Imaging Markers Of Cerebral Small Vessel Disease Research Articles

The possible causal relationship between COVID-19 and imaging markers of cerebral small vessel disease: a Mendelian randomization study

ABSTRACT Objectives Observational studies have suggested that SARS-CoV-2 infection may increase the burden of cerebral small vessel disease (CSVD). This study aims to explore the causal correlation between COVID-19 and the imaging markers of CSVD using Mendelian randomization (MR) methods. Methods Summary-level genome-wide association study (GWAS) statistics for COVID-19 susceptibility, hospitalization, and severity were utilized as proxies for exposure. Large-scale meta-analysis GWAS data on three neuroimaging markers of white matter hyperintensity, lacunar stroke, and brain microbleeds, were employed as outcomes. Our primary MR analysis employed the inverse variance weighted (IVW) approach, supplemented by MR-Egger, weighted median, and MR-PRESSO methods. We also conducted multivariable MR analysis to address confounding bias and validate the robustness of the established causal estimates. Comprehensive sensitivity analyses included Cochran’s Q test, Egger-intercept analysis, MR-PRESSO, and leave-one-out analysis. Results The MR analysis revealed a significant causal correlation between the severity of COVID-19 and an increased risk of lacunar stroke, as demonstrated by the IVW method (ORivw = 1.08, 95% CI: 1.03–1.16, pivw = 0.005, FDR = 0.047). Nevertheless, no causal correlations were observed between COVID-19 susceptibility or hospitalization and any CSVD imaging markers. The robustness and stability of these findings were further confirmed by multivariable MR analysis and comprehensive sensitivity analyses. Discussion This study provides compelling evidence of a potential causal effect of severe COVID-19 on the incidence of lacunar stroke, which may bring fresh insights into the understanding of the comorbidity between COVID-19 and CSVD.

A Nomogram Including Total Cerebral Small Vessel Disease Burden Score for Predicting Mild Vascular Cognitive Impairment in Patients with Type 2 Diabetes Mellitus.

Total cerebral small vessel disease (CSVD) burden score is an important predictor of vascular cognitive impairment (VCI). However, few predictive models of VCI in type 2 diabetes mellitus (T2DM) patients have included the total CSVD burden score, especially in the early stage of VCI. To develop and validate a nomogram that includes the total CSVD burden score to predict mild VCI in patients with T2DM. A total of 322 eligible participants with T2DM who were divided into mild and normal cognitive groups were enrolled in this retrospective study. Demographic data, laboratory data and imaging markers of CSVD were collected. The total CSVD burden score was calculated by combining the different CSVD markers. Step-backward multivariable logistic regression analysis with the Akaike information criterion was applied to select significant predictors and develop a best-fit predictive nomogram. The performance of the nomogram was assessed in terms of discriminative ability, calibrated ability, and clinical usefulness. The nomogram model consisted of five variables: age, education, hemoglobin A1c level, serum homocysteine level, and total CSVD burden score. A nomogram with these variables showed good discriminative ability (area under the receiver operating characteristic curve was 0.801 in internal verification). In addition, the Hosmer-Lemeshow test (χ2 =9.226, P=0.417) and bootstrap-corrected calibration plot indicated that the nomogram had good calibration. The Brier score of the predictive model was 0.178. Decision curve analysis demonstrated that when the threshold probability ranged between 16% and 98%, the use of the nomogram to predict mild VCI in patients with T2DM provide a greater net benefit. The nomogram, composed of age, education, stroke, HbA1c level, Hcy level, and total CSVD burden score, had good predictive accuracy and may provide clinicians with a practical tool for predicting the risk of mild VCI in T2DM patients.

Relationship of neutrophil/lymphocyte ratio with cerebral small vessel disease and its common imaging markers.

High neutrophil/lymphocyte ratio (NLR) is associated with poor prognosis in ischemic stroke. However, the role of NLR in cerebral small vessel disease (CSVD) is controversial. Herein, we evaluated the value of NLR in identifying CSVD and its relationship with the common imaging markers of CSVD. A total of 667 patients were enrolled in this study, including 368 in the CSVD group and 299 in the non-CSVD group. Clinical, laboratory, and imaging data were collected. The relationship of NLR with CSVD and common imaging markers of CSVD were analyzed with univariate and multivariate logistic regression analysis. The predictive value of NLR was assessed with the receiver operating characteristic curve. NLR (odds ratio [OR] = 1.929, 95% confidence interval [CI] = 1.599-2.327, p < .001) was an independent risk factor for CSVD. NLR was also independently associated with moderate to severe white matter hyperintensity (WMH) (OR = 2.136, 95% CI = 1.768-2.580, p < .001), moderate to severe periventricular WMH (OR = 2.138, 95% CI = 1.771-2.579, p < .001), and moderate to severe deep WMH (OR = 1.654, 95% CI = 1.438-1.902, p < .001), moderately to severely enlarged perivascular spaces (EPVS) (OR = 1.248, 95% CI = 1.110-1.402, p < .001), moderately to severely EPVS in the basal ganglia (OR = 1.136, 95% CI = 1.012-1.275, p = .030), and moderately to severely EPVS in the centrum semiovale (OR = 1.140, 95% CI = 1.027-1.266, p = .014). However, NLR was not statistically significantly associated with lacune. The optimal cutoff point of NLR in predicting CSVD was 2.47, with sensitivity and specificity of 84.2% and 66.9%, respectively (p < .01). The diagnostic effect was maximized when NLR was combined with other risk factors. NLR is an independent risk factor for CSVD and is independently associated with common imaging markers of CSVD. NLR may serve as a valid and convenient biomarker for assessing CSVD.

Analysis of the Relationship between Recent Small Subcortical Infarcts and Autonomic Nervous Dysfunction.

Autonomic Nervous System (ANS) dysfunction may be involved in the pathogenesis of Cerebral Small Vessel Disease (CSVD). The study aimed to explore the relationship between Recent Small Subcortical Infarct (RSSI) and Blood Pressure Variability (BPV), and Heart Rate Variability (HRV). A total of 588 patients from the CSVD registration research database of Henan Province were included in this study, and were divided into two groups according to the presence of RSSI. Clinical data, including demographic characteristics, disease history, laboratory indexes, 24-hour ambulatory blood pressure and electrocardiogram indicators, and imaging markers of CSVD, were collected. Univariate and binary logistic regression analyses were used to study the relationship between RSSI and indicators of laboratory, HRV and BPV in the CSVD population. Multivariate analysis showed that higher 24-hour mean Diastolic Blood Pressure (DBP)[Odds Ratios (OR)=1.083,95% Confidence Intervals (CI)=(1.038,1.129), p < 0.001], Standard Deviation (SD) of 24-hour DBP [OR=1.059,95%CI=(1.000,1.121), p = 0.049], nocturnal mean Systolic Blood Pressure (SBP) [OR=1.020,95%CI=(1.004,1.035), p = 0.012], nocturnal mean DBP [OR=1.025,95%CI=(1.009,1.040), p = 0.002] were independent risk factors for RSSI. In contrast, the decrease of the standard deviation of N-N intervals (SDNN) [OR=0.994,95%CI=(0.989,1.000), p = 0.035] was beneficial to the occurrence of RSSI. In addition, neutrophil counts [OR=1.138,95%CI=(1.030,1.258), p = 0.011], total cholesterol (TC) [OR=1.203,95%CI=(1.008,1.437), p = 0.041] and High-Density Lipoprotein (HDL) [OR=0.391, 95%CI=(0.195,0.786), p = 0.008] were also independently associated with the occurrence of RSSI. After adjusting for confounding factors, except for TC, the other factors remained associated with the occurrence of RSSI. Increased 24-hour mean DBP, nocturnal mean SBP and DBP, SD of 24-hour DBP and decreased SDNN were independently correlated with RSSI occurrence, suggesting that sympathetic overactivity plays a role in the pathogenesis of RSSI.

Hippocampal amide proton transfer values are associated with cerebral small vessel disease imaging markers and total burden: a community-based cross-sectional study.

Neurodegeneration has been suggested to be associated with cerebral small vessel disease (CSVD). The association between different CSVD imaging markers and the extent of neurodegeneration could be indirectly confirmed by examining the relationship between CSVD imaging markers and the hippocampal amide proton transfer (APT) values. The associations between hippocampal APT values with CSVD imaging markers and CSVD total load need to be further validated. The aim of this study was to investigate potential variations in hippocampal APT values among individuals with CSVD imaging markers and varying degrees of CSVD total burden. A cross-sectional study (retrospective analysis of prospectively-acquired data) was conducted at Nanxishan Hospital of Guangxi Zhuang Autonomous Region. From May 2020 to June 2021, 165 individuals (age, 40-76 years; male/female, 103/62) were included in this study. The inclusion criteria for the participants were as follows: The presence of lacunar infarction (LI), and/or cerebral microbleed (CMB); moderate-to-severe enlarged perivascular space (EPVS) (>20); deep white matter hyperintensity (WMH) > Fazekas 2 or periventricular WMH > Fazekas. The exclusion criteria comprised the following: History of craniocerebral operation; Cases with significant pathology incidentally identified during magnetic resonance (MR) scan; Drug or alcohol abuse. The differences of hippocampal APT values between CSVD imaging makers presence or absence groups and different CSVD total burden groups were compared using independent t-test and one-way analysis of variance (ANOVA). The correlations between APT values and CSVD imaging markers were analyzed using Pearson correlation analysis. A mediation analysis model was used to investigate the mediating effect of the hippocampal APT values in the association between CSVD total loads and Montreal Cognitive Assessment (MoCA) score was assessed. The hippocampal APT values among different CSVD total load groups were significantly different (P<0.001). The hippocampal APT values were significantly different between the imaging markers presence and absence groups. The P values for the LI, WMH EPVS, and CMB presence or absence groups were <0.001, <0.001, 0.034, and 0.002, respectively. The hippocampal APT values were significantly correlated with CMB (P<0.01), LI (P<0.01) and WMH (P<0.01). The mediation models demonstrated that the APT values of the hippocampus partially mediated the association between CSVD total load and MoCA score, the proportion of mediation attributable was calculated as 17.50%. Hippocampal APT values were associated with CSVD imaging markers and total burden. Hippocampal APT values may serve as a biomarker for the early detection of neurodegeneration in CSVD patients.

Peripheral apolipoprotein is an independent factor for enlarged perivascular space in small vessel disease

ObjectiveThe purpose of this study is to the relationship between peripheral apolipoproteins and cerebral small vessel disease (CSVD) imaging markers. MethodsWe reviewed the data of a population that above 40 years old with CSVD, while free of known dementia or acute stroke. We evaluated CSVD imaging markers, including white matter hyperintensities (WMHs), enlarged perivascular spaces (EPVS), lacunas, microbleeds by MRI scans, and measured peripheral apolipoproteins. ResultsAfter adjusting for age, sex and vascular risk factors,1) apoB and apoB/apoA-1 were related to grade of EPVS in basal ganglia(apoB:r=0.196,p<0.001;apoB/apoA-1:r=0.208,p<0.001), apoE was related to grade of EPVS in centrum semiovale (r=0.125,p=0.040); 2) apoB(OR=1.739, 95%CI=1.357–2.061, p<0.001), apoB/apoA-1(OR=1.116, 95%CI=1.037–1.761, p=0.005) and apoE(OR=1.287, 95%CI=1.036–1.599, p=0.023) were independent factors of presence of severer EPVS in basal ganglia, apoE was an independent factor of presence of severer EPVS in centrum semiovale (OR=1.235, 95%CI=1.021–1.494, p=0.029). ConclusionOur findings demonstrated peripheral apolipoproteins, including apoB, apoB/apoA-1, and apoE, were independent factor for EPVS in CSVD.

Causal relationship between inflammatory factors and cerebral small vessel disease: Univariate, multivariate, and summary-data-based mendelian randomization analysis.

To explore the impact of inflammatory factors on the incidence of cerebral small vessel disease (CSVD), we performed a mendelian randomization (MR) study to analyze the causal relationship between multiple inflammatory factors and CSVD imaging markers and utilized summary-data-based mendelian randomization (SMR) analysis to infer whether the impact of instrumental variables (IVs) on disease is mediated by gene expression or DNA methylation. Using public databases such as UKB and IEU, and original genome-wide association studies, we obtained IVs related to exposure (inflammatory factors) and outcome (CSVD imaging markers). We performed the inverse variance weighted, weighted median, and MR-Egger methods to assess causal effects between exposure and outcome in univariate MR analysis. To evaluate their heterogeneity, a series of sensitivity analyses were conducted, including the Cochrane Q test, MR-Egger intercept test, MR-Presso, and leave-one-out analysis. We also applied mediation and multivariate MR analysis to explore the interactions between positive exposures on the same outcome. Additionally, we conducted the SMR, which utilizes instruments within or near relevant genes in blood or brain tissues, to elucidate the causal associations with CSVD markers. ABO Univariate MR of multiple cohorts revealed that the risk of small vessel stroke (SVS) increases with elevated levels of TNF-related apoptosis-inducing ligand (TRAIL, OR, 1.23, 95% CI, 1.08-1.39) and interleukin-1 receptor-like 2, (IL-1RL2, OR, 1.29, 95% CI, 1.04-1.61). IL-18 was a potential risk factor for extensive basal ganglia perivascular space burden (BGPVS, OR, 1.02, 95% CI, 1.00-1.05). Moreover, the risk of extensive white matter perivascular space burden (WMPVS) decreased with rising levels of E-selectin (OR, .98, 95% CI, .97-1.00), IL-1RL2 (OR, .97, 95% CI, .95-1.00), IL-3 receptor subunit alpha (IL-3Ra, OR, .98, 95% CI, .97-1.00), and IL-5 receptor subunit alpha (IL-5Ra, OR, .98, 95% CI, .97-1.00). Mediation and multivariate MR analysis indicated that E-selectin and IL-3Ra might interact during the pathogenesis of WMPVS. SMR estimates showed that TRAIL-related IVs rs5030044 and rs2304456 increased the risk of SVS by increasing the expression of gene Kininogen-1 (KNG1) in the cerebral cortex, particularly in the frontal cortex (βsmr=.10, Psmr=.003, FDR=.04). Instruments (rs507666 and rs2519093) related to E-selectin and IL-3Ra could increase the risk of WMPVS by enhancing DNA methylation of the gene ABO in blood tissue (βsmr=.01-.02, Psmr=.001, FDR=.01-.03). According to MR and SMR analysis, higher levels of TRAIL increased the risk of SVS by upregulating gene expression of KNG1 in brain cortex tissues. In addition, protective effects of E-selectin and IL-3a levels on WMPVS were regulated by increased DNA methylation of gene ABO in blood tissue.

Discontinuity of deep medullary veins in SWI is associated with deep white matter hyperintensity volume and cognitive impairment in cerebral small vessel disease

BackgroundDiscontinuation of the deep medullary veins (DMVs) may be an early imaging marker for identifying cognitive impairment caused by cerebral small vessel disease (CSVD). However, this method lacks mechanistic exploration. We aimed to investigate whether the DMV score is related to CSVD imaging markers and cognitive impairment in patients with CSVD. MethodsThis retrospective study included patients with CSVD who completed DMV score and cognition (e.g., MMSE, MoCA) assessments, and underwent MRI scanning (T2-FLAIR for white matter hyperintensities (WMH) volume, T1-weighted MRI for brain parenchymal fractions (BPF) analysis, and SWI for assessment of DMV score). The CSVD imaging markers were quantitatively assessed using the AccuBrain® system. We assessed the diagnostic value of neuroimaging biomarkers for detecting CSVD-related cognitive impairment. In addition, we explored the relationship between the DMV score, CSVD imaging markers, and cognition using mediation analysis. ResultsNinety-four patients with CSVD were divided into a cognitive impairment group (n = 39) and a non-cognitive impairment group (n = 55). Higher DMV scores, larger WMH volumes, and smaller BPF were observed in the cognitive impairment group than those in the non-cognitive impairment group. Receiver operating characteristics (ROC) analysis revealed that the discovery value of the integration of patient age, BPF, whole WMH volume, and DMV score for cognitive impairment was 0.742, with a sensitivity and specificity of 79.5 % and 61.5 %, respectively. Mediation analysis showed mediation by WMH and BPF in the relationship between DMV score and cognitive impairment (all P < 0.05). LimitationsThis study did not evaluate the DMV score in subregions according to DMV anatomy. ConclusionsThe DMV score is significantly associated with cognitive impairment in patients with CSVD, and this association is mediated through WMH and BPF.

Cerebral Small Vessel Disease Is Associated with Motor, Cognitive, and Emotional Dysfunction in Multiple System Atrophy.

Cerebral small vessel disease (CSVD) has not been systematically studied in patients with multiple system atrophy (MSA). We sought to explore whether MSA patients suffer from a heavier CSVD burden relative to healthy individuals and whether CSVD has a relationship with motor, cognitive, and emotional dysfunction in patients with MSA. This study consecutively recruited 190 MSA patients and 190 matched healthy controls whose overall CSVD burden and single CSVD imaging markers (including white matter hyperintensity (WMH), microbleeds, lacunes, and enlarged perivascular spaces (EPVS)) were measured. Of the MSA patients, 118 completed multi-dimensional outcome assessments. Spearman's correlations and multivariable linear regressions were performed. We observed a greater burden of overall CSVD, WMH, and EPVS in MSA patients compared with controls, but not for microbleeds and lacunes. Motor dysfunction and cognitive impairment were significantly worse in subjects with severe CSVD than those with none-to-mild CSVD. In patients with MSA, the severity of CSVD burden was positively associated with motor impairments as measured by the Unified Multiple System Atrophy Rating Scale-II (β= 2.430, p = 0.039) and Scale for the Assessment and Rating of Ataxia (β= 1.882, p = 0.015). Of CSVD imaging markers, different associations with MSA outcomes were displayed. WMH was associated with motor, cognitive, and emotional deficits, while the EPVS in the centrum semiovale, basal ganglia, and hippocampus regions was correlated only with motor severity, anxiety, and cognition, respectively. Similar findings were noted in MSA-cerebellar and MSA-parkinsonian patients. Concomitant CSVD may be correlated with worse multi-dimensional dysfunction in patients with MSA.

Amide proton transfer could be a surrogate imaging marker for predicting vascular cognitive impairment

BackgroudEmerging evidence suggests an overlap in the underlying pathways contributing to both cerebral small vessel disease (CSVD) and the neurodegenerative disease. Studies investigating the progression of CSVD should incorporate markers that reflect neurodegenerative lesions. ObjectiveWe aim to investigate whether Amide proton transfer (APT) can serve as a potential marker for reflecting vascular cognitive impairment (VCI). MethodParticipants were categorized into one of three groups based on their Montreal Cognitive Assessment (MoCA) scores: normal control group (age,54.9 ± 7.9; male, 52.9%), mild cognitive impairment (MCI) group (age,55.7 ± 6.9; male, 42.6%), or vascular dementia (VaD) group (age,57.6 ± 5.5, male, 58.5%). One way analysis of variance was performed to compare the demographic and APT variables between groups. Multiple logistic regression analysis wwas constructed to examine the relationship between APT values and VCI grouping. A hierarchical linear regression model was employed to examine the associations between patients' demographic factors, imaging markers, APT values, and MoCA. ResultsThe APT values of frontal white matter, hippocampus, amygdala, and thalamus were significantly different among different groups (p < 0.05). The APT values of frontal white matter, amygdala, and thalamus indicate a significant positive effect on MCI grouping. the APT values of frontal white matter, amygdala, and thalamus indicate a significant positive effect on VaD grouping. The demographic data, CSVD imaging markers and APT values can account for 5.1%, 20.1% and 27.7% of the variation in MoCA, respectively. ConclusionAPT imaging can partially identifying and predicting the occurrence of VCI.

The association of intracranial atherosclerosis with cerebral small vessel disease imaging markers: a high-resolution magnetic resonance imaging study

To evaluate the association of intracranial non-stenotic atherosclerotic plaque with cerebral small vessel disease (CSVD) imaging markers in a CSVD population using 3.0 T high-resolution magnetic resonance imaging (HRMRI), which was validated in embolic stroke of undetermined source (ESUS) cohort. We retrospectively recruited consecutive patients who were diagnosed with CSVD or ESUS from January 2015 to December 2019. All patients underwent intracranial HRMRI to assess intracranial non-stenotic atherosclerotic plaques. Baseline and imaging data were collected and were measured among all patients. Among 153 patients with CSVD, there were 59 with intracranial atherosclerotic plaque (IAP) and 94 with non-IAP, including 36 with intracranial atherosclerotic complicated plaque (IACP). Among 227 ESUS patients, there were 155 with IAP and 72 with non-IAP, including 127 with IACP. In the CSVD population, we found that: (1) CSVD burden was associated with IAP (p = 0.036) and IACP (p = 0.008); (2) IAP was associated with white matter hyperintensity (51% vs. 34%; P = 0.039), and IACP was associated with lacunes (69% vs. 35%; P = 0.009) and enlarge perivascular space (69% vs. 39%; P = 0.022). A similar association of CSVD imaging markers with IAP or IACP was found in the ESUS population. Furthermore, the association of unilateral IAP or IACP with CSVD imaging markers of ipsilateral hemisphere was identified in the two cohorts. This is the first report that intracranial non-stenotic atherosclerotic plaque, especially complicated plaque, is closely associated with CSVD imaging markers, which provide further evidence for the association of large artery atherosclerosis with CSVD.

Prevalence and Risk Factors of Cerebral Small Vessel Disease from a Population-Based Cohort in China

Introduction: Cerebral small vessel disease (CSVD) is a significant burden of morbidity and mortality among elderly people around the world. Epidemiological data with complete CSVD evaluations and a large sample size in the general population are still limited. Methods: Community-dwelling residents in Lishui city in China from the cross-sectional survey of the Polyvascular Evaluation for Cognitive Impairment and Vascular Events (PRECISE) study were included in this study from 2017 to 2019. All participants underwent 3 Tesla brain magnetic resonance images to assess CSVD imaging markers. Demographic and risk factor data were collected. The general and age-specific prevalence of lacune, confluent white matter hyperintensity (WMH), moderate-severe enlarged perivascular spaces (EPVS), cerebral microbleed (CMB), and total CSVD score (an ordinal scale from 0 to 4, counting the presence of four imaging markers of CSVD) was evaluated. Associations between vascular risk factors and these markers were analyzed by multivariable logistic regression. Results: A total of 3,063 participants were enrolled. The mean age was 61.2 years and 46.5% were men. The most prevalent CSVD marker was confluent WMH (16.7%), followed by CMB (10.2%), moderate-severe EPVS in the basal ganglia (BG-EPVS) (9.8%), and lacune (5.6%). 30.5% of the participants have at least one of the four markers (total CSVD score ≥1 points). The prevalence of CSVD markers increases as age increases. Age and hypertension were independent risk factors for four CSVD markers and the total CSVD score. Conclusions: In this Chinese cohort with community-based adults aged 50–75 years, our findings showed a prevalence of 30.5% for CSVD. The most prevalent CSVD marker was confluent WMH, followed by CMB, moderate-severe BG-EPVS, and lacune. The risk factors for CSVD must be strictly screened and controlled in adults living in the community.

Basal Ganglia and Brainstem Located Cerebral Microbleeds Contributed to Gait Impairment in Patients with Cerebral Small Vessel Disease.

The mechanism of gait disorder in patients with cerebral small vessel disease (CSVD) remains unclear. Limited studies have compared the effect of cerebral microbleeds (CMBs) and lacunes on gait disturbance in CSVD patients in different anatomical locations. To investigate the relationship of quantitative gait parameters with varied anatomically located MRI imaging markers in patients with CSVD. Quantitative gait tests were performed on 127 symptomatic CSVD patients all with diffuse distributed white matter hyperintensities (WMHs). CMBs and lacunes in regard to anatomical locations and burdens were measured. The correlation between CSVD imaging markers and gait parameters was evaluated using general linear model analysis. Presence of CMBs was significantly associated with stride length (β= -0.098, p = 0.0272) and right step length (β= -0.054, p = 0.0206). Presence of CMBs in basal ganglia (BG) was significantly associated with stride length and step length. Presence of CMBs in brainstem was significantly associated with gait parameters including stride length, step length, step height, and step width. Presence of lacunes in brainstem was significantly associated with gait speed (β= -0.197, p = 0.0365). However, presence of lacunes in the other areas was not associated with worse gait performances. BG and brain stem located CMBs contributed to gait impairment in symptomatic CSVD patients.

Pathological Changes of Small Vessel Disease in Intracerebral Hemorrhage: a Systematic Review and Meta-analysis

In intracerebral hemorrhage (ICH) with pathology-proven etiology, we performed a systematic review and meta-analysis to elucidate the association between cerebral amyloid angiopathy (CAA) and arteriolosclerosis, and directly compared MRI and pathological changes of markers of cerebral small vessel disease (CSVD). Studies enrolling primary ICH who had received an etiological diagnosis through biopsy or autopsy were searched using Ovid MEDLINE, PubMed, and Web of Science from inception to June 8, 2022. We extracted pathological changes of CSVD for each patient whenever available. Patients were grouped into CAA + arteriolosclerosis, strict CAA, and strict arteriolosclerosis subgroups. Of 4155 studies identified, 28 studies with 456 ICH patients were included. The frequency of lobar ICH (p<0.001) and total microbleed number (p=0.015) differed among patients with CAA + arteriolosclerosis, strict CAA, and strict arteriolosclerosis. Concerning pathology, severe CAA was associated with arteriolosclerosis (OR 6.067, 95% CI 1.107–33.238, p=0.038), although this association was not statistically significant after adjusting for age and sex. Additionally, the total microbleed number (median 15 vs. 0, p=0.006) was higher in ICH patients with CAA evidence than those without CAA. The pathology of CSVD imaging markers was mostly investigated in CAA-ICH. There was inconsistency concerning CAA severity surrounding microbleeds. Small diffusion-weighted imaging lesions could be matched to acute microinfarct histopathologically. Studies that directly correlated MRI and pathology of lacunes, enlarged perivascular spaces, and atrophy were scarce. Arteriolosclerosis might be associated with severe CAA. The pathological changes of CSVD markers by ICH etiology are needed to be investigated further.

Associations of deep medullary veins with vascular risk factors, laboratory indicators, and cerebral small vessel disease: A population-based study.

Deep medullary veins (DMVs) were not considered a typical marker of cerebral small vessel disease (CSVD) due to limited understanding of their involvement in pathology of CSVD. This study aimsto investigate potential vascular risk factors for DMVs and their associations with CSVD. In total, 1909 community-dwelling participants were included in this analysis. Demographic, clinical, laboratory, and imaging data were collected. DMV scores (0-18) werecalculated as the sum of bilateral frontal, parietal, and occipital regional scores using a semiquantitative visual scale (0-3). The presence, total burden, and imaging markers of CSVD were assessed. Linear regression analyses were conducted to explore potential vascular factors for DMV scores. Binary and ordinal logistic regression analyses were performed to investigate the associations of DMV scores with CSVD and its markers. Mean age was 61.8(SD 6.5)years, and 1027 (53.8%) of participants were men. The median DMV scores were14 (IQR 12-16). DMV scores wererelated to age, male sex, body mass index, diastolic blood pressure, hypercholesterolaemia, atrial fibrillation, current drinking, total cholesterol, triglycerides, low-density lipoprotein, hemoglobin A1c, leukocytes, lymphocytes, hemoglobin, and platelets (p<.05). DMV scores wereassociated with the presence and total burden of CSVD (Rothwell's scale), modified white matter hyperintensity burden, and enlarged perivascular spaces in centrum semiovale (p<.05). However, these associations between DMV scoresand CSVD disappeared after adjusting for potential confounders. Several conventional vascular factors were associated with DMVs. The relationship between DMVs and CSVD was vulnerable, suggesting decreased visible and discontinuous DMVs may differ mechanistically from traditional markers of CSVD.

Disturbance of functional brain networks and cognitive decline in Parkinson's disease: Severe cerebral small vessel disease aggravates this relationship

IntroductionSeveral studies have identified a relationship between functional brain network disturbance and cognitive decline in people with Parkinson's disease (PwP); however, few studies have explored whether cerebral small vessel disease (CSVD) burden modifies this relationship. This study aimed to investigate the potential moderating effect of CSVD on the relationship between functional brain network disturbance and cognitive decline in PwP. MethodsWe prospectively recruited 61 PwP from Beijing Tiantan Hospital between October 2021 to September 2022. The Montreal Cognitive Assessment (MoCA) score was used to assess cognition. CSVD imaging markers were evaluated following the STandards for ReportIng Vascular changes on nEuroimaging instructions, and the CSVD burden score was calculated. The functional connectivity indicator was obtained and calculated using quantitative electroencephalography examination. The moderating effect of CSVD burden on the relationship between functional brain network disturbance and cognitive decline was examined using hierarchical linear regression. ResultsForty-six of 61 (75.4%) PwP had cognitive impairment. Higher global weighted phase lag index (wPLI) values in beta1 bands were significantly associated with lower adjusted MoCA scores. CSVD burden aggravated the effect of the global wPLI in beta1 bands on adjusted MoCA scores. This effect was reinforced by the high level of CSVD burden. ConclusionsHigher wPLI indicates a possible pathological activation of functional brain networks that are associated with cognitive decline in PwP, and the high level of CSVD burden aggravates this relationship.

Features of Cerebral Small Vessel Disease Contributes to the Differential Diagnosis of Alzheimer's Disease.

Cerebral small vessel disease (CSVD), which comprises the typical features of white matter hyperintensity (WMH) and Vichor-Robin spaces (VRSs) in the brain, is one of the leading causes of aging-related cognitive decline and, ultimately, contributes to the occurrence of dementia, including Alzheimer's disease (AD). To investigate whether CSVD imaging markers modify the pathological processes of AD and whether these markers improve AD diagnosis. 208 participants were enrolled in the China Aging and Neurodegenerative Initiative (CANDI). Fluid AD biomarkers were detected using a single-molecule array, and cerebral small vessel dysfunction was determined using magnetic resonance imaging. WMH contributed to AD pathology only within the NC and MCI groups (CDR ≤0.5), whereas VRSs had no effect on AD pathology. The associations between AD biomarkers and cognitive mental status were consistent with the presence of CSVD pathology. That is, within individuals without CSVD pathology, the MMSE scores were correlated with AD fluid biomarkers, except for plasma Aβ42 and Aβ40. Increased plasma p-Tau levels were associated with worse cognitive performance in individuals with WMH (β= -0.465, p = 0.0016) or VRSs (β= -0.352, p = 0.0257) pathology. Plasma AD biomarkers combined with CSVD markers showed high accuracy in diagnosing dementia. Findings from this cross-sectional cohort study support the notion that CSVD is a risk factor for dementia and highlights that vascular pathology can promote AD biomarker levels, especially in the early course of the disease. Moreover, our results suggest that adding a vascular category to the ATN framework improves the diagnostic accuracy of AD.

Cerebral Small Vessel Disease and Gait Speed in Older Adults without Dementia

AbstractBackgroundDisturbances in gait have been found to be predictors of dementia and mobility disability in older adults. The relationship between cerebral small vessel disease (CSVD) and gait speed during simple (normal pace walking; NPW) and complex walking (walking‐while talking; WWT) conditions are not well understood. The current study examined the relationship between CSVD (as assessed as white matter hyperintensities and lacunes), NPW and WWT in older adults without dementia.MethodsNPW and WWT speeds were measured in 113 older adults (46.9% female, 53.1%% male, mean age=78.6±6.3) without dementia enrolled in the LonGenity study. Using an established rating system, white matter hyperintensities (WMH) and lacunes of presumed vascular origin were quantified from Fluid Attenuated Inversion Recovery (FLAIR) images from the same participants. Linear regression models adjusted for age, gender, global health, cohort, and estimated total intracranial volume were used to examine the association between NPW and DTW velocity and markers of CSVD.ResultsNumber of WMH in both the basal ganglia and the temporal lobes were associated with slower NPW velocity in our adjusted models (β=‐3.274 cm/s p=.047, β=‐3.113 cm/s p=.048, respectively). Number of frontal lobe WMH was associated with slower NPW velocity in our unadjusted model (β=‐3.316 cm/s p=.017) but not in the adjusted model (β=‐1.521 cm/s p=.262). WMH were not found to be significantly associated with WWT velocity. Lacunes of presumed vascular origin were not found to be significantly associated with neither NPW or DTW velocity. Significant interactions between measures of CSVD and gender, age, or cohort were not found in our models.ConclusionGait is a complex task requiring the integration of both cognitive and motor function across different brain regions. We find here that higher CSVD burden as measured by the presence of WMH in the basal ganglia and temporal lobes are independently associated with slower normal gait velocity. Interestingly, no such association was seen with WWT, a task requiring a higher cognitive load. Further studies are needed to establish temporality of these lesions with declines in gait velocity. Doing so may show utility of CSVD imaging markers as predictors of gait disturbances and dementia.

Determinants of Perivascular Spaces in the General Population: A Pooled Cohort Analysis of Individual Participant Data.

Perivascular spaces (PVS) are emerging markers of cerebral small vessel disease (CSVD), but research on their determinants has been hampered by conflicting results from small single studies using heterogeneous rating methods. In this study, we therefore aimed to identify determinants of PVS burden in a pooled analysis of multiple cohort studies using 1 harmonized PVS rating method. Individuals from 10 population-based cohort studies with adult participants from the Uniform Neuro-Imaging of Virchow-Robin Spaces Enlargement consortium and the UK Biobank were included. On MRI scans, we counted PVS in 4 brain regions (mesencephalon, hippocampus, basal ganglia, and centrum semiovale) according to a uniform and validated rating protocol, both manually and automated using a deep learning algorithm. As potential determinants, we considered demographics, cardiovascular risk factors, APOE genotypes, and other imaging markers of CSVD. Negative binomial regression models were used to examine the association between these determinants and PVS counts. In total, 39,976 individuals were included (age range 20-96 years). The average count of PVS in the 4 regions increased from the age 20 years (0-1 PVS) to 90 years (2-7 PVS). Men had more mesencephalic PVS (OR [95% CI] = 1.13 [1.08-1.18] compared with women), but less hippocampal PVS (0.82 [0.81-0.83]). Higher blood pressure, particularly diastolic pressure, was associated with more PVS in all regions (ORs between 1.04-1.05). Hippocampal PVS showed higher counts with higher high-density lipoprotein cholesterol levels (1.02 [1.01-1.02]), glucose levels (1.02 [1.01-1.03]), and APOE ε4-alleles (1.02 [1.01-1.04]). Furthermore, white matter hyperintensity volume and presence of lacunes were associated with PVS in multiple regions, but most strongly with the basal ganglia (1.13 [1.12-1.14] and 1.10 [1.09-1.12], respectively). Various factors are associated with the burden of PVS, in part regionally specific, which points toward a multifactorial origin beyond what can be expected from PVS-related risk factor profiles. This study highlights the power of collaborative efforts in population neuroimaging research.

Triglyceride glucose index is associated with cerebral small vessel disease burden and cognitive impairment in elderly patients with type 2 diabetes mellitus.

ObjectiveTo investigate the relations of Triglyceride glucose (TyG) index with cerebral small vessel disease (CSVD) burden and cognitive function in aged patients with type 2 diabetes mellitus (T2DM).MethodsA total of 308 elderly patients with T2DM were included in this retrospective study. The standardized Chinese version of Mini-Mental State Examination was used to assess cognitive function. The total CSVD burden score was assessed by combining four imaging markers of CSVD, including the presence of white matter hyperintensity, cerebral microbleeds in the deep, lacunes and enlarged perivascular spaces in the basal ganglia. The TyG index was calculated as the formula of ln [fasting triglyceride (mg/dl) × fasting plasma glucose (mg/dl)/2]. We used logistic regression analysis and mediation analysis to investigate the relations of TyG index with CSVD and cognitive function.ResultsMultivariate binary logistic regression analysis showed that increased TyG index (OR: 2.241; 95% Confidence Interval(CI): 1.439 to 3.490; P <0.001), or severe CSVD burden (OR: 2.198; 95% CI: 1.283 to 3.763; P = 0.004) was associated with an increased risk of cognitive impairment in elderly patients with T2DM after adjusting for potential confounders. In addition, TyG index was an independent risk factor of severe CSVD burden (OR: 1.472; 95% CI: 1.003 to 2.160; P = 0.048) after controlling for potential confounders. Compared with the lowest TyG index tertile, the multivariable-adjusted OR of the highest tertile was 3.298 (95% CI: 1.685 to 6.452; P for trend <0.001) for cognitive impairment, 1.933 (95% CI: 1.010 to 3.698; P for trend = 0.047) for severe CSVD burden. Mediation analysis found a significant moderating effect of the severe CSVD burden on the association between higher TyG index levels and cognitive impairment.ConclusionsThe increased TyG index is an independent risk factor for cognitive impairment and severe CSVD burden in clinical practice. A proportion of the effect of increased TyG index on cognitive impairment may be due to the aggravation of CSVD burden.