Small Vessel Disease Markers Research Articles

Abstract WP158: Cortical Superficial Siderosis is Associated With Ischemia After Intracerebral Hemorrhage

Background: Ischemia on diffusion weighted imaging (DWI) after intracerebral hemorrhage (ICH) increases the risk of future ischemic stroke. Radiographic markers of small vessel disease, including cerebral microbleeds (CMB), are associated with DWI lesions. Though cortical superficial siderosis (cSS) is also a hemorrhagic small vessel disease subtype, it is unclear if cSS similarly relates to DWI lesions. We hypothesized that cSS would represent a more severe phenotype of small vessel disease and would associate with DWI lesions after ICH independent to other small vessel disease markers. Methods: Using the Intracerebral Hemorrhage Outcomes Project (ICHOP), we included all cases of spontaneous ICH who underwent DWI and susceptibility imaging/gradient echo. DWI hyperintensities were identified if >10mm from the hematoma with decreased ADC signal. cSS were identified as subarachnoid hemosiderin deposition without acute subarachnoid hemorrhage. The relationship of cSS with DWI lesion presence as the outcome was assessed with logistic regression adjusted for ICH score, blood pressure change within 24 hours, and small vessel disease markers (CMB and white matter hyperintensity). Sensitivity analyses were performed to adjust for demographics and ICH location. A secondary analysis using linear regression assessed the association with the number of DWI lesions adjusted for similar covariates. Results: Of 198 patients analyzed, DWI lesions were observed in 31.3% and cSS in 10.6%. The presence of cSS was associated with DWI lesions (adjusted OR 3.72, CI: 1.29-10.72), independent of other small vessel disease markers. Separate sensitivity analyses adjusting for sex, race, and ICH location did not change the association of cSS with DWI lesions. In secondary analyses, cSS was not associated with greater number of DWI lesions counts (b 0.213, CI -0.53-0.63). Discussion: cSS is associated with the presence of DWI lesions, independent to other small vessel disease markers. cSS may represent a severe phenotype of small vessel disease with a risk of ICH recurrence and ischemia. Further work is required to investigate underlying mechanisms and optimal strategies to mitigate competing risks of future hemorrhage and ischemic events in these patients.

Association of optic disc pallor and RNFL thickness with cerebral small vessel disease in the PREVENT-Dementia study.

We tested associations between two retinal measures (optic disc pallor, peripapillary retinal nerve fiber layer [pRNFL] thickness) and four magnetic resonance imaging markers of cerebral small vessel disease (SVD; lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces [ePVSs]). We used PallorMetrics to quantify optic disc pallor from fundus photographs, and pRNFL thickness from optical coherence tomography scans. Linear and logistic regression assessed relationships between retinal measures and SVD markers. Participants (N=108, mean age 51.6) were from the PREVENT Dementia study. Global optic disc pallor was linked to ePVSs in the basal ganglia in both left (β=0.12, standard error [SE]=0.05, P<0.05) and right eyes (β=0.13, SE=0.05, P<0.05). Associations were also noted in different disc sectors. No pRNFL associations with SVD markers were found. Optic disc pallor correlated with ePVSs in the basal ganglia, suggesting retinal examination may be a useful method to study brain health changes related to SVD. Optic disc pallor is linked to enlarged perivascular spaces in basal ganglia.There is no association between peripapillary retinal nerve fiber layer thickness and cerebral small vessel disease markers.Optic disc examination could provide insights into brain health.The sample included 108 midlife adults from the PREVENT Dementia study.

Abstract WMP70: Neuroradiological Markers of Cerebral Small Vessel Disease in Adults With Congenital Heart Disease After Fontan Surgery

Introduction: Fontan surgery performed during childhood enhances the lifespan and quality of life of patients with critical congenital heart disease. Post-Fontan circulation may impact function in multiple organ systems, but its long term effects on the brain microvasculature are not well characterized. We investigated brain MRI markers of cerebral small vessel disease (SVD) after exposure to Fontan circulation. Methods: We reviewed medical records and MRI images of 34 adults followed in an academic medical center after Fontan surgery, who had brain MRI for any reason from 08/01/1995-03/01/2022. We characterized Fontan physiological stage (a standardized measure of disease severity) at time of MRI, and identified SVD markers, including deep silent brain infarcts, small perivascular spaces in the basal ganglia, microhemorrhages, and white matter hyperintensities. We calculated SVD scores using a standardized scale of 0-4, where scores of ≥2 indicate moderate to severe SVD. We created ordinal logistic regression models to test the association between physiological stage and SVD score. Results: Characteristics of the patients are summarized in the Table, and distribution of SVD scores in the Figure. Adjusting for age at MRI, there was no association between physiological stage of disease and higher SVD score. Conclusion: In our sample of 34 young adult patients with long term exposure to Fontan circulation, the majority had evidence of moderate to severe SVD, which was not predicted by physiological stage of disease at time of MRI. Exposure to Fontan circulation may be associated with early onset of cerebral SVD, suggesting increased long term risk of stroke and dementia.

Research Advancements on the Correlation Between Spontaneous Intracerebral Hemorrhage of Different Etiologies and Imaging Markers of Cerebral Small Vessel Disease.

The purpose of this review is to identify the correlation between ICH and CSVD imaging markers under SMASH-U classification by searching and analyzing a large number of literatures in recent years, laying a theoretical foundation for future clinical research. At the same time, by collecting clinical data to evaluate patient prognosis, analyzing whether there are differences or supplements between clinical trial conclusions and previous theories, and ultimately guiding clinical diagnosis and treatment through the analysis of imaging biomarkers. In this review, by searching CNKI, Web of Science, PubMed, FMRS and other databases, the use of "spontaneous intracerebral hemorrhage", "hypertensive hemorrhagic cerebral small vessel disease", "cerebral small vessel disease imaging", "Based cerebral small vessel diseases", "SMASH the -u classification" and their Chinese equivalents for the main search term. We focused on reading and analyzing hundreds of relevant literatures in the last decade from August 2011 to April 2020, and also included some earlier literatures with conceptual data sources. After screening and ranking the degree of relevance to this study, sixty of them were cited for analysis and elaboration. In patients with ICH, the number of cerebral microbleeds in lobes, basal ganglia, and the deep brain is positively correlated with ICH volume and independently correlated with neurological functional outcomes; white matter hyperintensity severity is positively correlated with ICH recurrence risk; multiple lacunar infarction independently predict the risk of ICH; severe brain atrophy is an independent risk factor for a poor prognosis in the long term in patients diagnosed with ICH; and the number of enlarged perivascular spaces is correlated with ICH recurrence. However, small subcortical infarct and ICH are the subject of few studies. Higher CSVD scores are independently associated with functional outcomes at 90 days in patients diagnosed with ICH.

Abstract WMP16: Multi-Marker Cerebral Small Vessel Disease Score and Risk of Incident Dementia in the Framingham Heart Study

Background: Individual magnetic resonance imaging (MRI) markers of cerebral small vessel disease (CSVD) are associated with impaired cognition and dementia but may not reflect the overall burden of CSVD. It is unclear whether these markers provide additional value in evaluating the risk of dementia beyond assessments based solely on clinical risk factors. Thus, we aimed to determine whether the association of additive burden of multiple CSVD markers was independent of vascular risk factors and the Framingham Stroke Risk Profile (FSRP) and to also compare results with the FSRP. Methods: We included 1,152 Framingham Heart Study (FHS) participants over the age of 55, free of stroke and dementia, from the Original and Offspring cohorts with available MRI and FSRP data. CSVD score was calculated by summing the number of CSVD features detected in the MRI: cerebral microbleeds, cerebral brain infarcts, extensive white matter hyperintensities, severe perivascular spaces, and cortical superficial siderosis. Two Cox proportional hazards regression models were used to relate the multi-marker CSVD score to incident all-cause dementia and Alzheimer’s dementia. The first model adjusted for education, cohort, and clinical risk factors while the second adjusted for education, cohort, and FSRP. Results: Mean age was 70.9 years (SD: 8.7), 527 (46%) were male, and 211 (18%) had score ≥ 2. Over a median follow-up time of 6.4 years (Q1-Q3: 4.6-11.3), participants with score ≥ 2 had elevated risk of all-cause dementia compared to those with no CSVD markers after adjustment for FSRP (HR: 2.32; 95% CI: 1.46-3.69; p&lt;0.001) and vascular risk factors (HR: 1.76; 95% CI: 1.10-2.81; p=0.02). Score ≥ 2 was also significantly associated with AD after adjustment for FSRP (HR: 2.05; 95% CI: 1.19-3.62; p&lt;0.01), but not vascular risk factors (HR: 1.50; 95% CI: 0.87-2.60; p=0.15). In addition, a 5-percent increase in FSRP was independently associated with incident dementia after adjustment for education and FHS cohort (HR: 1.21; 95% CI: 1.13-1.30; p&lt;0.001). Conclusions: Our results support the use of CSVD score as an indicator for dementia risk and it may be as robust as the FSRP. Further studies are necessary to validate the use of CSVD score in quantifying dementia risk.

Abstract WMP22: Higher Burden of Cerebral Small Vessel Disease is Associated With Risk of Incident Stroke in Community-Dwelling Individuals

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

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

We sought to characterize cognitive profiles associated with enlarged perivascular spaces (EPVS) among Chinese older adults. This population-based study included 1191 dementia-free participants (age ≥60 years) in the MIND-China MRI Substudy (2018-2020). We visually evaluated EPVS in basal ganglia (BG) and centrum semiovale (CSO), white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), and cortical superficial siderosis. We used a neuropsychological test battery to assess cognitive function. Data were analyzed using general linear models. Greater BG-EPVS load was associated with lower z-scores in memory, verbal fluency, and global cognition (p<0.05); these associations became non-significant when controlling for other cerebral small vessel disease (CSVD) markers (e.g., WMHs, lacunes, and mixed CMBs).Overall, CSO-EPVS load was not associated with cognitive z-scores (p>0.05); among apolipoprotein E (APOE) -ε4 carriers, greater CSO-EPVS load was associated with lower verbal fluency z-score, even when controlling for other CSVD markers (p<0.05). The associations of BG-EPVS with poor cognitive function in older adults are largely attributable to other CSVD markers. The association of enlarged perivascular spaces (EPVS) with cognitive function in older people is poorly defined.The association of basal ganglia (BG)-EPVS with poor cognition is attributed to other cerebral small vessel disease (CSVD) markers.In apolipoprotein E (APOE) ε4 carriers, a higher centrum semiovale (CSO)-EPVS load is associated with poorer verbal fluency.

Immune regulation and blood–brain barrier permeability in cerebral small vessel disease: study protocol of the INflammation and Small Vessel Disease (INSVD) study – a multicentre prospective cohort study

IntroductionThe INflammation and Small Vessel Disease (INSVD) study aims to investigate whether peripheral inflammation, immune (dys)regulation and blood–brain barrier (BBB) permeability relate to disease progression in cerebral small vessel disease...

Impact of leukoaraiosis on the infarct growth rate and clinical outcome in acute large vessel occlusion stroke after endovascular thrombectomy.

As a marker of chronic cerebral small vessel disease, leukoaraiosis (LA) was reported to impact the recruitment of collaterals in acute ischemic stroke (AIS). We intended to explore the impact of LA on the infarct growth rate (IGR) and clinical outcome by impaired collateral development in AIS patients with large vessel occlusion (LVO) who underwent endovascular thrombectomy (EVT). Two hundred thirty-six AIS patients who underwent EVT were retrospectively reviewed. The severity of LA was graded using the Fazekas scale with non-contrast CT. IGR was calculated by the acute core volume on CT perfusion divided by the time from stroke onset to imaging. The collateral status after LVO was assessed using the ASITN/SIR collateral scale. The clinical outcomes after EVT were evaluated using a modified Rankin Scale (mRS). The Alberta stroke program early CT score (ASPECTS), the National Institutes of Health Stroke Scale (NIHSS) score at admission, and the modified treatment in cerebral infarction (mTICI) score after EVT were also included. Correlations between those factors were analyzed. Patients with severe LA had significantly larger core volume on CTP (p = 0.022) and lower collateral grade (p < 0.001). Faster IGR was significantly associated with higher LA severity (adjusted odds ratio [aOR]: 1.53; 95% CI: 1.02-2.33; p = 0.046), higher NIHSS (aOR: 1.04; 95% CI: 1.00-1.09; p = 0.032) and impaired collaterals (aOR: 2.26; 95% CI: 1.27-4.03; p = 0.005). In mediation analysis, collaterals explained 33% of the effect of LA on fast IGR. There was correlation between the severity of LA and mRS (p = 0.007). The increasing severity of LA is associated with impaired collateral status and fast infarct growth. These findings suggest that LA may become a predictive imaging biomarker for the likelihood of progression of tissue injury and clinical outcome after EVT in acute large vessel occlusion stroke.

Higher HbA1c Is Associated With Greater 2-Year Progression of White Matter Hyperintensities.

White matter hyperintensity (WMH) lesions on brain MRI images are surrogate markers of cerebral small vessel disease (CSVD). Longitudinal studies examining the association between diabetes and WMH progression have yielded mixed results. Thus, in this study we investigated the association between HbA1c, a biomarker for the presence and severity of hyperglycemia, and longitudinal WMH change after adjusting for known risk factors for WMH progression. We recruited 64 participants from South Korean memory clinics to undergo brain MRI at the baseline and a two-year follow-up. We found: First, higher HbA1c was associated with greater global WMH volume (WMHV) changes after adjusting for known risk factors (B = 7.7E-04, p = 0.025); Second, the association between baseline WMHV and WMHV progression was only significant at diabetic levels of HbA1c (p < 0.05, when HbA1c > 6.51%), and non-APOE ε4 carriers showed a stronger association between HbA1c and WMHV progression (B = -2.59E-03, p = 0.004); Third, associations of WMHV progression with HbA1c were particularly apparent for deep WMHV change (B = 7.17E-04, p < 0.01) compared to periventricular WMHV change, and for frontal (B = 5.00E-04, p < 0.001) and parietal (B = 1.534-04, p < 0.05) WMHV change compared to occipital and temporal WMHV change. In conclusion, higher HbA1c levels were associated with greater two-year WMHV progression, especially in non-APOE ε4 participants or those with diabetic levels of HbA1c. These findings demonstrate that diabetes may potentially exacerbate cerebrovascular and white matter disease.

Understanding the relationship between type-2 diabetes, MRI markers of neurodegeneration and small vessel disease, and dementia risk: a mediation analysis.

To explore to which extent neurodegeneration and cerebral small vessel disease (SVD) could mediate the association between type-2 diabetes and higher dementia risk.The analytical sample consisted in 2228 participants, out of the Three-City study, aged 65 and older, free of dementia at baseline who underwent brain MRI. Diabetes was defined by medication intake or fasting or non-fasting elevated glucose levels. Dementia status was assessed every 2 to 3 years, during up to 12 years of follow-up. Brain parenchymal fraction (BPF) and white matter hyperintensities volume (WMHV) were selected as markers of neurodegeneration and cerebral SVD respectively. We performed a mediation analysis of the effect of baseline BPF and WMHV (mediators) on the association between diabetes and dementia risk using linear and Cox models adjusted for age, sex, education level, hypertension, hypercholesterolemia, BMI, smoking and alcohol drinking status, APOE-ε4 status, and study site.At baseline, 8.8% of the participants had diabetes. Diabetes (yes vs. no) was associated with higher WMHV (βdiab = 0.193, 95% CI 0.040; 0.346) and lower BPF (βdiab=-0.342, 95% CI -0.474; -0.210), as well as with an increased risk of dementia over 12 years of follow-up (HRdiab=1.65, 95% CI 1.04; 2.60). The association between diabetes status and dementia risk was statistically mediated by higher WMHV (HRdiab=1.05, 95% CI 1.01; 1.11, mediated part = 10.8%) and lower BPF (HRdiab=1.12, 95% CI 1.05; 1.20, mediated part = 22.9%).This study showed that both neurodegeneration and cerebral SVD statistically explained almost 30% of the association between diabetes and dementia.

Small ischemic lesions accompanying intracerebral hemorrhage: The underlying influence of old lacunes and polyunsaturated fatty acids

Background and aimsSmall ischemic lesions (SILs) accompanying intracerebral hemorrhage (ICH) might be induced by small-vessel vulnerability and hypercoagulation. Some polyunsaturated fatty acids (PUFAs) have been associated with hypercoagulation in cardiovascular diseases. Our aim here is to determine how pre-existing small-vessel disease (SVD) and PUFAs may affect SILs. Methods and resultsWe screened consecutive ICH patients (October 2012–December 2021) meeting two inclusion criteria: (1) the patients were hospitalized for acute ICH and were undergoing magnetic resonance imaging and (2) the patients’ PUFA measurements were available. After excluding patients with isolated intraventricular hemorrhage, we evaluated whether three SVD markers (white matter hyperintensities, old lacunes, cerebral microbleeds) and PUFAs might be associated with the development of SILs. We selected 319 participants from 377 screened consecutive ICH patients (median age = 64, males = 207 [65 %]). Of the 319 patients, 45 patients (14 %) developed SILs. In a multivariable logistic regression analysis, the factors associated with SILs were old lacunes (OR 3.255, 95 % CI 1.101–9.622, p = 0.033) and DHA/AA ratio (OR 0.180, 95 % CI 0.046–0.704, p = 0.013). Furthermore, in our multivariable analysis using DHA/AA ratio tertiles with and without SILs, we observed a linear trend between SILs and the Higher Tertile of the DHA/AA ratio (DHA/AA ratio Mid-Tertile: OR 1.330, 95%CI 0.557–3.177, p = 0.521, and DHA/AA ratio Lower Tertile: OR 2.632, 95%CI 1.124–6.162, p = 0.026). ConclusionThe presence of old lacunes and lower DHA/AA ratios might be associated with SILs accompanying ICH.

Differential risk factor profile and neuroimaging markers of small vessel disease between lacunar ischemic stroke and deep intracerebral hemorrhage.

Lacunar ischemic stroke (LIS) and deep intracerebral hemorrhage (dICH) are two stroke phenotypes of deep perforator arteriopathy. It is unclear what factors predispose individuals with deep perforator arteriopathy to either ischemic or hemorrhagic events. We aimed to investigate risk factors and neuroimaging features of small vessel disease (SVD) associated with LIS versus dICH in a cross-sectional study. We included patients with clinically presenting, magnetic resonance imaging-confirmed LIS or dICH from two tertiary hospitals between 2010 and 2021. We recorded vascular risk factors and SVD markers, including lacunes, white matter hyperintensities (WMH), perivascular spaces (PVS), and cerebral microbleeds (CMB). Logistic regression modeling was used to determine the association between vascular risk factors, SVD markers, and stroke phenotype. We further created WMH probability maps to compare WMH distribution between LIS and dICH. A total of 834 patients with LIS (mean age 61.7 ± 12.1 years) and 405 with dICH (57.7 ± 13.2 years) were included. Hypertension was equally frequent between LIS and dICH (72.3% versus 74.8%, p = 0.349). Diabetes mellitus, hyperlipidemia, smoking, and prior ischemic stroke were more associated with LIS [odds ratio (OR) (95% confidence interval (CI)), 0.35 (0.25-0.48), 0.32 (0.22-0.44), 0.31 (0.22-0.44), and 0.38 (0.18-0.75)]. Alcohol intake and prior ICH were more associated with dICH [OR (95% CI), 2.34 (1.68-3.28), 2.53 (1.31-4.92)]. Lacunes were more prevalent in LIS [OR (95% CI) 0.23 (0.11-0.43)], while moderate-to-severe basal-ganglia PVS and CMB were more prevalent in dICH [OR (95% CI) 2.63 (1.35-5.27), 4.95 (2.71-9.42)]. WMH burden and spatial distribution did not differ between groups. The microangiopathy underlying LIS and dICH reflects distinct risk profiles and SVD features, hence possibly SVD subtype susceptibility. Prospective studies with careful phenotyping and genetics are needed to clarify the mechanisms underlying this difference.

Cerebral pulsatility in relation with various imaging markers of cerebral small vessel disease: a longitudinal community-based study.

Cerebral pulsatility is thought to reflect arterial stiffness and downstream microvascular resistance. Although previous studies indicated cerebral pulsatility might closely relate to development of cerebral small vessel disease (SVD), yet evidence remain controversial and longitudinal data are rare. We aimed to explore relationships of cerebral pulsatility with severity and progression of various SVD imaging markers among the community-dwelling elderly. A longitudinal cohort study. As part of the prospective community-based Shanghai Aging Study cohort, dementia- and stroke-free elderly were recruited for baseline assessment of cerebral pulsatility and SVD severity during 2010-2011 and traced for SVD progression during 2016-2017. Cerebral pulsatility was quantified for both anterior and posterior circulation with transcranial Doppler ultrasound. SVD imaging markers were measured with brain magnetic resonance imaging (MRI) including white matter hyperintensities (WMHs), enlarged perivascular spaces (ePVS), lacunes, and microbleeds. The cross-sectional and longitudinal relationships between cerebral pulsatility and SVD were analyzed by univariable and multivariable regression models. Totally, 188 eligible subjects were included at baseline and out of them, 100 (53.19%) returned for a 7-year follow-up. At baseline, increased pulsatility of posterior circulation was independently associated with more periventricular WMH (PWMH) and ePVS in basal ganglia (BG-ePVS) but not with other SVD markers. Longitudinally, higher posterior pulsatility predicted greater PWMH progression in participants with hypertension (β = 2.694, standard error [SE] = 1.112, p = 0.020), whereas pulsatility of anterior circulation was shown to prevent BG-ePVS progression among followed-up elderly (β = -6.737, SE = 2.685, p = 0.012). However, no significant relationship was found between cerebral pulsatility and burden of lacunes or cerebral microbleeds. Higher pulsatility of posterior circulation could worsen PWMH progression, especially for participants with hypertension. But for development of ePVS, increased cerebral pulsatility could play a compensatory role among several healthy elderly. The distinct relationships between cerebral pulsatility and various SVD markers emphasized the importance of individualized SVD management.

Association between enlarged perivascular spaces in basal ganglia and cerebral perfusion in elderly people.

Enlarged perivascular spaces in basal ganglia (BG-EPVS) are considered an imaging marker of cerebral small vessel disease (CSVD), but its pathogenesis and pathophysiological process remain unclear. While decreased cerebral perfusion is linked to other CSVD markers, the relationship between BG-EPVS and cerebral perfusion remains ambiguous. This study aimed to explore this association. Elderly individuals with severe BG-EPVS (n = 77) and age/sex-matched controls (n = 89) underwent head CT perfusion imaging. The cerebral perfusion parameters including mean transit time (MTT), time to maximum (TMAX), cerebral blood flow (CBF), and cerebral blood volume (CBV) were quantitatively measured by symmetric regions of interest plotted in the basal ganglia region. Point-biserial correlation and logistics regression analysis were performed to investigate the association between BG-EPVS and cerebral perfusion. There were no significant differences in MTT, TMAX, or CBF between BG-EPVS group and control group. CBV was significantly lower in the BG-EPVS group (p = 0.035). Point-biserial correlation analysis showed a negative correlation between BG-EPVS and CBV (r = -0.198, p = 0.011). BG-EPVS group and control group as the dependent variable, binary logistics regression analysis showed that CBV was not an independent risk factor for severe BG-EPVS (p = 0.448). All enrolled patients were divided into four groups according to the interquartile interval of CBV. The ordered logistic regression analysis showed severe BG-EPVS was an independent risk factor for decreased CBV after adjusting for confounding factors (OR = 2.142, 95%CI: 1.211-3.788, p = 0.009). Severe BG-EPVS is an independent risk factor for decreased CBV in the elderly, however, the formation of BG-EPVS is not solely dependent on changes in CBV in this region. This finding provides information about the pathophysiological consequence caused by severe BG-EPVS.

Mendelian Randomization Analysis to Assess Whether Magnetic Resonance Imaging Signs of Cerebral Small Vessel Disease Can Cause Cognitive Decline and Dementia.

Cognitive decline and dementia have been linked to cerebral small vessel disease, so we explored using Mendelian randomization whether cerebral small vessel disease visible as 10 neuroimaging signs may cause cognitive decline and dementia. We analyzed publicly available data from genome-wide association studies using two-sample Mendelian randomization involving inverse variance weighting, weighted median, MR-Egger, and MR-PRESSO approaches. Mendelian randomization suggested that cognitive decline can be caused by lacunar stroke (inverse variance weighting, β = -0.012, 95% CI -0.024 to -0.001, P = 0.033). Furthermore, an elevated burden of white matter hyperintensities was associated with an increased risk of Dementia due to Parkinson's disease (inverse variance weighting, OR 2.035, 95% CI 1.105 to 3.745, P = 0.023). Notably, no significant associations were observed between neuroimaging markers of Cerebral Small Vessel Disease and other types of dementia. This Mendelian randomization study provides evidence that lacunar stroke and white matter lesions can cause cognitive decline, and that white matter hyperintensity may increase risk of dementia due to Parkinson's disease. These results underscore the need for further investigations into the neurocognitive effects of cerebral small vessel disease.

Differences in impact of current and former shift work on cardiovascular risk factors, carotid atherosclerosis, and white matter integrity.

The association of shift work (SW) and disrupted circadian rhythm with markers of large artery atherosclerosis and cerebral small vessel disease is uncertain. We aimed to study the separate association of current and former SW with these markers. We included participants from the population-based Hamburg City Health Study. SW was defined by monthly working hours between 06:00 pm and 07:00 am containing night shifts for at least 12 months. Cross-sectional data were obtained from structured questionnaires, laboratory analyses, physical examinations, brain magnetic resonance imaging, and carotid ultrasound. We performed multivariable regression analysis with carotid intima-media thickness (CIMT), and peak-width skeletonized mean diffusivity (PSMD) as dependent variables. Three hundred and forty-four current, 238 former, and 7162 never-shift workers were included. The median age was 60 years for both current and former shift workers, and total duration of SW was comparable for the two groups. Current shift workers were less frequently female (27.3% vs. 44.5%; p < .001), had more frequent hyperlipidemia (31.5% vs. 22.3%; p = .024), and diabetes (16.2% vs. 3.2%; p < .001). After adjustment for age and sex, reduced quality of sleep (β = 1.61, p = .001) and low education (β = 2.63, p < .001) were associated with current but not former SW. Adjusted for age and sex, the current SW was associated with higher CIMT (β = 0.02, p = .001) and PSMD (β = 9.06e-06, p = .006), whereas former SW was not. Adjusted for risk factors, current SW remained associated with PSMD (β = 9.91e-06, p = .006) but not with CIMT. Current SW was associated with CIMT and with PSMD, with the latter association remaining after adjustment for risk factors. Former SW showed no associations with CIMT or PSMD. This may indicate that current SW is linked with increased neurovascular risk through disrupted circadian rhythms. The trial was submitted at http://www.clinicaltrials.gov, under NCT03934957 on January 4, 2019. The first participant was enrolled in February 2016.

Inferior Frontal Sulcal Hyperintensity on Fluid-Attenuated Inversion Recovery Is Related to Cerebrospinal Fluid Clearance via Putative Meningeal Lymphatics.

Inferior frontal sulcal hyperintensity (IFSH) on FLAIR sequence may indicate elevated cerebrospinal fluid (CSF) wastes. The objective of this study was to investigate its association with the clearance function of putative meningeal lymphatic vessels (mLVs). We included patients who underwent FLAIR sequence and dynamic contrast MRI with intrathecal administration of contrast agent. The visibility of IFSH was quantitatively assessed by measuring the mean signal intensity of inferior frontal sulci on 2D FLAIR. The clearance function of putative mLVs was defined as the percentage change of signal unite ratio in the parasagittal dura from baseline to 4.5, 15 and 39 hours after intrathecal injection on dynamic contrast MRI. Additionally, imaging markers of cerebral small vessel disease, including white matter hyperintensities and enlarged perivascular spaces, were measured. Correlation analysis and linear regression were employed to verify the association of IFSH with the clearance function of mLVs. A total of 76 patients were included in the study. The visibility of IFSH was found to be associated with the percentage change of signal unite ratio in parasagittal dura from baseline to 15 and 39 hours in adjusted analyses. Furthermore, the visibility of IFSH was positively related to the age, scores of both periventricular and deep white matter hyperintensities, and the grade of enlarged perivascular spaces in centrum semiovale. These findings suggest that the visibility of IFSH on 2D FLAIR may serve as an indicator of clearance dysfunction of mLVs and may be implicated in the development of cerebral small vessel disease.

Quantitative Analysis of Multimodal MRI Markers and Clinical Risk Factors for Cerebral Small Vessel Disease Based on Deep Learning.

Cerebral small vessel disease lacks specific clinical manifestations, and extraction of valuable features from multimodal images is expected to improve its diagnostic accuracy. In this study, we used deep learning techniques to segment cerebral small vessel disease imaging markers in multimodal magnetic resonance images and analyze them with clinical risk factors. We recruited 211 lacunar stroke patients and 83 control patients. The patients' cerebral small vessel disease markers were automatically segmented using a V-shaped bottleneck network, and the number and volume were calculated after manual correction. The segmentation results of the V-shaped bottleneck network for white matter hyperintensity and recent small subcortical infarction were in high agreement with the ground truth (DSC>0.90). In small lesion segmentation, cerebral microbleed (average recall=0.778; average precision=0.758) and perivascular spaces (average recall=0.953; average precision=0.923) were superior to lacunar infarct (average recall=0.339; average precision=0.432) in recall and precision. Binary logistic regression analysis showed that age, systolic blood pressure, and total cerebral small vessel disease load score were independent risk factors for lacunar stroke (P<0.05). Ordered logistic regression analysis showed age was positively correlated with cerebral small vessel disease load score and total cholesterol was negatively correlated with cerebral small vessel disease score (P<0.05). Lacunar stroke patients exhibited higher cerebral small vessel disease imaging markers, and age, systolic blood pressure, and total cerebral small vessel disease score were independent risk factors for lacunar stroke patients. V-shaped bottleneck network segmentation network based on multimodal deep learning can segment and quantify various cerebral small vessel disease lesions to some extent.

Long-range connections damage in white matter hyperintensities affects information processing speed.

White matter hyperintensities, one of the major markers of cerebral small vessel disease, disrupt the integrity of neuronal networks and ultimately contribute to cognitive dysfunction. However, a deeper understanding of how white matter hyperintensities related to the connectivity patterns of brain hubs at the neural network level could provide valuable insights into the relationship between white matter hyperintensities and cognitive dysfunction. A total of 36 patients with moderate to severe white matter hyperintensities (Fazekas score ≥ 3) and 34 healthy controls underwent comprehensive neuropsychological assessments and resting-state functional MRI scans. The voxel-based graph-theory approach-functional connectivity strength was employed to systematically investigate the topological organization of the whole-brain networks. The white matter hyperintensities patients performed significantly worse than the healthy controls in episodic memory, executive function and information processing speed. Additionally, we found that white matter hyperintensities selectively affected highly connected hub regions, predominantly involving the medial and lateral prefrontal, precuneus, inferior parietal lobule, insula and thalamus. Intriguingly, this impairment was connectivity distance-dependent, with the most prominent disruptions observed in long-range connections (e.g. 100-150 mm). Finally, these disruptions of hub connectivity (e.g. the long-range functional connectivity strength in the left dorsolateral prefrontal cortex) positively correlated with the cognitive performance in white matter hyperintensities patients. Our findings emphasize that the disrupted hub connectivity patterns in white matter hyperintensities are dependent on connection distance, especially longer-distance connections, which in turn predispose white matter hyperintensities patients to worse cognitive function.