Biomarker evidence for mild central nervous system injury after surgically-induced circulation arrest

Siman, Robert; Roberts, Veronica; McNeil, Elizabeth; Dang, Antony; Bavaria, Joseph E.; Ramchandren, Sindhu; McGarvey, Michael L.

doi:10.1016/j.brainres.2008.03.034

Cited by 55 publications

(43 citation statements)

References 59 publications

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“…20 Increased spectrin fragments were found in cerebrospinal fluid of patients with mild central nervous system injury. 21 Filamin A is cleaved by the proteases calpain, caspase, and granzyme B. 22,23 Evaluating caspase 3 and granzyme B activity in a subset of patients showed no difference between normal aorta and MFS aneurysm (data not shown), whereas calpain did.…”

Section: Discussionmentioning

confidence: 97%

Proteomic Analysis in Aortic Media of Patients With Marfan Syndrome Reveals Increased Activity of Calpain 2 in Aortic Aneurysms

et al. 2009

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Background-Marfan syndrome (MFS) is a heritable disorder of connective tissue, affecting principally skeletal, ocular, and cardiovascular systems. The most life-threatening manifestations are aortic aneurysm and dissection. We investigated changes in the proteome of aortic media in patients with and without MFS to gain insight into molecular mechanisms leading to aortic dilatation. Methods and Results-Aortic samples were collected from 46 patients. Twenty-two patients suffered from MFS, 9 patients had bicuspid aortic valve, and 15 patients without connective tissue disorder served as controls. Aortic media was isolated and its proteome was analyzed in 12 patients with the use of 2-dimensional difference gel electrophoresis and mass spectrometry. We found higher amounts of filamin A C-terminal fragment, calponin 1, vinculin, microfibrilassociated glycoprotein 4, and myosin-10 heavy chain in aortic media of MFS aneurysm samples than in controls.Regulation of filamin A C-terminal fragmentation was validated in all patient samples by immunoblotting. Cleavage of filamin A and the calpain substrate spectrin was increased in the MFS and bicuspid aortic valve groups. Extent of cleavage correlated positively with calpain 2 expression and negatively with the expression of its endogenous inhibitor calpastatin. Conclusions-Our observation demonstrates for the first time upregulation of the C-terminal fragment of filamin A in dilated aortic media of MFS and bicuspid aortic valve patients. In addition, our results present evidence that the cleavage of filamin A is highly likely the result of the protease calpain. Increased calpain activity might explain, at least in part, histological alterations in dilated aorta. Key Words: aneurysm Ⅲ aorta Ⅲ calpain Ⅲ Marfan syndrome Ⅲ proteomics M arfan syndrome (MFS) is a disorder of connective tissue caused by mutations in the fibrillin-1 gene (FBN-1) that may lead to abnormal regulation of transforming growth factor-␤ (TGF-␤) signaling. 1 Clinical manifestation implies principally the cardiovascular, skeletal, and ocular systems, and other systems such as skin, lung, and dura may also be affected. Cardiovascular defects involve dilatation of the ascending aortic root leading to aortic aneurysm and dissection, which are the main cause of morbidity and mortality in MFS, and mitral valve prolapse with or without regurgitation. 2 Clinical Perspective on p 991Molecular mechanisms of aneurysm formation and its treatment are the subject of intensive research. Three key proteins seem to directly contribute to aneurysm formation. First, defective fibrillin-1 is thought to alter targeting and sequestration of TGF-␤, leading to increased TGF-␤ activity. 1 Blocking TGF-␤ activity with antagonists such as TGF-␤-neutralizing antibodies prevents aneurysm formation in a mouse model of MFS. 3 Second, angiotensin II (Ang II) is upregulated in MFS. 4 Treatment of patients with Ang II type 1 (AT 1 ) receptor (AT 1 R) blocker or angiotensin-converting enzyme (ACE) inhibitors reduces progression of aortic d...

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Section: Discussionmentioning

confidence: 97%

Proteomic Analysis in Aortic Media of Patients With Marfan Syndrome Reveals Increased Activity of Calpain 2 in Aortic Aneurysms

et al. 2009

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“…38,51,[132][133][134] In addition to spectrin breakdown products, other potential markers of axonal injury include various phosphoforms of the neurofilament-H subunit as well as cleaved tau suggesting damage to the axon cytoskeleton. [135][136][137][138] Also, a decrease and proteolytic breakdown of myelin basic protein may be an indicator for ongoing Wallerian degeneration and its associated axonal destruction. [137][138][139][140][141][142][143] The potential utility of these biomarkers will be influenced by their different expression profiles over time post-injury because of their differential roles in the initiation of axonal damage and its progression.…”

Section: Biomarkersmentioning

confidence: 99%

“…These include calpain derivatives of aII-spectrin, NFH phosphoforms, and UCH-L1, as well as neuron-specific enolase and 14-3-3 b and z isoforms, found acutely after global or focal cerebral ischemia in both experimental animals and humans. 123,136,145,153 It is anticipated that TBI biomarker evaluation will play an essential role in assessing the burden of DAI and its potential therapeutic modulation. While there has been substantial progress, however, it remains unclear when a validated test will emerge.…”

Section: Biomarkersmentioning

confidence: 99%

Therapy Development for Diffuse Axonal Injury

Smith

Hicks

Povlishock

2013

Journal of Neurotrauma

174

146

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Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including routine postmortem neuropathology as well as advanced imaging, which is now capable of detecting the signatures of traumatically induced axonal injury across a spectrum of traumatically brain-injured persons. Despite the increased interest in DAI and its overall implications for brain-injured patients, many questions remain about this component of TBI and its potential therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of this component of TBI, the National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target-based therapies that have been used, to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic. Although all participants realize that various research gaps remained in our understanding and treatment of this complex component of TBI, this workshop refines these issues providing, for the first time, a comprehensive appreciation of what has been done and what critical needs remain unfulfilled.

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“…Previous studies in adults have demonstrated that it is increased after TBI Siman et al, 2008Siman et al, ,2009. In addition, it may be a marker of neuronal loss after aneurysmal subarachnoid hemorrhage (Lewis et al, 2010), as well as a marker of abnormal blood-brain barrier function after severe TBI (Blyth et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Serum Concentrations of Ubiquitin C-Terminal Hydrolase-L1 and αII-Spectrin Breakdown Product 145 kDa Correlate with Outcome after Pediatric TBI

Berger

Hayes

Richichi³

et al. 2012

Journal of Neurotrauma

131

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Predicting outcome after pediatric traumatic brain injury (TBI) is important for providing information to families and prescribing rehabilitation services. Previously published studies evaluating the ability of serum biomarkers to predict outcome after pediatric TBI have focused on three markers: neuron-specific enolase (NSE), S100B, and myelin-basic protein (MBP), all of which have important limitations. The study objectives were to measure serum concentrations of two novel serum biomarkers, ubiquitin C-terminal hydrolase (UCH-L1) and aII-spectrin breakdown product 145 kDa (SBDP145), in children with TBI and healthy controls and to assess the ability of these markers to predict outcome as assessed by a dichotomous Glasgow Outcome Scale (GOS) score. We also sought to compare the predictive ability of UCH-L1 and SBDP145 to that of the clinical gold standard, the Glasgow Coma Scale (GCS) score, and to that of the well-accepted biomarkers NSE, S100B, and MBP. Serum UCH-L1 and SBDP145 concentrations were significantly greater in subjects than in controls. The increase in UCH-L1 and SBDP145 was exclusively seen in subjects with moderate and severe TBI; there was no increase after mild TBI. Both markers had a significant negative partial correlation with the GCS after controlling for age. Both UCH-L1 and SBDP145 were correlated with GOS, and this correlation was stronger than the correlations with NSE, S100B, or MBP. These results suggest that these two markers may be useful in assessing outcome after moderate and severe pediatric TBI.

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Biomarker evidence for mild central nervous system injury after surgically-induced circulation arrest

Cited by 55 publications

References 59 publications

Proteomic Analysis in Aortic Media of Patients With Marfan Syndrome Reveals Increased Activity of Calpain 2 in Aortic Aneurysms

Proteomic Analysis in Aortic Media of Patients With Marfan Syndrome Reveals Increased Activity of Calpain 2 in Aortic Aneurysms

Therapy Development for Diffuse Axonal Injury

Serum Concentrations of Ubiquitin C-Terminal Hydrolase-L1 and αII-Spectrin Breakdown Product 145 kDa Correlate with Outcome after Pediatric TBI

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