WMHs-cognitive Impairment Mechanism Based On Cerebrovascular Structure And Function

Background and purposeWhite matter hyperintensities(WMHs)have a prevalence of more than 50% in middle-aged and elderly people.WMHs are closely related to cognitive impairment and are important risk factors for stroke and dementia.There is no definite curative effect for WMHs and related cognitive disorders currently.The relationship between WMHs and atherosclerosis is still controversial.Studies reported that carotid atherosclerosis played an important role in the occurrence and development of WMHs,and the mechanism of intracranial atherosclerosis(ICAS)plaque in the occurrence and development of WMHs has not been fully elucidated.Cerebrovascular function(cerebrovascular reactivity,CVR)impairment plays an important role in the occurrence and development of WMHs,however,the pathogenesis of CVR in WMHs-CI is still poorly understood.Moreover,it should be noted that BOLD signal is only an indirect measure of neuronal activity and is inherently regulated by neuronal activity and vascular physiology.A study in a normal young population found that there is a very strong positive correlation between CVR and resting state ALFF and functional connectivity indicators.However,the f MRI studies in WMHs-related CI have not considered the potential impact of cerebrovascular factors.Therefore,the present research will focus on the above issues,to clarify the mechanism of cerebrovascular structure(vessel wall plaque),cerebrovascular function(cerebrovascular reactivity)and brain function indicators in WMHs and related cognitive impairments,which is important for guiding the early intervention and individualized treatment.Materials and resultsThe asymmetry of white matter hyperintensity burden between hemispheres is associated with intracranial atherosclerotic plaque enhancement gradeA cross-sectional study of 41 patients with symptomatic unilateral ICAS was conducted.WMHs volume,lumen stenosis,plaque enhancement,and cerebral perfusion were evaluated.We analyzed the asymmetry of WMHs load between hemispheres,and explore the mechanism of cerebrovascular wall and perfusion in WMHs load.We found that the DWMH volume ipsilateral to the ICAS site was significantly greater than that of the contralateral site,while the PWMH volume difference between hemispheres did not reach statistical significance.The interhemispheric DWMH volume difference was significantly associated with a higher plaque enhancement grade and inversely associated with cerebral hypoperfusion(lower TTP-ASPECTS).In the betweensubjects multivariable regression analysis,while older age,hypoperfusion,and hypertension were independently associated with ipsilateral DWMH volume,plaque enhancement did not show an association with ipsilateral DWMH volume.The association between ipsilateral DWMH volume and lumen stenosis approached statistical significance(? = 0.274,P = 0.084).The neuroimaging mechanism of cerebrovascular reactivity in white matter hyperintensity with cognitive impairmentA total of 131 subjects with moderate to severe WMH(WMH with CI(WMH-CI,n=68)and WMH without CI(WMH-no-CI,n=63)),and 87 normal controls(NCs)were recruited.The CVR was derived using BOLD signal fluctuations obtained from restingstate functional magnetic resonance imaging data.CVR maps were compared among the three groups.Partial correlation analyses were performed to correlate impaired CVR with WMHs volume and cognitive test scores,controlling for age,sex,and years of education.Mediation analysis was conducted to determine whether WMHs acted as a mediating factor between CVR and cognitive function.We found that compared with the NC group,the WMH-no-CI group showed reduced CVR in the parietal area,and the WMH-CI group showed reduced CVR in the frontal,parietal,and occipital areas.When compared with WMH-no-CI subjects,WMH-CI subjects showed further decreased cerebrovascular reserve in the frontal area.In subjects with WMH-CI,after adjustment for age,sex,and education,the CVR in the left frontal area positively correlated with general cognition,executive function,and information processing speed and negatively correlated with periventricular WMH and total WMH.Meanwhile,high WMHs burden was a strong indicator of poor performance on language,information processing speed,executive function,and visuospatial processing function(all P value < 0.05).Mediation analyses with correction for age,sex and education showed that PWMH volume mediated the association between CVR and executive function,general cognition,and information processing speed.In general,PWMH volume in WMH-CI subjects has a mediating effect on CVR damage and cognitive dysfunction.The effect of CVR on the resting state ALFF analyses in WMHs related cognitive impairmentA total of 131 subjects with moderate to severe WMH(WMH with CI(WMH-CI,n=68)and WMH without CI(WMH-no-CI,n=63)),and 87 normal controls(NCs)were recruited.The WMHs load,cerebrovascular reactivity,and ALFF indexes of each subject were evaluated separately.The relative CVR map and ALFF map of each subject were analyzed using resting state BOLD data,and a voxel-based Pearson analysis was performed on MATLAB(Math Works,Natick,MA)to explore the relationship between CVR and ALFF index.To explore the ALFF differences among the three groups,a voxel-wise one-way analysis of variance(ANCOVA)and subsequent post hoc analysis were performed on the spatial maps of the ALFF,controlling for age,sex,years of education,and vascular risk factors(using DPABI v2.3).To test the effect of CVR on ALFF analysis,we conducted the ANCOVA analysis with and without CVR as covariate.To test the association between the mean ALFF values in each significant cluster and the cognitive test scores,as well as the WMHs volume in WMH-CI subjects,partial correlation analyses were conducted on SPSS 22.0 software.Finally,to assess the diagnostic performance of each variable(mean ALFF values in areas with significant cluster)and their combinations to determine the occurrence of cognitive impairment,a receiver operating characteristic(ROC)curve was constructed.We found that the voxel-wise Pearson analysis showed a significant widespread correlation between the CVR and ALFF map,mainly distributed in the DMN area/cortical area.The abnormal ALFF regions between the WMH groups and NC group with CVR as covariate were more than those without CVR as covariate,therefore,we included CVR as covariate in the subsequent statistical analysis.Compared with the NC group,both WMH-CI and WMH-no-CI groups showed abnormal ALFF regions.Specifically,the WMH-no-CI group showed reduced ALFF in frontal areas and increased ALFF in temporal area,the WMH-CI group showed reduced ALFF in the precuneus/PCC,frontal and parietal areas,and increased ALFF in frontal,temporal and parietal areas.In addition,when compared with WMH-no-CI subjects,WMH-CI subjects showed decreased ALFF in precuneus/PCC,and increased ALFF in IFG and MFG(P <0.05,Alpha Sim corrected).In subjects with WMH-CI,higher ALFF in the left IFG was significantly associated with worse language function,lower ALFF in PCC was significantly associated with worse executive function and general cognition after adjustment for age,sex,education,and vascular risk factors.Meanwhile,the correlation analysis between abnormal ALFF values and WMHs load showed a negative correlation between ALFF in PCC and lg PWMH.The AUC for determining the occurrence of cognitive impairment were 0.645 for IFG,0.696 for MFG,and 0.689 for PCC.The combination of IFG and MFG to PCC provided incremental contribution to the occurrence of cognitive impairment.The AUC improved to 0.803,significantly higher than that of IFG,MFG and PCC alone(P < 0.05 for all).Conclusion and significanceThe first part of the study found that in patients with unilateral intracranial atherosclerosis,the volume of WMHs between the cerebral hemispheres was asymmetry,mainly manifested as deep WMHs(DWMH),and interhemispheric periventricular WMHs(PWMH)load did not show significant difference.The association between the asymmetry of deep white matter lesions and plaque enhancement might suggest that increased deep white matter lesions are those ischemic lesions,which are more prone to the development of stroke.In our clinical work,attention should be paid to the assessment of cerebrovascular in cases of intracranial white matter hyperintensity asymmetry.The second part of the study found that the cerebrovascular reserve derived from the resting-state BOLD approach was impaired in patients with moderate to severe WMHs,with WMH-CI subjects showing a greater reduction in frontal areas than WMH-no-CI subjects.In addition,cognition was highly dependent on the integrity of cerebrovascular regulation and mediated by PWMH burden,providing new insight into the pathophysiology of CI in patients with WMHs.The third part of the study found that the CVR map obtained from resting state BOLD data was closely correlated with the ALFF map,and the CVR index had an effect on the between group ALFF analysis.Both two WMH subgroups showed abnormalities in ALFF,regardless of whether they have cognitive impairments,suggesting that when WMH patients have clinically detectable cognitive impairments,there have been changes in spontaneous brain activities.With the emergence of cognitive impairments,the abnormalities in spontaneous brain activities was more significant,and ALFF values of the damaged brain areas were closely related to poorer cognitive performance in the WMH-CI group.The ALFF damaged brain areas can proudly identify CI patients in WMH subjects.