Analysis of events from sudden isolated dysarthria to diagnosis of myasthenic crisis: myasthenia gravis mimicking acute lacunar stroke-a case report.

BACKGROUND: Myasthenic crisis (MC) is a life-threatening complication of myasthenia gravis (MG), necessitating ventilation. Achieving a safe and timely diagnosis of myasthenic crisis with atypical, isolated presentation is a considerable challenge particularly in elderly patients, where myasthenia gravis can present with isolated dysarthria in rare instances, giving a clinical impression of lacunar stroke. CASE PRESENTATION: We present a compelling case of a 73-year-old Caucasian female presenting with abrupt onset of isolated dysarthria. Despite initial treatment for a presumed lacunar stroke, subsequent evaluations led to her diagnosis of a myasthenic crisis. Within 72 h of admission, the patient developed dysphagia and shortness of breath, requiring supplemental oxygen. The case highlights the sequential progression of events from the atypical presentation of isolated dysarthria and its course to the management of a myasthenic crisis. CONCLUSION: Our reported case focuses on the discussion of myasthenia that mimicked a lacunar stroke and was finally diagnosed at a critical time of medical crisis. This case highlights the imperative notion that isolated dysarthria in elderly individuals warrants vigilant monitoring for possible myasthenia gravis, given the low incidence of lacunar stroke presenting with only dysarthria.

Serum erythropoietin in acute ischemic stroke: preliminary findings.

Ischemic stroke is the most common stroke, caused by occlusion of cerebral vessels and leading causes of disability. Erythropoietin (EPO) has non-hematopoietic effects as a neuroprotectant after ischemic event. This study aimed to learn the serum level of EPO in acute ischemic stroke. This cross-sectional study of ischemic stroke patients with onset < 24 h and consecutive sampling was used to collect the data from medical records review, physical examinations, head CT, 24-h EPO, 24-h and seventh-day NIHSS. A total of 47 patients consisting of 59.6% women, with a median age of 53 years old (21-70). The median 24 h EPO level was 808.6 pg/mL (134.2-2988.9). The relationship between 24 h-EPO and 24-h NIHSS were not significant (r = 0.101; p = 0.250), nor to 7th day NIHSS (r = - 0.0174; p = 0.121) and to delta NIHSS (r = 0.186; p = 0.106). The relationship of blood collection time (hour) and EPO was significant (r = - 0.260; p = 0.039). There was a statistically significant difference between serum EPO levels in ischemic stroke patients with lacunar stroke compared to non-lacunar stroke (288.5 vs. 855.4 ng/mL; p = 0.021). There was a relationship between the time of collection of blood and the level of EPO and also there was difference EPO level in lacunar stroke subtype compared with non-lacunar. The relationship between EPO and NIHSS lost significance after analysis. There is a need for a future study comparing each stroke risk factor and the same blood collection time.

European stroke organisation (ESO) guideline on cerebral small vessel disease, part 2, lacunar ischaemic stroke.

A quarter of ischaemic strokes are lacunar subtype, typically neurologically mild, usually resulting from intrinsic cerebral small vessel pathology, with risk factor profiles and outcome rates differing from other stroke subtypes. This European Stroke Organisation (ESO) guideline provides evidence-based recommendations to assist with clinical decisions about management of lacunar ischaemic stroke to prevent adverse clinical outcomes. The guideline was developed according to ESO standard operating procedures and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. We addressed acute treatment (including progressive lacunar stroke) and secondary prevention in lacunar ischaemic stroke, and prioritised the interventions of thrombolysis, antiplatelet drugs, blood pressure lowering, lipid lowering, lifestyle, and other interventions and their potential effects on the clinical outcomes recurrent stroke, dependency, major adverse cardiovascular events, death, cognitive decline, mobility, gait, or mood disorders. We systematically reviewed the literature, assessed the evidence and where feasible formulated evidence-based recommendations, and expert concensus statements. We found little direct evidence, mostly of low quality. We recommend that patients with suspected acute lacunar ischaemic stroke receive intravenous alteplase, antiplatelet drugs and avoid blood pressure lowering according to current acute ischaemic stroke guidelines. For secondary prevention, we recommend single antiplatelet treatment long-term, blood pressure control, and lipid lowering according to current guidelines. We recommend smoking cessation, regular exercise, other healthy lifestyle modifications, and avoid obesity for general health benefits. We cannot make any recommendation concerning progressive stroke or other drugs. Large randomised controlled trials with clinically important endpoints, including cognitive endpoints, are a priority for lacunar ischaemic stroke.

Trimethylamine N-Oxide and White Matter Hyperintensity Volume Among Patients With Acute Ischemic Stroke.

Importance: Although increasing evidence suggests that trimethylamine N-oxide (TMAO) is associated with atherosclerosis, little is known about whether TMAO and its related metabolites (ie, choline, betaine, and carnitine) are associated with small vessel disease. Objective: To evaluate the association between TMAO and its related metabolites with features of cerebral small vessel disease, including white matter hyperintensity volume (WMHV) and acute lacunar infarction. Design, Setting, and Participants: This cross-sectional study included patients enrolled in the Specialized Programs of Translational Research in Acute Stroke biorepository. The registry included 522 patients with acute ischemic stroke who were 18 years or older who presented at the Massachusetts General Hospital or Brigham and Women's Hospital within 9 hours after onset between January 2007 and April 2010. The analyses in this study were conducted between November 2022 and April 2023. Exposures: Plasma TMAO, choline, betaine, and carnitine were measured by liquid chromatography-tandem mass spectrometry. Main Outcomes and Measures: WMHV was quantified by a semiautomated approach using signal intensity threshold with subsequent manual editing. Ischemic stroke subtype was classified using the Causative Classification System. Results: Among 351 patients included in this study, the mean (SD) age was 69 (15) years; 209 patients (59.5%) were male and had a median (IQR) admission National Institute of Health Stroke Scale of 6 (3-13). The magnetic resonance imaging subgroup consisted of 291 patients with a mean (SD) age of 67 (15) years. Among these, the median (IQR) WMHV was 3.2 (1.31-8.4) cm3. TMAO was associated with WMHV after adjustment for age and sex (ß, 0.15; 95% CI, 0.01-0.29; P < .001). TMAO remained significant in a multivariate analysis adjusted for age, sex, hypertension, diabetes, and smoking (ß, 0.14; 95% CI, 0-0.29; P = .05). TMAO was associated with lacunar stroke but not other ischemic stroke subtypes in a model adjusted for age, sex, hypertension, diabetes, and smoking (OR, 1.67; 95% CI, 1.05-2.66; P = .03). Conclusions and Relevance: In this observational study, TMAO was associated with cerebral small vessel disease determined by WMHV and acute lacunar infarction. The association was independent of traditional vascular risk factors.

Brain MRI correlations with disease burden and biomarkers in Fabry disease.

OBJECTIVE: To quantitatively evaluate cerebral small vessel disease (CSVD) in brain magnetic resonance imaging (MRI) and its correlation with disease burden and markers in Fabry disease, a rare X-linked lysosomal storage disease. METHODS: We collected brain MRI data from seventy-one Chinese patients with Fabry disease. CSVD was evaluated using an age-related white matter change rating scale, Fazekas scale, enlarged perivascular spaces grading scale, lacunar infarction scale, Microbleed Anatomical Rating Scale, global cortical atrophy scale, and small-vessel disease score. Factors associated with MRI lesions, including sex, clinical subtype, disease severity, disease burden, genotype, and biomarkers, were also analyzed. RESULTS: Of 71 patients, 16 (22.5%) experienced ischemic stroke. The incidences of lacunar infarctions, white matter hyperintensities, and cerebral microbleeds were 55%, 62%, and 33%, respectively. The abnormal MRI group had later disease onset, longer disease duration, and a higher Mainz Severity Score Index (p < 0.05) than the normal MRI group. Patients with more severe clinical phenotypes also had higher CVSD-related scores. Sex and GLA mutational type were not closely associated with brain MRI lesions. Of the disease markers, the Mainz Severity Score Index and plasma globotriaosylsphingosine (Lyso-Gb3) were closely correlated with the majority of the MRI scores, whereas α-galactosidase A activity was not. CONCLUSION: Brain MRI revealed progressive lacunar infarctions, white matter hyperintensities, and decreased brain volume in patients with Fabry disease. Brain MRI lesions were closely related to onset-age; disease duration, severity, burden; and plasma Lyso-Gb3. However, they were not associated with sex, α-galactosidase A activity, or GLA mutation type.

Nocturnal Intermittent Hypoxia and the Risk of Cardiovascular Disease among Japanese Populations: The Circulatory Risk in Communities Study (CIRCS).

AIMS: Information is limited about the influence of obstructive sleep apnea (OSA) on developing cardiovascular disease (CVD) among Asian community-dwelling populations. We examined the association between nocturnal intermittent hypoxia as a surrogate marker of OSA and the risk of CVD in a Japanese community-based cohort study. METHODS: We used baseline surveys from 2000 to 2008 to study the cohort data of 5,313 residents from three Japanese communities who were between the ages of 40 and 74 years and initially free from ischemic heart disease and stroke. We assessed the number of 3% oxygen desaturation index (ODI) as the indicator of nocturnal intermittent hypoxia. We divided individuals into two groups depending on 3% ODI (3% ODI ≥ 5 or 3% ODI ＜5). Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD according to 3% ODI. Age, sex, body mass index, alcohol, and smoking were adjusted in the multivariable models. RESULTS: During 12.8 years of the median follow-up with 66,796 person-years, 185 cases with CVD (115 stroke and 70 coronary heart disease [CHD]) were recorded. The multivariable HRs (95% CIs) were 1.49 (1.09-2.03), 2.13 (1.08-4.22), and 1.93 (1.16-3.19) for the 3% ODI ≥ 5 group versus the 3% ODI ＜5 group of developing CVD, lacunar infarction, and CHD, respectively. CONCLUSIONS: Nocturnal intermittent hypoxia may increase the risk of developing lacunar infarction and CHD among community-dwelling Japanese populations. However, we could not find a significant risk of developing total stroke or stroke subtypes such as intraparenchymal hemorrhage, subarachnoid hemorrhage, and total ischemic stroke.

Exome-based gene panel analysis in a cohort of acute juvenile ischemic stroke patients:relevance of NOTCH3 and GLA variants.

BACKGROUND: Genetic variants are considered to have a crucial impact on the occurrence of ischemic stroke. In clinical routine, the diagnostic value of next-generation sequencing (NGS) in the medical clarification of acute juvenile stroke has not been investigated so far. MATERIAL AND METHODS: We analyzed an exome-based gene panel of 349 genes in 172 clinically well-characterized patients with magnetic resonance imaging (MRI)-proven, juvenile (age ≤ 55 years), ischemic stroke admitted to a single comprehensive stroke center. RESULTS: Monogenetic diseases causing ischemic stroke were observed in five patients (2.9%): In three patients with lacunar stroke (1.7%), we identified pathogenic variants in NOTCH3 causing cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Hence, CADASIL was identified at a frequency of 12.5% in the lacunar stroke subgroup. Further, in two male patients (1.2%) suffering from lacunar and cardioembolic stroke, pathogenic variants in GLA causing Fabry's disease were present. Additionally, genetic variants in monogenetic diseases lacking impact on stroke occurrence, variants of unclear significance (VUS) in monogenetic diseases, and (cardiovascular-) risk genes in ischemic stroke were observed in a total of 15 patients (15.7%). CONCLUSION: Genetic screening for Fabry's disease in cardioembolic and lacunar stroke as well as CADASIL in lacunar stroke might be beneficial in routine medical work-up of acute juvenile ischemic stroke.

[Clinical features, risk factors and prognosis of idiopathic dilated cardiomyopathy complicated by ischemic stroke].

Objective: To analyze the clinical features, risk factors and prognosis of idiopathic dilated cardiomyopathy (DCM) complicated with ischemic stroke (IS) (DCM-IS). Methods: The clinical data of patients with idiopathic DCM (n=613) in Beijing Anzhen Hospital, Liangxiang Hospital and Fuxing Hospital from January 2016 to December 2020 were retrospectively collected, and among them, 123 cases were DCM-IS. Clinical features of patients with DCM-IS were summarized and multivariate logistic regression model was utilized to analyze the independent risk factors of DCM-IS. Furthermore, 1-year follow-up was conducted and Kaplan-Meier curve was adopted to analyze the prognosis of DCM, using all-cause death and heart transplantation as adverse outcomes. Results: Among the 70 patients with DCM-IS, 6 patients (8.6%, 6/70) were in accordance with the subtype of large artery atherosclerosis, and 47 patients (67.1%, 47/70) were in line with the subtype of cardiogenic embolism, and small artery occlusion subtype (ie, lacunar infarction) were detected in 17 cases (24.3%, 17/70). Hypertension [odds ratio (OR)=1.617, 95% confidence interval (CI): 1.049-2.491, P=0.029], hyperlipidemia (OR=1.918, 95%CI: 1.198-3.073, P=0.007), atrial fibrillation (AF) (OR=1.617, 95%CI: 1.016-2.572, P=0.043), lower estimated glomerular filtration rate (eGFR) (OR=0.986, 95%CI: 0.977-0.996, P=0.005) and a higher incidence of intracardiac thrombus (OR=6.127, 95%CI: 3.174-11.827, P<0.001) were risk factors for DCM-IS. The overall 1-year survival rate was lower in DCM-IS patients (70.7%) than DCM patients without stroke (83.6%, P=0.004), and the main causes of death included obstinate heart failure (3 cases of DCM-IS, and 5 cases of non-DCM-IS) and malignant arrhythmia (DCM-IS) (22 cases of DCM-IS, and 18 cases of non-DCM-IS). Conclusions: Among IS patients with idiopathic DCM, cardioembolism is the most common, followed by lacunar infarction, and the large-artery atherosclerotic subtype is the least common.Hypertension, hyperlipidemia, AF, lower eGFR value and higher incidence of intracardiac thrombus are risk factors for DCM-IS. DCM patients complicated with IS have poor short-term prognosis, and obstinate heart failure and malignant arrhythmia are their main causes of death.

Annual exposure to PM10 is related to cerebral small vessel disease in general adult population.

Ambient air pollution is one of the most important global health issues. Although several studies have been reported the associations between air pollution and brain function or structure, impact of the air pollution on cerebral small vessel disease (cSVD) have rarely been explored in Asian adult population. We evaluated the association between exposure to air pollutants and cSVD in Korean asymptomatic adults. This cross-sectional study included 3257 participants of a health screening program from January 2006 to December 2013. All participants performed brain magnetic resonance imaging. To assess the cSVD, we considered three features such as white matter hyperintensities (WMH), silent lacunar infarction (SLI), and cerebral microbleeds (CMBs). The annual average exposure to air pollutants [particulate matter ≤ 10 µm in aerodynamic diameter (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO)] was generated. The mean [standard deviation (SD)] age of the total 3257 participants was 56.5 (9.5) years, and 54.0% of them were male. Among all the included participants, 273 (8.4%) had SLI and 135 (4.1%) had CMBs. The mean volume (± SD) of WMH was 2.72 ± 6.57 mL. In result of linear regression analysis, the volume of WMH was associated with various potential factors including age, height, weight, smoking and alcohol consumption status, blood pressure (BP), hypertension, and diabetes mellitus. SLI-positive group, compared to the SLI-negative group, was older, shorter, and had higher BP as well as higher frequency of hypertension and diabetes mellitus. After adjusting for covariates, the annual average concentration of PM10 was significantly associated with the volume of WMH [ß (95% CI) for Model 1 = 0.082 (0.038- 0.125), p < 0.001; ß (95% CI) for Model 2 = 0.060 (0.013, 0.107), p = 0.013]. CMBs were not associated with the annual average concentration of PM10. No significant associations of NO2, SO2, and CO with cSVD were observed. In conclusion, PM10 exposure is associated with significant increases in brain WMH' volume and silent lacunar infarcts in asymptomatic adults.

Characterization of the Retinal Microvasculature and FAZ Changes in Ischemic Stroke and Its Different Types.

Purpose: This study aimed to assess morphological changes in the retinal microvasculature and foveal avascular zone (FAZ) in patients with ischemic stroke and its different subtypes. Methods: Thirty-three patients with ischemic stroke (14 with nonlacunar infarction and 19 with lacunar infarction) and 27 control participants were enrolled in this study. Based on optical coherence tomography angiography (OCTA), three vascular parameters, including vascular area density, vascular fractal dimension (VFD), and vascular orientation distribution (VOD), and four FAZ-related parameters, including FAZ area, FAZ axis ratio (FAR), FAZ circularity (FC), and FAZ roundness, in the superficial capillary plexus (SCP) and deep capillary plexus (DCP) were extracted and analyzed. Results: Logistic regression results showed that worse best-corrected visual acuity (odds ratio [OR], 0.21), higher FAR (OR, 2.77) and lower FC (OR, 0.36) of the DCP were associated with ischemic stroke. Furthermore, lower VOD of the SCP was significantly associated with lacunar infarction compared with nonlacunar infarction. Conclusions: Our study shows that the FAR and FC of the DCP may be potential biomarkers of ischemic stroke. Moreover, we demonstrated that OCT showed specific damage patterns in retinal microvascular and macular morphology in different subtypes of ischemic stroke. Translational Relevance: This work lays the foundation for the pathophysiological characteristics of cerebrovascular diseases assisted by retinal imaging and artificial intelligence.

Allogeneic Hematopoietic Cell Transplantation for Patients With Deficiency of Adenosine Deaminase 2 (DADA2): Approaches, Obstacles and Special Considerations.

Deficiency of adenosine deaminase 2 (DADA2) is an inherited autosomal recessive disease characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages, end organ vasculitis), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure. Allogeneic hematopoietic cell transplantation (HCT) is curative for DADA2 as it reverses the hematological, immune and vascular phenotype of DADA2. The primary goal of HCT in DADA2, like in other non-malignant diseases, is engraftment with the establishment of normal hematopoiesis and normal immune function. Strategies in selecting a preparative regimen should take into consideration the specific vulnerabilities to endothelial dysfunction and liver toxicity in DADA2 patients. Overcoming an increased risk of graft rejection while minimizing organ toxicity, graft-versus-host disease, and infections can be particularly challenging in DADA2 patients. This review will discuss approaches to HCT in DADA2 patients including disease-specific considerations, barriers to successful engraftment, post-HCT complications, and clinical outcomes of published patients with DADA2 who have undergone HCT to date.

[A case of intravascular large B-cell lymphoma manifested as lacunar infarction].

A 79-year-old man was admitted to our hospital because of sudden onset of left ataxic hemiparesis. Brain MRI diffusion weighted images showed typical lacunar infarction on the right internal capsule. He had no risk factors of cerebrovascular disorder such as hypertension, diabetes mellitus, hyperlipidemia and arrhythmia. On admission, he had a slight fever and his laboratory data showed anemia, thrombocytopenia and elevation of CRP and LDH. Intravascular large B-cell lymphoma (IVLBCL) was suspected because the serum level of soluble IL-2 receptor was also elevated. Pathological diagnosis of IVLBCL was underwent by the skin biopsy from his senile hemangiomas. Although IVLBCL was known to demonstrate various CNS lesions, it is extremely rare to be manifested as a single lacunar infarction, and this case must be important for the differential diagnosis.

Asymptomatic cerebral findings on 3-Tesla MRI in patients with severe carotid artery stenoses.

BACKGROUND AND PURPOSE: Small vessel diseases (SVDs) are often asymptomatic. However, SVDs significantly influence the prognosis in patients with large vessel diseases (LVDs). We investigated asymptomatic cerebral findings on 3-Tesla MRI in patients with severe carotid artery (CA) stenoses, compared to peoples without a past history of neurological disorders, including strokes. METHODS: We retrospectively analyzed the prevalences of various asymptomatic cerebral findings which were intracerebral hemorrhages (ICHs), cortical superficial siderosis, ventricular dilatation (Evans' index) and SVDs including cerebral microbleeds (CMBs), lacunar infarctions (LIs), deep white matter hyperintensities (WMHs), periventricular hyperintensities (PVHs). The prevalence of each finding was compared using multivariate logistic regression models with adjustment for stroke risk factors. RESULTS: We evaluated the findings in 54 patients with severe CA stenosis treated by stenting (CA stenosis group) and 200 adults with health screening tests of the brain and no past history of neurological disorders (control group). Multivariate analyses adjusted for age ≥ 65 years old, female gender, hypertension, hyperlipidemia, diabetes mellitus, alcohol consumption, and smoking index revealed that the prevalences of severe PVHs, severe deep WMHs, asymptomatic deep ICHs, and asymptomatic LIs were significantly higher in the CA stenosis group than the control group. However, there were no significant differences in the prevalences of CMBs, or the remaining asymptomatic findings described above. CONCLUSIONS: With pathological differences between SVD and LVD, asymptomatic SVDs except CMBs and deep ICHs often co-exists severe CA stenosis as a presentative LVD.

sTWEAK is a leukoaraiosis biomarker associated with neurovascular angiopathy.

OBJECTIVE: Leukoaraiosis (LA) refers to white matter lesions of undetermined etiology associated with the appearance and worsening of vascular pathologies. The aim is to confirm an increased frequency and intensity of LA in symptomatic patients with neurovascular pathology compared with asymptomatic subjects, and its association with circulating serum levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK). METHODS: An observational study was conducted in which two groups of patients were compared. Group I (N = 242) comprised of asymptomatic subjects with arterial hypertension and/or diabetes or with a history of transient ischemic attacks, and Group II (N = 382) comprised patients with lacunar stroke or deep hemispheric intracerebral hemorrhage (ICH) of hypertensive origin. Serum levels of sTWEAK were analyzed and correlated with prevalence and intensity of LA according to the Fazekas scale. RESULTS: The prevalence of LA was higher in symptomatic (85.1%) versus asymptomatic patients (62.0%). Logistic regression model showed a significant relation of LA with neurovascular pathologies (OR: 2.69, IC 95%: 1.10-6.59, p = 0.003). When stratified according to the Fazekas scale, LA of grade II (OR: 3.53, IC 95%: 1.10-6.59, p = 0.003) and specially grade III (OR: 4.66, 95% CI: 1.09-19.84, p = 0.037) showed correlation with neurovascular pathologies. Increased sTWEAK levels were found in the symptomatic group in all LA grades (p < 0.0001), and associated with 5.06 times more risk of presenting clinical symptoms (OR: 5.06, 95% CI: 2.66-9.75, p < 0.0001). INTERPRETATION: LA showed a higher prevalence in patients with symptomatic lacunar stroke or deep hemispheric ICH. There is an association between sTWEAK levels and LA degree.

A Novel Mutation in COL4A1 Gene in a Chinese Family with Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy.

Pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) is a rare hereditary cerebral small vessel disease. We report a novel collagen type IV alpha 1 (COL4A1) gene mutation in a Chinese family with PADMAL. The index case was followed up for 6 years. Neuroimaging, whole-exome sequencing, skin biopsy, and pedigree analysis were performed. She initially presented with minor head injury at age 38. MRI brain showed chronic lacunar infarcts in the pons, left thalamus, and right centrum semiovale. Extensive workup was unremarkable except for a patent foramen ovale (PFO). Despite anticoagulation, PFO closure, and antiplatelet therapy, the patient had recurrent lacunar infarcts in the pons and deep white matter, as well as subcortical microhemorrhages. Whole-exome sequencing demonstrated a novel c.*34G > T mutation in the 3' untranslated region of COL4A1 gene. Skin biopsy subsequently demonstrated thickening of vascular basement membrane, proliferation of endothelial cells, and stenosis of vascular lumen. Three additional family members had gene testing and 2 of them were found to have the same heterozygous mutation. Of the 18 individuals in the pedigree of 3 generations, 12 had clinical and MRI evidence of PADMAL. The mechanisms of both ischemic and hemorrhagic stroke are likely the overexpression of COLT4A1 in the basement membrane and frugality of the vessel walls. Our findings suggest that the novel c.*34G > T mutation appears to have the same functional consequences as the previously reported COL4A1 gene mutations in patients with PADMAL and multi-infarct dementia of Swedish type.

Effect of folic acid combined with pravastatin on arteriosclerosis in elderly hypertensive patients with lacunar infarction.

ABSTRACT: This study aimed to assess the effect of folic acid combined with pravastatin on atherosclerosis-related indexes in elderly patients with hypertension complicated with lacunar cerebral infarction.A total of 134 elderly hypertensive patients with lacunar cerebral infarction were randomly divided into 3 groups using the random number table method. Group A, the folic acid group, had 45 cases and received low-dose folic acid (0.8 mg/d) treatment on the basis of antihypertensive treatment. Group B, the pravastatin group, had 45 cases and received pravastatin (20 mg/d) treatment on the basis of antihypertensive treatment. Group C, the folic acid combined with the pravastatin group, had 44 cases. Members of this group received pravastatin (20 mg/d) and low-dose folic acid (0.8 mg/d) based on antihypertensive treatment. Levels of folic acid, homocysteine (Hcy), tumor necrosis factor alpha (TNF-a), matrix metallopeptidase 9 (MMP-9), cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) were measured by ELISA before treatment in all 3 groups. Carotid intima-media thickness (IMT) was measured using ultrasound, and systolic and diastolic blood pressure were measured with a mercury column. After 8 weeks of treatment, the levels of folic acid, Hcy, TNF-a, MMP-9, TC, LDL-C, and systolic and diastolic blood pressure were compared among the 3 groups. IMT levels were measured at 12 weeks of treatment.After 8 weeks of treatment, compared with group B, patients in groups A and C had folic acid levels significantly higher than baseline levels, with significantly lower Hcy levels (both P < .05). Patients in group C presented significantly decreased TNF-a, MMP-9, TC, and LDL-C levels and systolic and diastolic blood pressure after 8 weeks of treatment, compared with those in groups A and B (both P < .05). These patients also showed significantly decreased IMT levels compared with those in the other groups (P < .05).Low-dose folic acid combined with pravastatin in elderly patients with lacunar cerebral infarction can reduce the level of homocysteine, improve the degree of carotid atherosclerosis, protect vascular endothelium, and reduce blood lipids and blood pressure, presenting better benefits than pravastatin alone.

Association of Left Ventricular Hypertrophy and Atrial Fibrillation with Hemorrhagic Evolution of Small Vessel Disease.

OBJECTIVES: Cerebral small vessel disease (SVD) is often associated with hypertension and may evolve towards intracerebral hemorrhage (ICH) or lacunar ischemic stroke. However, the factors favoring the evolution towards ICH or lacunar stroke are not well understood. MATERIALS AND METHODS: This retrospective study included 326 consecutive patients (71.1±13.2 years, 38% women): 143 with deep ICH and 183 with lacunar lesions (LL) <2 cm, which were visible in a deep location on brain CT scan. Among LL patients, 143 had a small-artery occlusion (SAO) stroke according to the TOAST classification. Clinical characteristics plus laboratory and neuroradiological variables of these patients had been prospectively collected and a subgroup underwent echocardiography. RESULTS: In multivariate analysis, ICH patients (97% hypertensive), compared to SAO patients (89% hypertensive), had greater left ventricular wall thickness (LVWT; OR 4.15, 95%CI 1.64-10.53, for those with LVWT ≥ 1.4 cm, 70% of whom were hemorrhagic) and lower prevalence of white matter lesions (OR 0.30, 95%CI 0.13-0.70), ever smokers (OR 0.39, 95%CI 0.18-0.82) and diabetics (OR 0.29, 95% CI 0.10-0.84). Moreover, ICH patients had a greater prevalence of atrial fibrillation than LL patients (OR 3.14, 95%CI 1.11-8.93), and so they were more often anticoagulated. CONCLUSIONS: Most SVD patients were hypertensive, but those evolving towards ICH were characterized by organ damage at the cardiac level (increase in LVWT and atrial fibrillation), while those evolving towards lacunar stroke were characterized by a higher prevalence of smokers and diabetics, and by organ damage at the cerebral level (white matter lesions).

Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies.

BACKGROUND: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. METHODS: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. FINDINGS: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. INTERPRETATION: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-ß signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. FUNDING: British Heart Foundation.

Transient Receptor Potential Melastatin 3 Is Functionally Expressed in Oligodendrocyte Precursor Cells and Is Upregulated in Ischemic Demyelinated Lesions.

Oligodendrocyte precursor cells (OPCs) are glial cells that differentiate into oligodendrocytes and myelinate axons. The number of OPCs is reportedly increased in brain lesions in some demyelinating diseases and during ischemia; however, these cells also secrete cytokines and elicit both protective and deleterious effects in response to brain injury. The mechanism regulating the behaviors of OPCs in physiological and pathological conditions must be elucidated to control these cells and to treat demyelinating diseases. Here, we focused on transient receptor potential melastatin 3 (TRPM3), a Ca2+-permeable channel that is activated by the neurosteroid pregnenolone sulfate (PS) and body temperature. Trpm3+/Pdgfra+ OPCs were detected in the cerebral cortex (CTX) and corpus callosum (CC) of P4 and adult rats by in situ hybridization. Trpm3 expression was detected in primary cultured rat OPCs and was increased by treatment with tumor necrosis factor α (TNFα). Application of PS (30-100 µM) increased the Ca2+ concentration in OPCs and this effect was inhibited by co-treatment with the TRP channel blocker Gd3+ (100 µM) or the TRPM3 inhibitor isosakuranetin (10 µM). Stimulation of TRPM3 with PS (50 µM) did not affect the differentiation or migration of OPCs. The number of Trpm3+ OPCs was markedly increased in demyelinated lesions in an endothelin-1 (ET-1)-induced ischemic rat model. In conclusion, TRPM3 is functionally expressed in OPCs in vivo and in vitro and is upregulated in inflammatory conditions such as ischemic insults and TNFα treatment, implying that TRPM3 is involved in the regulation of specific behaviors of OPCs in pathological conditions.

Chronic kidney disease correlates with MRI findings of cerebral small vessel disease.

Objective: Cerebral small vessel disease (CSVD) and chronic kidney disease (CKD) may be part of a multisystem small-vessel disorder. Since the kidney and brain share unique susceptibilities to vascular injury, kidney impairment may be predictive of the presence and severity of CSVD. This study explored the relationship between CSVD and CKD. Methods: Between December 2015 and December 2017 (follow-up 10-20 months) 52 patients with chronic nephritis and CKD were classified into a progressive group (n = 17) and stable group (n = 35). Age, gender, hypertension, diabetes and smoking were matched between groups. CSVD features of both groups, including enlarged Virchow-Robin spaces (VRS), white matter lesions (WML), lacunar infarcts (LI), and cerebral microbleeds (CMB) were evaluated by magnetic resonance (MR) imaging. Results: WML and CMB in the progressive group were exacerbated at follow-up compared to initial exam (p = 0.004 and 0.041, respectively). There was no significant change in VRS, WML, LI, or CMB in the stable group at follow-up compared to initial exam. CMB were significantly different between the progressive group and stable group at follow-up.etimtaed Glomerular filtration rate (eGFR) was significantly correlated with VRS, WML, and CMB at follow-up (p = 0.037, 0.041, and 0.009, respectively). Conclusions: Patients with progressive CKD have a higher prevalence and severity of CSVD, which correlates with deterioration of renal function as assessed by decreased eGFR. Thus EGFR may also be of value in the prediction of cerebral small vessel disease.