Perivascular fluid clearance links choroid plexus changes to cognitive performance in cerebral small vessel disease.

BackgroundSleep fragmentation was shown to be positively associated with cognitive impairment in patients with cerebral small vessel disease (CSVD); however, the underlying mechanisms are not well characterized. In this study, we sought to clarify this issue by investigating the relationship between non breathing-related sleep fragmentation and brain imaging markers in patients with CSVD.MethodsEighty-four CSVD patients and 24 age- and sex-matched healthy controls were prospectively recruited. All subjects underwent 3.0 T superconducting magnetic resonance imaging and overnight polysomnography. Polysomnography parameters including sleep onset latency (SOL), total sleep time (TST); sleep efficiency (SE), wake after sleep onset (WASO), percentage of each sleep stage (N1, N2, N3 and rapid eye movement [REM]), arousal index (ArI), periodic limb movement in sleep index (PLSMI), and periodic limb movement related arousal index (PLMAI) were compared between CSVD patients and healthy controls. The relationship between arousal index and CSVD markers was explored in the CSVD group.ResultsOn polysomnography, CSVD patients showed significantly higher ArI, WASO, PLSMI, and PLMAI, and lower sleep efficiency and N− 3 ratio compared to healthy controls (p < 0.05). On ordinal logistic regression, higher ArI showed a positive association with the severity of periventricular white matter hyperintensity (odds ratio [OR] 1.121, 95% confidence interval [CI] 0.138–2.185) and perivascular space (OR 2.108, 95% CI 1.032–4.017) in CSVD patients, after adjusting for potential confounding variables.ConclusionsThese preliminary results indicate that non breathing-related sleep fragmentation is common and related to the pathological markers of CSVD patients. Future prospective research is required to determine the causal relationship between sleep parameters and CSVD pathology.

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.

Disruption of cerebral hemodynamics may impair perivascular and glymphatic clearance, contributing to aging-related brain pathology. This study aimed to explore the interaction between large-vessel hemodynamics and glymphatic neuroimaging markers in cerebral small vessel disease (CSVD), a common age-related condition. Using 4D flow MRI, we quantified flow/area pulsatility index (PIflow/PIarea) and wall shear stress (WSS) in carotid arteries and superior sagittal sinus (SSS) among 66 CSVD patients and 34 healthy controls (HCs). Free water (FW) fraction and diffusivity along the perivascular space (ALPS) were measured as glymphatic markers via diffusion-weighted imaging. Multivariate regressions and mediation analyses were conducted to assess the relationships between vascular metrics and glymphatic markers, as well as disease burden, adjusting for age, sex, white matter hyperintensity (WMH) volume, and vascular risk factors. CSVD patients exhibited increased arterial and venous PIs and WSS alongside elevated FW in multiple brain regions. PIarea of common carotid artery (CCA) and higher WSS of internal carotid artery (ICA)-C1 correlated with increased FW of basal ganglia (FW-BG); PIflow of SSS linked to FW in the hippocampus; and PIarea of ICA-C4 correlated with ALPS (β = 0.188-0.267, p < .05). Contrastingly, HCs exhibited inverse associations between PIs/WSS and glymphatic markers (β = -0.517 to -0.317, p < .05). Interestingly, FW-BG mediated 42.1% of the effect between PIarea-CCA and CSVD burden (BootCI:0.015-0.956, p < .05). Elevated WSS of SSS predicted worse global cognition (β = -0.32, p = .005). Altered large-vessel hemodynamics correlated to glymphatic dysfunction and cognitive function in CSVD, highlighting the critical role of vascular health in preserving brain clearance and cognitive aging.

This study aimed to investigate thalamic microstructural alterations in cerebral small vessel disease (CSVD) patients with mild cognitive impairment (MCI) using diffusion kurtosis imaging (DKI), and to examine the associations between DKI parameters and cognitive performance. The study included 80 CSVD patients and 40 healthy controls (HC). Based on Montreal Cognitive Assessment (MoCA) scores, CSVD patients were divided into MCI (n = 40) and non-MCI (n = 40) groups. DKI parameters of the thalamus and its subregions were compared among the three groups and correlated with cognitive performance. CSVD-MCI patients exhibited significant alterations in DKI parameters, predominantly in the left thalamus. Compared to HC, CSVD-MCI patients showed reduced FA and decreased kurtosis parameters (KFA, MK, AK), along with increased diffusivity metrics (MD, AD, RD). Subregional analysis revealed the most pronounced changes in the left posterior, medial, and ventral groups. The lateral geniculate nucleus showed particularly significant reductions in FA and KFA. Cognitive assessments revealed significant correlations between DKI parameters and cognitive performance, with BNT and VFT scores showing strong correlations with DKI parameters in the left thalamus, particularly in the posterior nucleus and pulvinar. Thalamic microstructural alterations may play a crucial role in cognitive decline among CSVD patients. Diffusion kurtosis imaging parameters may provide novel perspectives for investigating the mechanisms of cognitive deterioration in CSVD patients.

BackgroundGait disturbance is a prevalent characteristic of cerebral small vessel disease (CSVD), yet the underlying mechanisms remain largely unclear.AimesTo test the hypothesis that enlarged perivascular spaces in the basal ganglia (BG-EPVS) are related to gait performance in individuals with CSVD and the elderly.MethodsThis cross-sectional study included 138 CSVD patients and 62 healthy elderly controls who underwent quantitative gait analysis. Neuroimaging markers, including BG-EPVS, white matter hyperintensities (WMH), lacunes, and cerebral microbleeds (CMB), were assessed using MRI. Principal component analysis (PCA) was used to reduce the dimensionality of multiple gait indicators. Linear regression models were employed to examine the relationship between BG-EPVS and the principal component values of gait performance, with WMH as a potential mediator.ResultsCompared to healthy controls, CSVD patients exhibited significantly prolonged stance and double-support phases, shortened swing phase, reduced gait speed, increased step width, and decreased stride length and step height (p < 0.05 for all comparisons). Higher BG-EPVS grades were independently associated with poorer gait performance in both CSVD patients (p = 0.012) and all subjects (p = 0.001), even after adjusting for other CSVD markers. WMH partially mediated the relationship between BG-EPVS and gait performance, accounting for 18.2% of the total effect in CSVD patients and 24.9% of the total effects in all subjects.ConclusionBG-EPVS is independently associated with gait disturbances in both CSVD patients and the elderly. These findings underscore the importance of early gait assessment in the aging population. Further longitudinal research is needed to confirm these associations.

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.

Objectives: To examine the effect of cerebral small vessel disease (CSVD) markers and CSVD burden on hematoma expansion and long-term functional outcomes in large spontaneous intracerebral hemorrhage (ICH) &gt;30 mL. Method: Retrospective analysis of 288 patients from the MISTIE III trial with qualified MRI sequences. MISTIE III evaluated minimally invasive surgery plus alteplase (vs medical management). We identified 6 CSVD markers including lacunes, cerebral microbleeds (CMB), enlarged perivascular space (EPVS), white matter hyperintensities (WMH), cortical superficial siderosis (cSS), and acute DWI positive lesions. First 5 components were reviewed on day 1 MRI and DWI lesions on day 7. The primary outcome was death or major disability at one year (modified Rankin score 4-6). Secondary outcome was post-surgical rebleeding, defined as symptomatic or asymptomatic hemorrhage expansion within 72 hours post last dose of alteplase. Result: Unfavorable outcome occurred in 65.9% at one year. Post-surgical ICH expansion occurred in 34 (22.9%) of 148 surgical patients. Mean time from symptom onset to first MRI was 0.94 (IQR 0.2-6.3) days. Most individual CSVD markers were more common in patients with unfavorable vs. favorable outcome: CMB≧5 (26.1% vs 15.0%, p=0.03), DWI lesions (65.8%vs 49.6%, p=0.006), cSS (16.8% vs 7.1%, p=0.02) severe WMH (67.7% vs 29.9%, p&lt;0.001) severe EPVS in basal ganglia (19.3% vs 10.2%, p=0.047), and lacunes (11.2% vs 6.3%, p=0.21), In the multivariable adjusted model, cumulative CSVD score (one point for each component: CMB≥5, severe EPVS in basal ganglia, lacunes, severe WMH and cSS) was independently associated with unfavorable outcome (OR 0.56, 95%CI 0.41-0.76, p&lt;0.001; AUC 0.855). We did not find a relationship between either independent CSVD markers or CSVD score with post-surgical ICH expansion. Cumulative CSVD score in multivariable analysis adjusted for predictors of hematoma expansion had OR 0.77 (95% CI 0.50-1.19, p=0.77; AUC 0.659). Conclusion: In large volume ICH patients with long-term follow-up, heavy burden of CSVD at ICH onset remains an independent predictor of unfavorable outcome, and particularly severe white matter hyperintensities. CSVD markers did not show association with post-surgical ICH expansion.

Data linking heart rate variability (HRV) and cognitive status remains controversial and scarce, particularly in cerebral small vessel disease (CSVD) patients. Whether the association between HRV and cognitive performance exists in CSVD patients is unclear. Hence, we aimed to investigate the association between HRV and cognitive performance in patients with CSVD. This cross-sectional study was conducted among 117 CSVD patients. All patients underwent HRV assessment and global cognitive evaluation by the Mini-Mental-State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Multivariable analyses were performed to evaluate the association between HRV and cognitive status. The mean age of study population was 59.5 ± 11.8 years and 39.3% were female. After adjusting for confounding factors, a higher high frequency (HF) norm was independently associated with better MMSE scores (β = 0.051; 95% confidence interval (CI): 0.012~0.090; p = 0.011) and MoCA scores (β = 0.061; 95% CI: 0.017~0.105; p = 0.007), while a higher low frequency (LF)/HF ratio was independently associated with worse MMSE scores (β = -0.492; 95% CI: -0.893~-0.092; p = 0.017) and MoCA scores (β = -0.691; 95% CI: -1.134~-0.248; p = 0.003). The HF norm was positively associated with global cognitive performance, whereas the LF/HF ratio was negatively associated with global cognitive performance among CSVD patients. Further study of the relationship between autonomic function and cognitive performance is warranted.

This study explored the relationships between brain iron levels, emotion, and cognitive and motor function in cerebral small vessel disease (CSVD) patients using quantitative susceptibility mapping (QSM). A total of 208 subjects were enrolled in this study. A brain QSM map was calculated from multiecho GRE data via morphology-enabled dipole inversion with an automatic uniform cerebrospinal fluid zero reference algorithm (MEDI+0). Multiple linear regression analysis was applied to explore the clinical factors influencing cerebral susceptibility in CSVD patients. Correlation analysis and pathway-specific mediation effects between brain iron levels and motor function were investigated. There were significant differences in the MoCA scores, depression scores, five-repetition sit-to-stand test (5R-STS) time, and susceptibility values of the caudate nucleus and putamen among the three groups (p < 0.05, FDR correction). Age and history of diabetes played crucial roles in brain iron levels in the caudate nucleus and putamen, which may increase iron levels in the basal ganglia, associated with cognitive decline. Notably, the susceptibility values of the left caudate nucleus and putamen were positively correlated with the 5R-STS time in CSVD subjects, and there were significant mediating effects of anxiety on the prediction of motor dysfunction with respect to iron levels in the left putamen in CSVD patients. Age, diabetes status, and anxiety may serve as effective intervention targets for individuals with CSVD, especially individuals with cognitive and motor dysfunction. A greater brain iron burden may be a quantitative imaging marker of cognitive and motor dysfunction in CSVD patients. ISRCTN20008650.

Abnormalities in the gray matter structure of cerebral small vessel disease (CSVD) have been observed throughout the brain. However, whether cortico-cortical connections exist between regions of gray matter atrophy in patients with CSVD has not been fully elucidated. This question was tested by comparing the gray matter covariance networks in CSVD patients with and without cognitive impairment (CI). We performed multivariate modeling of the gray matter volume measurements of 61 patients with CI (CSVD-CI), 85 patients without CI (CSVD-NC), and 108 healthy controls using source-based morphological analysis (SBM) to obtain gray matter structural covariance networks at the population level. Then, correlations between structural covariance networks and cognitive functions were analyzed in CSVD patients. Finally, a support vector machine (SVM) classifier was used with the gray matter covariance network as a classification feature to identify CI among the CSVD population. The results of the analysis of all the subjects showed that compared with healthy controls, the expression of the thalamic covariance network, cerebellum covariance network, and calcarine cortex covariance network was reduced in patients with CSVD. Moreover, CSVD-CI patients showed a significant reduction in the expression of the thalamic covariance network, encompassing the thalamus and the parahippocampal gyrus, relative to CSVD-NC patients, which persisted after excluding CSVD patients with thalamic lacunes. In patients with CSVD, cognitive functions were positively correlated with measures of the thalamic covariance network. More than 80% of CSVD patients with CI were correctly identified by the SVM classifier. Our findings provide new evidence to explain the distribution state of gray matter reduction in CSVD patients, and the thalamic covariance network is the core region for early gray matter reduction during the development of CSVD disease, which is related to cognitive deficits. Reduced expression of thalamic covariance networks may provide a neuroimaging biomarker for the early identification of cognitive impairment in CSVD patients.

Association of enlarged perivascular spaces with cognitive function in dementia-free older adults: A population-based study.

We aimed to investigate alterations in functional brain networks and assess the relationship between functional impairment and topological network changes in cerebral small vessel disease (CSVD) patients with and without cerebral microbleeds (CMBs). We constructed individual whole‐brain, region of interest (ROI) level functional connectivity (FC) networks for 24 CSVD patients with CMBs (CSVD‐c), 42 CSVD patients without CMBs (CSVD‐n), and 36 healthy controls (HCs). Then, we used graph theory analysis to investigate the global and nodal topological disruptions between groups and relate network topological alterations to clinical parameters. We found that both the CSVD and control groups showed efficient small‐world organization in FC networks. However, compared to CSVD‐n patients and controls, CSVD‐c patients exhibited a significantly decreased clustering coefficient, global efficiency, and local efficiency and an increased shortest path length, indicating a disrupted balance between local specialization and global integration in FC networks. Although both the CSVD and control groups showed highly similar hub distributions, the CSVD‐c group exhibited significantly altered nodal betweenness centrality (BC), mainly distributed in the default mode network (DMN), attention, and visual functional areas. There were almost no global or regional alterations between CSVD‐n patients and controls. Furthermore, the altered nodal BC of the right anterior/posterior cingulate gyrus and left cuneus were significantly correlated with cognitive parameters in CSVD patients. These results suggest that CSVD patients with and without CMBs had segregated disruptions in the topological organization of the intrinsic functional brain network. This study advances our current understanding of the pathophysiological mechanisms underlying CSVD.

PurposeThis study aims to investigate the potential effect of compromised structural integrity on cerebral aging and cognitive function in cerebral small vessel disease (CSVD).MethodsFifty-five CSVD patients and 42 controls underwent three-dimensional T1-weighted imaging and diffusion tensor imaging. Relative brain age (RBA) was computed to assess cerebral aging. Variables of structural integrity included cortical thickness, cortical volume, white matter hyperintensity (WMH) volume, peak width of skeletonized mean diffusivity (PSMD), ventricular volume, and choroid plexus volume. Mini-Mental State Examination (MMSE) was conducted to assess general cognition. Trail Making Test (TMT) and Auditory Verbal Learning Test were administered to evaluate executive function and episodic memory, respectively. Mediation analysis and multivariate linear regression with interaction terms were performed to explore the differential impacts of RBA on cognitive function and structural integrity between CSVD patients and controls.ResultsRBA was significantly increased in CSVD patients compared to controls (p < 0.001). White matter injuries as assessed with PSMD (mediation magnitude: 41.1%) and WMH volume (mediation magnitude: 56.9%) significantly mediated the relationship between CSVD pathologies and RBA (p < 0.001). Higher RBA was significantly correlated with poorer scores of MMSE, TMT-A, and TMT-B in CSVD patients (p < 0.01). Additionally, PSMD (mediation magnitude: 57.8% in MMSE, 48.3% in TMT-A, and 28.8% in TMT-B) and WMH volume (mediation magnitude: 55.1% in MMSE) significantly mediated the relationship between RBA and cognitive function (p < 0.05).ConclusionWhite matter injuries play a critical role in the cerebral aging and cognitive decline in CSVD patients.

Objective We investigated coefficient of variation (CV), gait asymmetry (GA) and phase coordination index (PCI) in cerebral small vessel disease (CSVD) patients during single-task walking (STW) and dual-task walking (DTW) and explored the relationship between above parameters with disease severity and cognitive function. Methods This cross-sectional study collected cognitive function indices and gait parameters from 23 healthy controls and 94 patients with CSVD during STW and DTW. According to the Fazekas scales, the severity of CSVD valued by white matter hyperintensity (WMH) were divided into control, mild, moderate, severe and control group. MRIs were analyzed for WMHs, CMB, lacunes, etc. Results The control group showed lower PCI than CSVD patients during STW; no differences were detected among the disease severity groups. During DTW, all four groups exhibited significant differences in PCI and CV. For the moderate and severe groups, coordination and variation significantly differed between the two walking methods. There were correlations between the PCI and GA in the moderate and severe groups (R = 0.376, R = 0.573 during DTW; R = 0.414, R = 0.643 during STW) and no correlations in the control group and mild CSVD group. Conclusion PCI and CV may be vital for detecting the symptoms in the early stage of CSVD disease. We also verified that the PCI could become the bridge across the cognition and motor disorder in CSVD, which was helpful for evaluating clinical symptoms comprehensively.

Background: Mild manifestations of individual cerebral small vessel disease (CSVD) markers are common and may not denote increased risk, but high CSVD burden identifies individuals at increased risk of stroke and dementia. Scores incorporating multiple CSVD markers may better identify a person’s risk, but it remains unclear if they offer benefit beyond tools based on clinical factors alone such as the revised Framingham Stroke Risk Profile (FSRP). Therefore, we related a multi-marker CSVD score to risk of incident stroke and compared the findings with the FSRP in community-dwelling individuals. Methods: Framingham Heart Study (FHS) participants aged ≥55 years, free of stroke and dementia and with brain magnetic resonance imaging (MRI) ratings of CSVD markers were included. A multi-marker CSVD score reflecting increasing CSVD burden was used (one point each for presence of cerebral microbleeds, severe perivascular spaces, extensive white matter hyperintensities, covert brain infarcts, and cortical superficial siderosis, ranging 0-5). Multivariable Cox proportional hazards regression analyses were used to relate CSVD score to incident stroke. Results: Among 1,154 participants (46% male, mean age 70.9±8.7), 590 (51%) had score 0, 352 (31%) had score 1, 164 (14%) had score 2, and 48 (4%) had score ≥ 3. Over a median follow-up of 8.2 years (Q1-Q3: 5.1-12.5) from the time of MRI, 92 (8%) developed stroke. In models adjusting for time interval between clinic exam and MRI, FHS cohort, and FSRP score, number of CSVD manifestations was associated with increased risk of stroke in a dose-dependent manner: score 1 (HR: 1.73; 95% CI 1.05-2.84), score 2 (HR 1.83; 95% CI: 1.01-3.30), and score ≥ 3 (HR: 3.31; 95% CI: 1.50-7.28) in relation to participants with no CSVD markers. In comparison, a 5-percent increase in FSRP alone was associated with increased risk of stroke (HR: 1.25; 95% CI 1.15-1.36). Interpretation: Higher CSVD burden is associated with increased risk of stroke, beyond the effect explained by risk factors in the FSRP. These findings support consideration of CSVD burden to identify risk of stroke in community-dwelling individuals.