Application Of Neurite Orientation Dispersion And Density Imaging And Proton Exchange Rate MRI To Characterize Brain Tissue Microstructural And Metabolic Changes In Ischemic Stroke

In China and worldwide,stroke is a cerebrovascular disease with characteristics of high morbidity,mortality,disability and recurrence rate,and is a serious threat to human life and health,as well as causes a huge economic burden for the society and families.Ischemia is the leading cause of stroke.Thus,accurate and noninvasive assessment of the progression of ischemic stroke is critical for early diagnosis,timely treatment and prognostic prediction.As we know,magnetic resonance imaging(MRI)plays a key role in the evaluation of ischemic stroke.Diffusion MRI(dMRI)is even more indispensable as the only imaging method for noninvasive detection the diffusion process of water molecular in vivo tissue.Diffusion weighted imaging(DWI)has been recognized as the most reliable inspection technique for acute ischemic stroke and become a routine clinical examination method.Diffusion tensor imaging(DTI)can visualize the white matter fiber bundles,so it has also been used in the study of micro structural changes in stroke.As the extension of DTI,diffusion kurtosis imaging(DKI)can better characterize the complexity of micro structure of brain tissue by virtue of its non-Gaussian diffusion model and kurtosis parameters,so it also plays a certain role in the study of ischemic stroke.However,the above dMRI methods are either limited by model assumptions or lack of specific biophysical parameters to specially assess the micro structural changes,they are limited in scientific research and clinical practice.As a novel advanced non-Gaussian biophysical diffusion technique,neurite orientation dispersion and density imaging(NODDI)can effectively overcome these shortcomings of the above diffusion imaging technologies,and also can more specifically and appropriately evaluate the micro structural changes of brain tissue due to ischemic stroke with its unique parameters orientation dispersion index(ODI)and intracellular volume fraction(Vic).Moreover,NODDI can provide more comprehensive information than traditional dMRI to evaluate the pathophysiological mechanism of ischemic stroke,as it focuses on micro structural changes not only in white matter but also in gray matter.In addition to the evaluation of the micro structural changes of brain tissue due to ischemic stroke,emerging imaging techniques such as magnetic resonance spectrum imaging(MRS),chemical exchange saturation transfer(CEST)have also been applied to characterize the metabolic changes of ischemic brain tissue in recent years.However,MRS and CEST MRI have not been widely applied in clinical practice due to these techniques are highly dependent on imaging conditions and parameters and their imaging results are susceptible to interference and influence by a large number of confounding factors.The recently proposed proton exchange rate MRI(kex MRI),which is based on the corrected omega plot,has overcome the dependence on imaging parameters and been successfully applied to the evaluation of proton exchange rate of healthy brain tissue in vivo for the first time.Thus,it can provide a unique perspective for the study of the underlying pathologic mechanisms and clinical management of ischemic stroke.Based on above clinical and technical background,NODDI was applied to the middle cerebral artery occlusion(MCAO)rats and a large cohort of ischemic stroke patients.In addition,kex MRI was applied to assess the metabolic changes of brain tissue due to ischemic stroke.This study mainly contains three parts:the first part is 'Brain micro structural changes in MCAO rats assessed using NODDI and histological analysis'.The aim is to demonstrate the feasibility of NODDI technique in characterizing the brain tissue micro structural changes of MCAO rats at 3 Tesla through comparison of the NODDI metrics among difference groups and analysis of metric evolution,as well as validation of NODDI parameters with histology,and to attempt to noninvasively explain the progression of ischemic stroke using NODDI.The second part is 'Application of NODDI to study brain micro structural changes in patients with ischemic stroke'.The aim is to assess the value of NODDI in studying of patients with ischemic stroke and to compare its sensitivity with DTI and DKI by quantitative analysis of 71 ischemic stroke patients in hyperacute,acute and subacute phases.The third part is 'Assessment of brain metabolic changes in ischemic stroke patients using kex MRI'.The purpose is to map and quantify the kex of brain tissues using improved omega plot in 17 ischemic stroke patients at 3T and to investigate whether kex can serve as a novel potential endogenous surrogate imaging biomarker for detecting the metabolic and pathologic changes due to ischemic stroke through the comparison with CEST,magnetic transfer(MT)and DWI.Part 1 Brain microstructural changes in MCAO rats assessed using NODDI and histological analysisPurpose:To demonstrate the feasibility of NODDI technique in characterizing the brain tissue microstructural changes of MCAO rats at 3 Tesla as well as to validate NODDI parameters with histology.Methods:A multishell dMRI protocol was performed for eleven MCAO rats and ten control rats at different time points of 0.5,2,6,12,24 and 72 h after operation respectively.The NODDI-related metrics of ODI and Vic were derived by the NODDI toolbox.Then,NODDI metrics were compared between infarct areas and contralateral tissues and control group among different time points respectively.Meanwhile,the temporal evolution of NODDI metrics were evaluated.Finally,the biological significances of NODDI metrics were confirmed by histological findings.Results:Infarction showed significantly increased ODI and Vic compared to control tissues at all time points(P<0.001,respectively).Lesion ODI increased gradually from 0.5 to 72 h,while its Vic showed a more complicated and fluctuated evolution.ODI and Vic were significantly different between hyperacute and acute stroke periods(P<0.001,respectively).Finally,NODDI metrics were consistent with histological findings.Conclusion:NODDI metrics could reflect microstructural and pathological changes due to ischemic stroke in MCAO rats at 3 Tesla.This study helps to prepare NODDI for the diagnosis and management of ischemic stroke in translational research and clinical practice.Part 2 Application of NODDI to study brain microstructural changes in patients with ischemic strokePurpose:To demonstrate the value of the NODDI technique in assessing the microstructural changes of brain tissues during ischemic stroke and to compare its sensitivity with DTI and DKI.Methods:Seventy-one patients with hyperacute/acute/subacute ischemic stroke were enrolled in the study.A multishell dMRI protocol was performed for each subject.Diffusion data were analyzed using the NODDI and diffusional kurtosis estimator toolboxes.Then,NODDI metrics between the lesions and the contralateral tissues were compared to evaluate their values in ischemic stroke patients.NODDI metrics among different stroke periods and the correlations between NODDI and the duration since stroke onset were analyzed as well.To compare the NODDI's sensitivity with established diffusion techniques,paired t-tests were performed to determine the absolute percentage changes of diffusion metrics between NODDI and DTI/DKI.Results:Compared with the contralateral tissues,lesions showed significantly increased values of ODI and Vic and decreased values of isotropic volume fraction(Viso).ODI value was significantly different among three periods and showed fair to good positive correlation with the duration since stroke onset(R=0.450,P<0.05).NODDI metrics showed significantly larger absolute percentage changes than that of DTI and DKI(P<0.05,respectively).Conclusion:NODDI allowed efficient evaluation of micro structural changes in brain tissues during ischemic stroke and showed increased sensitivity compared with DTI and DKI.The possible biophysical mechanisms underlying ischemia could be further elucidated using this advanced diffusion technique.Part 3 Assessment of brain metabolic changes in ischemic stroke patients using kex MRIPurpose:To map and quantify the kex of brain tissues using improved omega plot in ischemic stroke patients at 3T and to investigate whether kex can serve as a potential endogenous surrogate imaging biomarker for detecting the metabolic state and the pathologic changes due to ischemic stroke.Methods:Three sets of Z-spectra were acquired from seventeen ischemic stroke patients using a spin echo-echo planar imaging(SE-EPI)sequence with pre-saturation CEST pulse at B1 of 1.5,2.5,and 3.5 ?T,respectively.Image processing and analysis were performed using home-built programs developed in MATLAB.Then,kex between infarcts and contralateral normal brain tissues was compared using a two-tailed paired Student's t-test.In addition,kex imaging was compared to other conventional MRI methods including DWI,CEST,and semi-solid magnetization transfer(MT).Results:kex maps can differentiate infarcts from contralateral normal brain tissues with significantly increased signal(893±52 s-1 vs.739±34 s-1,P<0.001).kex maps were also found to be different from conventional contrasts from DWI,CEST,and MT MRI.In brief,kex MRI showed larger lesion areas than DWI with different degrees.While kex represents a physical parameter,CEST and MT contrasts are highly dependent on the saturation power, showing different lesion delineations under different B1s.Conclusion:The novel kex imaging based on DS-removed omega plots has been demonstrated for in vivo imaging of clinical ischemic stroke patients.As a noninvasive and unique molecular MRI contrast,kex MRI at 3T may serve as a potential surrogate imaging biomarker for detecting the metabolic changes of ischemic stroke.