurotrophic factors and inflammatory markers may play considerable roles in AD. In this study we measured, through Enzyme-Linked Immunosorbent Assay, the plasma levels of brain derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF) and neuronal growth factor (NGF), as well as tumor necrosis factor-alpha soluble receptors, sTNFR1 and sTNFR2, and soluble intercellular adhesion molecule 1 (sICAM-1), in 50 AD patients, 37 patients with mild cognitive impairment (MCI) and 56 healthy elderly controls. BDNF levels, expressed as median and interquartile range, were higher for AD patients (2545.3, 1497.4-4153.4 pg/ml) compared to controls (1503.8, 802.3-2378.4 pg/ml), P < 0.001. sICAM-1 was also higher in AD patients. sTNFR1 levels were increased in AD when compared to controls and also to MCI. GDNF, NGF and sTNFR2 levels showed no significant differences among the studied groups. The increase in BDNF might reflect a compensatory mechanism against early neurodegeneration and seems to be related to inflammation. sTNFR1 appears to mark not only the inflammatory state but also differentiates between MCI and AD, which may be an additional tool for differentiating degrees of cognitive impairment.
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            Epidemiology and genetics of intracranial aneurysms.

            Intracranial aneurysms are acquired lesions (5-10% of the population), a fraction of which rupture leading to subarachnoid hemorrhage with devastating consequences. Until now, the exact etiology of intracranial aneurysms formation remains unclear. The low incidence of subarachnoid hemorrhage in comparison with the prevalence of unruptured IAs suggests that the vast majority of intracranial aneurysms do not rupture and that identifying those at highest risk is important in defining the optimal management. The most important factors predicting rupture are aneurysm size and site. In addition to ambiental factors (smoking, excessive alcohol consumption and hypertension), epidemiological studies have demonstrated a familiar influence contributing to the pathogenesis of intracranial aneurysms, with increased frequency in first- and second-degree relatives of people with subarachnoid hemorrhage. In comparison to sporadic aneurysms, familial aneurysms tend to be larger, more often located at the middle cerebral artery, and more likely to be multiple. Other than familiar occurrence, there are several heritable conditions associated with intracranial aneurysm formation, including autosomal dominant polycystic kidney disease, neurofibromatosis type I, Marfan syndrome, multiple endocrine neoplasia type I, pseudoxanthoma elasticum, hereditary hemorrhagic telangiectasia, and Ehlers-Danlos syndrome type II and IV. The familial occurrence and the association with heritable conditions indicate that genetic factors may play a role in the development of intracranial aneurysms. Genome-wide linkage studies in families and sib pairs with intracranial aneurysms have identified several loci on chromosomes showing suggestive evidence of linkage, particularly on chromosomes 1p34.3-p36.13, 7q11, 19q13.3, and Xp22. For the loci on 1p34.3-p36.13 and 7q11, a moderate positive association with positional candidate genes has been demonstrated (perlecan gene, elastin gene, collagen type 1 A2 gene). Moreover, 3 of the polymorphisms analyzed in 2 genes (endothelial nitric oxide synthase T786C, interleukin-6 G572C, and interleukin-6 G174C) were found to be significantly associated with ruptured/unruptured aneurysms: the endothelial nitric oxide synthase gene single-nucleotide polymorphisms increased the risk, while IL-6 G174C seemed protective. More recently, two genomic loci (endothelin receptor A and cyclin-dependent kinase inhibitor 2BAS) have been found to be significantly associated with intracranial aneurysms in the Japanese population; endothelin-1 is a potent vasoconstrictor produced by the endothelial cells. Until now, there are no diagnostic tests for specific genetic risk factors to identify patients who are at a high risk of developing intracranial aneurysms. Knowledge of the genetic determinants may be useful in order to allow clues on stopping aneurysm formation and obtain diagnostic tools for identifying individuals at increased risk. Further multicenter studies have to be carried out. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
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              Critical role of TNF-alpha-TNFR1 signaling in intracranial aneurysm formation

              Background Intracranial aneurysm (IA) is a socially important disease due to its high incidence in the general public and the severity of resultant subarachnoid hemorrhage that follows rupture. Despite the social importance of IA as a cause of subarachnoid hemorrhage, there is no medical treatment to prevent rupture, except for surgical procedures, because the mechanisms regulating IA formation are poorly understood. Therefore, these mechanisms should be elucidated to identify a therapeutic target for IA treatment. In human IAs, the presence of inflammatory responses, such as an increase of tumor necrosis factor (TNF)-alpha, have been observed, suggesting a role for inflammation in IA formation. Recent investigations using rodent models of IAs have revealed the crucial role of inflammatory responses in IA formation, supporting the results of human studies. Thus, we identified nuclear factor (NF)-kappaB as a critical mediator of inflammation regulating IA formation, by inducing downstream pro-inflammatory genes such as MCP-1, a chemoattractant for macrophages, and COX-2. In this study, we focused on TNF-alpha signaling as a potential cascade that regulates NF-kappaB-mediated IA formation. Results We first confirmed an increase in TNF-alpha content in IA walls during IA formation, as expected based on human studies. Consistently, the activity of TNF-alpha converting enzyme (TACE), an enzyme responsible for TNF-alpha release, was induced in the arterial walls after aneurysm induction in a rat model. Next, we subjected tumor necrosis factor receptor superfamily member 1a (TNFR1)-deficient mice to the IA model to clarify the contribution of TNF-alpha-TNFR1 signaling to pathogenesis, and confirmed significant suppression of IA formation in TNFR1-deficient mice. Furthermore, in the IA walls of TNFR1-deficient mice, inflammatory responses, including NF-kappaB activation, subsequent expression of MCP-1 and COX-2, and infiltration of macrophages into the IA lesion, were greatly suppressed compared with those in wild-type mice. Conclusions In this study, using rodent models of IAs, we clarified the crucial role of TNF-alpha-TNFR1 signaling in the pathogenesis of IAs by inducing inflammatory responses, and propose this signaling as a potential therapeutic target for IA treatment.

                Author and article information

                Future Sci OA
                Future Sci OA
                Future Science OA
                Future Science Ltd (London, UK )
                05 November 2019
                January 2020
                05 November 2019
                : 6
                : 1
                : FSO431
                [1 ]Neurology Unit, Hospital Virgen Macarena, Seville, Spain
                [2 ]Neurovascular Laboratory, Instituto de Biomedicina de Sevilla, Seville, Spain
                [3 ]Neurovascular Research Laboratory, Institut de Recerca, Hospital Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain
                [4 ]Neuroradiology Department, Centro Hospitalar Lisboa Central, Lisboa, Portugal
                [5 ]Neuroradiology Department, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
                [6 ]Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, Lisboa, Portugal
                Author notes
                [* ]Author for correspondence: Tel.: +34 955 923 046; Fax: +34 955 013 292; jmontaner-ibis@ 123456us.es

                Co-first authors

                Author information
                © 2019 Joan Montaner

                This work is licensed under the Creative Commons Attribution 4.0 License

                : 29 July 2019
                : 27 September 2019
                : 05 November 2019
                Page count
                Pages: 7
                Research Article

                aneurysm,biomarker,spontaneous subarachnoid hemorrhage,stroke,tnfr1


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