| BackgroundCerebral small vessel disease(CSVD)is a common cerebrovascular disease in middle-aged and senior people,accounting for more than 1/4 of ischemic cerebrovascular disease.Generally,it refers to the clinical,cognitive,imaging and pathological manifestations of various lesions of small vessels of the brain.Unlike macrovascular lesions in ischemic stroke,the involved vessels in CSVD are mostly small perforating arteries and arterioles,and thereby its clinical manifestation is characterized by insidious onset and slow progression.Typical clinical symptoms of CSVD include: stroke symptoms,cognitive impairment,mood disturbance,motor symptoms(gait disturbance),and autonomic dysfunction(bowel and bladder disturbances).The common imaging markers include recent small subcortical infarct,lacunes of presumed vascular origin,white matter hyperintensity(WMH)of presumed vascular origin,enlarged perivascular space(EPVS),cerebral microbleeds and brain atrophy.Evidence from previous studies on cognitive function in CSVD is relatively scarce,and no consensus has been achieved especially on impaired patterns of memory function in CSVD across various studies.At present,there is a lack of standardized neuropsychological battery for CSVD in China,thus it cannot reflect the distribution characteristics of cognitive impairment in Chinese CSVD population.The development of multi-modality neuroimaging technology provides a new research method and perspective for us to deeply explore the possible mechanism of cognitive impairment in CSVD.Voxel-based Morphometry(VBM)can quantitatively describe the gray matter volume(GMV)of cortical regions and subcortical nuclei;Cerebral blood flow(CBF)perfusion analysis based on the arterial spin labeling(ASL)sequence and whole brain functional connectivity strength(FCS)based on the resting state functional Magnetic Resonance Imaging(rs-fMRI)sequence enable delineation of regional brain function activity and functional integration of the whole brain;Diffusion Tensor Imaging(DTI)based white matter tractography can evaluate the structural connectivity of fiber bundle across different brain nodes and topological properties of structural network by tracking the whole brain tract.Based on these imaging modalities,the possible neural mechanisms of cognitive impairment in the CSVD population can be revealed from a focal to a global perspective.ObjectiveBased on the previous literature review and referring to the recommendations of CSVD and relevant guidelines for vascular cognitive impairment,this study offers an exploratory set of multi-dimensional and multi-level neuropsychological evaluation battery suitable for Chinese population.We then use this neuropsychological battery to elucidate the damage spectrum across various cognitive domains of CSVD.The potential neural mechanisms of cognitive impairment in the CSVD population can be preliminarily explored by combining with multi-modality MRI technology.1)Study 1: The latest research evidence shows that the cognitive impairment pattern of CSVD is not only limited to the dimensions of executive function and information processing speed,but also may involve many other cognitive domains,including memory and visuospatial function.Firstly,we proposed a multi-dimensional neuropsychological evaluation battery which is suitable for Chinese CSVD population,and used this battery to systematically describe the impairment characteristics of cognitive domain in CSVD population.2)Study 2: The previous theory suggests that the lesion of CSVD contribute to cognitive impairment by disrupting the prefrontal-subcortical circuit.Therefore,on the basis of the first study,we applied several methods including structural MRI,functional MRI and DTI to observe the impairment patterns in the structural and functional properties of CSVD population from a local to global network perspective,and then discuss the possible neural mechanisms of cognitive impairment.Methods1)Study 1: Based on the previous research foundation of our team in the preparation of neuropsychological scales,this study selected a series of scales that have a good sensitivity and better time-consuming performance during clinical operation.These scales should also be convenient to offer a statistical measure.We then revised them to form a multi-dimensional neuropsychological evaluation battery,which covers several cognitive domains such as attention,memory,executive function,information processing speed,language,visuospatial function and emotion.We formed the CSVD total burden score to comprehensively reflect the cumulative synergistic effect of the different CSVD lesions by integrating the conventional radiographic markers(white matter hyperintensities,subcortical lacunes,perivascular spaces and cerebral atrophy).This part included 87 CSVD population and 38 age-,gender-and education-matched control population.By comparing the cognitive profile of multidimensional neuropsychological tests between these two groups,the cognitive impairment pattern of CSVD population was clarified.Multiple linear regressions were used to explore the correlation between CSVD total burden score,individual CSVD lesion characteristics(number and distribution location)and multidimensional cognitive function.2)Study 2: On the basis of study 1,the possible mechanism of cognitive impairment in CSVD was clarified by applying multi-modality MRI technology.There were three parts in this section: Experiment 1: this part included 62 CSVD population and 32 control population matched for age,gender and education.3D high-resolution T1 structural imaging sequences were acquired to explore the abnormal changes of GMV in the local brain regions of CSVD population based on VBM method.Correlation analysis was used to assess the correlation between GMV values extracted from brain regions of significant group difference and multidimensional cognitive functions;Experiment 2,this part included 60 CSVD population and 32 control population for the data analysis of cerebral perfusion,and included 65 CSVD population and 32 control population for the analysis of rs-fMRI data.3D pseudo-continuous ASL sequence and rs-fMRI sequence were acquired separately.Based on the whole-brain CBF analysis,the changes of CBF in the regional cerebral regions of CSVD population were analyzed.By treating the brain regions of significant CBF difference as the region of interest,the abnormal connectivity of the CSVD population was found based on the whole-brain functional connectivity analysis.Correlation analysis was conducted to evaluate the correlation between CBF and FCS in brain regions of significant group difference with multidimensional cognitive function.Experiment 3,this part included 39 CSVD population and 21 control population.DTI sequence was collected,and DTI structural network was constructed by applying the deterministic tractography method.By using network-based analysis and principles from graph theory,the differences of edge measurements and topological properties(including global properties and node properties)of whole-brain structural connectivity in CSVD population were studied.Correlation analysis was used to assess the correlation of edge indicators and network topological properties with multidimensional cognitive function.Results1)Study 1: Compared with the control group,a series of cognitive domains which consists of attention,executive function,information processing speed,immediate and delayed memory,visuospatial function and depressive symptoms were impaired in CSVD group,while the function of language and recognition memory were relatively preserved.With the increase of CSVD total burden score,the cognitive domains which include global cognition,memory,executive function,information processing speed and emotion were also significantly decreased in CSVD population.Multiple regression analyses showed that after adjusting for age,gender,education and other CSVD lesions,there was significant correlation between the periventricular WMH lesions locating in anterior horn of lateral ventricle and the information processing speed,executive function,depressive symptoms and memory function.The periventricular WMH lesions in posterior horn of lateral ventricle were significantly associated with information processing speed and memory function.In contrast,the periventricular WMH lesions along the lateral ventricles were associated with global cognition and information processing speed.There was a significant negative correlation between deep WMH lesions and memory in parietal,occipital and temporal lobes.There was a significant negative correlation between deep WMH lesions and visuospatial function in frontal and occipital lobes.Subcortical lancues were negatively correlated with visuospatial function.EPVS in basal ganglia region was significantly correlated with frontal fluency and delayed memory,while EPVS in the centrum semiovale was significantly correlated with the information processing speed and delayed memory.Deep brain atrophy was closely related to depressive symptoms,visuospatial function and attention function,whereas gyrus atrophy was not significantly related to any cognitive function.2)Study 2: The results of Experiment 1 showed that compared with the control group,the GMV of left rectus/ left medial superior frontal gyrus and left superior temporal gyrus in CSVD group was significantly decreased,while the GMV of left and right caudate nucleus was significantly increased.Correlation analysis showed that GMV of the left superior temporal gyrus in CSVD group was significantly correlated with global cognition,visuospatial function and frontal fluency(P < 0.05).The correlation between GMV of the left superior temporal gyrus and memory(P = 0.06)as well as information processing speed(P = 0.07)was of borderline significance.There was also a positive correlation of borderline significance between the GMV of left rectus/ left medial superior frontal gyrus and immediate memory(P = 0.06)as well as the GMV of left caudate and delayed memory(P = 0.07).The results of experiment 2 showed that compared with the control group,the CBF of left dorsolateral prefrontal cortex,right cerebellum and left lingual gyrus were significantly decreased in CSVD group,and the CBF of left and right putamen were significantly increased in CSVD group.Analysis of the whole-brain functional connectivity by using regions of significant CBF difference showed that the FCS of left dorsolateral prefrontal cortex-posterior cingulate cortex/ precuneus and right putamen-angular gyrus increased significantly.Correlation analysis showed that the CBF value of left dorsolateral prefrontal cortex in CSVD group was positively correlated with attention function and frontal fluency,while the negative correlation between the CBF of left dorsolateral prefrontal cortex and information processing speed was of borderline significance(P = 0.06).There was a significant positive correlation between the CBF of right cerebellum and frontal fluency.The left putamen was negatively correlated with frontal fluency and memory function.Additional subgroup analysis according to CSVD total burden score in the CSVD population showed that the negative correlations between the CBF value of left putamen and aforementioned cognitive function existed mainly in the severe group(interaction effect between the group was significant).The results of experiment 3 showed that,based on the network-based statistics,there was a significant decrease in the structural connectivity strength between the pairs of nodes such as dorsal lateral frontal gyrus,the medial superior frontal gyrus,orbital middle frontal gyrus,the orbital inferior frontal gyrus,the insula,the supplementary motor areas,the superior parietal gyrus and the cingulate gyrus,as well as the subcortical brain regions including the thalamus and caudate nucleus in CSVD group compared with the control group.In terms of network topological properties,the structural network of both groups has small-world properties.The average shortest path length of CSVD group was significantly higher than that of control group,and the global efficiency of CSVD group was significantly lower than that of control group.Local efficiency and nodal properties were not significantly different between the two groups.The correlation analysis showed that the small-world properties ? and ? were significantly correlated with the executive function in CSVD group.The correlation of average shortest path length(Lp)with frontal fluency(P = 0.07)and information processing speed(P = 0.06)was of borderline difference.Global efficiency was not significantly correlated with any cognitive function.The structural connectivity strength of the edge is significantly correlated with frontal fluency,executive function,information processing speed and visuospatial function.Conclusions1)Study 1: In cerebral small vessel disease,the cognitive impairment is observed in many dimensions,such as global cognition,attention,executive function,information processing speed,visuospatial function,delayed memory and depressive symptoms.The accumulation of various CSVD lesions can significantly have a synergistic effect on cognitive function,and each CSVD lesion per se is associated with specific cognitive function.This relationship mainly is due to the difference in spatial distribution location of these lesions.2)Study 2: In CSVD population,there was a significant decrease in GMV of orbital frontal cortex and superior temporal gyrus and a significant decrease CBF in the prefrontal cortex.The damage of structural connectivity of white matter fiber is mainly located in multiple brain regions within prefrontal-thalamic circuit,which involves several network systems such as frontoparietal network,dorsal attention network and default network.However,this study also found an increase in GMV of subcortical gray nuclei and an increase in CBF and functional connectivity in subcortical regions.We speculated that it may reflect the possibility that disruption of the blood-brain barrier secondary to CSVD lesions may result in compensatory increases in local structure,cerebral blood flow and functional connectivity.This compensatory mechanism lacks some theoretical basis now and needs more behavioral-imaging studies and prospective dynamic observational studies to confirm in the future.Based on a multidimensional neuropsychological evaluation protocol and a multi-modality neuroimaging approach,this study systematically demonstrates that a broad range of cognitive impairment profile exists in a population with small cerebral vascular disease,and initially reveals that regional brain atrophy,abnormal CBF changes and disruption of structural connectivity may be possible neural mechanism of cognitive impairment in CSVD.Our results reemphasize that cognitive impairment is an important clinical manifestation of cerebral small vessel disease,and also clarify that there may be a dual mechanism of both impairment and compensatory underlying cerebrovascular-related cognitive disorders.Future studies should focus on dynamic evolution patterns of imaging and cognitive function and their correlation with clinical outcomes. |
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