Structural And Functional Brain Alterations Measured By MRI In Asymptomatic Carotid Stenosis With Cognitive Impairment

Asymptomatic carotid stenosis(ACS)refers to carotid artery disease without a transient ischemic attack,ischemic stroke,or dementia.ACS is an independent risk factor for ischemic stroke and dementia.With the advancement of endovascular intervention and intensive medical treatment,the annual stroke risk of ACS has dropped to less than 1%.ACS-related cognitive impairment has increasingly become an urgent issue to be solved.This thesis first reviews how ACS as an independent risk factor affects the cognitive spectrum and the findings on brain morphology,structure,function,and lesions,etc.;then summarizes the theory,methodology and progress of multimodal MRI neuroimaging,including morphological,structural,functional,perfusion,lesions,brain connectomics and graph theory.Next,focusing on the core problem of "severe asymptomatic carotid stenosis(SACS)cognitive impairment of brain damage",this thesis applied multi-modality and multi-parameter MRI to describe the brain imaging basis of cognitive impairment.The ultimate goal is to understand the brain basis of SACS cognitive impairment and provide new theoretical framework and viewpoints for delaying the SACS-related cognitive problems.The main thesis includes the following parts:Part Ⅰ Lateral Temporal Asymmetries Mediate the Relationship between White Matter Hyperintensity and Recall Memory in Severe Asymptomatic Carotid StenosisObjective Severe asymptomatic carotid stenosis(SACS)is associated with cognitive impairment,but the neuroanatomical basis remains unclear.To investigate gray matter(GM)asymmetry and its potential mediation role through white matter hyperintensity(WMH)on cognitive declines in SACS.Methods In this retrospective study,T1-weighted anatomical and T2-weighted3D-FLAIR MRI were performed in 24 SACS(64.25 ± 7.18 years)and 24 comorbiditymatched controls(67.16 ± 6.10 years),and independent datasets of 84 elderly controls(57.92 ± 4.94 years)and 22 young adults(26.95 ± 3.37 years).T1-weighted voxel-wise asymmetry index(AI)and T2-weighted WMH were computed.A full-path of WMH burden,GM volume(atrophy)and AI(asymmetry),and neuropsychological variables were analyzed using a regression-based serial mediation model.Results SACS patients showed worse verbal recall memories(p < 0.005)and higher WMH burden(p < 0.005).Neuroanatomically,the SACS demonstrated significantly right-lateralized GM in several foci including lateral superior temporal and mouth-somatomotor regions(cluster-corrected p < 0.05).These significant differences extended to pars triangularis,cerebellar,and larger lateral temporal regions,when compared with the young adults(cluster-corrected p < 0.05).The serial mediation analysis identified that GM atrophy and asymmetry in the superior temporal gyrus significantly mediate the relationship between WMH burden and recall memory in patients with SACS.Conclusions SACS showed left-dominated atrophy and consequently rightlateralized GM in lateral temporal regions.Furthermore,unbalanced hemispheric atrophy in the lateral temporal is crucial in mediating relationship between WMH burden and verbal recall memories,which may underlie accelerated ageing and cognitive deterioration in SACS and other vascular cognitive impairment.Part Ⅱ Surface-Based Analyses of Anatomical Properties in Severe Asymptomatic Carotid StenosisObjective To investigate cortical geometry changes and understand betweengroup difference,vulnerable and convergent foci in SACS,using surface-based morphometry(SBM)derived cortical measures(cortical thickness,sulcal depth,gyrification,and cortical complexity)with T1 high-resolution anatomical images.Methods Twenty-four patients with SACS(19 males/ 5 females;64.25 ± 7.18 years)and 24 comorbidities-matched controls(19 males/ 5 females;67.16 ±6.10 years)were included.Using T1 high-resolution anatomical images,the four cortical measures--cortical thickness,sulcal depth,gyrification,and cortical complexity were calculated through central surface identification,spherical registration,spherical reconciliation and topological defect calculation.The cortical measures were then 15 mm spatial smoothed and entered into statistical model,with 1,000 non-parametric permutations and TFCE correction.Results The SACS patients exhibited significantly thinner cortex,including bilateral somatomotor,left inferior frontal gyrus,left superior temporal gyrus,left precuneus,left fusiform gyrus and paracentral lobule,right fusiform and inferior frontal gyri.For the sulcal depth,patients with SACS showed significantly shallower sulcus, including left superior temporal,lateral parietal,temporal pole,insular,fusiform,and somatomotor areas.For the gyrification,SACS patients demonstrated significantly increased gyrification in areas including left lateral occipital,superior temporal and supramarginal,and right middle/superior temporal gyri;and significantly reduced gyrification in areas including left middle temporal,inferior frontal,superior temporal,insular,and lateral parietal gyri,and right posterior cingulate and lateral orbitofrontal cortices.For the cortical complexity(fractal dimension),patients with SACS presented significantly reduced complexity,mainly including left insular and superior and right superior temporal gyri.These results were corrected by vertex-level p <0.001 and cluster-level FWE p <0.05.Further association analyses found that the changes of the above-mentioned cortical measures in patients with SACS were significantly correlated with verbal memory and white matter hyperintensity burden,suggesting that despite the clinically "asymptomatic",patients with SACS have been involved in cognitive impairment especially verbal memory,as well as significant impairment in cortical morphology and white matter integrity.Conclusions These results suggest that SACS patients present with left hemisphere-dominated injury pattern,especially in the Perisylvian areas,including the somatomotor,lateral temporal,inferior frontal,and insular areas and systems involved in somatomotor and language processing.These findings provide cortical anatomical basis for cognitive impairment and evidence for vulnerable anatomy of stroke risk.Part Ⅲ Severe asymptomatic carotid stenosis is associated with robust reductions in homotopic functional connectivityObjective Severe(> 70% narrowing)asymptomatic carotid stenosis(SACS)is associated with cognitive impairment and future strokes,and connectivity basis for the remote brain consequences is poorly understood.Here we explored homotopic connectivity and parenchymal lesions measured by multimodal magnetic resonance imaging(MRI)parameters in patients with SACS.Methods Twenty-four patients with SACS(19 males/ 5 females;64.25 ± 7.18 years),24 comorbidities-matched controls(19 males/ 5 females;67.16 ±6.10 years),and an independent sample of elderly healthy controls(39 females/45 males;57.92 ± 4.94 years)were included.Homotopic functional connectivity(FC)of resting-state functional MRI and structural connectivity(SC)of deterministic tractography were assessed.Arterial spin labeling based cerebral perfusion,susceptibility weighted imaging based microhemorrhagic lesions,and T2-weighted white matter hyperintensities were also quantified.Results Significant and robust homotopic reductions(validated by the independent dataset and support vector machine-based machine learning)were identified in the Perisylvian fissure in patients with SACS(false discovery rate corrected,p < 0.05).These involved regions span across several large-scale brain systems,which include the somatomotor,salience,dorsal attention,and orbitofrontallimbic networks.This significantly reduced homotopic FC can be partially explained by the corrected white matter hyperintensity size.Further association analyses suggest that the decreased homotopic FC in these brain regions is most closely associated with delayed memory recall,sensorimotor processing,and other simple cognitive functions.Conclusions These results suggest that SACS predominately affects the lowerorder brain systems,while higher-order systems,especially the topographies of default mode network,are least impacted initially,but may serve as a hallmark precursor to vascular dementia.Thus,assessment of homotopic FC may provide a means of noninvasively tracking the progression of downstream brain damage following asymptomatic carotid stenosis.Part Ⅳ On the nodal degree configuration of multimodal brain connectomics in severe asymptomatic carotid stenosisObjective Patients with severe asymptomatic carotid stenosis(SACS)are at high risk of cognitive impairment and future ischemic strokes.The basis of remote brain consequences of the SACS is less well known.This study aimed to investigate nodal degree configuration of brain connectomics derived from multimodal MRI in these patients.Methods Twenty-four patients with SACS and 24 comorbidities-matched controls were included and scanned multimodal MRI(including whole brain resting-state fMRI,diffusion weighted,pulsed arterial spin labeling,susceptibility weighted,and highresolution anatomical images).Nodal degree and degree-based centrality,hubs, efficiency,resilience,and wiring cost were computed based on the multimodal MRI derived connectomics.Results Patients with SACS showed significant converging decreases in nodal degree,mainly across sensorimotor,posterior cingulate/parietal,thalamic,and insular regions(p < 0.05,FDR corrected).Subsequent multimodal degree rank identified a shift in hub distribution from association to the sensorimotor cortex in the patients with SACS,and many of the hubs also appeared in the between-group difference of the nodal degree.In addition,a significantly higher efficiency of functional networks and a higher wiring cost of structural networks were found in the patients with SACS(p < 0.05).Conclusions Our results suggest that patients with SACS are predominantly characterized by hub pathology and maladaptive pattern of network efficiency and wiring cost,with across primary sensorimotor-transmodal cortical gradient.These results will contribute to a better understanding of the cognitive impairment and future cerebrovascular events in these patients,from multimodal information and network perspective.Part Ⅴ Default mode network integrity in severe asymptomatic carotid stenosisObjective A reduction in connectivity of the default mode network(DMN)is currently the most potential neuroimaging marker for cognitive impairment.This study aimed to explore whether and to what extent the DMN functional connectivity can distinguish between patients with SACS and vascular risk matched controls.Methods Twenty-four patients with SACS(19 males/ 5 females;64.25 ± 7.18 years)and 24 comorbidities-matched controls(19 males/ 5 females;67.16 ±6.10 years)were included.An 8-minute resting-state fMRI data was collected.Individual-level pair-wise functional connectivity and voxel-wise functional connectivity density(FCD)were calculated to assess changes in the DMN connectivity integrity.Results Patients with SACS showed significant reductions in the pair-wise functional connectivity within the DMN,including interhemispheric frontoparietal portion,intrahemispheric parahippocampal and posterior cingulate functional connectivity,and long-distance connectivity(connectivity level FDR correction,p <0.05).For the FCD,patients with SACS exhibited significantly decreased longdistance(> 75mm)functional connectivity in the posterior cingulate gyrus / precuneus(voxel-level FDR correction,p <0.05).Conclusions These results suggest that the SACS patients present prominent reduced DMN connectivity and long-range functional integration with the rest of the brain.These reductions may echo the neurobiological basis of SACS and other forms of vascular cognitive impairment,but further research is needed to explore its role in the progression to(vascular)dementia.Part Ⅵ Hemodynamic latency measured by resting-state fMRI signals in severe asymptomatic carotid stenosisObjective This study aimed to explore hemodynamic delay measured by restingstate BOLD signals in patients with severe asymptomatic carotid stenosis(SACS).Methods Twenty-four patients with SACS(19 males/ 5 females;64.25 ±7.18 years)and 24 comorbidities-matched controls(19 males/ 5 females;67.16 ±6.10 years)were included.Hemodynamic delay was assessed using temporal lag analysis of resting-state fMRI signals.Results Temporal lag analysis revealed both significant hemodynamic delay in the affected side and lead in the unaffected side in patients with about 2 seconds,predominately appeared in the lateral temporal regions.The temporal delay and delay lateralization score within the affected sides were significantly correlated with cognitive behavioral parameters,especially verbal memory and WMH burden.Conclusions Lag structure of resting BOLD signals in SACS patients is significantly impaired,which may echo the impairments in organizational activity and neurovascular couplings.Our results suggest that temporal lag analysis can be used as a possible clinical utility for functional reserve assessment in brain stenosis patients.