Angiogenesis And Inflammation In Intracranial Atherosclerotic Stenosis

ObjectiveIntracranial atherosclerosis（ICAS）is a substantial cause of ischemic stroke,with relatively high prevalence and recurrent risk,devoid of disease-modifying therapy,especially in Chinese population.Angiogenesis,as part of collateral circulation,is a crucial process which compensates blood perfusion in territory of stenotic vessels.Inflammation factorsplay a dual role in patients of acute ischemic stroke;in early phase theyfacilitate neuronal apoptosis and neural damage,whereas later they promote tissue repair and neuronal survival.Expression of inflammatory factors can be induced by either ischemia or hypoxia in ICAS patients;and they conduct regulatory effects in angiogenesis through mutual interactions with angiogenic factors.Few studies indicate correlation between angiogenesis and inflammation in real patients of ischemic cerebrovascular disease.MethodsThe study included seventeen severe ICAS or occlusion patients with at least one ischemic event history admitted between December 2016 and May 2017.Clinical and neuroimaging information was collected separately and functional outcomes were scaled by modified Rankin Scale and Mini-Mental Status Examination.Concentration of several inflammatory biomarkers in serum sample were measured through differentassays:highly-sensitive C reactive protein by automatic analyzer;avβ3-integrin and lipoprotein-phospholipase A2（Lp-PLA2）by sandwich ELISA;and other 13 factors,namely interleukins IL-1α,IL-1β,IL-4,IL-6,IL-8,IL-10,IL-17,tumor necrotic factor-a,interferon-γ,cellular adhesion molecules VCAM-1,ICAM-1,transformation growth factor-β and Insulin growth factor-1 by protein array（Raybiotech,US）.The level of above-mentioned 15 inflammatory factors were compared between ICAS patients and healthy controls.10 of 17 patients underwent head ⁶⁸Ga-PRGD2 PET/MR examination.Images were transferred to GE workstation for post-processing and analysis.Region-of-interest with relatively high PRGD2 uptake was outlined by vision analysis.Peak value（pSUV）and average value（SUVavg）of standard uptake value（SUV）were measured in ROI and the corresponding region in the contralateral side of brain;and corresponding cerebral blood flow（CBF）of these regions was measured simultaneously in CBF image processed from 3D Arterial Spin Labeling imaging.Lesion to contralateral side（LCR）of peak SUV and CBF was calculated between the side with high uptake and the other.Statistical analysis validated correlation between level of factors,SUV and other clinical or imaging manifestations.The patients were divided into symptomatic and asymptomatic subgroups according to history of ischemic events in recent six months for further analysis.ResultsSix of ten patients underwent PRGD2 PET/MR shower high uptake of radiotracer,irrelevant to post-ischemic time（PIT）,with pSUV 0.46±0.05 and SUVavg 0.32±0.13.LCR varied in a range of 3.75to68.00.Frequency of FLAIR vessel hyperintensity（FVH）and arterial transit artifacts（ATA）were significantly higher in symptomatic subgroup compared to asymptomatic subgroup（p=0.031）.Consistency of FVH and ATA was high with kappa 0.683.Concentrations of serum IL-6（p=0.009）,IGF-1（p=0.003）and VCAM-1（p=0.017）were significantly higher in case group with no difference between symptomatic subgroups.Correlation analysis revealed a negative correlation between levels of IL-4,IL-8 and PIT.As an indicator of recurrence,the cutoff value of IL-6 from receiver-operating-curve（ROC）was 6.6pg/ml.ConclusionsAngiogenesis was detected in both subacute and chronic ICAS patients by specific radiotracer PRGD2.Serum levels of IL-6,IGF-land VCAM-1 were significantly higher in ICAS patient group compared to healthy controls.High level of IL-6 is a probable indicator of high recurrence regarding to ischemic events.