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Etiopathogenesis, Diagnosis, Imaging and Treatment of Cervicocerebral Artery Dissections: A Multifactorial, Multidisciplinary and Translational Approach 2 (EDIT-CAD-2-Study)

English title Etiopathogenesis, Diagnosis, Imaging and Treatment of Cervicocerebral Artery Dissections: A Multifactorial, Multidisciplinary and Translational Approach 2 (EDIT-CAD-2-Study)
Applicant Arnold Marcel
Number 140340
Funding scheme SPUM
Research institution Universitätsklinik für Neurologie Inselspital Universität Bern
Institution of higher education University of Berne - BE
Main discipline Clinical Cardiovascular Research
Start/End 01.07.2012 - 30.09.2016
Approved amount 1'954'179.00
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All Disciplines (2)

Discipline
Clinical Cardiovascular Research
Immunology, Immunopathology

Keywords (10)

cyto- & chemokines; factor XIII activation peptide; transcranial Doppler sonography; coagulation markers; biomarker; insitu zymography; cervicocerebral artery dissection; diffusion-weighted MRI; endovascular treatment

Lay Summary (English)

Lead
The Etiopathogenesis, Diagnosis, Imaging and Treatment of Cervico-cerebral Artery Dissections: (EDIT-CAD-2)-project aims to gain knew knowledge in the understanding of the pathogenesis of CAD and to improve diagnosis and treatment of CAD.
Lay summary

Etiopathogenesis, Diagnosis, Imaging and Treatment of Cervicocerebral Artery Dissections: A Multifactorial, Multidisciplinary and Translational Approach 2 (EDIT-CAD-2-Study)
 
Cervicocerebral Artery Dissection (CAD) is one of the most frequent causes of stroke in young and middle-aged adults. A substantial proportion of patients with CAD remain disabled. Thus, understanding the pathomechanisms, and improvement of diagnosis and treatment of the disease have a large medical and socioeconomic impact.
 
The Etiopathogenesis, Diagnosis, Imaging and Treatment of Cervico-cerebral Artery Dissections: (EDIT-CAD-2)-project consist of four subprojects and aims to build and to strengthen multidisciplinary research networks and to gain knew knowledge in the understanding of the pathogenesis of CAD and to improve diagnosis and treatment of CAD.
 
The specific aims of the subprojects of the EDIT-CAD2 study are:
 
1) The subproject “Inflammatory Biochemical and Coagulation Markers in Cervico-cerebral Artery Dissection 2 (BIO-CAD2 ) is based on the interim results of an ongoing project (BIO-CAD) and aims to analyse the association between inflammatory biomarkers, vascular risk factors and CAD.
 
2) The subproject “Contrast Enhanced MRI in Spontaneous and Traumatic Cerviocerebral Artery Dissection (MRI-CAD)” focuses on new contrast-enhanced magnetic resonance imaging technology and aims (1) to investigate the relationship of focal and generalized high-resolution contrast-enhanced MRI signs of vessel wall inflammation with (a) clinical and laboratory signs of infection; (b) presenting clinical signs of CAD; c) the presence of multiple CAD d) the location and the volume of the mural hematoma on MRI and (e) the frequency of recurrent CAD and recurrent  stroke and TIA; and (2) to compare the frequency of focal and generalized perivascular CE and the morphology of the mural hematoma between patients with spontaneous CAD (sCAD) and traumatic CAD (tCAD).
 
3) The subproject “Local assessment of biomarkers in the ischemic brain circulation in acute stroke” (“BIO-STROKE”) aims 1)to assess the biochemical changes in the brain circulation beyond the occlusion in the setting of acute ischemic stroke caused by dissection compared to other aetiology of ischemic stroke; 2) to evaluate the influence of local biomarkers on haemorrhagic transformation of stroke in both subgroups; and 3) to assess differences in the pattern of biomarkers within the thrombus in both subgroups

4) The subproject “Biomarkers and antithrombotic treatment in cervical artery dissection (TREAT-CAD) is based on recent meta-analyses peformed by our groups and the interim results of the ongoing subproject BIO-CAD and aims to demonstrate the non-inferiority of anti-platelet treatment to anti-coagulant treatment in patients with cervical artery dissection (CAD). The secondary objective is to investigate whether inflammatory biomarkes are associated with efficacy and safety of treatment.

Direct link to Lay Summary Last update: 21.07.2014

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
156658 BIO-PLAQUE: The role of plaque imaging and biomarkers for plaque instability in selecting patients with carotid artery stenosis for endarterectomy or stenting - a translational randomised multi-centre study 01.11.2015 Project funding (Div. I-III)
124119 Etiopathogenesis, Diagnosis, Imaging and Treament of Cervicocerebral Artery Dissections: a multifiactorial, multidisciplinary and translational approach (EDIT-CAD-Study) 01.07.2009 SPUM

Abstract

Spontaneous Cervicocerebral artery dissection (CAD) is one of the most frequent causes of stroke in young and middle-aged adults .A substantial proportion of patients with sCAD remain disabled. Thus, understanding the pathomechanisms, and the improvement of diagnostic tools and treatment strategies have a large medical and socioeconomic impact.The ongoing and future projects of the Etiopathogenesis, Diagnosis, Imaging and Treatment of Cervico-cerebral Artery Dissections: A Multifactorial, Multidisciplinary and Translational Approach (EDIT-CAD)-Studies) aim to build and to strengthen multidisciplinary research networks to translationally combine the clinical research expertise of the Neurovascular research groups of the Dpts. of Neurology of the leading Swiss University Hospitals in the field of sCAD and the two most experienced Institutes of Interventional Neuroradiology (University of Berne and Geneva) with the expertise of basic research groups such as the Neuroinfection Laboratory at the Institute for Infectious Diseases, University of Berne; the Haemostasis Research Laboratory, University of Berne; the Laboratory of Thermodynamics in Emerging Technologies, Institute of Energy Technology; Swiss and the Institute for Biomedical Engineering, University and Swiss Federal Institute of Technology Zurich. The future global project EDIT-CAD-2 focuses on the translation of the knowledge and the ideas gained during the ongoing project in clinical practice, to improve diagnosis and management in CAD patients.In the ongoing (EDIT-CAD) und planned (EDIT-CAD-2) global research projects Etiopathogenesis, Diagnosis, Imaging and Treatment of Cervico-cerebral Artery Dissections: A Multifactorial, Multidisciplinary and Translational Approach (EDIT-CAD)-Studies, the consortium aims:1) to gain new insights into the underlying pathogenic mechanisms of CAD (ongoing subprojects BIO-CAD, CADD-CAD, IAT-CAD and HAEM-CAD, new subprojects BIO-CAD2, MRI-CAD, BIO-Stroke;2) to determine new diagnostic insights for the disease (ongoing subproject BIO-CAD, new subproject BIO-CAD2, MRI-CAD)3) to test the hypothesis that patients with focal or generalized inflammation can be identified by high-field contrast-enhanced MRI (new subproject MRI-CAD;4) to determine the optimal treatment strategies based on a randomized trial combining clinical and multimodal surrogate outcomes (new subproject TREAT-CAD); 5) to analyze the efficacy and safety of antithrombotic and endovascular treatment (ongoing subproject IAT-CAD and new subprojects BIO-Stroke and TREAT-CAD) and the influence of inflammatory biomarkers on treatment The specific aims of the ongoing subprojects of the EDIT-CAD study are:1) The subproject “Inflammatory Biochemical and Coagulation Markers in CAD (BIO-CAD) aims to assess inflammatory biomarkers and coagulation markers (D-dimer and Factor XIII-activation peptide, using a newly developed method, to directly measure this Factor in human plasma with a highly sensitive and specific ELISA) in plasma samples from patients with CAD, age- and sex-matched patients with TIA or stroke of other origin than CAD as one control group, and, in healthy individuals as a second control group, by multiplex cytokine array (Luminex). Then to analyse potential risk factors for CAD, and conventional vascular risk factors in patients with CAD and in the two control groups. 2) The subproject “The role of carotid anatomy, distension and displacement in the pathogenesis of carotid artery dissection (CADD-CAD)” will analyse the role of carotid anatomy, distension and displacement in the pathogenesis of carotid artery dissection using Ultrasound, 3 T-MRI, and computational studies. Spontaneous and endothelial-independent (nitroglycerin-mediated) absolute and relative dilatation of the carotid bulb will be measured by carotid ultrasound. High-resolution, diffusion based black-blood 3D imaging will be used to image the diameter and length of the carotid bulb in neutral head position and with head rotation and hyperextension. In addition, multi-directional velocity mapping will provides quantitative velocity values permitting calculation of wall shear stresses through modelling. The computational studies will be carried out using a finite-element structural model.3) The subproject “Ex-vivo and in-vivo evaluation of iatrogenic intimal damage and carotid artery dissection during intra-arterial treatment (IAT-CAD)” will use a carotid artery model to investigate the mechanical forces applied on the vessel wall by endovascular procedures and to evaluate the risk of intima damage and carotid artery dissection by duplicating the clinical situation of thrombus aspiration, thrombectomy, and percutaneous transluminal angioplasty. Measurements on vessel wall stress will be performed under laboratory conditions ex-vivo (cadaver porcine carotid arteries) and in an animal model (porcine). 4) The subproject “Wall Haematoma in Cervicocerebral Artery Dissection (HAEM-CAD)” will determine the association between the location and volume of the wall haematoma on MRI with the degree of carotid obstruction, the presence of local signs on the side of the internal carotid dissection (Horner’s syndrome, cranial nerve palsy) and the risk of cerebral ischemia.The specific aims of the planned subprojects of the EDIT-CAD2 study are:1) The subproject “Inflammatory Biochemical and Coagulation Markers in Cervico-cerebral Artery Dissection 2 (BIO-CAD2 ) is based on the interim results of the ongoing subproject BIO-CAD and aims to (1) confirm the hypotheses of BIO-CAD 1 by a larger sample size; (2) to add Factor H to the array of analytes based on a pilot study; (3) to determine differences in the biomarker pattern of spontaneous CAD and traumatic CAD by adding a patient group of traumatic CAD;(4) to perform gene expression analysis in the acute and late phase of CAD to add new and meaningful biomarkers, to get new insights in the pathogenesis and to identify potential targets for therapy2) The planned subproject “Contrast Enhanced MRI in Spontaneous and Traumatic Cerviocerebral Artery Dissection (MRI-CAD)” is based on the ongoing subprojects HAEM-CAD, BIO-CAD and CADD-CAD focuses on new contrast-enhanced MRI technology and aims (1) to investigate the relationship of focal and generalized high-resolution contrast-enhanced MRI signs of vessel wall inflammation with (a) clinical and laboratory inflammatory signs; (b) presenting clinical signs of cerebral or ocular ischemia; c) the presence of multiple CAD d) the location and the volume of the mural hematoma on MRI and (e) the frequency of recurrent CAD and recurrent cerebrovascular events; and (2) to compare the frequency of focal and generalized perivascular CE and the morphology of the mural hematoma between patients with spontaneous CAD (sCAD) and traumatic CAD (tCAD).3 ) The future subproject “Local assessment of biomarkers in the ischemic brain circulation in acute stroke” (“BIO-STROKE”) assess the biochemical changes in the brain circulation beyond the occlusion in the setting of acute ischemic stroke caused by dissection compared to other aetiology of ischemic stroke; 2) to evaluate the local predictive biomarkers for the haemorrhagic transformation in both subgroups; and 3) to assess differences in the pattern of biomarkers within the thrombus in both subgroups 4) The subproject “Biomarkers and antithrombotic treatment in cervical artery dissection (TREAT-CAD) is based on recent meta-analyses peformed by our groups and the interim results of the ongoing subproject BIO-CAD and aims to demonstrate the non-inferiority of anti-platelet treatment to anti-coagulant treatment in patients with cervical artery dissection (CAD). The secondary objective is to investigate whether the level of MMP9 and the ratio of MMP9 to TIMP2 will be associated with efficacy or safety measures stratified to the allocated treatment regimen.
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