Automated diffusion-weighted image analysis along the perivascular space index reveals glymphatic dysfunction in association with brain parenchymal lesions.

Brain glymphatic dysfunction is critical in neurodegenerative processes. While animal studies have provided substantial insights, understandings in humans remains limited. Recent attention has focused on the non-invasive evaluation of brain glymphatic function. However, its association with brain parenchymal lesions in large-scale population remains under-investigated. In this cross-sectional analysis of 1030 participants (57.14 ± 9.34 years, 37.18% males) from the Shunyi cohort, we developed an automated pipeline to calculate diffusion-weighted image analysis along the perivascular space (ALPS), with a lower ALPS value indicating worse glymphatic function. The automated ALPS showed high consistency with the manual calculation of this index (ICC = 0.81, 95% CI: 0.662-0.898). We found that those with older age and male sex had lower automated ALPS values (ß = -0.051, SE = 0.004, p < .001, per 10 years, and ß = -0.036, SE = 0.008, p < .001, respectively). White matter hyperintensity (ß = -2.458, SE = 0.175, p < .001) and presence of lacunes (OR = 0.004, 95% CI < 0.002-0.016, p < .001) were significantly correlated with decreased ALPS. The brain parenchymal and hippocampal fractions were significantly associated with decreased ALPS (ß = 0.067, SE = 0.007, p < .001 and ß = 0.040, SE = 0.014, p = .006, respectively) independent of white matter hyperintensity. Our research implies that the automated ALPS index is potentially a valuable imaging marker for the glymphatic system, deepening our understanding of glymphatic dysfunction.

Dynamic Mechanism of Cerebral Venous Disruption: Longitudinal Evidence From a Community-Based Cohort.

BACKGROUND: This study aims to investigate the temporal and spatial patterns of structural brain injury related to deep medullary veins (DMVs) damage. METHODS AND RESULTS: This is a longitudinal analysis of the population-based Shunyi cohort study. Baseline DMVs numbers were identified on susceptibility-weighted imaging. We assessed vertex-wise cortex maps and diffusion maps at both baseline and follow-up using FSL software and the longitudinal FreeSurfer analysis suite. We performed statistical analysis of global measurements and voxel/vertex-wise analysis to explore the relationship between DMVs number and brain structural measurements. A total of 977 participants were included in the baseline, of whom 544 completed the follow-up magnetic resonance imaging (age 54.97±7.83 years, 32% men, mean interval 5.56±0.47 years). A lower number of DMVs was associated with a faster disruption of white matter microstructural integrity, presented by increased mean diffusivity and radial diffusion (ß=0.0001 and SE=0.0001 for both, P=0.04 and 0.03, respectively), in extensive deep white matter (threshold-free cluster enhancement P<0.05, adjusted for age and sex). Of particular interest, we found a bidirectional trend association between DMVs number and change in brain volumes. Specifically, participants with mild DMVs disruption showed greater cortical enlargement, whereas those with severe disruption exhibited more significant brain atrophy, primarily involving clusters in the frontal and parietal lobes (multiple comparison corrected P<0.05, adjusted for age, sex, and total intracranial volume). CONCLUSIONS: Our findings posed the dynamic pattern of brain parenchymal lesions related to DMVs injury, shedding light on the interactions and chronological roles of various pathological mechanisms.

Association of Rare NOTCH3 Variants With Prevalent and Incident Stroke and Dementia in the General Population.

BACKGROUND: It is uncertain whether rare NOTCH3 variants are associated with stroke and dementia in the general population and whether they lead to alterations in cognitive function. This study aims to determine the associations of rare NOTCH3 variants with prevalent and incident stroke and dementia, as well as cognitive function changes. METHODS AND RESULTS: In the prospective community-based Shunyi Study, a total of 1007 participants were included in the baseline analysis. For the follow-up analysis, 1007 participants were included in the stroke analysis, and 870 participants in the dementia analysis. All participants underwent baseline brain magnetic resonance imaging, carotid ultrasound, and whole exome sequencing. Rare NOTCH3 variants were defined as variants with minor allele frequency <1%. A total of 137 rare NOTCH3 carriers were enrolled in the baseline study. At baseline, rare NOTCH3 variant carriers had higher rates of stroke (8.8% versus 5.6%) and dementia (2.9% versus 0.8%) compared with noncarriers. After adjustment for associated risk factors, the epidermal growth factor-like repeats (EGFr)-involving rare NOTCH3 variants were associated with a higher risk of prevalent stroke (odds ratio [OR], 2.697 [95% CI, 1.266-5.745]; P=0.040) and dementia (OR, 8.498 [95% CI, 1.727-41.812]; P=0.032). After 5 years of follow-up, we did not find that the rare NOTCH3 variants increased the risk of incident stroke and dementia. There was no statistical difference in the change in longitudinal cognitive scale scores. CONCLUSIONS: Rare NOTCH3 EGFr-involving variants are genetic risk factors for stroke and dementia in the general Chinese population.

Pattern of Brain Parenchymal Damage Related to Cerebral Small Vessel Disease in Carriers of Rare NOTCH3 Variants.

BACKGROUND AND OBJECTIVES: Previous studies reported that carriers of rare NOTCH3 variants comprised more than 10% of the general population and are susceptible to a heavy overall burden of cerebral small vessel disease while the injury patterns remain uncovered. This study aimed to investigate the imaging features in relation to rare NOTCH3 variants and the interaction between cortical atrophy and white matter lesions from a longitudinal view, with respect to spatial and dynamic patterns. METHODS: As part of a community-based cohort, we included participants with complete whole-exome sequencing and brain MRI in the baseline analysis. All participants were invited for a 5-year follow-up MRI, and those who did not complete the follow-up were excluded from the longitudinal analysis. NOTCH3 variants with minor allele frequency <1% in all 4 public population databases were defined as rare variants. We used general linear models to compare the volume of white matter hyperintensity (WMH) volume and brain parenchymal fraction between rare NOTCH3 variant carriers and noncarriers. In addition, we compared the WMH probability map and vertex-wise cortex maps at a voxel/vertex-wise level. RESULTS: A total of 1,054 participants were included in baseline analysis (13.56% carried rare NOTCH3 variants), among whom 661 had a follow-up brain MRI (13.76% carried rare NOTCH3 variants). Rare NOTCH3 variant carriers had a heavier white matter hyperintensity burden (1.65 vs 0.85 mL, p = 0.025) and had more extensive WMH distributed in the periventricular areas. We also found that rare NOTCH3 variant carriers were susceptible to worse cortical atrophy (ß = -0.004, SE = 0.002, p = 0.057, adjusted for age and sex). Cortical atrophy of multiple regions in the frontal and parietal lobes was related to white matter hyperintensity progression. DISCUSSION: Individuals with rare NOTCH3 variants have a distinct pattern of brain parenchymal damage related to CSVD. Our findings uncover the important genetic predisposition in age-related cerebral small vessel disease in the general population.

White matter and gray matter changes related to cognition in community populations.

Objective: Further studies are needed to improve the understanding of the pathological process underlying cognitive impairments. The purpose of this study is to investigate the global and topographic changes of white matter integrity and cortical structure related to cognitive impairments in a community-based population. Methods: A cross-sectional analysis was performed based on 995 subjects (aged 56.8 ± 9.1 years, 34.8% males) from the Shunyi study, a community-dwelling cohort. Cognitive status was accessed by a series of neurocognitive tests including Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), category Verbal Fluency Test (VFT), Digit Span Test (DST), and Trail Making Tests A and B (TMT-A and TMT-B). Structural and diffusional MRI data were acquired. White matter integrity was assessed using fractional anisotropy (FA), mean diffusivity (MD), and peak width of skeletonized mean diffusivity (PSMD). Cortical surface area, thickness, and volume were measured using Freesurfer. Probabilistic tractography was further conducted to track the white matter fibers connecting to the cortical regions related to cognition. General linear models were used to investigate the association between brain structure and cognition. Results: Global mean FA and MD were significantly associated with performances in VFT (FA, ß 0.119, p < 0.001; MD, ß -0.128, p < 0.001). Global cortical surface area, thickness, and volume were not related to cognitive scores. In tract-based spatial statistics analysis, disruptive white matter integrity was related to cognition impairment, mainly in visuomotor processing speed, semantic memory, and executive function (TMT-A and VFT), rather than verbal short-term memory and working memory (DST). In the whole brain vertex-wise analysis, surface area in the left orbitofrontal cortex, right posterior-dorsal part of the cingulate gyrus, and left central sulcus were positively associated with MMSE and MoCA scores, and the association were independent of the connecting white matter tract. Conclusion: Disrupted white matter integrity and regional cortical surface area were related to cognition in community-dwelling populations. The associations of cortical surface area and cognition were independent of the connecting white matter tract.

Association between Anatomical Variations of the Circle of Willis and Covert Vascular Brain Injury in the General Population.

BACKGROUND AND PURPOSE: The circle of Willis (COW) is a circulatory anastomosis located at the base of the brain. Little is known about the association between covert vascular brain injury and COW configurations in the general population. We explored this relationship in a community-based Chinese sample. METHODS: A total of 1,055 patients (mean age, 54.8 ± 8.9 years; 36.0% men) without intracranial arterial stenosis were included in the analysis. Magnetic resonance imaging was performed to evaluate the presence of imaging markers of covert vascular brain injury, including white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), enlarged perivascular spaces, and brain atrophy. Magnetic resonance angiography was used to classify the COW configurations according to the completeness, symmetry, and presence of the fetal posterior cerebral artery (FTP). The association between vascular lesions and variations in COW was analyzed. RESULTS: Among the 1,055 patients, 104 (9.9%) had a complete COW. Completeness correlated with age (p = 0.001). Incomplete COW was positively associated with WMH severity (OR = 2.071; 95% CI, 1.004-4.270) and CMB presence (OR = 1.542; 95% CI, 1.012-2.348), independent of age and sex. The presence of FTP was associated with lacunes (OR = 1.878; 95% CI, 1.069-3.298), more severe WMHs (OR = 1.739; 95% CI, 1.064-2.842), and less severe enlarged perivascular spaces (OR = 0.562; 95% CI, 0.346-0.915). CONCLUSIONS: COW configuration was significantly related to various covert vascular brain injuries.

Regional Disruption of White Matter Integrity and Network Connectivity Are Related to Cognition.

BACKGROUND: Cognitive impairment is common in the elderly population. Exploring patterns of white matter damage at the microstructural level would give important indications for the underlying mechanisms. OBJECTIVE: To investigate the spatial patterns of white matter microstructure and structural network alternations in relation to different cognition domainsMethods:Participants from the community-based Shunyi Study were included to investigate the association between white matter measurements and cognition cross-sectionally, via both global and local analysis. Cognitive functions were assessed using digit span, trail making test (TMT)-A/B, Fuld object Memory, and 12-Word Philadelphia Verbal Learning Test (PVLT). White matter measurements including fractional anisotropy (FA), mean diffusivity (MD), and structural network parameters were calculated based on diffusion tensor imaging. RESULTS: Of the 943 participants included, the mean (SD) age was 55.8 (9.1) years, and the mean (SD) education level was 6.7 (3.2) years. We found the whole set of cognitive measurements was related to diffused white matter microstructural integrity damage and lower global efficiency. Poor executive functions (TMTA/B complete time) were related to lower FA and higher MD predominantly on the anterior white matter skeleton, while verbal memory loss (PVLT test scores) was related to sub-network dysconnectivity in the midline and the right temporal lobe. CONCLUSION: The anterior brain is dominantly involved in executive dysfunction, while midline and right temporal brain disconnection are more prominent in verbal memory loss. Global and regional disruption of white matter integrity and network connectivity is the anatomical basis of the cognitive impairment in the aging population.

Investigating the Genetic Characteristics of Hippocampal Volume and Plasma ß-Amyloid in a Chinese Community-Dwelling Population.

BACKGROUND AND OBJECTIVES: The genetic characteristics and correlations of hippocampal volume and plasm Aß, probable endophenotypes for dementia, remain to be explored in Chinese community cohort. Using whole-exome sequencing and SNP-array genotyping, we sought to identify rare and common variants and genes influencing these two endophenotypes, and calculate their heritability and genetic correlation. METHODS: Association analyses with both whole-exome sequencing and SNP-array genotyping data were performed for hippocampal volumes and plasm Aß with mixed-effect linear regression model adjusted for sex, age, and total intracranial volume or APOE ε4 while considering familial relatedness. We also performed gene-level analysis for common and gene-burden analysis for rare variants. Heritability and genetic correlation were further examined. RESULTS: Totally 1,261 participants from a Chinese community cohort were included and we identified one gene, PTPRT, for hippocampal volume, with the top significant SNPs by whole genome-wide association study. rs6030076 (P=5.48×10-8, ß=-0.092, SE=0.017) from whole-exome sequencing and rs6030088 (P=8.24×10-9, ß=-105.22 SE=18.09) from SNP-array data, both located in this gene. Gene-burden analysis based on rare mutations detected 6 genes to be significantly associated with Aß. The SNP-based heritability was 0.43±0.13 for hippocampal volume and 0.2-0.3 for plasma Aß. The SNP-based genetic correlation between hippocampal volume and plasma Aß were negative. DISCUSSION: In this study, we identified several SNPs and one gene, PTPRT, which were not reported in previous GWASs, associated with hippocampal volume. Besides, the heritability and the genetic correlation gave an overview of hippocampal volume and plasma Aß. Our findings provide insights into the mechanisms behind the individual variances in these endophenotypes.

Different Types of Circulatory Inflammatory Biomarkers Associated with Cerebral Arterial Atherosclerosis and Dolichoectasia.

BACKGROUND: Although inflammation is found to be related to arteriopathy pathogenesis, it is yet to be determined the distinct correlations of specific inflammatory biomarker types contributing to different cerebral large vessel diseases. We aimed to investigate the association between multiple inflammatory biomarkers and cerebral atherosclerosis and dolichoectasia in a community-based sample. METHODS: A total of 960 participants of the Shunyi study were included. A panel of 14 circulatory inflammatory biomarkers was assessed and then grouped in three sets as systemic, endothelial-related, and media-related inflammation, based on underlying different inflammatory cascades. Intracranial atherosclerotic stenosis (ICAS), dolichoectasia estimated by magnetic resonance angiography, and carotid plaques estimated by ultrasound were also performed. RESULTS: Endothelial-related inflammatory group was related to the presence of ICAS (R2 = 0.215, p = 0.024) and carotid plaques (R2 = 0.342, p = 0.013). Backward stepwise elimination showed that E-selectin was prominent (ß = 0.67, 95% CI: 0.54-0.85, p = 0.001; ß = 0.79, 95% CI: 0.68-0.93, p = 0.005). Systemic inflammatory group was associated with an increased basilar artery diameter (R2 = 0.051, p < 0.001), and backward stepwise elimination showed that IL-6 was prominent (ß = 0.07, 95% CI: 0.03-0.11, p < 0.001). CONCLUSION: Different types of inflammatory biomarkers were associated with atherosclerosis and dolichoectasia, respectively, implying dissimilar inflammatory processes. Further confirming of their distinct anti-inflammatory roles as potential therapeutic targets is warrant.

Inflammatory biomarkers and cerebral small vessel disease: a community-based cohort study.

BACKGROUND AND PURPOSE: Although inflammation has been proposed to be a candidate risk factor for cerebral small vessel disease (CSVD), previous findings remain largely inconclusive and vary according to disease status and study designs. The present study aimed to investigate possible associations between inflammatory biomarkers and MRI markers of CSVD. METHODS: A group of 15 serum inflammatory biomarkers representing a variety of those putatively involved in the inflammatory cascade was grouped and assessed in a cross-sectional study involving 960 stroke-free subjects. The biomarker panel was grouped as follows: systemic inflammation (high-sensitivity C reactive protein (hsCRP), interleukin 6 and tumour necrosis factor α), endothelial-related inflammation (E-selectin, P-selectin, intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), CD40 ligand, lipoprotein-associated phospholipase A2, chitinase-3-like-1 protein and total homocysteine (tHCY)) and media-related inflammation (matrix metalloproteinases 2, 3 and 9, and osteopontin). The association(s) between different inflammatory groups and white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs), enlarged perivascular space (PVS) and the number of deep medullary veins (DMVs) were investigated. RESULTS: High levels of serum endothelial-related inflammatory biomarkers were associated with both increased WMH volume (R2=0.435, p=0.015) and the presence of lacunes (R2=0.254, p=0.027). Backward stepwise elimination of individual inflammatory biomarkers for endothelial-related biomarkers revealed that VCAM-1 was significant for WMH (ß=0.063, p=0.005) and tHCY was significant for lacunes (ß=0.069, p<0.001). There was no association between any group of inflammatory biomarkers and CMBs or PVS. Systemic inflammatory biomarkers were associated with fewer DMVs (R2=0.032, p=0.006), and backward stepwise elimination of individual systemic-related inflammatory biomarkers revealed that hsCRP (ß=-0.162, p=0.007) was significant. CONCLUSION: WMH and lacunes were associated with endothelial-related inflammatory biomarkers, and fewer DMVs were associated with systemic inflammation, thus suggesting different underlying inflammatory processes and mechanisms.

Deep medullary veins are associated with widespread brain structural abnormalities.

Our aim is to investigate the association of cerebral deep medullary veins (DMVs) with white matter microstructural integrity and regional brain atrophy in MRI. In a community-based cohort of 979 participants (mean age 55.4 years), DMVs were identified on susceptibility-weighted imaging. Brain structural measurements including gray matter and hippocampus volumes, as well as diffusion tensor metrics, were evaluated. The mean (SD)number of DMVs was 19.0 (1.7). A fewer number of DMVs was related to lower fractional anisotropy and higher mean diffusivity in multiple voxels on the white matter skeleton (threshold-free cluster enhancement corrected p < 0.05, adjusted for age and sex). Also, fewer DMVs were significantly related to a lower gray matter fraction and a hippocampal fraction (0.10 and 0.11 per DMV, respectively; SE, 0.03 for both; p < 0.001 for both). A significant correlation between DMVs' reduction and cortical atrophy was observed in the bilateral occipital lobes, temporal lobes, hippocampus, and frontal lobes (p < 0.001, adjusted for age, sex, and total intracranial volume). Our results provided evidence that cerebral small venules disease play a role in brain parenchymal lesions and neurodegenerative processes.

Rare NOTCH3 Variants in a Chinese Population-Based Cohort and Its Relationship With Cerebral Small Vessel Disease.

BACKGROUND AND PURPOSE: Researches on rare variants of NOTCH3 in the general Chinese population are lacking. This study aims to describe the spectrum of rare NOTCH3 variants by whole-exome sequencing in a Chinese community-based cohort and to investigate the association between rare NOTCH3 variants and age-related cerebral small vessel disease. METHODS: The cross-sectional study comprised 1065 participants who underwent whole-exome sequencing and brain magnetic resonance imaging. NOTCH3 variants with minor allele frequency<1% in all 4 public population databases (1000 Genomes, ESP6500siv2_ALL, GnomAD_ALL, and GnomAD_EAS) were defined as rare variants. Multivariable linear and logistic regressions were used to investigate the associations between rare NOTCH3 variants and volume of white matter hyperintensities and cerebral small vessel disease burden. Clinical and imaging characteristics of rare NOTCH3 variant carriers were summarized. RESULTS: Sixty-five rare NOTCH3 variants were identified in 147 of 1065 (13.8%) participants, including 57 missense single nucleotide polymorphisms (SNPs), 5 SNPs in splice branching sites, and 3 frameshift deletions. A significantly higher volume of white matter hyperintensities and heavier burden of cerebral small vessel disease was found in carriers of rare NOTCH3 EGFr (epidermal growth factor-like repeats)-involving variants, but not in carriers of EGFr-sparing variants. The carrying rate of rare EGFr-involving NOTCH3 variants in participants with dementia or stroke was significantly higher than those without dementia or stroke (12.4% versus 6.6%, P=0.041). Magnetic resonance imaging signs suggestive of CADASIL were found in 3.4% (5/145) rare EGFr cysteine-sparing NOTCH3 variant carriers but not in 2 cysteine-altering NOTCH3 variant carriers. CONCLUSIONS: Carriers of rare NOTCH3 variants involving the EGFr domain may be genetically predisposed to age-related cerebral small vessel disease in the general Chinese population.

Right ventricular systolic function is associated with health-related quality of life: a cross-sectional study in community-dwelling populations.

BACKGROUND: Considerable evidence has been presented that heart and health-related quality of life are directly linked in patients with various diseases. This exploratory study investigated whether cardiac structure and function were associated with health-related quality of life in the general population. METHODS: This cross-sectional study was performed in five villages of Shunyi, a suburban district of Beijing, from June 2013 to April 2016. All inhabitants aged 35 years or older living in five villages of Shunyi were invited to participate. Exclusion criteria were individuals who declined participation, who had incomplete Health-related quality of life (HRQoL) data, and who had suboptimal echocardiograms. HRQoL was evaluated by the Mandarin version of SF-36. The association between the echocardiography-derived cardiac structure and function and each domain of SF-36 was analyzed by the multivariate linear regression analysis after adjusted for conventional risk factors affecting HRQoL. RESULTS: The baseline data of 990 individuals were analyzed. The median age of the participants was 57 (50-63) years, and 367 (37.1%) were male, the average physical and mental component summary scores were 89.3 (79.8-94.3) and 90 (83.5-95) respectively. Tricuspid annular plane systolic excursion, an echocardiography-derived right ventricular parameter, was associated with all the subscales and summarized scores of SF-36 (all P<0.05). The independent association between tricuspid annular plane systolic excursion and physical/mental component summary scores remained after adjusting for age, gender, body mass index, education level, annual personal income, smoking and drinking status, and comorbidities (ß=0.65, 95% confidence interval 0.30-1.01, P<0.01 and ß=0.49, 95% confidence interval 0.23-0.76, P<0.01 for physical and mental component summary scores respectively). Compared with the participants with tricuspid annular plane systolic excursion ≥21 mm, the participants with tricuspid annular plane systolic excursion <21 mm had lower adjusted scores of physical and mental component summary scores (81.8 vs. 84.5, P=0.015, and 85.5 vs. 88.1, P<0.01 for physical and mental component summary scores respectively). CONCLUSIONS: In this population-based study, right ventricular systolic function assessed by tricuspid annular plane systolic excursion was independently associated with health-related quality of life assessed by SF-36.

Proteomic insights into the photosynthetic divergence between bark and leaf chloroplasts in Salix matsudana.

Bark chloroplasts play important roles in carbon balancing by recycling internal stem CO2 into assimilated carbon. The photosynthetic response of bark chloroplasts to interior stem environments has been studied recently in woody plants. However, the molecular regulatory mechanisms underlying specific characteristics of bark photosynthesis remain unclear. To address this knowledge gap, differences in the structure, photosynthetic activity and protein expression profiles between bark and leaf chloroplasts were investigated in Salix matsudana in this study. Bark chloroplasts exhibited broader and lower grana stacks and higher levels of starch relative to leaf chloroplasts. Concomitantly, decreased oxygen evolution rates and decreased saturated radiation point were observed in bark chloroplasts. Furthermore, a total of 293 differentially expressed proteins (DEPs) were identified in bark and leaf chloroplast profile comparisons. These DEPs were significantly enriched in photosynthesis-related biological processes or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with photosynthesis. All 116 DEPs within the KEGG pathways associated with photosynthesis light reactions were downregulated in bark chloroplasts, including key proteins responsible for chlorophyll synthesis, light energy harvesting, nonphotochemical quenching, linear electron transport and photophosphorylation. Interestingly, seven upregulated proteins involved in dark reactions were identified in bark chloroplasts that comprised two kinds of malic enzymes typical of C4-type photosynthesis. These results provide comprehensive proteomic evidence to understand the low photochemical capability of bark chloroplasts and suggest that bark chloroplasts might fix CO2 derived from malate decarboxylation.

Metabolic syndrome, intracranial arterial stenosis and cerebral small vessel disease in community-dwelling populations.

BACKGROUND AND PURPOSE: This study aimed to investigate the association of metabolic syndrome (MetS) with both intracranial atherosclerotic stenosis (ICAS) and imaging markers of cerebral small vessel disease (CSVD) in a community-based sample. METHODS: This study included 943 participants (aged 55.6±9.2 years, 36.1% male) from the community-based Shunyi cohort study. MetS was defined according to the joint interim criteria and quantified by the MetS severity Z-score. ICAS was evaluated by brain magnetic resonance angiography. The MRI markers of CSVD, including white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces (EPVS), were assessed. Multiple regression models were used to investigate the association of MetS severity Z-score with ICAS and these CSVD markers. RESULTS: We found that risk of ICAS (OR=1.75, 95% CI 1.39 to 2.21, p<0.001) increased consistently with MetS severity. MetS severity was significantly associated with higher risks of WMH volume (ß=0.11, 95% CI 0.01 to 0.20, p=0.02) and lacunes (OR=1.28, 95% CI 1.03 to 1.59, p=0.03) but not the presence of CMBs (OR=0.93, 95% CI 0.74 to 1.16, p=0.51) and PVS severity (EPVS in basal ganglia: OR=0.96, 95% CI 0.84 to 1.09, p=0.51 and EPVS in white matter: OR=1.09, 95% CI 0.96 to 1.23, p=0.21). CONCLUSIONS: Our findings suggest that WMH and lacunes share risk factors with atherosclerosis of the cerebral artery, whereas the impact of glucose and lipid metabolic disorder to CMB or EPVS might be weak.

Arterial Stiffness Is Associated with White Matter Disruption and Cognitive Impairment: A Community-Based Cohort Study.

BACKGROUND: Mechanisms through which arterial stiffness impacts cognitive function are crucial for devising better strategies to prevent cognitive decline. OBJECTIVE: To examine the associations of arterial stiffness with white matter integrity and cognition in community dwellings, and to investigate whether white matter injury was the intermediate of the associations between arterial stiffness and cognition. METHODS: This study was a cross-sectional analysis on 952 subjects (aged 55.5±9.1 years) who underwent diffusion tensor imaging and measurement of brachial-ankle pulse wave velocity (baPWV). Both linear regression and tract-based spatial statistics were used to investigate the association between baPWV and white matter integrity. The association between baPWV and global cognitive function, measured as the mini-mental state examination (MMSE) was evaluated. Mediation analysis was performed to assess the influence of white matter integrity on the association of baPWV with MMSE. RESULTS: Increased baPWV was significantly associated with lower mean global fractional anisotropy (ß= -0.118, p < 0.001), higher mean diffusivity (ß= 0.161, p < 0.001), axial diffusivity (ß= 0.160, p < 0.001), and radial diffusivity (ß= 0.147, p < 0.001) after adjustment of age, sex, and hypertension, which were measures having a direct effect on arterial stiffness and white matter integrity. After adjustment of age, sex, education, apolipoprotein E ɛ4, cardiovascular risk factors, and brain atrophy, we found an association of increased baPWV with worse performance on MMSE (ß= -0.093, p = 0.011). White matter disruption partially mediated the effect of baPWV on MMSE. CONCLUSION: Arterial stiffness is associated with white matter disruption and cognitive decline. Reduced white matter integrity partially explained the effect of arterial stiffness on cognition.

Association between large artery stenosis, cerebral small vessel disease and risk of ischemic stroke.

We aimed to assess the associations of large artery stenosis (LAS) and cerebral small vessel disease (CSVD) with the risk of ischemic stroke and to investigate their respective and combined contributions. In the prospective population-based Shunyi Study, 1,082 stroke-free participants aged 55.9±9.1 years were included. Participants were followed for incident stroke throughout the study period (2013-2019). Total small vessel disease score was used to measure CSVD burden. Cervico-cerebral large artery stenosis was evaluated via brain magnetic resonance angiography and carotid ultrasound. We estimated the risk of ischemic stroke in relation to LAS and CSVD with Cox regression models. During a mean follow-up of 4.2 years, 34 participants (3.1%) experienced at least one ischemic stroke. Severe LAS (≥50% stenosis versus no stenosis: HR=3.27 (95% CI: 1.31-8.18)) and high CSVD burden (total small vessel disease score 2-4 versus 0 point: HR=12.73 (4.83-33.53)) were associated with increased stroke risk independently. In multivariate models, CSVD burden (7.72%) explained a larger portion of the variation in stroke risk than severity of LAS (3.49%). Our findings identified that both LAS and CSVD were associated with future ischemic stroke in asymptomatic subjects, while those with high CSVD burden deserve more attention in primary prevention of stroke.

Arterial Stiffness is Associated with Intracranial Arterial Stenosis other than Dolichoectasia in the General Population.

AIMS: The relationship between central arterial stiffness and aging-related intracranial arteriopathy is not well investigated in the general population. In a population-based study, we investigated arterial stiffness in relation to intracranial atherosclerotic stenosis and intracranial arterial dolichoectasia. METHODS: This study was a cross-sectional analysis on 1,123 subjects (aged 56.0±9.3 years, 37.9% men) of the population-based Shunyi study in China. Arterial stiffness was assessed by measuring brachial-ankle pulse wave velocity (baPWV). Intracranial atherosclerotic stenosis and intracranial arterial dolichoectasia were evaluated via brain magnetic resonance angiography. Multivariate regression models were constructed to investigate the association between baPWV and intracranial large artery diseases. RESULTS: Increased baPWV was significantly associated with higher prevalence of intracranial atherosclerotic stenosis (odds ratio for the highest quartile of baPWV compared with the lowest quartile, 3.66 [95% confidence interval, 1.57- 8.54]), after adjustment for cardiovascular risk factors in multivariate analysis. BaPWV was not associated with the presence of basilar artery dolichoectasia and dilation of basilar artery and internal carotid artery. When the diameters of intracranial arteries were regarded as continuous variables, increased baPWV was inversely related to the internal carotid artery diameter in fully adjusted models (ß±SE, -0.083±0.042, p = 0.047). CONCLUSIONS: This population-based study demonstrates that arterial stiffness was more likely associated with intracranial stenotic arteriopathy other than intracranial dilative arteriopathy.

Brain deep medullary veins on 3-T MRI in a population-based cohort.

Our aim is to investigate whether vascular risk factors are associated with cerebral deep medullary veins (DMVs) and whether DMVs are associated with MRI markers of cerebral small vessel disease (CSVD) or risk of stroke. In a community-based cohort of 1056 participants (mean age 55.7 years), DMVs were identified on susceptibility-weighted imaging (SWI) and counted in periventricular regions. Neuroimaging markers including lacunes, whiter matter hyperintensity (WMH), microbleeds, enlarged perivascular space, and brain atrophy were evaluated. The number of DMVs decreased with age (p = 0.007). After adjusting for age and sex, the number of DMVs was not associated with traditional vascular risk factors. Fewer DMVs was associated with increase of WMH and lacunes, but the association vanished after adjustment for vascular risk factors. However, fewer DMVs were independently associated with brain atrophy (p < 0.001). DMVs were not associated with three-year risk of stroke. Our results suggest that DMV is significantly different from other MRI markers of CSVD regarding risk factors, association with other CSVD markers, and risk of stroke. Nonetheless, the significant association between DMV and brain atrophy suggested the potential role of venules in age-related neurodegenerative process, which deserves further investigation.