Subcortical Ischemic Vascular Disease Research Articles

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

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. 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. 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. 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.

Joint diffusional kurtosis magnetic resonance imaging analysis of white matter and the thalamus to identify subcortical ischemic vascular disease

Identifying subcortical ischemic vascular disease (SIVD) in older adults is important but challenging. Growing evidence suggests that diffusional kurtosis imaging (DKI) can detect SIVD-relevant microstructural pathology, and a systematic assessment of the discriminant power of DKI metrics in various brain tissue microstructures is urgently needed. Therefore, the current study aimed to explore the value of DKI and diffusion tensor imaging (DTI) metrics in detecting early-stage SIVD by combining multiple diffusion metrics, analysis strategies, and clinical-radiological constraints. This prospective study compared DKI with diffusivity and macroscopic imaging evaluations across the aging spectrum including SIVD, Alzheimer's disease (AD), and cognitively normal (NC) groups. Using a white matter atlas and segregated thalamus analysis with considerations of the pre-identified macroscopic pathology, the most effective diffusion metrics were selected and then examined using multiple clinical-radiological constraints in a two-group or three-group paradigm. A total of 122 participants (mean age, 74.6 ± 7.38 years, 72 women) including 42 with SIVD, 50 with AD, and 30 NC were evaluated. Fractional anisotropy, mean kurtosis, and radial kurtosis were critical metrics in detecting early-stage SIVD. The optimal selection of diffusion metrics showed 84.4–100% correct classification of the results in a three-group paradigm, with an area under the curve of .909–.987 in a two-group paradigm related to SIVD detection (all P < .001). We therefore concluded that greatly resilient to the effect of pre-identified macroscopic pathology, the combination of DKI/DTI metrics showed preferable performance in identifying early-stage SIVD among adults across the aging spectrum.

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

To explore the static and dynamic characteristics of intrinsic brain activity (IBA) in subcortical ischemic vascular disease (SIVD) patients with or without cognitive impairment. 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. 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. 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.

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). 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. 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. 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. 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.

Study of gray matter atrophy pattern with subcortical ischemic vascular disease-vascular cognitive impairment no dementia based on structural magnetic resonance imaging.

This study explored the structural imaging changes in patients with subcortical ischemic vascular disease (SIVD)-vascular cognitive impairment no dementia (VCIND) and the correlation between the changes in gray matter volume and the field of cognitive impairment to provide new targets for early diagnosis and treatment. Our study included 15 patients with SIVD-normal cognitive impairment (SIVD-NCI), 63 with SIVD-VCIND, 26 with SIVD-vascular dementia (SIVD-VD), and 14 normal controls (NC). T1-weighted images of all participants were collected, and DPABI and SPM12 software were used to process the gray matter of the four groups based on voxels. Fisher's exact test, one-way ANOVA and Kruskal-Wallis H test were used to evaluate all clinical and demographic data and compare the characteristics of diencephalic gray matter atrophy in each group. Finally, the region of interest (ROI) of the SIVD-VCIND was extracted, and Pearson correlation analysis was performed between the ROI and the results of the neuropsychological scale. Compared to the NC, changes in gray matter atrophy were observed in the bilateral orbitofrontal gyrus, right middle temporal gyrus, superior temporal gyrus, and precuneus in the SIVD-VCIND. Gray matter atrophy was observed in the left cerebellar region 6, cerebellar crural region 1, bilateral thalamus, right precuneus, and calcarine in the SIVD-VD. Compared with the SIVD-VCIND, gray matter atrophy changes were observed in the bilateral thalamus in the SIVD-VD (p < 0.05, family-wise error corrected). In the SIVD-VCIND, the total gray matter volume, bilateral medial orbital superior frontal gyrus, right superior temporal gyrus, middle temporal gyrus, and precuneus were positively correlated with Boston Naming Test score, whereas the total gray matter volume, right superior temporal gyrus, and middle temporal gyrus were positively correlated with overall cognition. Structural magnetic resonance imaging can detect extensive and subtle structural changes in the gray matter of patients with SIVD-VCIND and SIVD-VD, providing valuable evidences to explain the pathogenesis of subcortical vascular cognitive impairment and contributing to the early diagnosis of SIVD-VCIND and early warning of SIVD-VD.

Diagnosis of mixed dementia by double dichotomy

AbstractBackgroundProper classification of patients with dementia is critical in clinical trials. Dual Alzheimer’s disease (AD) and vascular pathology (mixed dementia‐MX) is the most common form of dementia estimated to be as high as 70% in pathological series. However, separation clinically is difficult, which has led to use of biomarkers. A biological definition of AD based on biomarkers has been proposed for research studies with identification of amyloid and tau in CSF or PET. Including in the ATN formula, biomarkers for vascular disease (V), obtained from MRI, separates MX subjects, improving diagnosis of AD and vascular cognitive impairment (VCI).MethodsWe used vascular disease biomarkers from MRI and AD biomarkers from CSF with a double dichotomy statistical approach to more precisely define four major groups of patients in the UNM and Alzheimers's Disease Neuroimaging Initiative (ADNI) cohorts. We compared the UNM dataset (N=80) with subjects from ADNI (N=538). Diffusion tensor imaging (DTI) biomarkers (mean free water and PSMD) were combined with CSF amyloid (A) and tau (T) to identify MX patients. We formed a composite vascular disease score (cVDS) with DTI, and a composite AD score (cADS) with CSF amyloid and phosphoTau181.ResultsPlotting cVDS on the x‐axis and cADS on the y‐axis placed subjects in one of four biologically defined quadrants: bAD (biological AD) in the upper left, bSIVD (biological subcortical ischemic vascular disease) in the lower right, bMX (biological mixed dementia) in the upper right, and bCN (biological controls) in the lower left quadrant (Figure). We identified MX, using a double dichotomy statistical method. The UNM cohort had 25% MX, while in ADNI there were 11.5% (Table). The ADNI group had a higher percentage of bCN (43%) and bAD (35%) than the UNM cohort; this was because UNM was one of 7 sites in the MarkVCID consortium with enriched VCI subjects and ADNI excluded vascular disease subjects.ConclusionsOur results show that adding a vascular factor (V) to the ATN formula creates a MX group, improving classification of patients by creating a more homogeneous AD group, which permits AD clinical trials with fewer subjects

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.

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 (Aβ) 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 Aβ 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 Aβ40 and Aβ42 levels, pseudo-continuous arterial spin labeling MRI scanning, and cognitive evaluation. Compared to the healthy controls (HCs), the level of serum Aβ40 and Aβ40/42 ratio increased and Aβ42 decreased in SIVD patients. The serum Aβ40 level and Aβ40/42 ratio in patients with SIVD-MCI were significantly higher than those in the HCs and SIVD-NCI, and the level of Aβ42 in the SIVD-MCI was lower than the HCs. In addition, the serum Aβ40/42 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 Aβ40/42 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 Aβ40/42 ratio, CBF, and cognition. The relationship between Aβ40/42 ratio and cognition was partially mediated by altered CBF. Based on these results, we conclude that the serum Aβ40/42 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 Aβ 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.

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

BackgroundSubcortical 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 methodsA 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.ResultsFor 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.ConclusionH-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.

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

Background and PurposePatients 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.MethodsA 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.ResultsAlmost 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.ConclusionSIVD 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.

Stage-Dependent Cerebral Blood Flow and Leukoaraiosis Couplings in Subcortical Ischemic Vascular Disease and Alzheimer's Disease.

Background: Alzheimer’s disease (AD) and subcortical ischemic vascular disease (SIVD) have both been associated with white matter hyperintensities (WMHs) and altered cerebral blood flow (CBF) although the etiology of AD is still unclear.Objective: To test the hypothesis that CBF and WMHs have differential effects on cognition and that the relationship between CBF and WMHs changes with the subtypes and stages of dementia.Methods: Forty-two patients with SIVD, 50 patients with clinically-diagnosed AD, and 30 cognitively-normal subjects were included. Based on the Clinical Dementia Rating (CDR), the patients were dichotomized into early-stage (CDR = 0.5) and late-stage (CDR = 1 or 2) groups. CBF and WMH metrics were derived from magnetic resonance imaging and correlated with cognition.Results: Hierarchical linear regression revealed that CBF metrics had distinct contribution to global cognition, memory, and attention, whereas WMH metrics had distinct contribution to executive function (all p < 0.05). In SIVD, the WMHs in frontotemporal areas correlated with the CBF in bilateral thalami at the early stage; the correlation then became between the WMHs in basal ganglia and the CBF in frontotemporal areas at the late stage. A similar corticosubcortical coupling was observed in AD but involved fewer areas.Conclusion: A stage-dependent coupling between CBF and WMHs was identified in AD and SIVD, where the extent of cortical WMHs correlated with subcortical CBF for CDR = 0.5, whereas the extent of subcortical WMHs correlated with cortical CBF for CDR = 1–2.

Prospective Memory and Default Mode Network Functional Connectivity in Normal and Pathological Aging.

Prospective memory (PM), the ability to execute a previously formed intention given the proper circumstance, has been proven to be vulnerable to Alzheimer's disease. Previous studies have indicated the involvement of the frontoparietal networks; however, it is proposed that PM may also be associated with other neural substrates that support stimulus-dependent spontaneous cognition. The present study aimed to examine the hypothesis that PM deficit in Alzheimer's disease is related to altered functional connectivity (FC) within the default mode network (DMN). Thirty-four patients with very mild or mild dementia (17 with Alzheimer's disease and 17 with subcortical ischemic vascular disease) and 22 cognitively-normal participants aged above 60 received a computerized PM task and resting-state functional magnetic resonance imaging study. Seed-based functional connectivity analysis was performed at group level within the DMN. We found that the dementia groups showed worse PM performance and altered FC within the DMN as compared to the normal aging individuals. The FC between the medial prefrontal cortices and precuneus/posterior cingulate cortex was significantly correlated with PM in normal aging, while the FC between the right precuneus and bilateral inferior parietal lobules was correlated with PM in patients with Alzheimer's disease. These findings support a potential role for the DMN in PM, and corroborate that PM deficit in Alzheimer's disease was associated with altered FC within the posterior hubs of the DMN, with spatial patterning different from normal aging.

Daily mocha coffee intake and psycho-cognitive status in non-demented non-smokers subjects with subcortical ischaemic vascular disease

Coffee intake has been recently associated with better cognition and mood in mild vascular cognitive impairment (mVCI). As tobacco can reduce the caffeine half-life, we excluded smokers from the original sample. Hamilton Depression Rating Scale (HDRS), mini-mental state examination (MMSE), Stroop Colour-Word Interference Test (Stroop), activities of daily living (ADL0) and instrumental ADL were the outcome measures. Significant differences were observed in higher consumption groups (moderate intake for HDRS; high intake for MMSE and Stroop) compared to the other groups, as well as in age and education. With age, education and coffee used as independent predictors, and HDRS, Stroop and MMSE as dependent variables, a correlation was found between age and both MMSE and Stroop, as well as between education and MMSE and between HDRS and Stroop; coffee intake negatively correlated with HDRS and Stroop. Higher coffee consumption was associated with better psycho-cognitive status among non-smokers with mVCI.

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

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). 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. 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. 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.

Multiscale functional connectome abnormality predicts cognitive outcomes in subcortical ischemic vascular disease.

Subcortical ischemic vascular disease could induce subcortical vascular cognitive impairments (SVCIs), such as amnestic mild cognitive impairment (aMCI) and non-amnestic MCI (naMCI), or sometimes no cognitive impairment (NCI). Previous SVCI studies focused on focal structural lesions such as lacunes and microbleeds, while the functional connectivity networks (FCNs) from functional magnetic resonance imaging are drawing increasing attentions. Considering remarkable variations in structural lesion sizes, we expect that seeking abnormalities in the multiscale hierarchy of brain FCNs could be more informative to differentiate SVCI patients with varied outcomes (NCI, aMCI, and naMCI). Driven by this hypothesis, we first build FCNs based on the atlases at multiple spatial scales for group comparisons and found distributed FCN differences across different spatial scales. We then verify that combining multiscale features in a prediction model could improve differentiation accuracy among NCI, aMCI, and naMCI. Furthermore, we propose a graph convolutional network to integrate the naturally emerged multiscale features based on the brain network hierarchy, which significantly outperforms all other competing methods. In addition, the predictive features derived from our method consistently emphasize the limbic network in identifying aMCI across the different scales. The proposed analysis provides a better understanding of SVCI and may benefit its clinical diagnosis.

Dissociable Functional Brain Networks Associated With Apathy in Subcortical Ischemic Vascular Disease and Alzheimer's Disease.

Few studies have investigated differences in functional connectivity (FC) between patients with subcortical ischemic vascular disease (SIVD) and Alzheimer’s disease (AD), especially in relation to apathy. Therefore, the aim of this study was to compare apathy-related FC changes among patients with SIVD, AD, and cognitively normal subjects. The SIVD group had the highest level of apathy as measured using the Apathy Evaluation Scale-clinician version (AES). Dementia staging, volume of white matter hyperintensities (WMH), and the Beck Depression Inventory were the most significant clinical predictors for apathy. Group-wise comparisons revealed that the SIVD patients had the worst level of “Initiation” by factor analysis of the AES. FCs from four resting state networks (RSNs) were compared, and the connectograms at the level of intra- and inter-RSNs revealed dissociable FC changes, shared FC in the dorsal attention network, and distinct FC in the salient network across SIVD and AD. Neuronal correlates for “Initiation” deficits that underlie apathy were explored through a regional-specific approach, which showed that the right inferior frontal gyrus, left middle frontal gyrus, and left anterior insula were the critical hubs. These findings broaden the disconnection theory by considering the effect of FC interactions across multiple RSNs on apathy formation.

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.

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.

Sex differences between serum total bilirubin levels and cognition in patients with schizophrenia

BackgroundCognitive deficits are common in patients with schizophrenia (SCZ). Abnormal serum total bilirubin (TBIL) levels have been involved in cognitive deficits associated with neuropsychiatric diseases such as mild cognitive impairment and subcortical ischemic vascular disease. However, this relationship has not yet been fully investigated in patients with SCZ. Therefore, the aim of this study was to investigate the association between the serum TBIL concentration and cognitive deficits in SCZ patients and to determine whether a sex difference exists in the association.MethodsA total of 455 participants were eligible and included in this cross-sectional study. Cognition was evaluated using the Montreal Cognitive Assessment. Serum TBIL concentration was measured with an automatic biochemistry analyzer according to the routine protocol in the hospital medical laboratory.ResultsSerum TBIL levels were lower in the cognition impairment group than in the cognition normal group in male patients. In contrast, serum TBIL levels tended to be increased in the cognition impairment group in female patients, although the difference was not significant. Further stepwise multiple regression analysis stratified by sex showed that serum TBIL was independently and positively associated with cognitive function in male patients but not in female patients. Moreover, the association between serum TBIL level and cognitive function was also identified by the propensity score matching (PSM) method in male patients, but not in female patients.ConclusionThese findings suggest that lower serum TBIL levels may be associated with cognitive impairment in male SCZ patients.

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

ObjectiveEmerging 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.MethodWe 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.ResultsThe 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).ConclusionLong 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.