Progression Of Cerebral Small Vessel Disease Research Articles

Linking peripheral atherosclerosis to blood-brain barrier disruption: elucidating its role as a manifestation of cerebral small vessel disease in vascular cognitive impairment.

Aging plays a pivotal role in the pathogenesis of cerebral small vessel disease (CSVD), contributing to the onset and progression of vascular cognitive impairment and dementia (VCID). In older adults, CSVD often leads to significant pathological outcomes, including blood-brain barrier (BBB) disruption, which in turn triggers neuroinflammation and white matter damage. This damage is frequently observed as white matter hyperintensities (WMHs) in neuroimaging studies. There is mounting evidence that older adults with atherosclerotic vascular diseases, such as peripheral artery disease, ischemic heart disease, and carotid artery stenosis, face a heightened risk of developing CSVD and VCID. This review explores the complex relationship between peripheral atherosclerosis, the pathogenesis of CSVD, and BBB disruption. It explores the continuum of vascular aging, emphasizing the shared pathomechanisms that underlie atherosclerosis in large arteries and BBB disruption in the cerebral microcirculation, exacerbating both CSVD and VCID. By reviewing current evidence, this paper discusses the impact of endothelial dysfunction, cellular senescence, inflammation, and oxidative stress on vascular and neurovascular health. This review aims to enhance understanding of these complex interactions and advocate for integrated approaches to manage vascular health, thereby mitigating the risk and progression of CSVD and VCID.

Atherosclerotic burden and cerebral small vessel disease: exploring the link through microvascular aging and cerebral microhemorrhages.

Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) are a critical but frequently underestimated aspect of cerebral small vessel disease (CSVD), bearing substantial clinical consequences. Detectable through sensitive neuroimaging techniques, CMHs reveal an extensive pathological landscape. They are prevalent in the aging population, with multiple CMHs often being observed in a given individual. CMHs are closely associated with accelerated cognitive decline and are increasingly recognized as key contributors to the pathogenesis of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). This review paper delves into the hypothesis that atherosclerosis, a prevalent age-related large vessel disease, extends its pathological influence into the cerebral microcirculation, thereby contributing to the development and progression of CSVD, with a specific focus on CMHs. We explore the concept of vascular aging as a continuum, bridging macrovascular pathologies like atherosclerosis with microvascular abnormalities characteristic of CSVD. We posit that the same risk factors precipitating accelerated aging in large vessels (i.e., atherogenesis), primarily through oxidative stress and inflammatory pathways, similarly instigate accelerated microvascular aging. Accelerated microvascular aging leads to increased microvascular fragility, which in turn predisposes to the formation of CMHs. The presence of hypertension and amyloid pathology further intensifies this process. We comprehensively overview the current body of evidence supporting this interconnected vascular hypothesis. Our review includes an examination of epidemiological data, which provides insights into the prevalence and impact of CMHs in the context of atherosclerosis and CSVD. Furthermore, we explore the shared mechanisms between large vessel aging, atherogenesis, microvascular aging, and CSVD, particularly focusing on how these intertwined processes contribute to the genesis of CMHs. By highlighting the role of vascular aging in the pathophysiology of CMHs, this review seeks to enhance the understanding of CSVD and its links to systemic vascular disorders. Our aim is to provide insights that could inform future therapeutic approaches and research directions in the realm of neurovascular health.

Abstract TP221: Progression of Intracranial Artery Stenosis and Cerebral Small Vessel Disease and Associations Between the Two Entities: A Prospective Community-Based Cohort Study

Background: Both intracranial artery stenosis (ICAS) and cerebral small vessel disease (CSVD) can cause heavy socioeconomic burdens. However, their longitudinal changes remain controversial. To investigate the risk factors for ICAS and CSVD progression and their associations in a community population. Methods: This longitudinal analysis included 756 participants who underwent both baseline and follow-up brain magnetic resonance imaging (MRI) and magnetic resonance angiography from Shunyi cohort. The follow-up duration was 5.58±0.49 years. Incident ICAS was defined as new stenosis occurring in at least one artery or increased severity of the original artery stenosis. CSVD markers included lacunes, cerebral microbleeds (CMB), and white matter hyperintensities (WMH). Results: Of the 756 participants (aged 53.7±8.0 years, 34.9% men), 8.5% had incident ICAS. Body mass index (BMI) and diabetes mellitus are independent risk factors for ICAS. Hypertension is an independent risk factor for incident lacunes and CMB, whereas WMH progression is primarily affected by BMI. Higher LDL cholesterol level independently protects against WMH progression. Baseline ICAS burden predicted an increased risk of incident lacunes (odds ratio [OR] = 2.17, 95% confidence interval [CI] = 1.10-4.29, p = 0.025) after adjusting for age, sex, follow-up time, vascular risk factors, and baseline lacunes burden. Incident ICAS was also significantly associated with incident lacunes (OR = 3.29, 95% CI = 1.61-6.72, p = 0.001). No significant correlation was identified between ICAS and CMB or WMH. Conclusions: Patients with ICAS and CSVD progression had different modifiable risk factor profiles. The disparate association between ICAS and progressions of different MRI markers of CSVD imply vital differences of their underline mechanism.

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.

Diffusion tensor free water MRI predicts progression of FLAIR white matter hyperintensities after ischemic stroke.

The progression of FLAIR white matter hyperintensities (WMHs) on MRI heralds vascular-mediated cognitive decline. Even before FLAIR WMH progression, adjacent normal appearing white matter (NAWM) already demonstrates microstructural deterioration on diffusion tensor imaging (DTI). We hypothesized that elevated DTI free water (FW) would precede FLAIR WMH progression, implicating interstitial fluid accumulation as a key pathological step in the progression of cerebral small vessel disease. Participants at least 3 months after an ischemic stroke or TIA with WMH on MRI underwent serial brain MRIs every 3 months over the subsequent year. For each participant, the WMHs were automatically segmented, serial MRIs were aligned, and a region of WMH penumbra tissue at risk was defined by dilating lesions at any time point and subtracting baseline lesions. Penumbra voxels were classified as either stable or progressing to WMH if they were segmented as new lesions and demonstrated increasing FLAIR intensity over time. Aligned DTI images included FW and FW-corrected fractional anisotropy (FATissue) and mean diffusivity (MDTissue). Logistic regression and area under the receiver-operator characteristic curve (AUC) were used to test whether baseline DTI predicted voxel-wise classification of stable penumbra or progression to WMH while covarying for clinical risk factors. In the included participants (n = 26, mean age 71 ± 9 years, 31% female), we detected a median annual voxel-wise WMH growth of 2.9 ± 2.6 ml. Each baseline DTI metric was associated with lesion progression in the penumbra, but FW had the greatest AUC of 0.732 (0.730 - 0.733) for predicting voxel-wise WMH progression pooled across participants. Baseline increased interstitial fluid, estimated as FW on DTI, predicted the progression of NAWM to WMH over the following year. These results implicate the presence of FW in the pathogenesis of cerebral small vessel disease progression.

Exosomal miR-320e through wnt2targeted inhibition of the Wnt/β-catenin pathway allevisate cerebral small vessel disease and cognitive impairment.

Exosomal miRNAs play crucial roles in many central nervous system diseases. Cerebral small vessel disease (CVSD) is a small vessel disease that is affected by various factors. This study aimed to investigate the role of exosomal miR-320e in the Wnt/β-catenin pathway stimulated by oxidative stress and assess its clinical correlation with psychiatric symptoms in patients with CVSD. To explore whether exosomal miR-320e could suppress the Wnt/β-catenin pathway and play a protective role in CVSD progression, as well as examine its potential correlation with cognitive impairment and depression in patients with CVSD. Differentially expressed exosomal miRNAs were filtered by sequencing plasma exosomes from patients with CVSD and healthy controls. Bioinformatics and dual luciferase analyses were used to confirm the binding of miR-320e to Wnt2, and the mRNA and protein levels of downstream components in the Wnt/β-catenin pathway were evaluated when overexpressed or with knockdown of miR-320e under H2O2-induced oxidative stress. In addition, Wnt2-targeting siRNA was used to confirm the role of miR-320e in the Wnt2-mediated inhibition of the Wnt/β-catenin pathway. A retrospective analysis was conducted among patients with CVSD to confirm the correlation between miR-320e expression and the severity of cognitive impairment and depression, which were quantified using the Montreal Cognitive Assessment (MoCA)/Executive Function Assessment (EFA), and the Hamilton Depression Scale (HAMD)/Beck Depression Inventory (BDI), respectively. High-throughput sequencing revealed that exosomal miR-320e was downregulated in patients with CVSD. Bioinformatics analysis and dual-luciferase reporter gene experiments showed that exosomal miR-320e inhibited the Wnt/β-catenin pathway in response to oxidative stress by targeting the 3' noncoding region of Wnt2. Uptake of exosomes carrying miR-320e into endothelial cells could also target Wnt2 and inhibit the Wnt2/β-catenin pathway. Elevated miR-320e expression may protect patients with CVSD from relatively severe cognitive impairment and depression, as it was found to have a positive correlation with the MoCA/EFA and HAMD/BDI scores. Our results suggest that exosomal miR-320e suppresses the Wnt/β-catenin pathway and may play a protective role in CVSD progression.

Excessive salt intake accelerates the progression of cerebral small vessel disease in older adults

BackgroundIt is unclear whether excessive salt intake accelerates the progression of cerebral small vessel disease (CSVD). The major objective of this study was to investigate the harmful effect of excessive salt intake on the progression of CSVD in older individuals.MethodsBetween May 2007 and November 2010, 423 community-dwelling individuals aged 60 years and older were recruited from the Shandong area, China. Salt intake was estimated using 24-hour urine collection for 7 consecutive days at baseline. Participants were classified into low, mild, moderate and high groups according to the salt intake estimation. CSVD including white matter hyperintensities (WMHs), lacunes, microbleeds and an enlarged perivascular space (EPVS) were determined using brain magnetic resonance imaging.ResultsDuring an average of five years of follow-up, the WMH volume and WMH-to-intracranial ratio were increased in the four groups. However, the increasing trends in the WMH volume and WMH-to-intracranial ratio were significantly faster in the higher salt intake groups compared with the lower salt intake groups (Padjusted < 0.001). The cumulative hazard ratios of new-incident WMHs (defined as those with Fazekas scale scores ≥ 2), new-incident lacunes, microbleeds or an EPVS, as well as composites of CSVD, were respectively 2.47, 2.50, 3.33, 2.70 and 2.89 for the mild group; 3.72, 3.74, 4.66, 4.01 and 4.49 for the moderate group; and 7.39, 5.82, 7.00, 6.40 and 6.61 for the high group, compared with the low group after adjustment for confounders (Padjusted < 0.001). The risk of new-incident WMHs, lacunes, microbleeds or an EPVS, and composites of CSVD was significantly increased with each 1-standard-deviation increment in salt intake (Padjusted < 0.001).ConclusionOur data indicates that excessive salt intake is an important and independent contributor to the progression of CVSD in older adults.

Effect of dynamic cerebral autoregulation on the association between deep medullary vein changes and cerebral small vessel disease.

Changes in the deep medullary vein (DMV) are reported to be associated with cerebral small vessel disease (CSVD). While the mechanisms of this association are unclear, dynamic cerebral autoregulation (dCA) has been speculated to participate in this association. Thus, we aimed to verify the association between DMV changes and total CSVD burden and further investigate the effect of dCA function on this correlation. In this prospective study, 95 Asian patients aged ≥18 years were included in the final assessment. DMV scores and total CSVD burden were determined using magnetic resonance imaging sequences. Transfer function analysis was performed to analyze dCA function. Generalized linear regressions were used to assess the relationship between DMV changes and total CSVD burden as well as between DMV changes and dCA function. An interaction model was utilized to assess the effect of dCA function on the association between DMV changes and total CSVD burden. Generalized linear models showed a significant positive association between DMV changes and total CSVD burden (p = 0.039) and a significant negative association between DMV changes and dCA function (p = 0.018). The interaction model demonstrated a significant positive interaction of dCA impairment on the association between DMV changes and the total CSVD burden (p = 0.02). Thus, we came to the conclusion that changes in DMV were correlated independently with both CSVD and dCA impairment and furthermore, impaired dCA function play an interaction effect on the association between DMV changes and the total CSVD burden. Our results can help improve the understanding of the complex pathogenesis and progression of CSVD, thereby facilitating early intervention and treatment development.

Women's reproductive traits and cerebral small-vessel disease: A two-sample Mendelian randomization study.

Observational studies have suggested that women's reproductive factors (age at menarche (AAM), age at first birth (AFB), age at first sexual intercourse (AFS), age at natural menopause (ANM), and pregnancy loss) may influence the risk of cerebral small-vessel disease (CSVD) although the causality remains unclear. We conducted two-sample univariable Mendelian randomization (UVMR) and multivariable MR (MVMR) to simultaneously investigate the causal relationships between five women's reproductive traits and CSVD clinical [intracerebral hemorrhage (ICH) by location or small-vessel ischemic stroke (SVS)] and subclinical measures [white matter hyperintensities (WMH), fractional anisotropy (FA), and mean diffusivity (MD)], utilizing data from large-scale genome-wide association studies of European ancestry. For both UVMR and MVMR, the inverse-variance-weighted (IVW) estimates were reported as the main results. The MR-Egger, weighted median, generalized summary-data-based MR (GSMR), and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods for UVMR and MVMR-Egger, and the MVMR-robust methods for MVMR were used as sensitivity analyses. Sex-combined instruments for AFS and AFB were used to assess the impact of sex instrumental heterogeneity. Positive control analysis was implemented to measure the efficacy of selected genetic instruments. We found no evidence to support causal associations between genetic liability for women's reproductive factors and the risk of CSVD in UVMR (all P-values > 0.05). Using MVMR, the results were consistent with the findings of UVMR after accounting for body mass index and educational attainment (all P-values > 0.05). Sensitivity analyses also provided consistent results. The putative positive causality was observed between AAM, ANM, and ovarian cancer, ensuring the efficacy of selected genetic instruments. Our findings do not convincingly support a causal effect of women's reproductive factors on CSVD. Future studies are warranted to investigate specific estrogen-related physiological changes in women, which may inform current researchers on the causal mechanisms involved in cerebral small-vessel disease progression.

Soluble TREM2, Alzheimer's Disease Pathology, and Risk for Progression of Cerebral Small Vessel Disease: A Longitudinal Study.

BackgroundUntil recently, studies on associations between neuroinflammation in vivo and cerebral small vessel disease (CSVD) are scarce. Cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a candidate biomarker of microglial activation and neuroinflammation, were found elevated in Alzheimer's disease (AD), but they have not been fully explored in CSVD.ObjectiveTo determine whether CSF sTREM2 levels are associated with the increased risk of CSVD progression.MethodsA total of 426 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included in this study. All participants underwent measurements of CSF sTREM2 and AD pathology (Aβ1-42, P-tau181P). The progression of CSVD burden and imaging markers, including cerebral microbleeds (CMBs), white matter hyperintensities and lacunes, were estimated based on neuroimaging changes. Logistic regression and moderation effect models were applied to explore associations of sTREM2 with CSVD progression and AD pathology.Results Higher CSF sTREM2 levels at baseline were associated with increased CSVD burden (OR = 1.28 [95% CI, 1.01-1.62]) and CMBs counts (OR = 1.32 [95% CI, 1.03-1.68]). Similarly, increased change rates of CSF sTREM2 might predict elevated CMBs counts (OR = 1.44 [95% CI, 1.05-1.98]). Participants with AD pathology (Aβ1-42 and P-tau181P) showed a stronger association between CSF sTREM2 and CSVD progression.ConclusionThis longitudinal study found a positive association between CSF sTREM2 and CSVD progression, suggesting that neuroinflammation might promote CSVD. Furthermore, neuroinflammation could be a shared pathogenesis of CSVD and AD at the early stage. Targeting neuroinflammation to intervene the progression of CSVD and AD warrants further investigation.

Cerebral Small Vessel Disease Progression Increases Risk of Incident Parkinsonism.

Cerebral small vessel disease (SVD) is associated with motor impairments and parkinsonian signs cross-sectionally, however, there are little longitudinal data on whether SVD increases risk of incident parkinsonism itself. We investigated the relation between baseline SVD severity as well as SVD progression, and incident parkinsonism over a follow-up of 14 years. This study included 503 participants with SVD, and without parkinsonism at baseline, from the RUN DMC prospective cohort study. Baseline inclusion was performed in 2006 and follow-up took place in 2011, 2015, and 2020, including magnetic resonance imaging (MRI) and motor assessments. Parkinsonism was diagnosed according to the UK Brain Bank criteria, and stratified into vascular parkinsonism (VaP) and idiopathic Parkinson's disease (IPD). Linear mixed-effect models were constructed to estimate individual rate changes of MRI-characteristics. Follow-up for incident parkinsonism was near-complete (99%). In total, 51 (10.2%) participants developed parkinsonism (33 VaP, 17 IPD, and 1 progressive supranuclear palsy). Patients with incident VaP had higher SVD burden compared with patients with IPD. Higher baseline white matter hyperintensities (hazard ratio [HR]=1.46 per 1-SD increase, 95% confidence interval [CI]=1.21-1.78), peak width of skeletonized mean diffusivity (HR=1.66 per 1-SD increase, 95% CI=1.34-2.05), and presence of lacunes (HR=1.84, 95% CI=0.99-3.42) were associated with increased risk of all-cause parkinsonism. Incident lacunes were associated with incident VaP (HR=4.64, 95% CI=1.32-16.32). Both baseline SVD severity and SVD progression are independently associated with long-term parkinsonism. Our findings indicate a causal role of SVD in parkinsonism. Future studies are needed to examine the underlying pathophysiology of this relation. ANN NEUROL 2023;93:1130-1141.

Periodic limb movements in sleep and cerebral small vessel disease progression: a prospective cohort study

To determine the predictive role of periodic limb movements in sleep (PLMS) in cerebral small vessel disease (cSVD) progression rate. Fifty patients with cSVD, aged 60-75 y.o., were enrolled. The study protocol included MRI assessment of white matter hyperintensities (WMH), nocturnal actigraphy and cognitive assessment. Depending on the PLMS, the main (PLM index ≥15) and the control (PLM index <15) groups were formed. The second visit was carried out in one year follow-up period, the examination consisted of brain MRI and cognitive assessment under the same protocol. ANCOVA was performed to determine if PLMS influence the degree of MRI- and neuropsychological changes. A significant effect of PLMS on the increase in the volume of WMH was revealed, both in the form of an increase in the index by more than 15 movements per hour (p=0.03), and quantitatively in the form of a connection with the index value (p=0.048). The influence of PLMS on the progression of cognitive dysfunction has not been found, however, it has been shown that the presence of PLMS is associated with lesions in the deep white matter (r=0.42, p<0.0001), and the results of neuropsychological tests are associated with lesions in the periventricular and juxtacortical WMH (p < 0.05 for each test). PLMS predict WMH progression in cSVD.

Brain morphometry and its relevance in cerebral small vessel disease

Cerebral small vessel disease (CSVD) is a heterogeneous group of disorders which affect small perforating vessels of the brain. Clinically CSVD manifest with various constellations of symptoms, like cognitive, functional, affective as well as lacunar stroke or intracerebral hemorrhage. It is responsible for 25 % of all strokes and are the second contributor to dementia after Alzheimer’s disease. The gold standard for CSVD diagnostic is neuroimaging. The main key features are white matter hyperintensity (WMH), lacunes, enlarged perivascular spaces (EPVS), brain atrophy. Brain atrophy have been recognized to play a synergistic role in both cerebrovascular and neurodegenerative disorders occurring in the aging brain. It reflects a final common pathway for pathological processes, which progress in time. CSVD progression results in gradual decrease of brain volume, which is seen as changes of ventricles size and cortical sulci span of the brain. But not much is known about its extent, correlates and consequences. The aim of the research is to investigate whether brain morphometric changes correlate with CSVD features. In this study, we included 129 CSVD patients and 165 non-CSVD controls, both with acute stroke. All participants underwent neuroimaging assessment with magnetic resonance imaging (MRI) and computed tomography (CT). We used both univariate and multivariate regression analysis, as well as correlation analysis to identify differences in brain morphometric parameters between groups. Multivariable regression analysis, adjusted for age and sex, revealed significant impact of Evans index (OR 1.09, 95 %; CI 1.01-1.16, p=0.018), the third ventricle index (OR 1.42, 95 %; CI 1.21-1.67, p&lt;0.001), Schaltenbrand and Nürnberger index (OR 1.42, 95 %; CI 1.21-1.67, p&lt;0.001), the fourth ventricle index (OR 1.31, 95 %; CI 1.13-1.51, p&lt;0,001), bicaudate index (OR 1.19, 95 %; CI 1.10-1.30, p&lt;0.001), cella media index (Schiersmann’s index) (OR 0.55, 95 %; CI 0.42-0.72, p&lt;0.001), Huckman number (OR 1.05, 95 %; CI 1.02-1.08, p&lt;0.001), width of the longitudinal cerebral fissure in the anterior part of the frontal lobes (OR 1.46, 95 %; CI 1.22-1.75, p&lt;0.001), width of the left insular cistern (OR 1.24, 95 %; CI 1.11-1.39, p&lt;0.001), width of the right insular cistern (OR 1.31, 95 %; CI 1.17-1.46, p&lt;0.001), width of the right and left insular cisterns in sum (OR 1.17, 95 %; CI 1.10-1.25, p&lt;0.001), width of the cerebral fissure in the area of the skull vault (OR 1.49, 95 %; CI 1.21-1.84, p&lt;0.001) on the CSVD presence. Width of the longitudinal cerebral fissure in the anterior part of the frontal lobes in CSVD was 6.13±1.56 mm vs 5.10±1.38 mm in non-CSVD, p&lt;0.001 and width of the right and left insular cisterns in sum in CSVD was 16.98±4.60 mm vs 13.41±4.16 mm in non-CSVD, p&lt;0.001. Width of the cerebral fissure in the area of the skull vault (parietal cortex) was also greater in CSVD patients: 5.04±1.85 mm vs 4.12±1.29 mm, p&lt;0.001. Thus, all ventricular and cortical indices were increased in the group of patients with CSVD. Our results indicate that morphometric indicators of the brain are closely related to CSVD and can be useful for predicting the consequences of a stroke and ascertaining the decline of cognitive functions.

Serum glial fibrillary acidic protein is sensitive to acute but not chronic tissue damage in cerebral small vessel disease

BackgroundSerum glial fibrillary acidic protein (sGFAP) has been proposed as a biomarker in various neurological diseases but has not yet been systematically investigated in patients with cerebral small vessel disease (CSVD). We explored whether sGFAP levels are increased in stroke patients with MRI-confirmed recent small subcortical infarcts (RSSI) and analyzed the subsequent course and determinants of sGFAP longitudinally.MethodsIn a prospectively-collected cohort of stroke patients with a single RSSI (n = 101, mean age: 61 years, 73% men), we analyzed brain MRI and sGFAP using a SIMOA assay at baseline and at 3- and 15-months post-stroke. Community-dwelling age- and sex-matched individuals (n = 51) served as controls.ResultsRSSI patients had higher baseline sGFAP levels compared to controls (median: 187.4 vs. 118.3 pg/ml, p < 0.001), with no influence of the time from stroke symptom onset to baseline blood sampling (median 5 days, range 1–13). At the 3- and 15-months follow-up, sGFAP returned to control levels. While baseline sGFAP correlated with larger infarct size (rs = 0.28, p = 0.01), neither baseline nor follow-up sGFAP levels were associated with chronic CSVD-related lesions (white matter hyperintensities, lacunes, microbleeds) after adjusting for age, sex and hypertension. Furthermore, sGFAP levels did not relate to the occurrence of new vascular brain lesions on follow-up MRI.ConclusionssGFAP is increased in patients with CSVD-related stroke and correlates with the size of the RSSI. However, sGFAP levels were not related to chronic neuroimaging features or progression of CSVD, suggesting that sGFAP is sensitive to acute but not chronic cerebrovascular tissue changes in this condition.

Associations of Life's Simple 7 With Cerebral Small Vessel Disease.

The purpose of this study is to examine the associations of Life's Simple 7 (LS7) with risks of cerebral small vessel disease (CSVD) and its magnetic resonance imaging markers. Community-dwelling residents in Lishui city in China from the cross-sectional survey of the PRECISE study (Polyvascular Evaluation for Cognitive Impairment and Vascular Events) were included in this study from 2017 to 2019. LS7 was analyzed as the total score, medical score (derived from the 3 metrics based on medical history and testing), and behavioral score (based on 4 metrics based on behaviors), and categorized as poor, intermediate, or ideal. A CSVD score or a modified CSVD score was derived from 4 magnetic resonance imaging markers (lacunes, microbleeds, perivascular spaces, and white matter hyperintensity) at baseline. Binary logistic regression or ordinal logistic regression model was used to estimate the relationship of LS7 scores with CSVD and magnetic resonance imaging markers. A total of 3061 participants were included in this study. Compared with poor total LS7 score, ideal LS7 total score was associated with reduced adjusted odds of higher CSVD score (common odds ratio [cOR], 0.73 [95% CI, 0.58-0.90]) and higher modified CSVD score (cOR, 0.78 [95% CI, 0.64-0.95]). Compared with poor LS7 medical score, ideal LS7 medical score was associated with reduced adjusted odds of higher CSVD score (cOR, 0.65 [95% CI, 0.53-0.80]) and higher modified CSVD score (cOR, 0.67 [95% CI, 0.56-0.81]). Higher total LS7 score and LS7 medical score were associated with a lower risk of white matter hyperintensities and lacunes. Higher LS7 behavioral score was associated with lower risk of lacunes. Ideal LS7 score, indicating excellent cardiovascular health, was associated with lower total CSVD burden. Optimizing the risk factors captured by LS7 may reduce the progression of CSVD.

Excessive Visit-to-Visit Small and Dense Low-Density Lipoproteins Elevate Cerebral Small Vessel Disease Progression Risk in the Elderly.

ObjectiveSmall and dense low-density lipoprotein (sdLDL) elevation may be among the most sensitive early biomarkers for nascent cardiovascular disease. This study, therefore, investigated the association between visit-to-visit changes in sdLDL and cerebral small vessel disease (CSVD) progression in older individuals, and the influence of Apolipoprotein E (APOE) genotype on this association.MethodsBetween April 2007 and July 2009, 1,143 participants ≥60 years old were recruited from the Shandong region of China, and sdLDL was measured at baseline and at each follow-up visit. White matter hyperintensities (WMHs), lacunes, microbleeds, and enlarged perivascular spaces (EPVSs) were assessed by magnetic resonance imaging. The APOE genotype was determined and participants were stratified as ε4-positive or ε4-negative.ResultsDuring an average follow-up of 86.0 months, 225 participants (19.7%) developed WMH progression, 193 (16.9%) lacune progression, 170 (14.9%) microbleed progression, and 185 (16.2%) EPVS progression. Compared with patients in the first (lowest) tertile of visit-to-visit mean sdLDL, those in the second and third tertiles demonstrated significantly greater risks of WMH progression (53.5 and 105.3% higher), lacune progression (53.3 and 60.8%), microbleed progression (47.2 and 127.6%), and EPVS progression (54.0 and 135.0%) after adjustment for confounders (all adjusted P values for trends <0.001). Compared with patients in the first tertile of visit-to-visit sdLDL SD, those in the second and third tertiles also demonstrated significantly greater risks of WMH progression (49.9% and 143.6%), lacune progression (75.3 and 178.0%), microbleed progression (12.7 and 64.7%), and EPVS progression (41.7 and 114.6%) after adjustment (all P < 0.001). There were significant and positive visit-to-visit mean sdLDL × visit-to-visit sdLDL SD, visit-to-visit mean sdLD×ε4-positive, visit-to-visit sdLDL SD×ε4-positive, and visit-to-visit mean sdLDL×visit-to-visit sdLDL SD×ε4-positive interactions influencing CSVD progression after confounder adjustment (all P < 0.05).ConclusionLarge and variable visit-to-visit changes in sdLDL are independent predictors of aggressive CSVD progression, and this association is strongly influenced by APOE ε4 allele genotype.

Relation Between Sex, Menopause, and White Matter Hyperintensities: The Rhineland Study.

Mounting evidence implies that there are sex differences in white matter hyperintensity (WMH) burden in older people. Questions remain regarding possible differences in WMH burden between men and women of younger age, sex-specific age trajectories and effects of (un)controlled hypertension, and the effect of menopause on WMH. Therefore, our aim was to investigate these sex differences and age dependencies in WMH load across the adult life span and to examine the effect of menopause. This cross-sectional analysis was based on participants of the population-based Rhineland Study (30-95 years) who underwent brain MRI. We automatically quantified WMH using T1-weighted, T2-weighted, and fluid-attenuated inversion recovery images. Menopausal status was self-reported. We examined associations of sex and menopause with WMH load (logit-transformed and z-standardized) using linear regression models while adjusting for age, age-squared, and vascular risk factors. We checked for an age × sex and (un)controlled hypertension × sex interaction and stratified for menopausal status comparing men with premenopausal women (persons aged 59 years or younger), men with postmenopausal women (persons aged 45 years or older), and premenopausal with postmenopausal women (age range 45-59 years). Of 3,410 participants with a mean age of 54.3 years (SD = 13.7), 1,973 (57.9%) were women, of which 1,167 (59.1%) were postmenopausal. We found that the increase in WMH load accelerates with age and in a sex-dependent way. Premenopausal women and men of similar age did not differ in WMH burden. WMH burden was higher and accelerated faster in postmenopausal women compared with men of similar age. In addition, we observed changes related to menopause, in that postmenopausal women had more WMH than premenopausal women of similar age. Women with uncontrolled hypertension had a higher WMH burden compared with men, which was unrelated to menopausal status. After menopause, women displayed a higher burden of WMH than contemporary premenopausal women and men and an accelerated increase in WMH. Sex-specific effects of uncontrolled hypertension on WMH were not related to menopause. Further studies are warranted to investigate menopause-related physiologic changes that may inform on causal mechanisms involved in cerebral small vessel disease progression.

The Underlying Role of the Glymphatic System and Meningeal Lymphatic Vessels in Cerebral Small Vessel Disease.

There is a growing prevalence of vascular cognitive impairment (VCI) worldwide, and most research has suggested that cerebral small vessel disease (CSVD) is the main contributor to VCI. Several potential physiopathologic mechanisms have been proven to be involved in the process of CSVD, such as blood-brain barrier damage, small vessels stiffening, venous collagenosis, cerebral blood flow reduction, white matter rarefaction, chronic ischaemia, neuroinflammation, myelin damage, and subsequent neurodegeneration. However, there still is a limited overall understanding of the sequence and the relative importance of these mechanisms. The glymphatic system (GS) and meningeal lymphatic vessels (mLVs) are the analogs of the lymphatic system in the central nervous system (CNS). As such, these systems play critical roles in regulating cerebrospinal fluid (CSF) and interstitial fluid (ISF) transport, waste clearance, and, potentially, neuroinflammation. Accumulating evidence has suggested that the glymphatic and meningeal lymphatic vessels played vital roles in animal models of CSVD and patients with CSVD. Given the complexity of CSVD, it was significant to understand the underlying interaction between glymphatic and meningeal lymphatic transport with CSVD. Here, we provide a novel framework based on new advances in main four aspects, including vascular risk factors, potential mechanisms, clinical subtypes, and cognition, which aims to explain how the glymphatic system and meningeal lymphatic vessels contribute to the progression of CSVD and proposes a comprehensive insight into the novel therapeutic strategy of CSVD.

Effect of Antihypertensives by Class on Cerebral Small Vessel Disease: A Post Hoc Analysis of SPRINT-MIND.

Treatment of uncontrolled arterial hypertension reduces the risk of cerebral small vessel disease (CSVD) progression, although it is unclear whether this reduction occurs due to blood pressure control or class-specific pleiotropic effects, such as improved beat-to-beat arterial pressure variability with calcium channel blockers. The goal of this study was to investigate the influence of antihypertensive medication class, particularly with calcium channel blocker, on accumulation of white matter hyperintensities (WMH), a radiographic marker of CSVD, within a cohort with well-controlled hypertension. We completed an observational cohort analysis of the SPRINT-MIND trial (Systolic Blood Pressure Trial Memory and Cognition in Decreased Hypertension), a large randomized controlled trial of participants who completed a baseline and 4-year follow-up brain magnetic resonance image with volumetric WMH data. Antihypertensive medication data were recorded at follow-up visits between the magnetic resonance images. A percentage of follow-up time participants were prescribed each of the 11 classes of antihypertensive was then derived. Progression of CSVD was calculated as the difference in WMH volume between 2 scans and, to address skew, dichotomized into a top tertile of the distribution compared with the remaining. Among 448 individuals, vascular risk profiles were similar across WMH progression subgroups except age (70.1±7.9 versus 65.7±7.3 years; P<0.001) and systolic blood pressure (128.3±11.0 versus 126.2±9.4 mm Hg; P=0.039). Seventy-two (48.3%) of the top tertile cohort and 177 (59.2%) of the remaining cohort were in the intensive blood pressure arm. Those within the top tertile of progression had a mean WMH progression of 4.7±4.3 mL compared with 0.13±1.0 mL (P<0.001). Use of angiotensin-converting enzyme inhibitors (odds ratio, 0.36 [95% CI, 0.16-0.79]; P=0.011) and dihydropyridine calcium channel blockers (odds ratio, 0.39 [95% CI, 0.19-0.80]; P=0.011) was associated with less WMH progression, although dihydropyridine calcium channel blockers lost significance when WMH was treated as a continuous variable. Among participants of SPRINT-MIND trial, angiotensin-converting enzyme inhibitor was most consistently associated with less WMH progression independent of blood pressure control and age.

Cerebral small vessel disease and blood pressure variability

Annotation. Cerebral small vessel disease (CSVD) contributes up to about 25% of strokes and is the second most common cause of dementia and cognitive decline. Hypertensive arteriolosclerosis is the leading cause of CSVD, hence understanding its relationships with blood pressure changes, including blood pressure variability (BPV), is crucial. The aim of the research was to find out relationships between blood pressure parameters and such MRI-features of CSVD, as white matter hyperintensity (WMH), lacunes, perivascular spaces (PVS), brain atrophy in acute-stroke patients during hospitalization time. 160 participants enrolled in our study (56,3% were male, average age – 61,05±10,95, hospitalization time – 10,46 days). Statistical analysis was performed in the GNU Project software packages (2020). GNU PSPP (Version 1.4.1) [Computer Software]. Free Software Foundation. Boston, MA and The jamovi project (2021). Jamovi (Version 2.0) [Computer Software]. MRI was assessed according to “STRIVE” guidelines for cerebral vessel disease. We measured such BP parameters as mean systolic BP, mean diastolic BP, standard deviation and coefficient of variability for both systolic and diastolic BP. A moderate positive correlation was found between systolic BP variability and WMH severity (r=0.3, p=0.03). There was also a tendency for association between systolic BP variability and enlarged PVS at the basal ganglia level, but it was not significant (p=0.09). There was also a significant relationship between mean systolic BP and WMH severity (r=0.3, p&lt;0.005), mean systolic BP and enlarged PVS at the basal ganglia level (r=0.3, p&lt;0.01), mean systolic BP and total CSVD burden (r=0.3, p&lt;0.005). Systolic BP and its variability are associated with WMH and enlarged PVS, which may provide valuable diagnostic and prognostic data about subtypes of CSVD and the consequences of vascular damage to the brain. Systolic BP variability targeting might be beneficial for prevention of CSVD progression.