Evaluation Of Development Of Venous Collaterals And Biological Mechanisms Underlying Early Deterioration Of Parenchymal Lesions In Cerebral Venous And Sinus Thrombosis

Part 1 Significance of Venous Collateral Grading of Cerebral Venous and Sinus Thrombosis Based on Magnetic Resonance VenogramBackground:The hypothesis that venous collaterals prevent the deterioration of venous infarction was not established in patients with cerebral venous sinus thrombosis(CVST).Evidence is also scarce on the associations between clinical outcomes and the grades of venous collaterals.Purpose:This study aimed to analyze,(1)the venous collateral scores of cerebral venous collaterals,(2)whether the grading system of venous collaterals can identify the risk of the early deterioration of parenchymal lesions.And(3)the impact of venous collaterals grading on the clinical outcome of patients with CVST.Methods:A retrospective study was conducted on CVST patients who were hospitalized at The First Affiliated Hospital of Guangxi Medical University between January 2012 and August 2020.Clinical features,risk factors,laboratory and imaging findings were included.The venous collateral scores(VCS)were used to assess the grades of venous collaterals.The early deterioration of parenchymal lesions on MRI was evaluated at day 8±2 and identified as early worsening of nonhemorrhagic lesion,early worsening of hemorrhagic lesion.The clinical outcome was evaluated on the modified Rankin Scale(m RS)at discharge and 90 days after discharge.The association between collaterals grades and the deterioration of parenchymal lesions and clinical outcomes was evaluated.Results:Two hundred and forty-three CVST patients were included,of whom 204(83%)presented with venous collaterals: the venous collateral score was 1 for 77(31.7%)patients,2 for 127(52.3%)patients,and 0 for 39(16%)patients.In patients with superior sagittal sinus thrombosis(SSST)the odds ratio of VCS 0 to VCS 2 is 0.381(95% CI=0.671-0.858,P=0.001).Venous collaterals with VCS 0 is associated with the higher risk of early deterioration of nonhemorrhagic and hemorrhagic lesion(P<0.05).Patients with VCS 2 had a hazard ratio of 0.201 for poor prognosis compared with patients with VCS 0 at 90 days.(OR=0.201,95% CI=0.068-0.595,P=0.004).No correlation between early prognosis and grades of venous collaterals was found.Conclusions: The VCS based on MRV provides a measure of the type and quality of venous collaterals.SSST is a key factor for the development of efficient venous collaterals.Lacking or insufficient venous collaterals is related to the risk of early deterioration of brain parenchymal lesions.Efficient venous collaterals is an independent predictor of a positive outcome in late evaluation for patients with CVST.Part 2 Evaluation of the Development of Venous Collaterals in Cerebral Venous and Sinus Thrombosis Patients by Transcranial Doppler SonographyBackground: The development of venous collaterals is an important factor in the prognosis of patients with CVST.The sensitivity and specificity of Transcranial Doppler sonography(TCD)are effective in the monitoring and evaluation of intracranial hemodynamic and the development of venous collaterals.TCD is non-invasive,cost-effective,and repetitive.There are yet any systematic studies on the use of TCD on the hemodynamic patterns of CVST and its impact on the prognosis of CVST.Purpose: We use TCD to study the hemodynamic patterns of CVST and its impact on the prognosis of CVST in order to assess the effectiveness of venous collaterals.Methods: A prospective study was conducted on patients diagnosed with CVST at the neurology department of four affiliated hospitals of Guangxi Medical University in the period from July 2018 to January 2021.Peak Systolic velocity(PSV)of intracranial venous was assessed with TCD within 24 hours of admission and 3,7,30 days after admission.We studied the intracranial hemodynamic pattern and assessed the relations between PSV and its declining rate and the grading of venous collaterals.We also evaluated the impact on the prognosis.Results: Pathological increased PSV on the affected side of intracranial venous was observed in 32 CVST patients out of a total of 40 CVST patients.PSV on the affected side of intracranial venous,including Deep Middle Cerebral Venous(DMCV),the basal vein of Rosenthal(BVR),Inferior Petrosal Sinus(IPS),and Parasellar Region(PR),peaked within 3 days of admission and gradually declined,the rate of declining is the highest from day 3 to day 7 and stabilized on day 30 in DMCV,BVR and IPS.On the affected side,the PSV in BVR on day 7 and the declining rate of PSV in IPS between day 3 to day 7 are independent factors for the grading of venous collaterals.Patients with high PSV on the affected side in BVR on day 1 and in PR on day 7 or a low declining rate of PSV in DMCV on day 7 were at a high risk of early poor prognosis(P<0.05).Patients with lower PSV on the affected side in BVR on day 7 and a low declining rate of PSV in DMCV on day 7 to day 30 were at a higher risk of late poor prognosis(P<0.05).Conclusions: The PSV of intracranial venous and its declining rate provide by TCD can be used to grade the venous collaterals in patients with CVST.Low PSV and its high declining rate are significant markers of the ineffectiveness of venous collaterals and can used to predict the poor prognosis of CVST.Part 3 Biological Mechanisms Underlying Early Deterioration of Parenchymal Lesions of Cerebral Venous and Sinus Thrombosis Based on miRNABackground: Micro-ribonucleic acids(miRNAs)are involved in the pathological development of ischemic stroke,especially in the occurrence of early neurological deterioration.However,the mechanism of the miRNA expression and function in the early deterioration of parenchymal lesions(EDPL)in patients with cerebral venous and sinus thrombosis(CVST)remain unclear.Purpose: To identify EDPL-related target genes and miRNA expression profiles,and to explore the biological mechanism of miRNAs in EDPL at the molecular level.Methods: We use complete transcription sequencing to identify the differentially expressed mRNA and miRNA in three CVST patients with EDPL and three without EDPL.The significantly enriched molecular pathways were identified by enrichment analysis screening.The differentially expressed mRNAs were used to construct the protein-protein interaction(PPI)network for the screening of the target genes and their transcribed proteins which play a key role in the occurrence of EDPL.miRNAs were screened,through differential expression analysis,for those that may regulate key target genes to construct the miRNA-mRNA regulatory network.Subsequently the possible miRNA-mRNA molecular regulatory network mechanism of EDPL was constructed.Results: 1.The target genes of EDPL may be HIST1H2 BD,HIST1H4C,HIST1H4 E,HIST1H4F,HIST1H4 J,HIST1H4K,HIST2H4 B.The major regulatory pathways include Negative regulation of megakaryocyte differentiation,Telomere capping,DNA replication-independent nucleosome assembly,Telomere organization and DNA replication-dependent nucleosome assembly.2.A total of 40 differential miRNAs were involved in the regulation of mRNA,and together with the 7 target genes mentioned above,a molecular regulation network of miRNA-mRNA was constructed.Among the 40 differential miRNAs involved in the regulation of target genes,hsa-mi R-193a-5p,hsa-mi R-4717-3p,hsa-mi R-320 b,hsa-mi R-320a-3p,hsa-mi R-4741,hsa-mi R-93-5p,hsa-mi R-363-5p,hsa-mi R-3918,hsa-mi R-3184-5p,and hsa-mi R-877-5p may play a crucial role in the occurrence of EDPL in CVST patients.Conclusion: 1.Target genes associated with EDPL were identified in CVST patients,and the signaling pathways involved in the occurrence and development of EDPL were predicted.2.Key miRNAs that regulate EDPL-related target genes were identified,and a miRNA-target gene regulatory network was constructed,which suggest that key miRNAs may play a crucial role in the occurrence of EDPL by regulating related target genes.