Neurovascular Unit Dysfunction and Cerebral Small Vessel Disease in Parkinson Disease: A Systematic Review and a Meta Analysis.

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

Our study aimed to investigate the glucose levels in PD and controls. We also examine whether glucose control is associated with PD severity regardless of diabetic status, and test whether the correlation is mediated by cerebral small vessel disease (CSVD) burden. A total of 100 patients with idiopathic PD and 100 age- and sex-matched controls who underwent brain magnetic resonance imaging (MRI) were enrolled in this study. We collected the clinical data and blood parameters, including fasting blood glucose (FBG), glycated hemoglobin A1c (HbA1c), and blood lipid. Patients with PD were divided into early (n = 61) and advanced (n = 39) subgroups, based on Hoehn and Yahr (H&Y) stages. Differences between the PD and controls, PD with and without diabetes, and between two PD subgroups were compared. CSVD markers were assessed, including lacunes, white matter hyperintensities, enlarged perivascular spaces, and cerebral microbleeds. Multivariable logistic regressions were used to test the association between HbA1c and H&Y stages. Interaction between HbA1c and CSVD burden in relation to H&Y stages was also analyzed. PD group exhibited higher HbA1c (p < 0.001), lower high-density lipoprotein cholesterol (p < 0.001) and triglyceride (p = 0.049) than controls. Advanced PD patients showed higher HbA1c than early PD group (p = 0.022). Increasing HbA1c (OR = 1.54, 95% CI 1.03-2.32, p = 0.036) along with longer disease duration (OR = 1.14, 95% CI 1.01-1.27, p = 0.028) and higher UPDRS III score (OR = 1.07, 95% CI 1.02-1.11, p = 0.002) increased the risk of belonging to the higher H&Y stage. However, interaction between HbA1c and CSVD burden in relation to H&Y stages was not significant. HbA1c is independently associated with H&Y stages in PD, and this correlation may not be mediated by CSVD burden.

White matter hyperintensities regress at a high rate at three months after minor ischemic stroke or transient ischemic attack.

This study aimed to investigate how cerebral small vessel disease (CSVD) burden and its imaging markers are related to alterations in different gait parameters in Parkinson's disease (PD) and whether they affect attention, information processing speed, and executive function when global mental status is relatively intact. Sixty-five PD patients were divided into the low CSVD burden group (n = 43) and the high CSVD burden group (n = 22). All patients underwent brain magnetic resonance imaging scans, clinical scale evaluations, and neuropsychological tests, as well as quantitative evaluation of gait and postural control. Multivariable linear regression models were conducted to investigate associations between CSVD burden and PD symptoms. Between-group analysis showed that the high CSVD group had worse attention, executive dysfunction, information processing speed, gait, balance, and postural control than the low CSVD group. Regression analysis revealed that greater CSVD burden was associated with poor attention, impaired executive function, and slow gait speed; white matter hyperintensity was associated with slow gait speed, decreased cadence, increased stride time, and increased stance phase time; the presence of lacune was associated only with poor attention and impaired executive function; enlarged perivascular space in the basal ganglia was associated with gait speed. CSVD burden may worsen gait, postural control, attention, and executive function in patients with PD, and different imaging markers play different roles. Early management of vascular risks and treatment of vascular diseases provide an alternate way to mitigate some motor and cognitive dysfunction in PD.

Objective: Patients with unruptured intracranial aneurysms (UIAs) often experience cognitive decline. Cerebral small vessel disease is one of the important causes of cognitive impairment. This study investigates the clinical factors and magnetic resonance imaging (MRI) characteristics of cerebral small vessel disease (SVD) burden associated with cognitive impairment in patients with UIAs. Methods: We retrospectively analyzed patients with UIAs treated at our hospital between 2018 and 2023. Clinical data, MRI, and cognitive function assessments were evaluated. MRI sequences included T1-weighted, T2-weighted, fluid-attenuated inversion recovery, diffusion-weighted imaging, and susceptibility-weighted imaging. Cerebral MRIs were assessed for lacunes, white matter hyperintensities (WMH), cerebral microbleeds (CMBs), and perivascular spaces (PVS). The total SVD score was calculated using the presence of each SVD feature. Cognitive impairment was defined as a Montreal Cognitive Assessment (MoCA) score of less than 26. We explored the associations between clinical features, aneurysm characteristics, MRI-based SVD markers, and total SVD scores with cognitive impairment. Results: The study included 171 patients with UIAs who underwent both multimodal MR imaging and cognitive assessments. The average age was 58.0 years, with 59% being women. The mean aneurysm size was 4.9 mm, and 43 patients had aneurysms larger than 7 mm. Among the participants, 156 had saccular aneurysms, 59 had irregular aneurysm morphology, and 38 had multiple aneurysms. The SVD markers of lacunes, WMH, CMBs, and PVS were present in 43.9%, 18.7%, 13.5%, and 28.1% of patients, respectively. The total SVD score was 1.00 (0.00-2.00). Cognitive impairment was observed in 74.9% of patients. Multivariate logistic regression identified lacunes (OR 4.805, 95% CI 2.069-11.162, p&lt;0.001), WMH (OR 6.276, 95% CI 1.433-27.487, p=0.015), and PVS (OR 3.012, 95% CI 1.179-7.696, p=0.021) and CSVD score (OR 2.163, 95% CI 1.401-3.341, p=0.001) as independent risk factors for cognitive impairment. Linear regression showed that hypertension and age were positively correlated with CSVD score. Conclusions: Total SVD score on MRI is an independent risk factor for cognitive impairment in patients with UIAs. Hypertension positively correlates with cerebral small vessel disease burden, indicating its importance in preventing cognitive impairment in the UIA patient population.

We aimed to investigate the correlation between an overall cerebral small vessel disease (CSVD) burden and outcomes after endovascular treatment (EVT) for patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO). In a multicenter registry study, we enrolled patients with EVT for anterior-circulation LVO-stroke. In 3.0-T MR imaging, we assessed 4 CSVD imaging markers, lacunes, white matter hyperintensities, cerebral microbleeds, and enlarged perivascular spaces, each assigned a score of 0 or 1 and summed up to an overall CSVD burden score of 0-4. We dichotomized the overall CSVD severity as none to mild (score 0-2) and moderate to severe (3-4). Primary outcome was 90-day functional dependence or death (modified Rankin Scale (mRS) 3-6). Secondary outcomes included increase in NIH Stroke Scale ≥ 4 within 24 h (early neurological deterioration (END)) and within 7 days, symptomatic intracranial hemorrhage, 90-day mRS 2-6, and 90-day mortality. Among 311 patients (63.0% male; mean age 65.1 ± 12.7 years), 260 (83.6%) had none-to-mild and 51 (16.4%) had moderate-to-severe overall CSVD burden. Moderate-to-severe CSVD burden was not significantly associated with the primary outcome (47.1% versus 45.4%; p > 0.05 in univariate and multivariate logistic regression), or the secondary outcomes except for a higher risk of END (11.8% versus 3.1%; p < 0.05 in multivariate analyses). Sensitivity analyses with 0-1 versus 2-4 of the CSVD burden score, and the score as an ordinal variable, showed similar results. An overall moderate-to-severe CSVD burden was not associated with 90-day functional dependence or death, after EVT for anterior-circulation LVO. ChiCTR1900022154 KEY POINTS: • Moderate-to-severe cerebral small vessel disease burden on MRI should not be an exclusion indicator in determining the eligibility of an acute ischemic stroke patient for endovascular treatment.

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.

We hypothesized that cerebral small vessel disease (CSVD) burden might not relevantly affect leptomeningeal collateral supply in patients with acute ischemic stroke (AIS) due to large-vessel occlusion (LVO). In n = 154 patients with anterior circulation LVO, CSVD imaging markers (white matter hyperintensities [WMH], lacunes, cerebral microbleeds and enlarged perivascular spaces) were assessed with MRI, using established criteria. Besides the extent of WMH, assessed using total Fazekas sum score, overall CSVD burden was determined with a total CSVD summary score ranging from 0-4. A quantitative and rater-independent collateral vessel index was computed from automated processing of T2*-weighted time series in perfusion-weighted imaging (PWI) to assess the pial collateral status. The overall burden of WMH and CSVD were not significantly associated with poor collaterals (adjusted odds ratios 0.830 (0.328-2.104) and 0.995 (0.666-1.488), p = 0.695 and p = 0.982) and did not modify the significant relationship of leptomeningeal collaterals with clinical stroke severity, ischemic core volume and infarct growth rate. Quantitative and objective analysis of collaterals with a signal variance-based approach in PWI revealed no overt association between CSVD burden and collaterals in LVO patients. Factors favoring or impairing collateral supply in case of acute cerebral ischemia warrant further exploration in future studies.

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.

Albumin (ALB), globulin (GLB) and albumin-to-globulin ratio (AGR) are linked to vascular diseases, but their relationships with cerebral small vessel disease (CSVD) remain inadequately explored. This study aimed to examine the associations between these biomarkers and CSVD burden. Participants from the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study were included. CSVD severity was assessed using total and modified CSVD burden scores derived from white matter hyperintensity (WMH), enlarged perivascular spaces in basal ganglia (BG-EPVS), lacunes and cerebral microbleeds. Logistic regression and two-sample Mendelian randomisation (MR) were employed to estimate associations and potential causal effects. Among 3042 subjects (mean age 61.2 years), lower ALB, higher GLB and lower AGR were significantly associated with greater total and modified CSVD burden after adjusting for confounders. Specifically, the risk of total CSVD burden was significantly increased for the lowest ALB tertile (cOR 1.31, 95% CI 1.07 to 1.60), highest GLB tertile (cOR 1.33, 95% CI 1.09 to 1.63) and lowest AGR tertile (cOR 1.46, 95% CI 1.19 to 1.79) compared with their respective reference tertiles. Similar patterns were observed for WMH and BG-EPVS. MR analysis revealed that genetically predicted ALB was inversely associated with WMH volume (β -0.07, 95% CI -0.13 to -0.01), while genetically predicted GLB was positively associated with WMH volume (β 0.05, 95% CI 0.01 to 0.10). Lower ALB, higher GLB and lower AGR are associated with increased CSVD burden. Genetic evidence supports the causal roles of ALB and GLB in WMH development.

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.

Arteriosclerotic cerebral small vessel disease (aCSVD) is a cause of cognitive impairment, dementia, and stroke. Developing a better understanding of the risk factor of aCSVD is key to reducing the incidence of these conditions. This study investigated the association between intracranial arterial calcification (IAC) and total cerebral small vessel disease (CSVD) burden score. This is a retrospective study, the subjects were transient ischemic attack (TIA) or acute ischemic stroke (AIS) patients. The data of 303 inpatients admitted to our study hospital between December 2018 and July 2020 were analyzed. Four imaging markers of CSVD (lacunes, white matter hyperintensities, cerebral microbleeds, and enlarged perivascular spaces) were evaluated by magnetic resonance imaging, and a total CSVD burden score was calculated. The experimental group was divided into four subgroups according to total CSVD burden score (1-4 points). Patients without CSVD (0 points) served as the control group. Head computerized tomography (CT) scans were used to assess ICA, using Babiarz's method. The correlations between IAC and single imaging markers of CSVD were determined using Spearman's rank correlation. Binary logic regression analysis and multivariate ordered logic regression analysis were used to determine the associations between IAC and aCSVD. IAC was positively correlated with total CSVD burden score (r = 0.681), deep white matter hyperintensities (r = 0.539), periventricular white matter hyperintensities (r = 0.570), cerebral microbleeds (r = 0.479), lacunes (r = 0.541), and enlarged perivascular spaces (r = 0.554) (all p < 0.001). After adjusting for the confounding factors of age, diabetes, and hypertension, aCSVD was independently associated with IAC grade 1-2 [odds ratio (OR) = 23.747, 95% confidence interval (CI) = 8.376-67.327] and IAC grade 3-4 (OR = 30.166, 95% CI = 8.295-109.701). aCSVD severity was independently associated with IAC grade 3-4 (OR = 4.697, 95% CI = 1.349-16.346). IAC is associated with the total CSVD burden score and single imaging signs.

Association of plasma p-tau217 levels with cerebral small vessel disease burden: Cross-sectional insights from the Hefei Aging Study.

Objective We investigated the association between middle cerebral artery atherosclerotic plaque features and cerebral small vessel disease (CSVD) imaging markers as well as the total CSVD burden, in patients with branch atheromatous disease (BAD). Methods Plaque parameters were quantified using high-resolution magnetic resonance imaging (HR-MRI) with ImageJ software, to characterize distribution, lumen stenosis, remodeling patterns, and other relevant features. Conventional MRI assessed CSVD imaging markers and total CSVD burden. Multivariate logistic regression analysis was performed following adjustment for potential confounders. Receiver operating characteristic (ROC) curve analysis with the DeLong test assessed the predictive value of plaque features for total CSVD burden. Results Compared with the non-plaque group, the plaque group showed significantly higher proportions of severe white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and moderate-to-severe CSVD burden (p < 0.05). In multivariate analysis, the presence of plaque was an independent risk factor for WMHs (OR = 2.920), CMBs (OR = 1.995), and moderate-to-severe CSVD burden (OR = 2.853); plaque distribution was an independent risk factor for WMHs (OR = 3.367); eccentric plaques were independent risk factors for lacunar infarction (OR = 8.670) and CMBs (OR = 7.891); positive remodeling (OR = 9.285) and eccentric plaques (OR = 10.355) were independent risk factors for moderate-to-severe CSVD burden. ROC analysis demonstrated plaque vulnerability effectively predicted moderate-to-severe CSVD burden (AUC = 0.8808, p < 0.05). Conclusion In ischemic stroke patients, distinct intracranial atherosclerotic stenosis (ICAS) plaque features correlate with specific CSVD phenotypes. Vulnerable plaques not only significantly increase total CSVD burden but also effectively predict CSVD severity. These findings elucidate how ICAS influences CSVD burden progression from an HR-MRI perspective and facilitate clinical risk stratification.

White matter (WM) microstructural deterioration is associated with a higher total cerebral small vessel disease (CSVD) burden, as assessed by magnetic resonance imaging (MRI) markers, and with more pronounced cognitive decline in CSVD patients. However, the relationships among CSVD burden, cognitive impairment and WM changes remain unclear. We aimed to characterize WM microstructural abnormalities in patients with different CSVD burdens and investigate the mechanism linking different CSVD burdens to cognitive decline. This study included 56 patients with severe CSVD burden (CSVD-s), 109 patients with mild CSVD burden (CSVD-m) and 81 healthy controls. We used diffusion tensor imaging (DTI) and tract-based spatial statistics to detect WM diffusion changes between groups and then explored the relationships between different CSVD burdens, WM diffusion changes and cognitive function, especially to quantitatively analyze the possible mediating effect of WM microstructural alterations on CSVD burden and cognitive function. The CSVD-s group presented significantly decreased FA and increased AD, RD and MD in the forceps minor, bilateral anterior thalamic radiation (ATR), superior longitudinal fasciculus (SLF), corticospinal tract (CST) and inferior fronto-occipital fasciculus (IFOF). The simple mediation model revealed that the mean MD value of forceps minor and right IFOF, the mean FA value of the left CST and right IFOF, and the mean RD value of the left CST, SLF and right IFOF partially mediated the correlations between the CSVD burden and multiple cognitive scores. Our findings offer potential neuroimaging targets for intervening in and improving cognitive dysfunction in patients with different CSVD burdens.