Altered static and dynamic indices of intrinsic brain activity in patients with subcortical ischemic vascular disease: a resting-state functional magnetic resonance imaging analysis.

PURPOSE: To explore the static and dynamic characteristics of intrinsic brain activity (IBA) in subcortical ischemic vascular disease (SIVD) patients with or without cognitive impairment. METHODS: In total, 90 participants were recruited, including 32 SIVD patients with cognitive impairment (SIVD-CI, N = 32), 26 SIVD patients with no cognitive impairment (SIVD-NCI, N = 26), and 32 healthy controls (HC, N = 32) matched for age, gender, and education. All subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning and neuropsychological tests. Amplitude of low-frequency fluctuation (ALFF) was calculated to reflect static alterations of regional IBA. Sliding window analysis was conducted in order to explore the dynamic characteristics. RESULTS: Both SIVD-CI and SIVD-NCI group showed significantly decreased ALFF in left angular gyrus (ANG), whereas SIVD-CI group showed increased ALFF in right superior frontal gyrus (SFG), compared with HCs. Furthermore, SIVD-CI group showed significantly decreased ALFF dynamics (dALFF) in right precuneus (PreCu) and left dorsal anterior cingulate cortex (dACC), compared with HC and SIVD-NCI groups (Gaussian random field-corrected, voxel-level P < 0.001, cluster-level P < 0.05). No dynamic changes were detected between SIVD-NCI group and HC group. The mean ALFF value in left ANG of SIVD-CI group was correlated with the score of delayed memory scale. CONCLUSION: ANG may be a vulnerable brain region in SIVD patients. Temporal dynamic analysis could serve as a sensitive and promising method to investigate IBA alterations in SIVD patients.

Unsupervised machine learning model to predict cognitive impairment in subcortical ischemic vascular disease.

INTRODUCTION: It is challenging to predict which patients who meet criteria for subcortical ischemic vascular disease (SIVD) will ultimately progress to subcortical vascular cognitive impairment (SVCI). METHODS: We collected clinical information, neuropsychological assessments, T1 imaging, diffusion tensor imaging, and resting-state functional magnetic resonance imaging from 83 patients with SVCI and 53 age-matched patients with SIVD without cognitive impairment. We built an unsupervised machine learning model to isolate patients with SVCI. The model was validated using multimodal data from an external cohort comprising 45 patients with SVCI and 32 patients with SIVD without cognitive impairment. RESULTS: The accuracy, sensitivity, and specificity of the unsupervised machine learning model were 86.03%, 79.52%, and 96.23% and 80.52%, 71.11%, and 93.75% for internal and external cohort, respectively. DISCUSSION: We developed an accurate and accessible clinical tool which requires only data from routine imaging to predict patients at risk of progressing from SIVD to SVCI. HIGHLIGHTS: Our unsupervised machine learning model provides an accurate and accessible clinical tool to predict patients at risk of progressing from subcortical ischemic vascular disease (SIVD) to subcortical vascular cognitive impairment (SVCI) and requires only data from imaging routinely used during the diagnosis of suspected SVCI. The model yields good accuracy, sensitivity, and specificity and is portable to other cohorts and to clinical practice to distinguish patients with SIVD at risk for progressing to SVCI. The model combines assessment of diffusion tensor imaging and functional magnetic resonance imaging measures in patients with SVCI to analyze whether the "disconnection hypothesis" contributes to functional and structural changes and to the clinical presentation of SVCI.

Abnormal static and dynamic functional connectivity of networks related to cognition in patients with subcortical ischemic vascular disease.

PURPOSE: To investigate the specific features of static functional connectivity (SFC) and dynamic functional connectivity (DFC) of networks related to cognition in patients with subcortical ischemic vascular disease (SIVD). METHODS: In this retrospective study, resting-state functional MRI data and a series of cognitive scores were obtained from 38 patients with SIVD and 23 normal controls. Independent component analysis, sliding window method, k-means clustering analysis and graph theory method were used to examine FC between the default mode network (DMN), dorsal attention network (DAN), frontoparietal network (FPN), salience network (SN) and executive control network (ECN) in patients with SIVD. Then, correlations between abnormal FC features and cognition were assessed. RESULTS: Compared with normal controls, SFC within the DMN significantly increased and SFC between the DMN and DAN significantly decreased in patients with SIVD. The decreased DFC mainly occurred in weakly connected states, especially the DFC of the SN; but the increased DFC, global network efficiency and local network efficiency and the decreased mean dwell time (MDT) and frequency mainly occurred in strongly connected states in SIVD patients. Moreover, aberrant SFC, DFC and MDT were significantly correlated with patients' cognitive scores. CONCLUSION: The overall results are suggestive of abnormal functional segregation and integration of SFC and DFC among networks related to cognition, especially in the SN. This may advance our comprehensive understanding of the abnormal changes in brain network connectivity in patients with SIVD. Our findings also highlight DFC may be an effective neuroimaging marker for the clinical diagnosis of SIVD.

Discriminating subcortical ischemic vascular disease and Alzheimer's disease by diffusion kurtosis imaging in segregated thalamic regions.

Differentiating between subcortical ischemic vascular disease (SIVD), Alzheimer's disease (AD), and normal cognition (NC) remains a challenge, and reliable neuroimaging biomarkers are needed. The current study, therefore, investigated the discriminative ability of diffusion kurtosis imaging (DKI) metrics in segregated thalamic regions and compare with diffusion tensor imaging (DTI) metrics. Twenty-three SIVD patients, 30 AD patients, and 24 NC participants underwent brain magnetic resonance imaging. The DKI metrics including mean kurtosis (MK), axial kurtosis (Kaxial ) and radial kurtosis (Kradial ) and the DTI metrics including diffusivity and fractional anisotropy (FA) were measured within the whole thalamus and segregated thalamic subregions. Strategic correlations by group, thalamo-frontal connectivity, and canonical discriminant analysis (CDA) were used to demonstrate the discriminative ability of DKI for SIVD, AD, and NC. Whole and segregated thalamus analysis suggested that DKI metrics are less affected by white matter hyperintensities compared to DTI metrics. Segregated thalamic analysis showed that MK and Kradial were notably different between SIVD and AD/NC. The correlation analysis between Kaxial and MK showed a nonsignificant relationship in SIVD group, a trend of negative relationship in AD group, and a significant positive relationship in NC group. A wider spatial distribution of thalamo-frontal connectivity differences across groups was shown by MK compared to FA. CDA showed a discriminant power of 97.4% correct classification using all DKI metrics. Our findings support that DKI metrics could be more sensitive than DTI metrics to reflect microstructural changes within the gray matter, hence providing complementary information for currently outlined pathogenesis of SIVD and AD.

Generation of directly reprogrammed human endothelial cells derived from fibroblast using ultrasound.

Physical microenvironment plays an important role in determining cellular reprogramming. In this study, we first generated directly reprogrammed human dermal fibroblasts (HDFs) into endothelial cells (ECs) mediated by environmental transition-guided cellular reprogramming (e/Entr) using ultrasound and characterized e/Entr. Ultrasound stimulus was introduced to ECs culture media and HDFs and induced into ECs-like cells. We performed microarray, RT-PCR, protein analysis, matrigel plug assay and e/Entr were transplanted into ischemic hindlimb mice model. Here we show that the activation of MAPK signaling pathways and the modulation of histone proteins such as Hp1-α, H3K27me3 and H3K4me3 in e/Entr contribute to the changes in chromatin configuration and reprogramming. Microarray data demonstrated that e/Entr highly expressed genes associated with ECs transcription factors and angiogenesis. In addition, the transplantation of e/Entr into hindlimb ischemia showed a high recovery of blood perfusion, limb salvage and e/Entr contributed to the formation of new vessels. In conclusion, the present study provided the first evidence that ultrasound reprogramming can induce postnatal cells to functional ECs. Therefore, our data suggest that physical stimulus-mediated reprogramming is a highly effective and safe strategy for the novel therapeutic alternatives.

Incidence of Upper and Lower Gastrointestinal Bleeding in New Users of Low-Dose Aspirin.

BACKGROUND & AIMS: There are few data on the incidence of upper and lower gastrointestinal bleeding (UGIB and LGIB) from observational studies of low-dose aspirin users. We aimed to estimate incidence rates of UGIB and LGIB in a large cohort of new users of low-dose aspirin in the United Kingdom, with subanalyses of hospitalization status and fatalities. METHODS: We performed a population-based study of 199,079 new users of low-dose aspirin (median age, 64.0 years) identified from the Health Improvement Network primary care database (2000-2012). Individuals were followed for a median 5.4 years (maximum, 14 years) to identify new cases of UGIB and LGIB. Following multistep validation, we calculated overall and age- and sex-specific incidence rates; we performed subanalyses for health care use and death within 30 days of GIB. We also estimated rates within a matched (1:1) cohort of nonusers of low-dose aspirin at the start of the follow-up period. RESULTS: The low-dose aspirin users had 1115 UGIB events and 1936 LGIB events; most subjects with UGIB events (58.9%) were hospitalized, whereas most subjects with LGIB events were referred to secondary care (72.8%). Crude incidence rates of GIB per 1000 person-years were 0.97 for subjects with UGIB (95% CI, 0.91-1.02) and 1.68 for subjects with LGIB (95% CI, 1.60-1.75). Incidence rates per 1000 person-years for patients hospitalized for GIB were 0.57 for UGIB (95% CI, 0.53-0.61) and 0.45 for LGIB (95% CI, 0.42-0.49); for referred (but not hospitalized) cases, these values were 0.39 for UGIB (95% CI, 0.36-0.43) and 1.22 for LGIB (1.16-1.29). Incidence rates per 1000 person-years were 0.06 for fatal UGIB (95% CI, 0.04-0.07), 0.01 for fatal LGIB (95% CI, 0.01-0.02), 0.91 for nonfatal UGIB (95% CI, 0.86-0.97), and 1.66 for nonfatal LGIB (95% CI, 1.59-1.74). Among nonusers of low-dose aspirin, incidence rates per 1000 person-years were 0.67 (95% CI, 0.63-0.75) for UGIB and 0.76 (95% CI, 0.72-0.82) for LGIB. CONCLUSION: In a population-based study of low-dose aspirin users, the incidence of LGIB was higher than the incidence of UGIB. However, incidence rates of hospitalized GI bleeds and 30-day mortality rates were lower for LGIB than for UGIB. These estimates are valuable for benefit-risk assessments of low-dose aspirin for cardiovascular and colorectal cancer prevention.

Altered static and dynamic functional network connectivity in Alzheimer's disease and subcortical ischemic vascular disease: shared and specific brain connectivity abnormalities.

Subcortical ischemic vascular disease (SIVD) is a major subtype of vascular dementia with features that overlap clinically with Alzheimer's disease (AD), confounding diagnosis. Neuroimaging is a more specific and biologically based approach for detecting brain changes and thus may help to distinguish these diseases. There is still a lack of knowledge regarding the shared and specific functional brain abnormalities, especially functional connectivity changes in relation to AD and SIVD. In this study, we investigated both static functional network connectivity (sFNC) and dynamic FNC (dFNC) between 54 intrinsic connectivity networks in 19 AD patients, 19 SIVD patients, and 38 age-matched healthy controls. The results show that both patient groups have increased sFNC between the visual and cerebellar (CB) domains but decreased sFNC between the cognitive-control and CB domains. SIVD has specifically decreased sFNC within the sensorimotor domain while AD has specifically altered sFNC between the default-mode and CB domains. In addition, SIVD has more occurrences and a longer dwell time in the weakly connected dFNC states, but with fewer occurrences and a shorter dwell time in the strongly connected dFNC states. AD has both similar and opposite changes in certain dynamic features. More importantly, the dynamic features are found to be associated with cognitive performance. Our findings highlight similar and distinct functional connectivity alterations in AD and SIVD from both static and dynamic perspectives and indicate dFNC to be a more important biomarker for dementia since its progressively altered patterns can better track cognitive impairment in AD and SIVD.

Comparison of neuropsychiatric symptoms and diffusion tensor imaging correlates among patients with subcortical ischemic vascular disease and Alzheimer's disease.

BACKGROUND: The causes of behavioral and psychological symptoms of dementia (BPSD) vary according to the dementia subtype and associated neuropathology. The present study aimed to (i) compare BPSD between patients with subcortical ischemic vascular disease (SIVD) and Alzheimer's disease (AD) across stages, and (ii) explore the associations with diffusion tensor imaging (DTI) in the corpus callosum (CC) and other major fibers. METHODS: Twenty-four patients with SIVD and 32 with AD were recruited. Four domains of the Neuropsychiatric Inventory (NPI) (hyperactivity, psychosis, affective, and apathy) and two DTI parameters [fractional anisotropy (FA) and mean diffusivity (MD)] within the genu, body (BCC), and splenium (SCC) of the CC and other major fibers were assessed. RESULTS: Overall, the patients with clinical dementia rating (CDR) 1 ~ 2 had higher scores in apathy domain than those with CDR0.5. Among those with CDR1 ~ 2, SIVD had higher scores in apathy domain than AD. MD values in the BCC/SCC were positively correlated with total NPI score and psychosis, hyperactivity, and apathy domains. FA values in the SCC were inversely correlated with total NPI score and psychosis domain. The correlations were modified by age, the CASI, and CDR scores. Stepwise linear regression models suggested that FA value within the left superior longitudinal fasciculus predicted the hyperactivity domain. MD value within the SCC/left uncinate fasciculus and FA value within the GCC/left forceps major predicted the psychosis domain. MD value within the right superior longitudinal fasciculus and CDR predicted the apathy domain. Further analysis suggested distinct patterns of regression models between SIVD and AD patients. CONCLUSION: White matter integrity within the BCC/SCC had associations with multi-domains of BPSD. Our study also identified important roles of regions other than the CC to individual domain of BPSD, including the left superior longitudinal fasciculus to the hyperactivity domain, the left uncinate fasciculus/forceps major to the psychosis domain, and the right superior longitudinal fasciculus to the apathy domain. The neuronal substrates in predicting BPSD were different between SIVD and AD patients. Of note, apathy, which was more profound in SIVD, was associated with corresponding fiber disconnection in line with dementia severity and global cognition decline.

White matter hyperintensities in mild cognitive impairment: clinical impact of location and interaction with lacunes and medial temporal atrophy.

This study was to evaluate the influence on cognition and activities of daily living (ADL) by white matter hyperintensities (WMHs) based on the severity and location, as well as the interactions among WMHs, lacunes, and medial temporal atrophy (MTA). In 150 patients with amnestic mild cognitive impairment, WMHs were quantified with the use of a semiautomated volumetric method. Lacune counting and MTA assessment were performed by visual rating. The severer WMHs were, the more executive functions decreased. The influence on executive functions such as verbal fluency test and Stroop color reading test were greater in periventricular (PV) WMHs than deep WMHs, as well as bigger in anterior, middle, and posterior areas in order. The instrumental (I) ADL was strongly associated with the anterior (P = .028) and middle area (P = .014) of PVWMHs only. WMHs had synergistic interactions with lacunes in Controlled Oral Word Association Task-semantic (ß = -1.12; R(2) = .24; P = .039), Stroop color (ß = -2.07; R(2) = .15; P = .049), and IADL (ß = .23; R(2) = .20; P = .009). Anterior PVWMHs demonstrated the most powerful impact on frontal executive dysfunction and poor performance of IADL. WMHs had synergistic effects with the number of lacunes on them. Therefore, it is desirable to consider WMHs and lacunes simultaneously as potential imaging biomarkers for predicting cognition and IADL in aMCI.

Efficacy and Safety of Long-Term Dual Antiplatelet Therapy: A Systematic Review and Meta-Analysis.

BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is a standard therapy in patients with ischemic vascular diseases (IVD) including coronary artery, cerebrovascular and peripheral arterial diseases, although the optimal duration of this treatment is still debated. Previous meta-analyses reported conflicting results about the effects of long-term and short-term as well as non-DAPT use in various clinical settings. Herein, we conducted a comprehensive meta-analysis to assess the efficacy and safety of different durations of DAPT. METHODS: We reviewed relevant articles and references from database, which were published prior to April 2023. Data from prospective studies were processed using RevMan5.0 software, provided by Cochrane Collaboration and transformed using relevant formulas. The inclusion criteria involved randomization to long-term versus short-term or no DAPT; the endpoints included at least one of total or cardiovascular (CV) mortalities, IVD recurrence, and bleeding. RESULTS: A total of 34 randomized studies involving 141 455 patients were finally included. In comparison with no or short-term DAPT, long-term DAPT reduced MI and stroke, but did not reduce the total and CV mortalities. Meanwhile, bleeding events were increased, even though intracranial and fatal bleedings were not affected. Besides, the reduction of MI and stroke recurrence showed no statistical significance between long-term and short-term DAPT groups. CONCLUSION: Long-term DAPT may not reduce the mortality of IVD besides increasing bleeding events, although reduced the incidences of MI and stroke early recurrence to a certain extent and did not increase the risk of fatal intracranial bleeding.

Unraveling the link: white matter damage, gray matter atrophy and memory impairment in patients with subcortical ischemic vascular disease.

Introduction: Prior MRI studies have shown that patients with subcortical ischemic vascular disease (SIVD) exhibited white matter damage, gray matter atrophy and memory impairment, but the specific characteristics and interrelationships of these abnormal changes have not been fully elucidated. Materials and methods: We collected the MRI data and memory scores from 29 SIVD patients with cognitive impairment (SIVD-CI), 29 SIVD patients with cognitive unimpaired (SIVD-CU) and 32 normal controls (NC). Subsequently, the thicknesses and volumes of the gray matter regions that are closely related to memory function were automatically assessed using FreeSurfer software. Then, the volume, fractional anisotropy (FA), mean diffusivity (MD), amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) values of white matter hyperintensity (WMH) region and normal-appearing white matter (NAWM) were obtained using SPM, DPARSF, and FSL software. Finally, the analysis of covariance, spearman correlation and mediation analysis were used to analyze data. Results: Compared with NC group, patients in SIVD-CI and SIVD-CU groups showed significantly abnormal volume, FA, MD, ALFF, and ReHo values of WMH region and NAWM, as well as significantly decreased volume and thickness values of gray matter regions, mainly including thalamus, middle temporal gyrus and hippocampal subfields such as cornu ammonis (CA) 1. These abnormal changes were significantly correlated with decreased visual, auditory and working memory scores. Compared with the SIVD-CU group, the significant reductions of the left CA2/3, right amygdala, right parasubiculum and NAWM volumes and the significant increases of the MD values in the WMH region and NAWM were found in the SIVD-CI group. And the increased MD values were significantly related to working memory scores. Moreover, the decreased CA1 and thalamus volumes mediated the correlations between the abnormal microstructure indicators in WMH region and the decreased memory scores in the SIVD-CI group. Conclusion: Patients with SIVD had structural and functional damages in both WMH and NAWM, along with specific gray matter atrophy, which were closely related to memory impairment, especially CA1 atrophy and thalamic atrophy. More importantly, the volumes of some temporomesial regions and the MD values of WMH regions and NAWM may be potentially helpful neuroimaging indicators for distinguishing between SIVD-CI and SIVD-CU patients.

Therapeutic angiogenesis and tissue revascularization in ischemic vascular disease.

Ischemic vascular disease is a major healthcare problem. The keys to treatment lie in vascular regeneration and restoration of perfusion. However, current treatments cannot satisfy the need for vascular regeneration to restore blood circulation. As biomedical research has evolved rapidly, a variety of potential alternative therapeutics has been explored widely, such as growth factor-based therapy, cell-based therapy, and material-based therapy including nanomedicine and biomaterials. This review will comprehensively describe the main pathogenesis of vascular injury in ischemic vascular disease, the therapeutic function of the above three treatment strategies, the corresponding potential challenges, and future research directions.

Progressive alteration of dynamic functional connectivity patterns in subcortical ischemic vascular cognitive impairment patients.

Alterations in the temporal evolution of brain states in the process of cognitive impairment aggravation due to subcortical ischemic vascular disease (SIVD) is not understood. The dynamic functional connectivity was investigated to identify the abnormal temporal properties of brain states associated with cognitive impairment caused by SIVD. Eighteen patients with subcortical ischemic vascular cognitive impairment with no dementia (SIVCIND), 19 dementia patients (SIVaD) and 26 normal controls were enrolled. We found that the occupancy rate and mean lifetime of brain states were associated with cognitive performance. SIVCIND had a higher occupancy rate and longer mean lifetime in weakly connected states than normal controls. SIVaD had similar but more extensive changes in the temporal properties of brain states. In addition, switching from weakly connected states to more strongly connected states was more difficult in SIVCIND and SIVaD patients than in normal controls, especially in SIVaD patients. The results revealed that not only the transition to but also maintenance in strongly connected states became increasingly difficult when SIVD-related cognitive impairment progressed into a more severe stage.

Gender difference in association between H-type hypertension and subcortical ischemic vascular disease.

Background: Subcortical ischemic vascular disease (SIVD) is a leading cause of vascular dementia. The present study tries to explore not only the gender-specific association between H-type hypertension and SIVD but also the indirect effects of H-type hypertension on cognition through the ischemic brain injury caused by SIVD. Materials and methods: A total of 601 SIVD patients were included, comprising 322 males and 279 females. H-type hypertension was defined as hypertension accompanied with elevated serum total homocysteine (tHcy) level. The imaging manifestations of ischemic brain injury caused by SIVD were also evaluated, including white matter lesions (WML), lacunar infarction (LI) and brain atrophy (BA). Gender-specific subgroup analyses in association between H-type hypertension and SIVD were conducted, followed by a structural equation model based evaluation of the gender-specific mediating effects of SIVD on the relationship between H-type hypertension and cognition. Results: For males, there was no noticeable difference in WML, LI and BA scores among control group, isolated hypertension group, isolated high tHcy group, and H-type hypertension group in most brain regions, but significant difference was found in all brain regions for females. Multiple regression analyses showed that H-type hypertension was significantly associated with WML, LI and BA for females, but not for males. For males, H-type hypertension mainly affected cognition through direct effect, while the H-type hypertension effect was mediated by ischemic brain injury caused by SIVD for females. Conclusion: H-type hypertension was more closely related to SIVD for females than males, suggesting a gender-specific difference in association patterns between H-type hypertension and cognition.

Altered serum amyloid beta and cerebral perfusion and their associations with cognitive function in patients with subcortical ischemic vascular disease.

Subcortical ischemic vascular disease (SIVD) is one of the important causes of cognitive dysfunction, altered amyloid-beta (Aß) and cerebral perfusion may be involved in the pathophysiological mechanism of SIVD and are closely related to cognitive function. We aimed to investigate altered serum Aß and cerebral perfusion in patients with SIVD and their correlation with cognitive function. Seventy-four healthy controls (HCs) and 74 SIVD patients, including 38 SIVD patients with no cognitive impairment (SIVD-NCI) and 36 SIVD patients with mild cognitive impairment (SIVD-MCI) underwent the measurement of serum Aß40 and Aß42 levels, pseudo-continuous arterial spin labeling MRI scanning, and cognitive evaluation. Compared to the healthy controls (HCs), the level of serum Aß40 and Aß40/42 ratio increased and Aß42 decreased in SIVD patients. The serum Aß40 level and Aß40/42 ratio in patients with SIVD-MCI were significantly higher than those in the HCs and SIVD-NCI, and the level of Aß42 in the SIVD-MCI was lower than the HCs. In addition, the serum Aß40/42 ratio provided high diagnostic accuracy for SIVD and SIVD-MCI, it was further identified as an independent risk factor for cognitive impairment. Patients with SIVD-NCI and SIVD-MCI exhibited both increased and decreased cerebral blood flow (CBF) in regional. The Aß40/42 ratio was associated with global CBF, while altered global and regional CBF was associated with cognitive deficits. In addition, white matter hyperintensities volume (WMHV) correlated with Aß40/42 ratio, CBF, and cognition. The relationship between Aß40/42 ratio and cognition was partially mediated by altered CBF. Based on these results, we conclude that the serum Aß40/42 ratio may be a potential biomarker that can complement current methods for the prediction and diagnosis of cognitive impairment in SIVD patients. In addition, serum Aß may play a role in cognitive function by regulating CBF, which provides new insights into the intervention, treatment, and prevention of cognitive impairment in SIVD.

Relationships Between Memory Impairments and Hippocampal Structure in Patients With Subcortical Ischemic Vascular Disease.

Background and Purpose: Patients with subcortical ischemic vascular disease (SIVD) suffer from memory disorders that are thought to be associated with the hippocampus. We aimed to explore changes in hippocampal subfields and the relationship between different hippocampal subfield volumes and different types of memory dysfunction in SIVD patients. Methods: A total of 77 SIVD patients with cognitive impairment (SIVD-CI, n = 39) or normal cognition (HC-SIVD, n = 38) and 41 matched healthy controls (HCs) were included in this study. Memory function was measured in all subjects, and structural magnetic resonance imaging (MRI) was performed. Then, the hippocampus was segmented and measured by FreeSurfer 6.0 software. One-way ANOVA was used to compare the volume of hippocampal subfields among the three groups while controlling for age, sex, education and intracranial volume (ICV). Then, post hoc tests were used to evaluate differences between each pair of groups. Finally, correlations between significantly different hippocampal subfield volumes and memory scores were tested in SIVD patients. Results: Almost all hippocampal subfields were significantly different among the three groups except for the bilateral hippocampal fissure (p = 0.366, p = 0.086, respectively.) and left parasubiculum (p = 0.166). Furthermore, the SIVD-CI patients showed smaller volumes in the right subiculum (p < 0.001), CA1 (p = 0.002), presubiculum (p = 0.002) and molecular layer of the hippocampus (p = 0.017) than the HC-SIVD patients. In addition, right subiculum volumes were positively related to Rey's Auditory Verbal Learning Test (RAVLT) word recognition (r = 0.230, p = 0.050), reverse digit span test (R-DST) (r = 0.326, p = 0.005) and Rey-Osterrieth Complex Figure Test (ROCF) immediate recall (r = 0.247, p = 0.035) scores, right CA1 volumes were positively correlated with RAVLT word recognition (r = 0.261, p = 0.026), and right presubiculum volumes showed positive relationships with R-DST (r = 0.254, p = 0.030) and ROCF immediate recall (r = 0.242, p = 0.039) scores. Conclusion: SIVD might lead to general reductions in volume in multiple hippocampal subfields. However, SIVD-CI patients showed atrophy in specific subfields, which might be associated with memory deficits.

Altered Dynamic Functional Connectivity in Subcortical Ischemic Vascular Disease With Cognitive Impairment.

Subcortical ischemic vascular disease (SIVD) can cause cognitive impairment and affect the static functional connectivity of resting functional magnetic resonance imaging (fMRI). Numerous previous studies have demonstrated that functional connectivities (FCs) fluctuate dynamically over time. However, little is known about the impact of cognitive impairment on brain dynamic functional connectivity (DFC) in SIVD patients with MCI. In the present study, the DFC analysis method was applied to the resting functional magnetic resonance imaging (fMRI) data of 37 SIVD controls (SIVD-Control) without cognitive impairment, 34 SIVD patients with amnestic MCI (SIVD-aMCI) and 30 SIVD patients with nonamnestic MCI (SIVD-naMCI). The results indicated that the cognitive impairment of SIVD mainly reduced the mean dwell time of State 3 with overall strong positive connections. The reduction degree of SIVD-aMCI was larger than that of SIVD-naMCI. The memory/execution function impairment of SIVD also changed the relationship between the mean dwell time of State 3 and the behavioral performance of the memory/execution task from significant to non-significant correlation. Moreover, SIVD-aMCI showed significantly lower system segregation of FC states than SIVD-Control and SIVD-naMCI. The system segregation of State 5 with overall weak connections was significantly positive correlated with the memory performance. The results may suggest that the mean dwell time of State 3 and the system segregation of State 5 may be used as important neural measures of cognitive impairments of SIVD.

Altered Neurovascular Coupling in Subcortical Ischemic Vascular Disease.

Patients with subcortical ischemic vascular disease (SIVD) exhibit a high risk of cognitive impairment that might be caused by neurologic deficits and vascular injuries. However, the mechanism remains unknown. In current study, 24 normal controls (NC) and 54 SIVD patients, including 26 SIVD patients with no cognitive impairment (SIVD-NCI) and 28 SIVD patients with mild cognitive impairment (SIVD-MCI) underwent the resting-state functional MRI (rs-fMRI) and neuropsychological assessments. We combined regional homogeneity (ReHo) and cerebral blood flow (CBF) by using the global ReHo-CBF correlations coefficient and the ReHo/CBF ratio to detect the inner link between neuronal activity and vascular responses. Correlations between the ReHo/CBF ratio and neuropsychological assessments were explored in patients with SIVD. As a result, we identified significantly decreased global ReHo-CBF coupling in the SIVD-NCI group and SIVD- MCI group with respect to the NC. The SIVD-MCI group showed more serious decoupling of the global ReHo-CBF correlation. We also found a significantly abnormal ReHo/CBF ratio predominantly located in cognitive-related brain regions, including the left insula, right middle temporal gyrus, right precuneus, left precentral gyrus, and left inferior parietal lobule but not the supramarginal and angular gyri. The SIVD-MCI group showed more severe disorders of neurovascular coupling than the other two groups. Moreover, the ReHo/CBF ratio in the left precentral gyrus of the SIVD-NCI group exhibited a positive correlation with the MMSE scores. These findings suggested that patients with SIVD show abnormal neurovascular coupling at the early stage of the disease and during disease development. It might be associated with disease severity and cognitive impairment. Neurovascular decoupling in brain may be a possible neuropathological mechanism of SIVD.

Prospective Memory and Regional Functional Connectivity in Subcortical Ischemic Vascular Disease.

Objectives: Patients with subcortical ischemic vascular disease (SIVD) often have prominent frontal dysfunction. However, it remains unclear how SIVD affects prospective memory (PM), which strongly relies on the frontoparietal network. The present study aimed to investigate PM performance in patients with early stage SIVD as compared to those with Alzheimer's disease (AD) and to older adults with normal cognition, and to explore the neural correlates of PM deficits. Method: Patients with very-mild to mild dementia due to SIVD or AD and normal controls (NC) aged above 60 years were recruited. Seventy-three participants (20 SIVD, 22 AD, and 31 NC) underwent structural magnetic resonance imaging (MRI), cognitive screening tests, and a computerized PM test. Sixty-five of these participants (19 SIVD, 20 AD, and 26 NC) also received resting-state functional MRI. Results: The group with SIVD had significantly fewer PM hits than the control group on both time-based and non-focal event-based PM tasks. Among patients in the very early stage, only those with SIVD but not AD performed significantly worse than the controls. Correlational analyses showed that non-focal event-based PM in SIVD was positively correlated with regional homogeneity in bilateral superior and middle frontal gyri, while time-based PM was not significantly associated with regional homogeneity in any of the regions of interest within the dorsal frontoparietal regions. Conclusions: The findings of this study highlight the vulnerability of non-focal event-based PM to the disruption of regional functional connectivity in bilateral superior and middle frontal gyri in patients with SIVD.

The Associations Between White Matter Disruptions and Cognitive Decline at the Early Stage of Subcortical Vascular Cognitive Impairment: A Case-Control Study.

OBJECTIVE: Emerging evidence suggests that white matter (WM) disruption is associated with the incidence of subcortical vascular cognitive impairment (SVCI). However, our knowledge regarding this relationship in the early stage of SVCI is limited. We aimed to investigate the associations between WM disruptions and cognitive declines at the early stage of SVCI. METHOD: We performed a case-control study, involving 22 cases and 19 controls. The cases were patients at the early stage of SVCI, which was defined as subcortical ischemic vascular disease with normal global cognitive measures (pre-SVCI). The controls were healthy people matched by age, sex, and education years. We assessed the differences in a battery of neuropsychological tests between the two groups, investigated the diffusion changes in 40 WM tracts among the participants via an atlas-based segmentation strategy, and compared the differences between the cases and controls by multiple linear regression analysis. We then evaluated the relationships between diffusion indices and cognitive assessment scores by Pearson's correlation. RESULTS: The pre-SVCI group exhibited significant differences in the Montreal cognitive assessment (MoCA), Rey-Osterrieth Complex Figure (R-O)-copy, and Trail Making Test (TMT)-B test compared with the controls. Compared with the controls, some long associative and projective bundles, such as the right anterior corona radiata (ACR), the right inferior fronto-occipital fasciculus (IFOF), and the left external capsule (EC), were extensively damaged in cases after Bonferroni correction (p < 0.05/40). Damages to specific fibers, such as the right ACR, IFOF, and posterior thalamic radiation (PTR), exhibited significant correlations with declines in MoCA, R-O delay, and the Mini-Mental State Examination (MMSE), respectively, after Bonferroni correction (p < 0.05/14). CONCLUSION: Long WM tracts, especially those in the right hemisphere, were extensively damaged in the pre-SVCI patients and correlated with declines in executive functions and spatial processing. Patients of pre-SVCI are likely at an ultra-early stage of SVCI, and there is a very high risk of this condition becoming SVCI.