Interaction Between Cerebral Small Vessel Diseases And Iron Deposition In Grey Nucleus:Quantitative Susceptibility Mapping Study

Objective To analyze the relationship between cerebral small vessel diseases(CSVDs)such as lacunar infarction(LI),white matter hyperintensity(WMH),cerebral microbleed(CMB),brain atrophy and iron deposition in gray matter nucleus in the elderly using Magnetic Resonance Imaging(MRI)and quantitative magnetic sensitivity maps(QSM),and further explore the interactive effect of two entities.Methods Patients was collected from November 2013 to November 2018 in Tianjin First Central hospital who performed MRI examination because of head discomfort,but no obvious structural lesion such as acute ischemia,hemorrhage and malacia was detected.A total of 128 patients were enrolled in the study,including 89 patients with single or multiple cerebral microbleeds(CMBs)and 39 patients with no abnormalities in the susceptibility weighted imaging(SWI).All patients enrolled had complete imaging data such as conventional T1 WI,T2WI,diffusion weighted imaging(DWI),apparent diffusion coefficient(ADC),magnetic sensitive weighted imaging(SWI).Patients' clinical data such as gender,age,history of hyperlipidemia,hyperhomocysteinemia,diabetes,coronary heart disease,hypertension,and history of previous infarction were all recorded.SWI images were post-processed to obtain QSM images,and SPIN(signal processing in nuclear magnetic resonance)software was used to measure susceptibility of 14 gray matter nucleus on QSM images including bilateral caudate nucleus,putamen,globus pallidus,thalamus,red nucleus,substantia nigra and dentate nucleus.The location and number of CMBs were evaluated on SWI and recorded,the volume of CMBs were measured on QSM images;the severity of white matter sparsity was scored according to the Fazekas scale on T2 WI images;the severity of brain atrophy was graded according to the cortical brain atrophy scale;the lacunar infarction was evaluated and counted on T2 WI images.The intraclass correlation coefficient and Bland-Altman was used to analyze the inter and intra observer repeatability of the iron deposition measurement.The Spearman test was used to analyze the correlation between susceptibility of gray matter nucleus and imaging markers of cerebral small vessel.Multivariate linear stepwise regression analysis was used to investigate the correlation between iron deposition of each nucleus and cerebral CSVDs markers such as number and volume of CMBs,white matter hyperintensity,lacunar infarcts and brain atrophy,with clinical data such as age,gender,history of hyperlipidemia,hyperhomocysteinemia,diabetes,coronary heart disease,hypertension,and previous infarction correlated.Patients were divided into 4 groups according to the number of microbleeds,one-way ANOVA was used to analyze differences between 4 groups in the clinical data and susceptibility of the gray matter nucleus.Results(1)Feasibility of measure iron deposition using QSM: The magnetic susceptibility of deep gray matter nuclei in 48 CMB-negative subjects was measured using QSM.The results were correlated with the brain iron concentrations obtained in cadaver brain tissue reported in the literature.The significant positive correlation(r = 0.857,p = 0.014)indicates that it is feasible to measure nuclear deposits using QSM.(2)The test-retest reliability and inter-observer reliability in measuring the iron susceptibility of nucleus: Both the test-retest reliability and inter-observer reliability are good(ICC = 0.987,ICC = 0.920 respectively).(3)The correlation between susceptibility of grey matter nucleus and imaging markers of CSVDs:(1)The susceptibility of left caudal nucleus was positively correlated with the total volume of CMBs(r=0.242,p=0.006**)(2)The susceptibility of right thalamus was positively correlated with the number of subtentorial CMBs,the volume of subtentorial CMBs,the total number of CMBs,total volume of CMBs,the number of sub-deep CMBs and the volume of sub-deep CMBs(r=0.283,p=0.001**;r=0.300,p=0.001**;r=0.296,p=0.001**;r=0.261,p=0.003**;r=0.253,p=0.004**;r=0.256,p=0.004**,respectively)(3)The right substantia nigra was significantly positively correlated with number of subtentorial CMBs,the volume of sub-deep CMBs,the total number of CMBs,total volume of CMBs(r=0.243,p=0.006**;r=0.232,p=0.009**;r=0.253,p=0.004**;r=0.261,p=0.003**,respectively)?(4)Multiple linear regression analysis of iron content and CSVDs markers in each nucleus: Multivariate linear stepwise regression analysis showed that(1)the sub-deep volume of CMBs was the independent risk factor for left caudate nuclear deposition(P < 0.05);(2)periventricular white matter hyperintensity is the independent risk factor for left globus pallidus iron deposition(P < 0.05);(3)lacunar infarction,number of sub-deep CMBs,volume of sub-deep CMBs is the risk factors for iron deposition in the left putamen(P < 0.05).(4)Brain atrophy is an independent risk factor for iron deposition in the right putamen(P < 0.05).(5)The number of deep CMBs and the total number of microbleeds were risk factors for left thalamic iron deposition(P < 0.05).(6)The number of subtentorial CMBs is the independent risk factor for the iron deposition of right thalamus(P < 0.05);(7)The volume of subtentorial CMBs is the independent risk factor for the iron deposition of left substantia nigra(P <0.05);(8)The number of subtentorial CMBs is the independent risk factor for the iron deposition of right substantia nigra(P <0.05).(5)The interaction between CSVDs and gray nuclear iron deposition: the MRI image markers of cerebral small vessel disease were used as the dependent variable,and the iron deposition of each nucleus was used as an independent variable to analyze the effect of nuclear iron content on CSVDs.Stepwise regression analysis showed that the right thalamic iron content was the risk factor for all small vessel diseases(P < 0.05),the right thalamus,the right substantia nigra was the risk factors for total number and volume of infratentorial microbleeds,the number and volume of sub-deep microbleeds,and deep white matter hyperintensity(P <0.05).The iron content of right thalamus and left globus pallidus was risk factors for paraventricular white matter hyperintensity(P < 0.05).The right thalamus,the right substantia nigra,and the left globus pallidus are risk factors for the total score of white matter hyperintensities(P < 0.05).The right thalamus and the right putaman are risk factors for brain atrophy.(P <0.05).(6)Clinical data of subjects after grouping according to the number of microbleeds: a total of the 128 patients were divided into 4 groups,including group 1(CMB = 0,N = 39),group 2(CMB = 1-5,N = 34),group 3(CMB = 6-10,N = 24),group 4(CMB > 10,n = 31).The number of patients with hyperhomocysteinemia in group 1 and group 2 was lower than group 4(Bonferroni correction,P <0.0167).The number of patients with hypertension in group 1 was lower than group 3 and 4(Bonferroni correction,P <0.0167).(7)One-way analysis of variance of four groups: there is statistical significance between four groups in left caudate nucleus(p = 0.016),right thalamus(p = 0.002),left substantia nigra(p = 0.026),right substantia nigra(p = 0.043),mean value of substantia nigra(p = 0.011).In the left caudate nucleus and bilateral substantia nigra,there is significantly increase of susceptibility compare any other group to group 1.In the right thalamus,when the number of CMBs is greater than 10,the iron deposits of the nuclei are significantly increased.Conclusion:(1)The QSM images can directly quantify the magnetic susceptibility information in the brain tissue,and can be applied to quantitatively measure the iron deposition of deep gray matter nucleus.(2)The iron deposition of several deep brain nucleus(caudal nucleus,putamen,thalamus,substantia nigra and dentate nucleus)is positively correlated with the severity of various CSVDs.(3)Compared with other SVDs such as white matter hyperintensity and lacunar infarction,microbleeds is more closely related with some gray matter nuclei(caudate nucleus,putamen,thalamus and substantia nigra).(4)The iron overload of some gray nucleus(right thalamus,right substantia nigra,right caudate nucleus,left globus pallidus)may contributed to the occurrence or development of CSVDs.(5)Once the microbleed appear,the iron content of the left caudate nucleus and bilateral substantia nigra increased significantly.When the intracranial microbleeds reached a certain number,the iron content in the right thalamus increased significantly.