Large-Vessel Hemodynamics Are Associated with Glymphatic Dysfunction and Cognitive Impairment in Cerebral Small Vessel Disease.

To observe the hemodynamics of intracranial arteries and veins in patients with cerebral small vessel disease (CSVD) with cognitive impairment (CI), and to explore the association between these flow features and white matter hyperintensities (WMH). A total of 53 patients with CSVD were included in the study, comprising 30 patients with CI (CI group) and 23 patients with non-CI (NCI group); Meanwhile, 25 age-matched cognitively healthy volunteers were recruited. WMH burden was evaluated using a 2D axial T2-FLAIR sequence. A 4D flow MRI was employed to measure intracranial hemodynamic features, including cross-sectional area, flow rate, blood flow velocity, wall shear stress (WSS), pulsatility index, and resistive index in the internal carotid artery (ICA), middle cerebral artery, basilar artery (BA), transverse sinus (TS), straight sinus (SS), and superior sagittal sinus (SSS). CSF-Q flow, a 2D PC MRI sequence, was performed to calculate the CSF fluid dynamics in the midbrain aqueduct. The CSVD with CI population reported a statistically significant decrease in flow rate, blood flow velocity, and WSS, as well as an increase in PI, RI, CSF flow quantity, and velocity compared to age-matched cognitively healthy control participants. There was a moderately positive correlation between MMSE, MoCA score and flow rate, flow velocity, and WSS (r = 0.226-0.544, all P < 0.05), and a moderately negative correlation between MMSE, MoCA score and PI, RI (r = -0.230 to -0.406, all P < 0.05). Multiple linear regression indicated that, the flow rate and mean velocity in venous sinuses (β = -0.472 to -0.381, all P < 0.05) and the WSS in arterial segments (β = -0.771 to -0.441, all P < 0.05) had independently negative association with WMH burden; Meanwhile, a significant positive relationship was found between PI in arterial segments and specific-distributed WMH (PVWMH and S-CC WMH) (β = 0.239 to 0.356, all P < 0.05). The intracranial hemodynamics were associated with CI and WMH in patients with CSVD. 4D flow MRI can be used as a non-invasive method to assess cerebrovascular hemodynamics and helps to identify patients who may benefit from interventions to improve the functions of the cerebral circulatory system and provides a potential new path for clinical treatment.

Decreased visibility of deep medullary veins (DMVs) on susceptibility-weighted imaging (SWI) has been reported in individuals with cerebral small vessel disease (CSVD). This study aims to explore the relationship between the decreased visibility of the DMV, interstitial fluid (ISF), and the CSVD burden. Patients with CSVD (n = 128) were enrolled with multimode MRI. The DMV score was used to score visibility of DMVs on SWI. ISF was evaluated by mean free water (FW) on diffusion tensor imaging in white matter. CSVD burden was evaluated, including the severity of each CSVD marker at MRI and total CSVD MR score. The DMV score was associated with the severity of each CSVD imaging marker and total CSVD MR score (P < .05). Further, the indirect effect of the DMV score on the severity of CSVD imaging makers [white matter hyperintensity (WMH), cerebral microbleed (CMB) and lacunar infarct (LI)] and total CSVD MR score mediated by FW was significant [WMH: β, 95% CI: 0.13 (0.05, 0.24); LI: β, 95% CI: 0.19 (0.06, 0.32); CMB: β, 95% CI: 0.13 (0.01, 0.30); total CSVD MR score: β, 95% CI: 0.16 (0.05, 0.29)] controlling with age and vascular risk factors. The DMV score was associated with the CSVD burden through FW in white matter in individuals with CSVD and may describe a venous aspect of the pathogenesis of the CSVD burden.

ObjectiveTo explore the role of extracellular fluid, assessed by diffusion tensor imaging (DTI) metrics of free water (FW), in the white matter of patients with cerebral small vessel disease (CSVD).Materials and methodsThe baseline clinical and imaging data of 129 patients with CSVD were collected and reviewed. CSVD MR markers, including periventricular white matter hyperintensity (PWMH), deep white matter hyperintensity (DWMH), cerebral microbleed (CMB), enlarged perivascular space (PVS), and lacunar infarction (LI), were identified, and CSVD burden was calculated. According to total CSVD MR marker score, cases were classified as mild, moderate, or severe. The mean FW and fractional anisotropy (FA) values were calculated using DTI images.ResultsThe mean white matter FW was associated with the CSVD MR markers, including PWMH, DWMH, LI and PVS (P < 0.05). Moreover, age, hypertension, diabetes mellitus, and FW value were associated with total CSVD MR marker score (P < 0.05). Ordinal logistic regression analysis revealed that FW and age were independently associated with CSVD burden (P < 0.05). Finally, FW in white matter was associated with FA (r = –0.334, P < 0.001).ConclusionExtracellular fluid changes, assessed by DTI metrics of FW in white matter, were associated with CSVD markers and burden. An increased extracellular fluid volume in the white matter was associated with lower FA.

The mediation effects of white matter microstructural abnormalities on the associations between cerebral small vessel disease burden and cognitive impairment.

Aims to explore the relationship between neutrophil/lymphocyte ratio (NLR) and the total burden of imaging markers and cognitive function in patients with cerebral small vessel disease (CSVD). A retrospective study was conducted on 148 hospitalized CSVD patients at Hebei General Hospital from January 2022 to September 2024, with complete clinical and laboratory data. NLR was calculated as neutrophil count/lymphocyte count. According to the Mini-Mental State Examination (MMSE) score, patients were divided into a cognitive impairment group (n = 89) and a non-cognitive impairment group (n = 59). The total CSVD burden was assessed based on magnetic resonance imaging (MRI). We used logistic regression models, restricted cubic spline plots, Spearman correlation, and mediation analysis to evaluate the relationship between NLR in CSVD patients and CSVD burden and cognitive impairment. The results of the multivariate logistic regression showed that after adjusting for all potential confounding factors, an elevated NLR in CSVD patients was significantly associated with the risk of cognitive impairment (OR: 3.263; 95% CI: 1.577 to 6.752; p = 0.001) and severe CSVD burden (OR = 2.246, 95% CI: 1.346 ~ 3.750, p = 0.002). The restricted cubic spline plot shows that after adjusting for confounding factors, the NLR level is linearly associated with the risk of CI (P for total = 0.022, P for non-linear = 0.231) and the total burden of CSVD (P for total = 0.005, P for non-linear = 0.448). Correlation analysis shows that NLR is positively correlated with the CSVD score (rs = 0.246, p = 0.003). Furthermore, the results of the mediation analysis indicate that after adjusting for confounding factors, the burden of CSVD has a significant mediating effect on the relationship between NLR levels and cognitive impairment (ab = 0.028, 95% CI: 0.004 to 0.070, p = 0.012); 20.9% of the total effect of NLR on cognitive impairment in CSVD patients can be attributed to the presence of CSVD burden. Elevated NLR in CSVD patients is associated with the burden of CSVD and cognitive impairment. The mediating role of CSVD burden suggests that elevated NLR may lead to cognitive impairment by exacerbating the burden of CSVD.

Objective To investigate the relationship between total cerebral small vessel disease (CSVD) burden and intracranial hemorrhage transformation (HT) after intravenous thrombolysis in patients with acute ischemic stroke (AIS). Methods One hundred and fifty-four patients who suffered from ischemic stroke within 4.5 hours of onset and received recombinant tissue plasminogen activator thrombolytic therapy in the emergency green channel of the First Affiliated Hospital of Soochow University from August 2016 to January 2018 were enrolled. HT examined by computed tomography scan within 24 hours after thrombolysis was included. The magnetic resonance imaging examination was performed within 48 hours. The patients were divided into two groups: HT group and control group according to the presence or absence of HT. Periventricular white-matter hyperintensities (WMH) with Fazekas score of 3 or deep WMH with Fazekas score of 2 or 3 was recorded as 1 point, MRI of cerebral microbleeds (CMBs) or lacunar infarction (LI) was recorded as 1 point respectively, and peripheral vascular space (PVS) in basal ganglia graded 2-4 (≥11) was counted 1 point. Single-factor analysis was used to compare total CSVD burden score, baseline data and clinical data between the two groups. Multivariate Logistic regression analysis was performed to explore the relationship between total CSVD burden score and HT. Results The age of the 154 patients was 66.00 (59.00,74.25) years, males accounted for 66.9% (103/154), onset to treatment time (OTT) was 174.50 (131.50, 200.00) minutes and the NIHSS score before thrombolytic therapy was 6.00 (3.00, 10.25). There were 43 cases (27.9%) with moderate to severe WMH, 35 cases (22.7%) with CMBs, 52 cases (33.8%) with PVS graded 2-4, and 96 cases (62.3%) with LI. There were 21 enrolled patients (13.6%) who suffered from HT. Symptomatic intracranial hemorrhage occurred in nine cases (5.8%). In the multivariate Logistic regression model, the results demonstrated that baseline diastolic pressure (OR=1.072, 95%CI 1.027-1.118, P=0.001) and atrial fibrillation (OR=28.564, 95%CI 6.217-131.241, P=0.000) were independently associated with HT. After using the mild CSVD burden score as a reference, moderate CSVD burden (OR=0.810, 95% CI 0.154-4.257, P=0.804) was not associated with HT after thrombolysis, and severe CSVD burden (OR=8.429, 95% CI 1.643-43.227, P=0.011) was independently associated with HT. Conclusions The severity of total CSVD burden in patients with AIS was closely related to HT after thrombolysis. Severe CSVD was an independent risk factor for HT after thrombolysis. Key words: Stroke; Intravenous thrombolysis; Cerebral small vessel disease; Hemorrhagic transformation

Cerebral small vessel disease (CSVD) is a universal neurological disorder in older adults that occurs in connection with cognitive dysfunction and is a chief risk factor for dementia and stroke. While whole-brain voxelwise structural and functional abnormalities in CSVD have been heavily explored, the degree of structure-function coupling abnormality possible in patients with different CSVD burdens remains largely unknown. This study included 53 patients with severe CSVD burden (CSVD-s), 108 patients with mild CSVD burden (CSVD-m) and 76 healthy controls. A voxelwise coupling metric of low frequency fluctuations (ALFF) and voxel-based morphometry (VBM) was used to research the important differences in whole-brain structure-function coupling among groups. The correlations between ALFF/VBM decoupling and cognitive parameters in CSVD patients were then investigated. We found that compared with healthy controls, CSVD-s patients presented notably decreased ALFF/VBM coupling in the bilateral caudate nuclei and increased coupling in the right inferior temporal gyrus (ITG). In addition, compared with the CSVD-m group, the CSVD-s group demonstrated significantly decreased coupling in the bilateral caudate nuclei, right putamen and inferior frontal gyrus (IFG) and increased coupling in the left middle frontal gyrus and medial superior frontal gyrus. Notably, the ALFF/VBM decoupling values in the caudate, IFG and ITG not only showed significant correlations with attention and executive functions in CSVD patients but also prominently distinguished CSVD-s patients from CSVD-m patients and healthy controls in receiver operating characteristic curve research. Our discoveries demonstrated that decreased ALFF/VBM coupling in the basal ganglia and increased coupling in the frontotemporal lobes were connected with more severe burden and worse cognitive decline in CSVD patients. ALFF/VBM coupling might serve as a novel effective neuroimaging biomarker of CSVD burden and provide new insights into the pathophysiological mechanisms of the clinical development of CSVD.

BACKGROUND This study aimed to investigate the relationship between the coagulation function measured by thromboelastography (TEG) in patients with acute ischemic stroke (AIS) and total burden of cerebral small vessel disease (CSVD), to further establish a nomogram tool based on regular clinical risk factors and TEG, to conveniently predict the risk of high-grade white matter hyperintensities (WMH) and CSVD burden in AIS patients. MATERIAL AND METHODS A cross-sectional study included 143 AIS patients who underwent TEG tests and 3.0T head MRI scans after admission. They were grouped according to total burden CSVD score and WMH Fazekas score. Differences in regular clinical data (RCD), TEG, and conventional coagulation tests (CCT) between groups were compared. Three sets of logistic regression models were established: RCD model, and models combining RCD with TEG and CCT respectively, to evaluate their predictive performance for WMH and SVD in patients with AIS. RESULTS Univariate analysis revealed age, hypertension, stroke history, fibrinogen, and TEG indicators maximum amplitude, Angle, K, and coagulation index were risk factors for increased WMH Fazekas score and CSVD burden in patients with AIS (OR>1, P<0.05). Logistic regression model combining RCD and TEG had a higher AUC value in predicting WMH (Fazekas score ≥2) and SVD (SVD burden score ≥3). CONCLUSIONS TEG parameters of patients with AIS are related to CSVD burden and its imaging features. Based on regular clinical risk factors, TEG can provide additional predictive information on the severity of WMHs and the burden of CSVD in patients with AIS.

PurposeExcessive daytime sleepiness (EDS) and cerebral small vessel disease (CSVD) are common problems among older adults; however, their association is not clear. The present study aimed to investigate the frequency of EDS in CSVD patients and the relationship between EDS and neuroimaging markers of CSVD.Patients and MethodsWe conducted a cross-sectional study among 1076 community-dwelling older adults aged 55–85 years. EDS was measured using the Epworth Sleepiness Scale (ESS), and EDS was defined as an ESS score greater than 10. Binary logistic regression was performed to assess the association between EDS and neuroimaging markers of CSVD.ResultsOf the 1076 participants (mean age: 65.58 ± 6.46 years, 60.5% female), the prevalence of EDS was 10.0%. EDS was more frequent in participants with CSVD than in the total sample (20.0% vs 10.0%, p <0.001). In fully adjusted models, EDS was significantly correlated with CSVD burden (OR = 1.39, 95% CI 1.16 to 1.68, p <0.001), the severity of white matter hyperintensities (WMH) (OR = 1.33, 95% CI 1.14 to 1.54, p <0.001), and presence of lacunes (OR = 2.47, 95% CI 1.53 to 4.00, p <0.001) but not with the presence of cerebral microbleeds (CMBs) (OR=1.54, 95% CI 0.92 to 2.56, p = 0.099) or severity of enlarged perivascular spaces (EPVS) in basal ganglia (OR = 1.16, 95% CI 0.70 to 1.92, p = 0.564).ConclusionWe found a high frequency of EDS symptoms in CSVD individuals. Further, EDS was significantly associated with WMH, lacunes, and CSVD burden. Our findings further suggest patients with CSVD may exhibit abnormal sleep-wake patterns.

Objective: To investigate the correlation between cerebral small vessel disease (CSVD) burden and motor performance of lower and upper extremities in community-dwelling populations.Methods: We performed a cross-sectional analysis on 770 participants enrolled in the Shunyi study, which is a population-based cohort study. CSVD burden, including white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs), perivascular spaces (PVS), and brain atrophy were measured using 3T magnetic resonance imaging. All participants underwent quantitative motor assessment of lower and upper extremities, which included 3-m walking speed, 5-repeat chair-stand time, 10-repeat pronation–supination time, and 10-repeat finger-tapping time. Data on demographic characteristics, vascular risk factors, and cognitive functions were collected. General linear model analysis was performed to identify potential correlations between motor performance measures and imaging markers of CSVD after controlling for confounding factors.Results: For motor performance of the lower extremities, WMH was negatively associated with gait speed (standardized β = -0.092, p = 0.022) and positively associated with chair-stand time (standardized β = 0.153, p < 0.0001, surviving FDR correction). For motor performance of the upper extremities, pronation–supination time was positively associated with WMH (standardized β = 0.155, p < 0.0001, surviving FDR correction) and negatively with brain parenchymal fraction (BPF; standardized β = -0.125, p = 0.011, surviving FDR correction). Only BPF was found to be negatively associated with finger-tapping time (standardized β = -0.123, p = 0.012). However, lacunes, CMBs, or PVS were not found to be associated with motor performance of lower or upper extremities in multivariable analysis.Conclusion: Our findings suggest that cerebral microstructural changes related to CSVD may affect motor performance of both lower and upper extremities. WMH and brain atrophy are most strongly associated with motor function deterioration in community-dwelling populations.

Background and objectivesAtrial fibrillation (AF) has been linked to dementia risk, partly explained by cerebral small vessel disease (CSVD). Since AF and cardiovascular comorbidities were associated with cardiac dysfunction, we aimed to determine the association between echocardiographic parameters and neuroimaging markers of CSVD in patients with AF-related ischemic stroke.MethodsThis cross-sectional study enrolled patients with AF-related ischemic stroke from March 2013 to December 2019 who underwent transthoracic echocardiography and brain 3T MRI, including T1, T2, Flair, and SWI imaging sequences. We assessed the presence of lacunes and cerebellar microbleeds (CMBs), the severity of white matter hyperintensity (WMH) scored by the Fazekas scale (0-6), and the severity of enlarged perivascular spaces (EPVS) in basal ganglia (BG) and centrum semiovale (CSO) classified into three categories (0–10, 10–25, and >25). CSVD burden was rated on a 0-to-4 ordinal scale. Generalized linear regression analysis and post hoc comparisons with Bonferroni correction were performed to assess the association between various echocardiographic parameters and these lesions, adjusted for demographics and potential confounders.Results119 patients (68.38 ± 12.692 years; male 45.4 %) were included for analysis, of whom 55 (46.2%) had lacunes, 40 (33.6%) had CMBs, and median severity for WMH, BG-EPVS, CSO-EPVS, and CSVD burden were 2 (IQR: 1–3), 1 (IQR: 1–2), 1 (IQR: 0–1), and 1 (IQR: 1–2) respectively. In multivariable, fully adjusted models, left ventricular posterior wall thickness (LVPW) was associated with a higher risk of lacunes (RR 1.899, 95% CI: 1.342–2.686) and CSVD burden (RR = 2.081, 95%CI: 1.562–2.070). Right atrial diameter (RAD) was associated with greater CSO-EPVS (RR = 2.243, 95%CI: 1.234–4.075). No echocardiographic parameters were revealed to be associated with CMBs and WMH.ConclusionIn patients with AF-related ischemic stroke, LVPW is associated with a higher risk of lacunes and CSVD burden, while RAD was associated with greater CSO-EPVS. Larger studies are required to determine these associations and to elucidate if these associations can help facilitate cognitive evaluation and brain MRI screening.

Objectives: This study aimed to investigate the relationship between osteoporosis and cerebral small vessel disease (CSVD) burden in stroke-free individuals, as well as its specific imaging markers, including lacunes, enlarged perivascular spaces (EPVSs), white matter hyperintensities (WMHs), and brain atrophy (BA). Methods: A total of 684 stroke-free patients who underwent both bone mineral density (BMD) assessments and brain MRI were included. Clinical data, CSVD burden scores, imaging markers of CSVD, and bone density parameters were collected. Logistic regression models were used to evaluate the relationship between BMD and CSVD burden and imaging markers. Results: Osteoporosis, including hip and vertebral osteoporosis, was independently associated with CSVD burden (OR = 2.332, 95%CI: [1.345, 4.039], p = 0.003; OR = 2.598, 95%CI: [1.540, 4.384], p < 0.001; OR = 1.515, 95%CI: [1.010, 2.272], p = 0.044). Increased BMD in the hip and spine correlated with reduced CSVD burden (OR = 0.929, 95%CI: [0.887, 0.972], p = 0.001; OR = 0.952, 95%CI: [0.917, 0.989], p = 0.012). Hip osteoporosis was a risk factor for lacunes (OR = 2.215, 95%CI: [1.197, 4.1], p = 0.011), multiple lacunes (OR = 2.274, 95%CI: [1.039, 4.980], p = 0.04), severe WMH (OR = 2.611, 95%CI: [1.171, 5.823], p = 0.019), and EPVS ≥ 2 (OR = 1.99, 95%CI: [1.133, 3.495], p = 0.017). No significant association was found between osteoporosis and BA (p = 0.928). In sex-stratified analyses, both hip and vertebral osteoporosis were independently associated with a higher CSVD burden in female patients (hip: OR = 2.529, 95%CI: [1.122, 5.703], p = 0.025; vertebral: OR = 3.129, 95%CI: [1.517, 6.455], p = 0.002; general osteoporosis: OR = 1.755, 95%CI: [1.057, 2.912], p = 0.03), whereas no significant association was observed in male patients (all p > 0.05). Conclusions: Osteoporosis was independently associated with an increased burden of CSVD, particularly evident in female patients. These findings suggest that bone health may be important in CSVD management, particularly for women.

Based on susceptibility-weighted imaging (SWI) visibility, deep medullary vein (DMV) scores are related to white matter damage (WMD) in patients with cerebral small vessel disease (CSVD). However, whether mechanisms are associated with DMV changes is unclear. We examined extracellular fluid (ECF) roles in white matter associations between DMV scores and white matter integrity (WMI) in patients with CSVD. We examined magnetic resonance imaging (MRI) and clinical data from 140 patients with CSVD. DMV scores (0-18) were assigned on SWI according to DMV anatomic regions and signal continuity/visibility. WMI and ECF volumes were evaluated using free water (FW) and fractional anisotropy (FA) values by diffusion tensor imaging (DTI). DMV scores were independently associated with FA after adjusting for vascular risk factors, age, white matter hyperintensity (WMH) volume, and CSVD burden [β (95% confidence interval (CI)): -0.219 (-0.375, -0.061), p = 0.006]. We also observed a significant indirect effect of DMV scores on FA in white matter (mediated by FW in white matter) after controlling for age, vascular risk factors, WMH volume, and CSVD burden. DMV scores were independently related to WMI and mediated by ECF in the white matter of patients with CSVD.

PurposeTo investigate the associations between concentrations of Aβ40 and Aβ42 and vascular cognitive impairment (VCI) in cerebral small vessel disease (CSVD) patients and evaluate the value of combination of levels of Aβ40 or Aβ42 and the total CSVD score in predicting VCI.Patients and MethodsA total of 199 CSVD patients were divided into VCI group and non-VCI group according to the criteria of VCI. Demographic data, MRI markers of CSVD, blood pressure, vascular risk factors, laboratory markers, and serum Aβ40 and Aβ42 concentration were collected. Univariate analysis was performed with the Student’s t-test, Mann–Whitney U-test or Chi-square test. Variables with P<0.10 in univariate analysis were then included in multivariate analysis that used a backward stepwise logistic regression model. The predictive values were assessed with receiver operating characteristic (ROC) curve.ResultsVCI was determined in 112 CSVD patients (56.3%). Hyperlipidemia (OR: 1.618, 95% CI: 1.265–3.049), the total CSVD score (OR: 1.414, 95% CI: 1.213–2.278) and serum Aβ42 concentration (OR: 1.401, 95% CI: 1.212–1.946) were independent risk factors for VCI in CSVD patients with adjustment for age, education years, diabetes and fasting blood-glucose (FBG). The area under curves (AUCs) were 0.640 (SE: 0.040, 95% CI: 0.563–0.718), 0.733 (SE: 0.035, 95% CI: 0.664–0.802) and 0.827 (SE: 0.030, 95% CI: 0.768–0.887), respectively, for the total CSVD score, serum Aβ42 concentration and their combination applied in predicting VCI in CSVD patients. Z test demonstrated that the AUC of combination prediction was significantly higher than individual prediction (0.827 vs 0.640, Z=3.740, P<0.001; 0.827 vs 0.733, Z=2.039, P=0.021).ConclusionCombination of Aβ42 and total CSVD score could significantly elevate the predictive value of cognitive impairment in CSVD patients.

Inflammation plays a role in cerebral small vessel disease (CSVD) pathophysiology. This study aimed to explore the association of the fibrinogen-to-albumin ratio (FAR), a novel inflammatory marker, with CSVD burden in patients with transient ischemic attack (TIA). From October 1, 2022, to November 30, 2023, continuous patients with TIA were recruited in the study. The total CSVD burden score and modified total CSVD burden score were used to assess the severity of CSVD. Multivariable regression analysis was used to explore the correlation between the FAR and CSVD in TIA patients. A total of 455 participants were recruited, of whom 225 (48.35%), according to the total CSVD burden score, and 181 (40.67%), according to the modified CSVD burden score were finally identified as moderate-severe CSVD. Spearman correlation analysis showed that levels of FAR correlated with the total CSVD (r=0.392, P<0.001) and the modified total CSVD burden scores (r=0.379, P<0.001). Multivariable logistic regression analysis showed that FAR was independently associated with moderate-severe CSVD, both as a continuous variable and as a tertile variable (P<0.001). The level of FAR on admission was independently associated with the severity of CSVD in patients with TIA.