Small Subcortical Infarcts Research Articles

Redefining Infarction Size for Small-Vessel Occlusion in Acute Ischemic Stroke: A Retrospective Case-Control Study.

Small-vessel occlusion, previously referred to as lacunar infarcts, accounts for approximately one-third of all ischemic strokes, using an axial diameter of less than 20 mm on diffusion-weighted imaging. However, this threshold may not adequately differentiate small-vessel occlusion from other pathologies, such as branch atheromatous disease (BAD) and embolism. This study aimed to assess the clinical significance and pathological implications of acute small subcortical infarctions (SSIs) based on infarct diameter. We conducted a retrospective case-control study using data from stroke patients recorded between 2016 and 2021 of the Stroke Registry in Chang Gung Healthcare System. Patients with acute SSIs in penetrating artery territories were included. Key variables such as patient demographics, stroke severity, and medical history were collected. Infarcts were categorized based on size, and the presence of early neurological deterioration (END) and favorable functional outcomes were assessed. Among the 855 patients with acute SSIs, the median age was 70 years and the median National Institutes of Health Stroke Scale (NIHSS) score at arrival was four. END occurred in 97 patients (11.3%). Those who experienced END were significantly less likely to achieve a favorable functional outcome compared to those who did not (18.6% vs. 59.9%, p < 0.001). The incidence of END increased progressively with infarct sizes of 15 mm or larger, with the optimal threshold for predicting END identified as 15.5 mm and for BAD, it was 12.1 mm. A multiple logistic regression analysis revealed that motor tract involvement [adjusted odds ratio (aOR) 2.3; 95% confidence interval (CI) 1.1-4.7], an initial heart rate greater than 90 beats per minute (aOR 2.3; 95% CI 1.2-4.3), and a larger infarct size (15 mm to less than 20 mm vs. 10 mm to less than 15 mm; aOR 3.0; 95% CI 1.4-6.3) were significantly associated with END. Our findings suggest that setting the upper limit for small-vessel occlusion at 15 mm would be more effective in distinguishing it from BAD. However, these findings should be interpreted in the context of the retrospective design and study population. Further multi-center research utilizing high-resolution vessel wall imaging is necessary to refine this threshold and enhance diagnostic accuracy.

Baseline Blood Pressure Was Associated with Hemispheric Cerebral Blood Flow in Acute Small Subcortical Infarcts

Introduction: While increased baseline blood pressure (BP) is a prevalent comorbidity in the acute phase of ischemic stroke, the association between baseline BP and the state of hemispheric perfusion in patients with acute small subcortical infarcts (SSIs) has not been studied in detail. The aim of this study was to investigate the relationship between baseline BP and hemispheric cerebral blood flow (CBF) in acute SSIs. Methods: This retrospective study included 101 patients with acute SSIs. Baseline hemispheric CBF was assessed through co-registration of baseline CT perfusion imaging and follow-up diffusion-weighted imaging. The association between baseline BP, CBF, and different cerebral small vessel disease (CSVD) biomarkers was assessed. Results: Baseline systolic BP (SBP) and diastolic BP (DBP) were negatively associated with contralateral hemispheric CBF after multivariate-adjusted linear analysis (SBP: β = −0.001, 95% CI: −0.002 to 0.000, p = 0.030; DBP: β = −0.002, 95% CI: −0.003∼0.001, p = 0.006). Among other CSVD biomarkers, the presence of any cerebral microbleeds showed a significant association with lower CBF in the contralateral hemisphere of the infarct lesion (r = −0.270, p = 0.035). Conclusion: In patients with acute SSIs, increased baseline BP was associated with reduced CBF in the contralateral hemisphere of the infarct lesion, which probably could be interpreted by the exacerbation of the CSVD burden, suggesting a potential mechanistic link between BP autoregulation dysfunction and the aggravation of neurovascular impairment in SSIs.

Factors associated with the distribution of brain metastases in lung cancer: a retrospective study.

The distribution of brain metastases (BMs) in patients with lung cancer may be associated with the primary tumor-related factors and cerebral small vascular diseases (CSVDs). The aim of this study was to investigate the potential effects of the above factors on the distribution of BMs. A total of 5,788 lesions in 823 patients with BMs from lung cancer were enrolled. The numbers of BMs and CSVDs in 15 brain regions were determined. CSVDs include recent small subcortical infarcts (RSSIs), perivascular spaces, and lacunes of presumed vascular origin (LPVOs). We collected the number of CSVDs, and primary tumor-related factors (including clinical and imaging features) in lung cancer patients with BMs. Univariate and multivariate linear regression were utilized to analyze the potential influence of the above factors on the number of BMs in 15 brain regions. In addition, we performed subgroup analyses of all patients with adenocarcinoma (AD), female patients with AD, male patients with AD, and patients with small cell lung cancer. Univariate linear regression analyses showed that bone metastasis, adrenal metastasis, RSSIs, and LPVOs were associated with the number of BMs in over half of the examined brain regions. Only the independent association of LVPOs persisted in the multivariate linear regression analyses, and similar phenomenon was found in the subgroup analyses. In conclusion, the distribution of BMs in lung cancer patients appears to be associated with the presence of LVPOs, while primary tumor-related factors have less influence.

Incident Infarcts in Patients With Stroke and Cerebral Small Vessel Disease: Frequency and Relation to Clinical Outcomes.

Factors associated with cerebral small vessel disease (SVD) progression, including incident infarcts, are unclear. We aimed to determine the frequency of incident infarcts over 1 year after minor stroke and their relation to baseline SVD burden, vascular risks, and recurrent stroke and cognitive outcomes. We recruited patients with lacunar or nondisabling cortical stroke. After diagnostic imaging, we repeated structural MRI at 3-6 monthly intervals for 12 months, visually assessing incident infarcts on diffusion-weighted imaging or FLAIR. We used logistic regression to determine associations of baseline vascular risks, SVD score, and index stroke subtype with subsequent incident infarcts. We assessed cognitive and functional outcomes at 1 year using Montreal Cognitive Assessment (MoCA) and modified Rankin scale (mRS), adjusting for baseline age, mRS, MoCA, premorbid intelligence, and SVD score. We recruited 229 participants, mean age 65.9 (SD 11.1). Over half of all participants, 131 of 229 (57.2%) had had an index lacunar stroke. From baseline to 1-year MRI, we detected 117 incident infarcts in n = 57/229 (24.8%) participants. Incident infarcts were mainly of the small subcortical (86/117 [73.5%] in n = 38/57 [66.7%]) vs cortical infarct subtype (n = 19/57 [33.3%]). N = 39/57 participants had incident infarcts at 1 visit; 18 of 57 at 2 or more visits; and 19 of 57 participants had multiple infarcts at a single visit. Only 7 of 117 incident infarcts corresponded temporally to clinical stroke syndromes. The baseline SVD score was the strongest predictor of incident infarcts (adjusted odds ratio [OR] 1.87, 95% CI 1.39-2.58), while mean arterial pressure was not associated. All participants with incident infarcts were prescribed an antiplatelet or anticoagulant. Lower 1-year MoCA was associated with lower baseline MoCA (β 0.47, 95% CI 0.33-0.61), lower premorbid intelligence, and older age. Higher 1-year mRS was associated with higher baseline mRS only (OR 5.57 [3.52-9.10]). Neither outcome was associated with incident infarcts. In the year after stroke in a population enriched for lacunar stroke, incident infarcts occurred in one-quarter and were associated with worse baseline SVD. Most incident infarcts detected on imaging did not correspond to clinical stroke/transient ischemic attack. Worse 1-year cognition and function were not associated with incident infarcts.

Causal relationship of inflammatory cytokines and serum metabolites in cerebral small vessel disease: a two-step Mendelian randomization study.

The aim was to investigate the causal relationships of inflammatory cytokines and serum metabolites in cerebral small vessel disease (CSVD). Bidirectional Mendelian randomization was first conducted to screen inflammatory cytokines and serum metabolites that were associated with imaging features of CSVD, including white matter hyperintensities, recent small subcortical infarcts, cortical cerebral microinfarcts, cerebral microbleeds, lacunes and enlarged perivascular spaces. Sensitivity analyses were performed to evaluate the robustness and pleiotropy of these results. Subsequently, inflammatory cytokines and serum metabolites that were associated with CSVD were subjected to functional enrichment. Finally, mediation analysis was employed to investigate whether inflammatory cytokines or serum metabolites acted as an intermediary for the other in their causal relationship with CSVD. Of the inflammatory cytokines, five were risk factors (e.g., tumour-necrosis-factor-related apoptosis-inducing ligand) and five (e.g., fibroblast growth factor 19) were protective factors for CSVD. Eleven serum metabolites that increased CSVD risk and 13 metabolites that decreased CSVD risk were also identified. The majority of these markers of CSVD susceptibility were lipid metabolites. Natural killer cell receptor sub-type 2B4 was determined to act as a mediating factor of an unidentified metabolite for the enlargement of perivascular spaces. Several inflammatory cytokines and serum metabolites had causal relationships with imaging features of CSVD. A natural killer cell receptor mediated in part the promotional effect of a metabolite on perivascular space enlargement.

Cerebral Small Vessel Disease and Infarct Growth in Acute Ischemic Stroke Treated with Intravenous Thrombolysis.

We investigated relations between cerebral small vessel disease (cSVD) markers and evolution of the ischemic tissue from ischemic core to final infarct in people with acute ischemic stroke treated with intravenous thrombolysis. Data from the Stroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA) were used. Any pre-existing lacunar infarcts and white matter hyperintensities (WMH) were assessed on magnetic resonance (MR) before thrombolytic therapy. Acute ischemic core and final infarct volume were then assessed by two independent radiologists. The relationship among baseline markers of cSVD, acute ischemic core volume, final infarct volume, infarct growth (IG = final infarct - ischemic core), and infarct growth ratio (IGR = final infarct/ischemic core) was then assessed using linear and ordinal regression adjusted for age, sex, onset-to-treatment time, and stroke severity. We included 165 patients, mean (± SD) age 69.5 (± 15.7) years, 74 (45%) males, mean (± SD) ischemic core volume 25.48 (± 42.22) ml, final infarct volume 52.06 (± 72.88) ml, IG 26.58 (± 51.02) ml, IGR 8.23 (± 38.12). Seventy (42%) patients had large vessel occlusion, 20 (12%) acute small subcortical infarct. WMHs were present in 131 (79%) and lacunar infarcts in 61 (37%) patients. Final infarct volumes were 53.8ml and 45.2ml (WMHs/no WMHs), p = 0.139, and 24.6ml and 25.9ml (lacunar infarcts/no lacunar infarcts), p = 0.842. In linear and ordinal regression analyses, presence of lacunar infarcts was associated with smaller IG (β = - 0.17; p = 0.024; cOR = 0.52; 95%CI = 0.28-0.96, respectively) and WMHs were associated with smaller IGR (β = - 0.30; p = 0.004; cOR = 0.27; 95%CI = 0.11-0.69, respectively). In people with acute ischemic stroke treated with intravenous thrombolysis, cSVD features were associated with smaller growth of the acute ischemic area, suggesting less salvageable tissue at time of reperfusion therapy.

Application of artificial intelligence-based magnetic resonance imaging in diagnosis of cerebral small vessel disease.

Cerebral small vessel disease (CSVD) is an important cause of stroke, cognitive impairment, and other diseases, and its early quantitative evaluation can significantly improve patient prognosis. Magnetic resonance imaging (MRI) is an important method to evaluate the occurrence, development, and severity of CSVD. However, the diagnostic process lacks quantitative evaluation criteria and is limited by experience, which may easily lead to missed diagnoses and misdiagnoses. With the development of artificial intelligence technology based on deep learning, the extraction of high-dimensional features in imaging can assist doctors in clinical decision-making, and it has been widely used in brain function and mental disorders, and cardiovascular and cerebrovascular diseases. This paper summarizes the global research results in recent years and briefly describes the application of deep learning in evaluating CSVD signs in MRI imaging, including recent small subcortical infarcts, lacunes of presumed vascular origin, vascular white matter hyperintensity, enlarged perivascular spaces, cerebral microbleeds, brain atrophy, cortical superficial siderosis, and cortical cerebral microinfarct.

Association between blood-brain barrier permeability and changes in pulse wave velocity following a recent small subcortical infarct.

Cerebral small vessel disease (cSVD) is associated with increased blood-brain barrier (BBB) permeability. We sought to evaluate whether arterial stiffness might be associated with BBB permeability in patients with cSVD. We assessed BBB permeability using Dynamic Contrast-Enhanced MRI (DCE-MRI) in 29 patients that had suffered a recent small subcortical infarct (RSSI). BBB permeability in the whole brain (WB), gray matter (GM) and white matter (WM) was assessed with the parameter Ktrans. We used ambulatory blood pressure monitoring to measure 24-h systolic blood pressure (24-h SBP), diastolic blood pressure (24-h DBP), and pulse wave velocity (24-h PWV) both after stroke and following a 2-year follow-up. The differences between both measurements were calculated as Δ24-h SBP, Δ24-h DBP and Δ24-h PWV. DCE-MRI was acquired at a median (IQR) of 24 (19-27) months after stroke. Median age was 66.7 (9.7) years, and 24 (83%) patients were men. Median (IQR) Δ24-h PWV was 0.3 (-0.1, 0.5) m/s. WB-Ktrans, GM-Ktrans, and WM-Ktrans were associated with Δ24-h PWV (Spearman's, r [95% CI], WB 0.651 [0.363-0.839]; GM 0.657 [0.373-0.845], WM 0.530[0.197-0.777]) but not with Δ24-h SBP or Δ24-h DBP. These associations remained significant after adjustment with linear regression models, controlling for age, sex, body mass index, and Δ24-h SBP (b[95% CI], WB 0.725[0.384-1.127], GM 0.629 [0.316-1.369], WM 0.865 [0.455-0.892]) or Δ24-h DBP (b[95% CI], WM 0.707 [0.370-1.103], GM 0.643 [0.352-1.371], WM 0.772 [0.367-0.834]). Our results suggest that an increment on arterial stiffness in the months following a RSSI might increase BBB permeability.

A novel rat model of cerebral small vessel disease based on vascular risk factors of hypertension, aging, and cerebral hypoperfusion.

Cerebral small vessel disease (CSVD) is a major cause of vascular cognitive impairment and functional loss in elderly patients. Progressive remodeling of cerebral microvessels due to arterial hypertension or other vascular risk factors, such as aging, can cause dementia or stroke. Typical imaging characteristics of CSVD include cerebral microbleeds (CMB), brain atrophy, small subcortical infarctions, white matter hyperintensities (WMH), and enlarged perivascular spaces (EPVS). Nevertheless, no animal models that reflect all the different aspects of CSVD have been identified. Here, we generated a new CSVD animal model using D-galactose (D-gal) combined with cerebral hypoperfusion in spontaneously hypertensive rats (SHR), which showed all the hallmark pathological features of CSVD and was based on vascular risk factors. SHR were hypodermically injected with D-gal (400 mg/kg/d) and underwent modified microcoil bilateral common carotid artery stenosis surgery. Subsequently, neurological assessments and behavioral tests were performed, followed by vascular ultrasonography, electron microscopy, flow cytometry, and histological analyses. Our rat model showed multiple cerebrovascular pathologies, such as CMB, brain atrophy, subcortical small infarction, WMH, and EPVS, as well as the underlying causes of CSVD pathology, including oxidative stress injury, decreased cerebral blood flow, structural and functional damage to endothelial cells, increased blood-brain barrier permeability, and inflammation. The use of this animal model will help identify new therapeutic targets and subsequently aid the development and testing of novel therapeutic interventions. Main process of the study: Firstly, we screened for optimal conditions for mimicking aging by injecting D-gal into rats for 4 and 8 weeks. Subsequently, we performed modified microcoil BCAS intervention for 4 and 8 weeks in rats to screen for optimal hypoperfusion conditions. Finally, based on these results, we combined D-gal for 8 weeks and modified microcoil BCAS for 4 weeks to explore the changes in SHR.

Optimal use of antithrombotic agents in recent small subcortical strokes accompanied by atrial fibrillation.

This study aimed to evaluate the efficacy and safety of anticoagulants (AC) and antiplatelets (APT) in patients with recent small subcortical infarctions (RSSI) and atrial fibrillation (AF). We utilized a prospective multicenter stroke registry database to identify patients with RSSI with a concurrent diagnosis of AF. Propensity score matching analysis was used to balance baseline differences among the AC-only, APT-only, and their combination groups. The main outcomes of interest were time to occurrence of minor and major bleeding, stroke recurrence, and all-cause mortality. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for each outcome were calculated using the multivariable Cox proportional hazard regression analysis. Of the 404 eligible patients, 28.2% received APT only, 53.0% received AC only, and 18.9% received a combination of both. Notable differences were observed between these groups in terms of the 1-year stroke recurrence (APT, 32.5%; AC, 5.6%; APT + AC, 9.2%) and all-cause mortality (APT, 21.9%; AC, 6.1%; APT + AC, 14.5%), whereas the rates of bleeding events were comparable. The multivariable analysis indicated a significant association of AC alone with reduced risks of severe bleeding, stroke recurrence, and all-cause mortality compared with APT alone (aHR 0.64, 95% CI 0.41-0.98; aHR 0.11, 95% CI 0.06-0.22; aHR 0.22, 95% CI 0.11-0.44, respectively). The combination group showed a reduced risk of stroke recurrence compared to APT alone (aHR 0.19, 95% CI 0.08-0.46). These findings remained consistent with the propensity score-matched analysis. AC showed better clinical outcomes than APT in patients with RSSI and AF. Additionally, combination therapy with AC and APT was associated with a lower risk of stroke recurrence than APT alone.

Recurrent cerebrovascular events after recent small subcortical infarction

BackgroundRecent small subcortical infarcts (RSSI) are the neuroimaging hallmark feature of small vessel disease (SVD)-related acute lacunar stroke. Long-term data on recurrent cerebrovascular events including their aetiology after RSSI are scarce.Patients and methodsThis retrospective study included all consecutive ischaemic stroke patients with an MRI-confirmed RSSI (in the supply area of a small single brain artery) at University Hospital Graz between 2008 and 2013. We investigated associations between clinical and SVD features on MRI (STRIVE criteria) and recurrent cerebrovascular events, using multivariable Cox regression adjusted for age, sex, vascular risk factors and MRI parameters.ResultsWe analysed 332 consecutive patients (mean age 68 years, 36% women; median follow-up time 12 years). A recurrent ischaemic cerebrovascular event occurred in 70 patients (21.1%; 54 ischaemic strokes, 22 transient ischaemic attacks) and was mainly attributed to SVD (68%). 26 patients (7.8%) developed intracranial haemorrhage. In multivariable analysis, diabetes (HR 2.43, 95% CI 1.44–3.88), severe white matter hyperintensities (HR 1.97, 95% CI 1.14–3.41), and cerebral microbleeds (HR 1.89, 95% CI 1.32–3.14) on baseline MRI were related to recurrent ischaemic stroke/TIA, while presence of cerebral microbleeds increased the risk for intracranial haemorrhage (HR 3.25, 95% CI 1.39–7.59). A widely used SVD summary score indicated high risks of recurrent ischaemic (HR 1.22, 95% CI 1.01–1.49) and haemorrhagic cerebrovascular events (HR 1.57, 95% CI 1.11–2.22).ConclusionPatients with RSSI have a substantial risk for recurrent cerebrovascular events—particularly those with coexisting chronic SVD features. Recurrent events are mainly related to SVD again.

Analysis of the Relationship between Recent Small Subcortical Infarcts and Autonomic Nervous Dysfunction.

Autonomic Nervous System (ANS) dysfunction may be involved in the pathogenesis of Cerebral Small Vessel Disease (CSVD). The study aimed to explore the relationship between Recent Small Subcortical Infarct (RSSI) and Blood Pressure Variability (BPV), and Heart Rate Variability (HRV). A total of 588 patients from the CSVD registration research database of Henan Province were included in this study, and were divided into two groups according to the presence of RSSI. Clinical data, including demographic characteristics, disease history, laboratory indexes, 24-hour ambulatory blood pressure and electrocardiogram indicators, and imaging markers of CSVD, were collected. Univariate and binary logistic regression analyses were used to study the relationship between RSSI and indicators of laboratory, HRV and BPV in the CSVD population. Multivariate analysis showed that higher 24-hour mean Diastolic Blood Pressure (DBP)[Odds Ratios (OR)=1.083,95% Confidence Intervals (CI)=(1.038,1.129), p < 0.001], Standard Deviation (SD) of 24-hour DBP [OR=1.059,95%CI=(1.000,1.121), p = 0.049], nocturnal mean Systolic Blood Pressure (SBP) [OR=1.020,95%CI=(1.004,1.035), p = 0.012], nocturnal mean DBP [OR=1.025,95%CI=(1.009,1.040), p = 0.002] were independent risk factors for RSSI. In contrast, the decrease of the standard deviation of N-N intervals (SDNN) [OR=0.994,95%CI=(0.989,1.000), p = 0.035] was beneficial to the occurrence of RSSI. In addition, neutrophil counts [OR=1.138,95%CI=(1.030,1.258), p = 0.011], total cholesterol (TC) [OR=1.203,95%CI=(1.008,1.437), p = 0.041] and High-Density Lipoprotein (HDL) [OR=0.391, 95%CI=(0.195,0.786), p = 0.008] were also independently associated with the occurrence of RSSI. After adjusting for confounding factors, except for TC, the other factors remained associated with the occurrence of RSSI. Increased 24-hour mean DBP, nocturnal mean SBP and DBP, SD of 24-hour DBP and decreased SDNN were independently correlated with RSSI occurrence, suggesting that sympathetic overactivity plays a role in the pathogenesis of RSSI.

Enlarged Perivascular Space in the Basal Ganglia is Associated with Cerebral Venous Reflux in Patients with Recent Small Subcortical Infarction.

Research has linked enlarged perivascular spaces (EPVS) to cerebral venous reflux (CVR) in patients with hypertensive intracerebral hemorrhage, but it is unclear whether this association exists in recent small subcortical infarct (RSSI) patients. This study aimed to investigate the correlation between EPVS and CVR in patients with RSSI. This study included 297 patients, selected from patients with RSSI in the lenticulostriate artery admitted to the Department of Neurology of the First Affiliated Hospital of Zhengzhou University. CVR was assessed by time-of-flight magnetic resonance angiography (TOF-MRA). The relationship between EPVS and CVR was studied using multiple logistic regression analysis. This study included patients with an average age of 59.84±12.27 years, including 201 males (67.7%). CVR was observed in 40 (13.5%) patients. Compared to the group without CVR, the proportions of male patients and patients with a history of smoking and drinking were higher in the CVR group. The proportions of high-grade EPVS in the centrum semiovale region [23 cases (57.5%) vs. 108 cases (42.0%), p =0.067] and the basal ganglia region [30 cases (75.0%) vs. 133 cases (51.8%), p =0.006] were higher in the CVR group. After multiple logistic regression analysis, high-grade EPVS in the basal ganglia region was still associated with CVR (OR, 2.68; 95% CI, 1.22-5.87;p=0.014). In the population with RSSI, EPVS in basal ganglia is significantly associated with CVR, suggesting a close relationship between venous dysfunction and the formation of EPVS.

Lesion Indexes Predict Early Neurologic Deterioration in Lenticulostriate Single Small Subcortical Infarction.

Early neurologic deterioration (END) often occurs during hospitalization in single small subcortical infarction (SSSI). The objective was to identify imaging predictors of END. SSSIs in the lenticulostriate artery within 72 hours of stroke onset from January 2015 to June 2021 were consecutively enrolled. The posteriority and laterality indexes were assessed on the second section from the top of the corona radiata section showing the lateral ventricle on DWI. A multivariate logistic analysis was used to explore the predictors of END. A total of 402 patients were included in this study, among whom 93 (23.1%) experienced END. The optimal cutoff points of the posteriority and laterality indexes for predicting END were given by a receiver operating characteristic curve. A multivariate logistic analysis showed that the posteriority index of ≥0.669 (OR: 2.53; 95% CI: 1.41-4.56; P = .002) and the laterality index of ≥0.950 (OR: 2.03; 95% CI: 1.03-4.00; P = .042) were independently associated with the risk of END. Accordingly, the SSSIs were further divided into 4 types: anterior lateral type (AL-type), anterior medial type (AM-type), posterior lateral type (PL-type), and posterior medial type (PM-type). After the multivariate analysis, in comparison with the AL-type, the AM-type (OR: 3.26; 95% CI: 1.10-9.65), PL-type (OR: 4.68; 95% CI: 1.41-15.56), and PM-type (OR: 6.77; 95% CI: 2.53-18.04) carried significantly elevated risks of END. The PM-type was associated with the highest risk of END. The PM-type was found to be associated with the highest risk of END.

Clinical Phenotypes Associated With Cerebral Small Vessel Disease: An Overview of Systematic Reviews.

Cerebral small vessel disease (cSVD) causes lacunar and hemorrhagic stroke and is an important contributor to vascular cognitive impairment. Other potential physical and psychological consequences of cSVD have been described across various body systems. Descriptions of cSVD are available in journals specific to those individual body systems, but a comprehensive assessment of clinical manifestations across this disparate literature is lacking. We conducted an overview of systematic reviews describing clinical cSVD phenotypes. We searched multidisciplinary databases from inception to December 2023. We included reviews describing concurrent clinical phenotypes in individuals with neuroimaging evidence of cSVD, defined using the STandards for ReportIng Vascular changes on nEuroimaging criteria. We broadly classified phenotypes into cognitive, mood and neuropsychiatric, respiratory, cardiovascular, renal-urinary, peripheral nervous system, locomotor, and gastrointestinal. We included both studies assessing multiple cSVD features and studies examining individual cSVD markers. We extracted risk factor-adjusted effect estimates, where possible, and assessed methodologic quality using the Assessment of Multiple Systematic Reviews-2 tool. After screening 6,156 publications, we included 24 systematic reviews reporting on 685 original studies and 1,135,943 participants. Cognitive and neuropsychiatric phenotypes were examined most often, particularly in relation to white matter hyperintensities (range of risk ratios [RRs] for cognitive phenotypes 1.21-1.49, range of 95% CI 1.01-1.84; for neuropsychiatric, RR 1.02-5.71, 95% CI 0.96-19.69). Two reviews focused solely on perivascular spaces. No reviews assessed lacunes or small subcortical infarcts separately from other cSVD features. Reviews on peripheral nervous system, urinary, or gastrointestinal phenotypes were lacking. Fourteen reviews had high methodologic quality, 5 had moderate quality, and 5 had low quality. Heterogeneity in cSVD definitions and phenotypic assessments was substantial. Neuroimaging markers of cSVD are associated with various clinical manifestations, suggesting a multisystem phenotype. However, features classically associated with cSVD, for example, gait, had limited supporting evidence, and for many body systems, there were no available reviews. Similarly, while white matter hyperintensities were relatively well studied, there were limited data on phenotypes associated with other cSVD features. Future studies should characterize the full clinical spectrum of cSVD and explore clinical associations beyond neurocognitive and neuropsychiatric presentations.

Correlations of Plasma Biomarkers and Imaging Characteristics of Cerebral Small Vessel Disease.

Cerebral small vessel disease (CSVD), which is a group of pathological processes affecting cerebral microvessels, leads to functional loss in the elderly population and mostly presents as cognitive impairment and gait decline. CSVD is diagnosed based on brain imaging biomarkers, but blood biomarkers are of great significance for the early diagnosis and progression prediction of CSVD and have become a research focus because of their noninvasiveness and easy accessibility. Notably, many blood biomarkers have been reported to be associated with CSVD in a relatively large population, particularly serum neurofilament light chain (NfL), which has been regarded as a promising biomarker to track the variation trend in WMH and to predict the further status of white matter hyperintensities (WMH) and lacunar infarcts. And neuro-glio-vascular unit structure and blood-brain barrier function have been proposed as underlying mechanisms of CSVD. The article starts from the neuroimaging markers of CSVD, including recent small subcortical infarcts (RSSI), white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMB), enlarged perivascular spaces (EPVS), cerebral atrophy, and the combined small vessel disease score, and attempts to systematically review and summarize the research progress regarding the blood biomarkers of CSVD that form the changes in the neuro-glio-vascular unit structure and blood-brain barrier function.

Modified Magnetic Resonance Imaging Burden of Cerebral Small Vessel Disease and Related Risk Factors in Patients With Thalassemia.

This study aimed to explore the burden of magnetic resonance imaging (MRI) of cerebral small vessel disease (CSVD) in patients with thalassemia and related risk factors. The clinical data and MRI of patients with thalassemia were retrospectively analyzed, and non-thalassemia controls with matched sex and age were selected. The modified MRI burden of CSVD included recent small subcortical infarct, presumed vasogenic white matter hyperintensity, presumed vasogenic lacunae, perivascular space (PVS), and brain atrophy. This study included 110 patients in each of the thalassemia and control groups. There was no significant difference in sex, age, and common cerebrovascular disease risk factors between the 2 groups. The patients with thalassemia had a higher red blood cell count and lower content of hemoglobin. The PVS and modified MRI burden scores in the thalassemia group were higher than in the control group. With the increase in age, patients with thalassemia have a more severe CSVD burden. Patients with thalassemia have a heavier modified MRI burden of CSVD than non-thalassemia patients, particularly PVS, and aging is an important risk factor for CSVD changes.

Abstract WP136: Impaired Venous Outflow Impacts Functional Outcomes in Acute Small Subcortical Infarcts: A Single-Center Retrospective Analysis

Introduction: Acute small subcortical infarcts (SSI), colloquially acute lacunar stroke, are a radiographic diagnosis representing a myriad of pathophysiologic processes. One such pathophysiologic subgroup is venous collagenosis which serves as a pathologic indicator that aberrant venous outflow may contribute to SSI development. We aimed to identify whether impaired venous outflow (IVO) impacted functional outcomes in individuals presenting with SSI. Methods: We performed a single-center retrospective study of individuals who presented to the Rhode Island Hospital Comprehensive Stroke Center. Included individuals were ≥ 18 years with the diagnosis of SSI, as defined per consensus criteria, on brain MRI diffusion weighted imaging. The primary exposure is the presence of impaired venous outflow (IVO) defined radiologically in accordance with prior studies, as hyperintensity of the jugular, sigmoid, or transverse sinuses along the skull base on MR angiogram time of flight, Figure. The primary outcome was a favorable function outcome at hospital discharge defined as a modified Rankin Scale (mRS) of ≤ 3. Standard descriptive and regression statistical techniques were used for data interpretation. Results: We identified 39 patients who met criteria with 12 (30.8%) with IVO. Age and vascular risk factors did not significantly differ amongst the cohort. Twenty-six (66.7%) had a favorable hospital discharge outcome favorable functional outcome with IVO being less common [IVO present: 5/26 (19.2%) versus LVO absent: 21/26, (80.8%), p = 0.034]]. After adjusting for age and hypertension, IVO was associated with an odds ratio of 8.33 (95%CI 1.41-49.3, p =0.019). Conclusion: We found that IVO may be an independent contributor to fewer favorable functional outcomes. This data highlights that not only the arterial vessels are of relevance in acute SSI.

Abstract 124: Pre-Stroke Aspirin Use Does Not Impact Small Subcortical Stroke Size: A Secondary Analysis of the SPS3 Trial

Introduction: The use of pre-stroke aspirin is associated with smaller stroke size in first-time stroke related to large vessel occlusion. However, it is unknown whether pre-stroke aspirin use impacts stroke size for an acute small subcortical infarct (SSI). We hypothesized that pre-stroke aspirin use would be associated with a smaller sized SSI. Methods: We performed a secondary analysis of the Secondary Prevention of Small Subcortical Strokes (SPS3) dataset which enrolled between 2003 and 2007. We included participants ≥ 55 years old with brain-MRI confirmed SSI being ≤ 20 mm in maximal diameter on diffusion weighted imaging. Stroke size was determined retrospectively by the study team on the index event brain MRI. Pre-stroke medications were recorded at the time of enrollment. Chi-squared and student’s T test were used for categorical and continuous variables, respectively. Binary logistic regression models were fitted for likelihood ratios. Results: Of the 3020 participants enrolled in SPS3, a total of 2183 met inclusion criteria: 663 with pre-stroke aspirin monotherapy and 1520 without pre-stroke antithrombotic use, Table 1. Those with aspirin use were older with a higher incidence of diagnoses of hypertension, hyperlipidemia, and diabetes mellitus, though otherwise sex, and tobacco use did not differ. The mean maximal stroke width, trended towards, but was not statistically impacted by pre-stroke aspirin use [pre-stroke aspirin: 11.8 (4.1) mm vs 11.4 (4.1) mm, p =0.065]. After adjustment for significant variables, pre-stroke aspirin use did not impact the odds of a larger infarct size (OR 0.779, 95%CI 0.615-1.04, p =0.092). Conclusion: Despite those with pre-stroke aspirin use having more vascular risk factors, its use did not impact stroke size amongst those with an acute SSI enrolled in the SPS3 trial.

Abstract TP253: Early Neurological Deterioration Following Small Subcortical Infarcts: A Systematic Review and Meta-Analysis

Background and Objectives: Acute small subcortical infarcts (SSI) result in high rates of early neurological deterioration (END) despite best medical management. Those with SSI-related END have worse functional outcomes after stroke leading to increased morbidity. Presently, it is unknown in a robust manner the incidence or risk factors for END within this demographic. The aim of this study was to perform a systematic review and meta-analysis to understand the incidence and risk factors of SSI-related END. Methods: We searched PubMed, Cochrane Library, and Google Scholar between January 1, 2000, and June 1, 2022, including both retrospective cross-sectional and prospective observational studies. The primary outcome was development of END based on publishing authors’ definition. Abstracted data included age, sex, cohort size, diagnoses of hypertension, hyperlipidemia, diabetes mellitus, study definition of END and SSI, and presence of branch atheromatous disease (BAD) and lesion diameter. Results: We identified 31 studies enrolling 6376 patients. Most studies were conducted in East Asia (27/31, 87%) and had a least some concern for risk of bias. Funnel plot illustrated a high level of publication bias favoring high incidence studies. END was commonly defined as ≥ 2 overall NIHSS change or ≥ 1 motor change within 3 to 7 days from admission (average: 5 days). A pooled proportion of END was 22% (95%CI 0.19 - 0.25, I2 = 91.2%, 31 studies). Meta-regression identified that female sex [risk ratio (RR) 1.23, 95%CI 1.09-1.39, I2=30.8%, 31 studies], diabetes mellitus (RR 1.16 95%CI 1.01-1.33, I2=38.4%, 30 studies), and BAD (RR 1.99 95%CI 1.61-2.46, I2=50.7%, 17 studies) as risk factors for END. Discussion: Our data identified primarily within an East Asian cohort that risk factors for SSI-related END include diabetes mellitus and branch atheromatous disease with a pooled prevalence of END occurring in 1 in 4 patients. Future studies are needed to understand treatment and preventative strategies for this patient population.