Subcortical Vascular Mild Cognitive Impairment Research Articles

Selective vulnerability of hippocampal sub-regions in patients with subcortical vascular mild cognitive impairment.

Early diagnosis of subcortical vascular mild cognitive impairment (svMCI) is clinically essential because it is the most reversible subtype of all cognitive impairments. Since structural alterations of hippocampal sub-regions have been well studied in neurodegenerative diseases with pathophysiological cognitive impairments, we were eager to determine whether there is a selective vulnerability of hippocampal sub-fields in patients with svMCI. Our study included 34 svMCI patients and 34 normal controls (NCs), with analysis of T1 images and Montreal Cognitive Assessment (MoCA) scores. Gray matter volume (GMV) of hippocampal sub-regions was quantified and compared between the groups, adjusting for age, sex, and education. Additionally, we explored correlations between altered GMV in hippocampal sub-fields and MoCA scores in svMCI patients. Patients with svMCI exhibited selectively reduced GMV in several left hippocampal sub-regions, such as the hippocampal tail, hippocampal fissure, CA1 head, ML-HP head, CA4 head, and CA3 head, as well as decreased GMV in the right hippocampal tail. Specifically, GMV in the left CA3 head was inversely correlated with MoCA scores in svMCI patients. Our findings indicate that the atrophy pattern of patients with svMCI was predominantly located in the left hippocampal sub-regions. The left CA3 might be a crucial area underlying the distinct pathophysiological mechanisms of cognitive impairments with subcortical vascular origins.

Method of differential diagnosis of mild cognitive impairment of various origins: cross sectional study

INTRODUCTION:The differential diagnosis of mild cognitive impairment (MCI), due to the high prevalence in the population and the rapid increase in incidence, is an urgent task. The most common causes leading to the development of cognitive impairment are Alzheimer’s disease (AD), cerebrovascular pathology, and their combination. AD usually manifests as an amnestic type of mild cognitive impairment (aMCI) at the pre-dementia stage. Subcortical vascular mild cognitive impairment (svMCI) is considered as the prodromal stage of subcortical vascular dementia. According to the results of pathomorphological studies, it was found that subfields of the hippocampal formation are selective vulnerability to AD, ischemia/hypoxia, and aging.Currently, using the FreeSurfer 6.0 software, it is possible to obtain quantitative indicators of the hippocampal formation subfieldsin vivo.The current trend in medicine is the development and implementation of new diagnostic solutions based on artificial intelligence and machine learning. One of the machine learning algorithms is binary logistic regression, which we used in the course of the study for the differential diagnosis of MCI of various origins.OBJECTIVE:To develop a method for the differential diagnosis of mil cognitive impairment of various origins.MATERIALS AND METHODS:The study included patients with the syndrome of mild cognitive impairment who were examined in the department of geriatric psychiatry of the V.M.Bekhterev National Medical Research Center for Psychiatry and Neurology, from which two groups were formed: group 1 — patients with aMCI, group 2 — patients with svMCI. Conditionally healthy volunteers, comparable in age, sex and level of education, made up the 3rdgroup (control). MRI examination was performed using a Excelart Vantage Atlas XGV magnetic resonance imaging system (Toshiba, Japan) with a magnetic field strength of 1.5 T, followed by MR morphometry of the subfields of the hippocampal formation.Statistics:Statistical analysis was carried out using data that was converted from a database in Microsoft Excel to the statistical package IBM SPSS 21. To develop a differential diagnosis method, based on the data obtained, the binary regression method and ROC analysis were used.RESULTS:Based on the obtained MR-morphometry data, a method was developed using the binary logistic regression equation. The value of p≥0.5 makes it possible to classify the patient to the aMCI group, and the value of p<0.5 — to the svMCI. The sensitivity of the method is 90%, the specificity is 80%, and the accuracy is 85%.DISCUSSION:Using binary logistic regression, the selection of variants of sets of variables (quantitative indicators) was carried out, for which ROC curves were constructed. The selection criterion was the area under the ROC curve — the AUC criterion (Area Under the Curve). The largest area under the curve (AUC=0.824) in the differential diagnosis of aMCI from svMCI was determined for the combination of the volume of the left subiculum and the thickness of the right entorhinal cortex.Since patients in the aMCI group have a significantly lower number of vascular foci than in the svMCI group (p<0.05), at the next stage, one more variable, the volume fraction, was added to the selected combination of two variables (volume of the left subiculum and thickness of the right entorhinal cortex) hypointense foci. When conducting an ROC analysis with a combination of three variables, an increase in AUC to 0.892 was noted. Further, using a combination of three variables and a binary logistic regression equation, a method for differential diagnosis of aMCI from svMCI was developed.CONCLUSION:The method of differential diagnosis based on binary logistic regression using MR morphometry data allows to distinguish patients with aMCI from patients with svMCI with high sensitivity and specificity.

Structural atrophy and functional dysconnectivity patterns in the cerebellum relate to cerebral networks in svMCI.

Subcortical vascular mild cognitive impairment (svMCI) is associated with structural and functional changes in the cerebral cortex affecting major brain networks. While recent studies have shown that the intrinsic cerebral connectivity networks can be mapped onto the cerebellum, and the cortex and cerebellum are interconnected via the cortico-basal ganglia-cerebellar circuit, structural and functional disruptions in cerebellum in svMCI are rarely studied. In this study, we conducted voxel-based morphometry analysis to investigate gray matter atrophy pattern across cerebellar regions in 40 svMCI patients, and explored alterations in functional connectivity between the basal ganglia and cerebellum. The results showed that the amount of cerebellar atrophy within the default mode, salience, and frontoparietal networks correlated with their counterpart in the cerebral cortex. Moreover, key regions of the cerebellum, including the lobule VI, VIIb, VIII, and Crus I, which are reported to have a role in cognitive function, showed both anatomical atrophy and decreased functional connectivity with the striatum. These atrophy and connectivity patterns in the cerebellum also correlated with memory performances. These findings demonstrate that there are coupled changes in cerebral and cerebellar circuits, reflecting that degeneration patterns in svMCI are not limited to the cerebral cortex but similarly extend to the cerebellum as well, and suggest the cortico-basal ganglia-cerebellar circuit may play an important role in the pathology of svMCI.

Alzheimer’s and vascular disease classification using regional texture biomarkers in FLAIR MRI

Interactions between subcortical vascular disease and dementia due to Alzheimer’s disease (AD) are unclear, and clinical overlap between the diseases makes diagnosis challenging. Existing studies have shown regional microstructural changes specific to each disease, and that textures in fluid-attenuated inversion recovery (FLAIR) MRI images may characterize abnormalities in tissue microstructure. This work aims to investigate regional FLAIR biomarkers that can differentiate dementia cohorts with and without subcortical vascular disease. FLAIR and diffusion MRI (dMRI) volumes were obtained in 65 mild cognitive impairment (MCI), 21 AD, 44 subcortical vascular MCI (scVMCI), 22 Mixed etiology, and 48 healthy elderly patients. FLAIR texture and intensity biomarkers were extracted from the normal appearing brain matter (NABM), WML penumbra, blood supply territory (BST), and white matter tract regions of each patient. All FLAIR biomarkers were correlated to dMRI metrics in each region and global WML load, and biomarker means between groups were compared using ANOVA. Binary classifications were performed using Random Forest classifiers to investigate the predictive nature of the regional biomarkers, and SHAP feature analysis was performed to further investigate optimal regions of interest for differentiating disease groups. The regional FLAIR biomarkers were strongly correlated to MD, while all biomarker regions but white matter tracts were strongly correlated to WML burden. Classification between Mixed disease and healthy, AD, and scVMCI patients yielded accuracies of 97%, 81%, and 72% respectively using WM tract biomarkers. Classification between scVMCI and healthy, MCI, and AD patients yielded accuracies of 89%, 84%, and 79% respectively using penumbra biomarkers. Only the classification between AD and healthy patients had optimal results using NABM biomarkers. This work presents novel regional FLAIR biomarkers that may quantify white matter degeneration related to subcortical vascular disease, and which indicate that investigating degeneration in specific regions may be more important than assessing global WML burden in vascular disease groups.

Lateralized brain activities in subcortical vascular mild cognitive impairment with differential Chinese medicine patterns: A resting-state functional magnetic resonance imaging study.

BackgroundSubcortical vascular mild cognitive impairment (svMCI) is one of the most treatable cognitive impairments, but could be hampered by the high clinical heterogeneities. Further classification by Chinese Medicine (CM) patterns has been proved to stratify its clinical heterogeneities. It remains largely unknown of the spontaneous brain activities regarding deficiency patterns (DPs) and excess patterns (EPs) of svMCI patients based on fMRI data.ObjectiveWe aim to provide neuroimaging evidence of altered resting-state brain activities associated with DPs and EPs in svMCI patients.MethodsThirty-seven svMCI patients (PAs) and 23 healthy controls (CNs) were consecutively enrolled. All patients were categorized into either the EP group (n = 16) and the DP group (n = 21) based on a quantitative CM scale. The fractional amplitude of low-frequency fluctuation (fALFF) value was used to make comparisons between different subgroups.ResultsThe DP group showed significant differences of fALFF values in the right middle frontal gyrus and the right cerebellum, while the EP group showed significant differences in the left orbitofrontal gyrus and the left cerebellum, when compared with the CN group. When compared with the EP group, the DP group had markedly increased fALFF values in the left superior temporal gyrus, right middle temporal gyrus and brainstem. The decreased fALFF values was shown in the right anterior cingulate and paracingulate gyri. Among the extensive areas of frontotemporal lobe, the Montreal Cognitive Assessment (MoCA) scores were significantly correlated with the reduced fALFF value of the right middle frontal gyrus and the left orbitofrontal gyrus.ConclusionOur results indicated that the DPs and EPs presented the lateralization pattern in the bilateral frontal gyrus, which will probably benefit the future investigation of the pathogenesis of svMCI patients.

Written Spelling in Patients with Subcortical Vascular Dementia and Subcortical Vascular Mild Cognitive Impairment

Objectives: The purpose of this study is to examine the spelling processing patterns in patients with subcortical vascular dementia (SVaD) and subcortical vascular mild cognitive impairment (svMCI).Methods: The subjects consisted of 10 patients with SVaD, 15with svMCI, and 30 normal controls (NC) subjects. Prior to this study, Korean- Mini Mental Status Examination (K-MMSE), Montreal Cognitive Assessment (MoCA-K), and health screening questionnaires were conducted as pre-tests. After that, subjects were presented with 20 words grouped according to word type (regular word, irregular word, non-word), and then they were asked to dictate the words they heard. After the tests were completed, the number of correct responses and the number of error patterns were compared between groups.Results: First, by word type between groups, the svMCI and SVaD groups showed a significantly lower number of correct responses for regular and irregular words compared to the NC group. In addition, the SVaD group showed a significantly lower number of forward responses than the svMCI group in irregular words. Non-words showed significantly lower number of forward responses in the SVaD group compared to the NC and svMCI groups. Second, the comparison of the number of error types between groups showed a significant difference between the three groups in terms of grapheme substitution; and the SVaD group showed significantly more errors compared with the NC and svMCI groups in addition and omission of graphemes. Third, the SVaD group showed significantly more errors in comparison to the NC and svMCI groups for phonological implausible errors, and the svMCI and SVaD groups showed significantly more errors than the NC group for phonological plausible errors. Fourth, lexicalization errors within non-words were observed only in the SVaD group.Conclusion: For early detection of svMCI, it is necessary to pay attention to irregular word performance.

Quantitative Assessment Method of Force Tracking Capabilities for Detection of Motor Intentional Disorders

Early detection of motor intentional disorders associated with dysfunction in the action–intention system of the brain is clinically important to provide timely intervention. This study developed a force tracking system that can record forces exerted by the index finger while tracking 5 N, 10 N, 15 N, and 20 N of target forces varying over time. The force tracking system quantified force control measures (initiation time IT; development time, DT, maintenance error, ME; termination time, TT; tracking error, TE) for the individual and overall force control phases. This study evaluated the effectiveness of the force tracking system for a normal control group (n = 12) and two patient groups diagnosed with subcortical vascular mild cognitive impairment (svMCI, n = 11) and subcortical vascular dementia (SVaD, n = 13). Patients with SVaD showed significantly worse force control capabilities in IT (0.84 s) and ME (1.71 N) than those with svMCI (0.64 s in IT, and 1.38 N in ME). Patients with svMCI had significantly worse capabilities in IT, ME, and TE (3.80 N) than the control group (0.49 s in IT, 0.78 N in ME, and 3.07 N in TE). The prevalence rates of force control capabilities lower than the 99% confidence interval of the control group ranged from 17% to 62% for the two patient groups. The force tracking system can sensitively quantify the severity of the force control deficiencies caused by dysfunction in the action–intention system of the brain.

Comparison of Longitudinal Changes of Cerebral Small Vessel Disease Markers and Cognitive Function Between Subcortical Vascular Mild Cognitive Impairment With and Without NOTCH3 Variant: A 5-Year Follow-Up Study.

No study yet has compared the longitudinal course and prognosis between subcortical vascular cognitive impairment patients with and without genetic component. In this study, we compared the longitudinal changes in cerebral small vessel disease markers and cognitive function between subcortical vascular mild cognitive impairment (svMCI) patients with and without NOTCH3 variant [NOTCH3(+) svMCI vs. NOTCH3(–) svMCI]. We prospectively recruited patients with svMCI and screened for NOTCH3 variants by sequence analysis for mutational hotspots in the NOTCH3 gene. Patients were annually followed-up for 5 years through clinical interviews, neuropsychological tests, and brain magnetic resonance imaging. Among 63 svMCI patients, 9 (14.3%) had either known mutations or possible pathogenic variants. The linear mixed effect models showed that the NOTCH3(+) svMCI group had much greater increases in the lacune and cerebral microbleed counts than the NOTCH3(–) svMCI group. However, there were no significant differences between the two groups regarding dementia conversion rate and neuropsychological score changes over 5 years.

Loss of Integrity of Corpus Callosum White Matter Hyperintensity Penumbra Predicts Cognitive Decline in Patients With Subcortical Vascular Mild Cognitive Impairment.

Loss of white matter (WM) integrity contributes to subcortical vascular mild cognitive impairment (svMCI). Diffusion tensor imaging (DTI) has revealed damage beyond the area of WM hyperintensity (WMH) including in normal-appearing WM (NAWM); however, the functional significance of this observation is unclear. To answer this question, in this study we investigated the relationship between microstructural changes in the WMH penumbra (WMH-P) and cognitive function in patients with svMCI by regional tract-based analysis. A total of 111 patients with svMCI and 72 patients with subcortical ischemic vascular disease (SIVD) without cognitive impairment (controls) underwent DTI and neuropsychological assessment. WMH burden was determined before computing mean values of fractional anisotropy (FA) and mean diffusivity (MD) within WMHs and WMH-Ps. Pearson’s partial correlations were used to assess the relationship between measurements showing significant intergroup differences and composite Z-scores representing global cognitive function. Multiple linear regression analysis was carried out to determine the best model for predicting composite Z-scores. We found that WMH burden in the genu, body, and splenium of the corpus callosum (GCC, BCC, and SCC respectively); bilateral anterior, superior, and posterior corona radiata; left sagittal stratum was significantly higher in the svMCI group than in the control group (p < 0.05). The WMH burden of the GCC, BCC, SCC, and bilateral anterior corona radiata was negatively correlated with composite Z-scores. Among diffusion parameters showing significant differences across the 10 WM regions, mean FA values of WMH and WMH-P of the BCC were correlated with composite Z-scores in svMCI patients. The results of the multiple linear regression analysis showed that the FA of WMH-P of the BCC and WMH burden of the SCC and GCC were independent predictors of composite Z-score, with the FA of WMH-P of the BCC making the largest contribution. These findings indicate that disruption of the CC microstructure—especially the WMH-P of the BCC—may contribute to the cognitive deficits associated with SIVD.

Selective Aberrant Functional–Structural Coupling of Multiscale Brain Networks in Subcortical Vascular Mild Cognitive Impairment

Subcortical vascular mild cognitive impairment (svMCI) is a common prodromal stage of vascular dementia. Although mounting evidence has suggested abnormalities in several single brain network metrics, few studies have explored the consistency between functional and structural connectivity networks in svMCI. Here, we constructed such networks using resting-state fMRI for functional connectivity and diffusion tensor imaging for structural connectivity in 30 patients with svMCI and 30 normal controls. The functional networks were then parcellated into topological modules, corresponding to several well-defined functional domains. The coupling between the functional and structural networks was finally estimated and compared at the multiscale network level (whole brain and modular level). We found no significant intergroup differences in the functional-structural coupling within the whole brain; however, there was significantly increased functional-structural coupling within the dorsal attention module and decreased functional-structural coupling within the ventral attention module in the svMCI group. In addition, the svMCI patients demonstrated decreased intramodular connectivity strength in the visual, somatomotor, and dorsal attention modules as well as decreased intermodular connectivity strength between several modules in the functional network, mainly linking the visual, somatomotor, dorsal attention, ventral attention, and frontoparietal control modules. There was no significant correlation between the altered module-level functional-structural coupling and cognitive performance in patients with svMCI. These findings demonstrate for the first time that svMCI is reflected in a selective aberrant topological organization in multiscale brain networks and may improve our understanding of the pathophysiological mechanisms underlying svMCI.

The Effects of Longitudinal White Matter Hyperintensity Change on Cognitive Decline and Cortical Thinning over Three Years.

White matter hyperintensity (WMH) has been recognised as a surrogate marker of small vessel disease and is associated with cognitive impairment. We investigated the dynamic change in WMH in patients with severe WMH at baseline, and the effects of longitudinal change of WMH volume on cognitive decline and cortical thinning. Eighty-seven patients with subcortical vascular mild cognitive impairment were prospectively recruited from a single referral centre. All of the patients were followed up with annual neuropsychological tests and 3T brain magnetic resonance imaging. The WMH volume was quantified using an automated method and the cortical thickness was measured using surface-based methods. Participants were classified into WMH progression and WMH regression groups based on the delta WMH volume between the baseline and the last follow-up. To investigate the effects of longitudinal change in WMH volume on cognitive decline and cortical thinning, a linear mixed effects model was used. Seventy patients showed WMH progression and 17 showed WMH regression over a three-year period. The WMH progression group showed more rapid cortical thinning in widespread regions compared with the WMH regression group. However, the rate of cognitive decline in language, visuospatial function, memory and executive function, and general cognitive function was not different between the two groups. The results of this study indicated that WMH volume changes are dynamic and WMH progression is associated with more rapid cortical thinning.

Different patterns of functional and structural alterations of hippocampal sub-regions in subcortical vascular mild cognitive impairment with and without depression symptoms

In addition to cognitive impairments, depression symptoms were reported in subcortical vascular mild cognitive impairment. Although hippocampal alterations were associated with cognitive decline in subcortical vascular mild cognitive impairment, the neural mechanism underlying depression symptoms remains unclear. Thus, a cohort of 18 patients with depression symptoms, 17 patients without depression symptoms, and 23 normal controls was used. Functionally, significantly altered resting-state functional connectivity between hippocampal emotional sub-region and right posterior cingulate cortex, between hippocampal cognitive sub-region and right inferior parietal gyrus and between hippocampal perceptual sub-region and left inferior temporal gyrus were identified among three groups. Structurally, significantly altered structural associations between hippocampal emotional sub-region and 6 frontal regions/right pole part of superior temporal gyrus/right inferior occipital gyrus, between hippocampal cognitive sub-region and right orbital part of inferior frontal gyrus /right anterior cingulate cortex, and between hippocampal perceptual and right orbital part of inferior frontal gyrus / left inferior temporal gyrus / left thalamus were identified among the three groups. Further analyses also showed correlations between functional connectivity and depression symptoms and/or cognitive impairments of patients. Together, these results showed different patterns of functional and structural alterations of the hippocampal sub-regions in the subcortical vascular mild cognitive impairment with and without depression, which might be specially associated with the depression symptoms and cognitive impairments in these patients.

Alterations of White Matter Microstructure in Subcortical Vascular Mild Cognitive Impairment with and without Depressive Symptoms.

Depressive symptoms were thought to increase the risk of vascular dementia. Previous studies reported widespread white matter damages in the subcortical vascular mild cognitive impairment (svMCI), but little is known about the mechanism of depressive symptoms in svMCI. In the current study, we aim to explore the white matter microstructural alterations in svMCI with depressive symptoms, and their associations with clinical measurements. Fifty-eight subjects including 18 svMCI with depression (svMCI+D), 17 svMCI without depression (svMCI-D), and 23 normal controls (NC) were included in the study. Voxel-based analyses were performed on fractional anisotropy (FA) and mean diffusivity (MD). Compared to NC, both svMCI groups showed decreased FA in the bilateral insula and the left precentral gyrus, and increased MD in the cerebellum. Compared to svMCI-D, svMCI+D showed increased FA in left precentral gyrus. Moreover, svMCI+D showed significant correlation between the increased MD in the cerebellum and the Hamilton Depression Rating Scale (HAMD) scores. Our findings of white matter alterations might be associated with executive function and memory performance in the svMCI patients. Moreover, the structural alterations in the cerebellum might underlie the mechanism of depressive symptoms in svMCI patients.

Cortical Alterations Are Associated with Depression in Subcortical Vascular Mild Cognitive Impairment Revealed by Surface-Based Morphometry.

Late-life depression often coexists with vascular cognitive impairment and affects the quality of life for elders. However, little is known about cortical morphometric interactions between subcortical vascular mild cognitive impairment (svMCI) and concomitant mild depressive symptoms at the early stage. We aimed to investigate cortical alterations of svMCI with and without depressive symptoms and determine whether these parameters are associated with depression symptoms and/or cognitive impairments. Surface based morphometry was performed on 18 svMCI patients with depressive symptoms (svMCI + D), 16 svMCI patients without depressive symptoms (svMCI-D), and 23 normal controls (NC). Compared to NC, both svMCI + D and svMCI-D patients exhibited significantly decreased surface area (SA) in many cortical areas. Interestingly, svMCI + D patients showed significantly increased rather than decreased SA in right lateral occipital gyrus (LOG.R), and a consistent trend of increased SA in these areas compared to svMCI-D. In addition, the svMCI + D showed increased gray matter volume of left pericalcarine (periCAL.L) than svMCI-D, whereas svMCI-D showed decreased gray matter volume of periCAL.L than NC. Further correlation analyses revealed that the SA of left superior temporal gyrus (STG.L) and right lateral orbital part of frontal gyrus (lorbFG.R) were significantly correlated with Hamilton depression rating scale of svMCI + D. In conclusion, these results extend our insight into svMCI and add weight to reevaluation of concomitant early stage depressive symptoms. Moreover, we suggest that LOG.R∖periCAL.L∖STG.L∖lorbFG.R might serve as sensitive and trait-dependent biomarkers to detect concomitant depressive symptoms in svMCI patients.

Structural and Functional Disruptions in Subcortical Vascular Mild Cognitive Impairment With and Without Depressive Symptoms.

Many previous studies have revealed structural and functional abnormalities in patients with the subcortical vascular mild cognitive impairment (svMCI). Although depression symptoms were suggested to serve as a potential marker of conversion to dementia in patients with svMCI, whether these disruptions or other new findings will be identified in the svMCI comorbid with depression symptoms has not been established. In the current study, we combined voxel-based morphometry (VBM) and the resting-state functional magnetic resonance imaging (fMRI) to investigate the structural and functional disruptions in the svMCI with and without depression symptoms using a cohort of 18 svMCI with depression symptoms (svMCI+D), 17 svMCI without depression symptoms (svMCI−D), and 23 normal controls (NC). As a result, we identified significantly decreased gray matter density in the left parahippocampus (ParaHIPP.L), the right hippocampus (HIPP.R), and the right middle cingulate cortex (MCC.R) in both svMCI+D and svMCI−D compared to NC. Most importantly, we also identified increased gray matter density in the MCC.R accompanied by increased resting-state functional connectivity (RSFC) with right parahippocampus (ParaHIPP.R) in the svMCI+D compared to svMCI−D. Moreover, the gray matter density of MCC.R and ParaHIPP.L was correlated with cognitive impairments and depression symptoms in the svMCI, respectively. In conclusion, these results extended previous studies and added weight to considerations of depression symptoms in the svMCI. Moreover, we suggested that a processing loop associated with HIPP, ParaHIPP, and MCC might underlie the mechanism of depression symptoms in the svMCI.

Amyloid and cerebrovascular burden divergently influence brain functional network changes over time.

To examine the effects of baseline Alzheimer disease and cerebrovascular disease markers on longitudinal default mode network (DMN) and executive control network (ECN) functional connectivity (FC) changes in mild cognitive impairment (MCI). We studied 30 patients with amnestic MCI (aMCI) and 55 patients with subcortical vascular MCI (svMCI) with baseline Pittsburgh Compound B (PiB)-PET scans and longitudinal MRI scans. Participants were followed up clinically with annual MRI for up to 4 years (aMCI: 26 with 2 timepoints, 4 with 3 timepoints; svMCI: 13 with 2 timepoints, 16 with 3 timepoints, 26 with 4 timepoints). β-Amyloid (Aβ) burden was associated with longitudinal DMN FC declines, while cerebrovascular burden was associated with longitudinal ECN FC changes. When patients were divided into PiB+ and PiB- groups, PiB+ patients showed longitudinal DMN FC declines, while patients with svMCI showed longitudinal ECN FC increases. Direct comparisons between the 2 groups without mixed pathology (aMCI PiB+ and svMCI PiB-) recapitulated this divergent pattern: aMCI PiB+ patients showed steeper longitudinal DMN FC declines, while svMCI PiB- patients showed steeper longitudinal ECN FC increases. Finally, using baseline PiB uptake and lacune numbers as continuous variables, baseline PiB uptake showed inverse U-shape associations with longitudinal DMN FC changes in both MCI subtypes, while baseline lacune numbers showed mainly inverse U-shape relationships with longitudinal ECN FC changes in patients with svMCI. Our findings underscore the divergent effects of Aβ and cerebrovascular burden on longitudinal FC changes in the DMN and ECN in the predementia stage, which reflect the underlying pathology and may be used to track early changes in Alzheimer disease and cerebrovascular disease.

Characterizing the Penumbras of White Matter Hyperintensities and Their Associations With Cognitive Function in Patients With Subcortical Vascular Mild Cognitive Impairment.

Normal-appearing white matter (NAWM) surrounding white matter hyperintensities (WMHs), frequently known as the WMH penumbra, is associated with subtle white matter injury and has a high risk for future conversion to WMHs. The goal of this study was to define WMH penumbras and to further explore whether the diffusion and perfusion parameters of these penumbras could better reflect cognitive function alterations than WMHs in subjects with subcortical vascular mild cognitive impairment (svMCI). Seventy-three svMCI subjects underwent neuropsychological assessments and 3T MRI scans, including diffusion tensor imaging (DTI) and arterial spin labeling (ASL). To determine the extent of cerebral blood flow (CBF) and DTI penumbras. A NAWM layer mask was generated for periventricular WMHs (PVWMHs) and deep WMHs (DWMHs) separately. Mean values of CBF, fractional anisotropy (FA), mean diffusivity (MD) within the WMHs and their corresponding NAWM layer masks were computed and compared using paired t-tests. Pearson's partial correlations were used to assess the relations of the mean CBF, FA, and MD values within the corresponding penumbras with composite z-scores of global cognition and four cognitive domains controlling for age, sex, and education. For both PVWMHs and DWMHs, the CBF penumbras were wider than the DTI penumbras. Only the mean FA value of the PVWMH-FA penumbra was correlated with the composite z-scores of global cognition before correction (r = 0.268, p = 0.024), but that correlation did not survive after correcting the p-value for multiple comparisons. Our findings showed extensive white matter perfusion disturbances including white matter tissue, both with and without microstructural alterations. The imaging parameters investigated, however, did not correlate to cognition.

The impact of education on cortical thickness in amyloid-negative subcortical vascular dementia: cognitive reserve hypothesis

BackgroundThe protective effect of education has been well established in Alzheimer’s disease, whereas its role in patients with isolated cerebrovascular diseases remains unclear. We examined the correlation of education with cortical thickness and cerebral small vessel disease markers in patients with pure subcortical vascular mild cognitive impairment (svMCI) and patients with pure subcortical vascular dementia (SVaD).MethodsWe analyzed 45 patients with svMCI and 47 patients with SVaD with negative results on Pittsburgh compound B positron emission tomographic imaging who underwent structural brain magnetic resonance imaging. The main outcome was cortical thickness measured using surface-based morphometric analysis. We also assessed the volumes of white matter hyperintensities (WMH) and numbers of lacunes as other outcomes. To investigate the correlation of education with cortical thickness, WMH volume, and number of lacunes, multiple linear regression analyses were performed after controlling for covariates, including Mini Mental State Examination, in the svMCI and SVaD groups.ResultsIn the SVaD group, higher education was correlated with more severe cortical thinning in the bilateral dorsolateral frontal, left medial frontal, and parahippocampal areas, whereas there was no correlation of education with cortical thickness in the svMCI group. There was no correlation between education and cerebral small vessel disease, including WMH and lacunes, in both patients with svMCI and patients with SVaD.ConclusionsOur findings suggest that the compensatory effects of education on cortical thinning apply to patients with SVaD, which might be explained by the cognitive reserve hypothesis.

Total MRI Small Vessel Disease Burden Correlates with Cognitive Performance, Cortical Atrophy, and Network Measures in a Memory Clinic Population.

Recent evidence suggests that combining individual imaging markers of cerebral small vessel disease (SVD) may more accurately reflect its overall burden and better correlate with clinical measures. We wished to establish the clinical relevance of the total SVD score in a memory clinic population by investigating the association with SVD score and cognitive performance, cortical atrophy, and structural network measures, after adjusting for amyloid-β burden. We included 243 patients with amnestic mild cognitive impairment (MCI), Alzheimer's disease dementia, subcortical vascular MCI, or subcortical vascular dementia. All underwent MR and [11C] PiB-PET scanning and had standardized cognitive testing. Multiple linear regression was used to evaluate the relationships between SVD score and cognition, cortical thickness, and structural network measures. Path analyses were performed to evaluate whether network disruption mediates the effects of SVD score on cortical thickness and cognition. Total SVD score was associated with the performance of frontal (β - 4.31, SE 2.09, p = 0.040) and visuospatial (β - 0.95, SE 0.44, p = 0.032) tasks, and with reduced cortical thickness in widespread brain regions. Total SVD score was negatively correlated with nodal efficiency, as well as changes in brain network organization, with evidence of reduced integration and increasing segregation. Path analyses showed that the associations between SVD score and frontal and visuospatial scores were partially mediated by decreases in their corresponding nodal efficiency and cortical thickness. Total SVD burden has clinical relevance in a memory clinic population and correlates with cognition, and cortical atrophy, as well as structural network disruption.

Altered Whole-Brain Structural Covariance of the Hippocampal Subfields in Subcortical Vascular Mild Cognitive Impairment and Amnestic Mild Cognitive Impairment Patients.

The hippocampus plays important roles in memory processing. However, the hippocampus is not a homogeneous structure, which consists of several subfields. The hippocampal subfields are differently affected by many neurodegenerative diseases, especially mild cognitive impairment (MCI). Amnestic mild cognitive impairment (aMCI) and subcortical vascular mild cognitive impairment (svMCI) are the two subtypes of MCI. aMCI is characterized by episodic memory loss, and svMCI is characterized by extensive white matter hyperintensities and multiple lacunar infarctions on magnetic resonance imaging. The primary cognitive impairment in svMCI is executive function, attention, and semantic memory. Some variations or disconnections within specific large-scale brain networks have been observed in aMCI and svMCI patients. The aim of this study was to investigate abnormalities in structural covariance networks (SCNs) between hippocampal subfields and the whole cerebral cortex in aMCI and svMCI patients, and whether these abnormalities are different between the two groups. Automated segmentation of hippocampal subfields was performed with FreeSurfer 5.3, and we selected five hippocampal subfields as the seeds of SCN analysis: CA1, CA2/3, CA4/dentate gyrus (DG), subiculum, and presubiculum. SCNs were constructed based on these hippocampal subfield seeds for each group. Significant correlations between hippocampal subfields, fusiform gyrus (FFG), and entorhinal cortex (ERC) in gray matter volume were found in each group. We also compared the differences in the strength of structural covariance between any two groups. In the aMCI group, compared to the normal controls (NC) group, we observed an increased association between the left CA1/CA4/DG/subiculum and the left temporal pole. Additionally, the hippocampal subfields (bilateral CA1, left CA2/3) significantly covaried with the orbitofrontal cortex in the svMCI group compared to the NC group. In the aMCI group compared to the svMCI group, we observed decreased association between hippocampal subfields and the right FFG, while we also observed an increased association between the bilateral subiculum/presubiculum and bilateral ERC. These findings provide new evidence that there is altered whole-brain structural covariance of the hippocampal subfields in svMCI and aMCI patients and provide insights to the pathological mechanisms of different MCI subtypes.