Cerebrotendinous xanthomatosis with tremor as the main manifestation: A case report.

INTRODUCTION: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid metabolism disorder. It is caused by a defect in the sterol-27-hydroxylase gene, leading to the deposition of cholesteryl and bile alcohol in large amounts, causing a variety of clinical manifestations; however, tremor as the main manifestation of CTX has not been reported. PATIENTS CONCERNS AND CLINICAL FINDINGS: Herein, we report a 27-year-old woman, who developed head and body tremors at the age of 12 years. Many hospitals misdiagnosed her condition as idiopathic tremor and Parkinson disease, with a poor curative effect. PRIMARY DIAGNOSIS AND INTERVENTION: We diagnosed her with CTX and treated with chenodeoxycholic acid and clonazepam. CONCLUSION: The patient's condition considerably improved. This case could help avoid misdiagnosis and mistreatment in clinical practice.

Clopidogrel Plus Aspirin vs Aspirin Alone in Patients With Acute Mild to Moderate Stroke: The ATAMIS Randomized Clinical Trial.

Importance: Dual antiplatelet therapy has been demonstrated to be superior to single antiplatelet in reducing recurrent stroke among patients with transient ischemic attack or minor stroke, but robust evidence for its effect in patients with mild to moderate ischemic stroke is lacking. Objective: To evaluate whether dual antiplatelet therapy is superior to single antiplatelet among patients with mild to moderate ischemic stroke. Design, Setting, and Participants: This was a multicenter, open-label, blinded end point, randomized clinical trial conducted at 66 hospitals in China from December 20, 2016, through August 9, 2022. The date of final follow-up was October 30, 2022. The analysis was reported on March 12, 2023. Of 3065 patients with ischemic stroke, 3000 patients with acute mild to moderate stroke within 48 hours of symptom onset were enrolled, after excluding 65 patients who did not meet eligibility criteria or had no randomization outcome. Interventions: Within 48 hours after symptom onset, patients were randomly assigned to receive clopidogrel plus aspirin (n = 1541) or aspirin alone (n = 1459) in a 1:1 ratio. Main Outcomes and Measures: The primary end point was early neurologic deterioration at 7 days, defined as an increase of 2 or more points in National Institutes of Health Stroke Scale (NIHSS) score, but not as a result of cerebral hemorrhage, compared with baseline. The superiority of clopidogrel plus aspirin to aspirin alone was assessed based on a modified intention-to-treat population, which included all randomized participants with at least 1 efficacy evaluation regardless of treatment allocation. Bleeding events were safety end points. Results: Of the 3000 randomized patients, 1942 (64.6%) were men, the mean (SD) age was 65.9 (10.6) years, median (IQR) NIHSS score at admission was 5 (4-6), and 1830 (61.0%) had a stroke of undetermined cause. A total of 2915 patients were included in the modified intention-to-treat analysis. Early neurologic deterioration occurred in 72 of 1502 (4.8%) in the dual antiplatelet therapy group vs 95 of 1413 (6.7%) in the aspirin alone group (risk difference -1.9%; 95% CI, -3.6 to -0.2; P = .03). Similar bleeding events were found between 2 groups. Conclusions and Relevance: Among Chinese patients with acute mild to moderate ischemic stroke, clopidogrel plus aspirin was superior to aspirin alone with regard to reducing early neurologic deterioration at 7 days with similar safety profile. These findings indicate that dual antiplatelet therapy may be a superior choice to aspirin alone in treating patients with acute mild to moderate stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT02869009.

A case of recurrent intracranial hemorrhage in CADASIL caused by NOTCH3 c.1759C>T heterozygous mutation.

BACKGROUND: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebrovascular disease that is closely related to the NOTCH3 gene. Recurrent ischemic stroke, progressive cognitive dysfunction, and mental symptoms are the main clinical manifestations, whereas symptomatic intracranial hemorrhage is rare. METHODS: We detected a heterozygous mutation of c.1759C>T in exon 11 of the NOTCH3 gene that caused recurrent intracranial hemorrhage in CADASIL. RESULTS: Second-generation sequencing of a sample of the patient's genome revealed a heterozygous mutation of c.1759C>T in exon 11 of NOTCH3, which resulted in amino acid changes (p.R587C). This variation may be rated as a CADASIL clinical variation. CONCLUSION: The discovery of this mutation site provides an important theoretical basis for a gene-based diagnosis and treatment of recurrent intracranial hemorrhage.

Chronic remote ischaemic conditioning in patients with symptomatic intracranial atherosclerotic stenosis (the RICA trial): a multicentre, randomised, double-blind sham-controlled trial in China.

BACKGROUND: Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide, and it is associated with a high risk of recurrent stroke with currently recommended treatments. We aimed to evaluate the effect of chronic remote ischaemic conditioning on prevention of ischaemic events in patients with symptomatic ICAS. METHODS: The RICA trial is a multicentre, randomised, double-blind, sham-controlled trial at 84 stroke centres in China. Patients aged 40-80 years with ischaemic stroke or transient ischaemic attack attributable to angiographically verified 50-99% stenosis of a major intracranial artery were randomly assigned (1:1), via an interactive web-based system by computer-generated randomisation code, to either remote ischaemic conditioning or sham remote ischaemic conditioning once daily for 12 months and voluntarily thereafter. All investigators and patients were masked to treatment allocation. The primary efficacy endpoint was the time to first occurrence of non-fatal or fatal ischaemic stroke, with survival analysed by the Kaplan-Meier method. Primary and safety analyses were done in the intention-to-treat population. The RICA trial is registered with ClinicalTrials.gov, number NCT02534545. FINDINGS: Between Oct 28, 2015, and Feb 28, 2019, 3033 patients were enrolled and randomly assigned to either remote ischaemic conditioning (n=1517; intervention group) or sham remote ischaemic conditioning (n=1516; sham group). Median follow-up was 3·5 years (IQR 2·7-4·4). A non-fatal or fatal ischaemic stroke occurred in 257 (16·9%) patients in the intervention group compared with 288 (19·0%) patients in sham group. There was no difference in the survival distribution for time to first occurrence of non-fatal or fatal ischaemic stroke (hazard ratio 0·87, 95% CI 0·74-1·03; p=0·12). In the intervention group, 79 (5·2%) patients died from any cause, and in the sham group, 84 (5·5%) patients died from any cause (hazard ratio 0·93, 95% CI 0·68-1·27; p=0·65). No intervention-related serious adverse events were observed. INTERPRETATION: No evidence was found for a difference between remote ischaemic conditioning and sham remote ischaemic conditioning in lowering the risk of ischaemic stroke in patients with symptomatic ICAS. The benefit of remote ischaemic conditioning might have been diluted by poor compliance. Future studies of remote ischaemic conditioning in this population should address challenges in patients' compliance and assess longer term treatment. FUNDING: Ministry of Science and Technology China, Beijing Municipal Education Commission, Beijing Municipal Finance Bureau. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Stroke incidence and cognitive outcomes of intracranial atherosclerotic stenosis: study protocol for a multicenter, prospective, observational cohort study.

Background: Intracranial atherosclerotic stenosis (ICAS) is one of the leading causes of stroke worldwide. Current diagnostic evaluations and treatments remain insufficient to assess the vulnerability of intracranial plaques and reduce the recurrence of stroke in symptomatic ICAS. On the other hand, asymptomatic ICAS is associated with an increased risk of cognitive impairment. The pathogenesis of ICAS related cognitive decline is largely unknown. The aim of SICO-ICAS study (stroke incidence and cognitive outcomes of ICAS) is to elucidate the pathophysiology of stroke and cognitive impairment in ICAS population, comprehensively evaluating the complex interactions among life-course exposure, genomic variation, vascular risk factors, cerebrovascular burden and coexisting neurodegeneration. Methods: SICO-ICAS is a multicenter, prospective, observational cohort study. We aim to recruit 3,000 patients with symptomatic or asymptomatic ICAS (>50% or occlusion) who will be followed up for ≥12 months. All participants will undergo pre-designed magnetic resonance imaging packages, blood biomarkers testing, as well as detailed cognitive domains assessment. All participants will undergo clinical visits every 6 months and telephone interviews every 3 months. The primary outcome measurement is ischemic stroke or cognitive impairment within 12 months after enrollment. Discussion: This study will establish a large prospective ICAS cohort, hopefully discover new biomarkers associated with vulnerable intracranial plaques, identify subjects at high risk for incident ischemic stroke or cognitive impairment, and eventually propose a precise diagnostic and treatment strategy for ICAS population. Trial Registration: Chinese Clinical Trials Register ChiCTR2200061938.

Distanct ischemic postconditioning in acute mild to moderate ischemic stroke: A randomized clinical study.

OBJECTIVE: Distant ischemic postconditioning (DIPC) has been confirmed to have a neuroprotective effect in animal models of ischemia. However, there are only a few studies on its efficacy and safety in clinical applications. METHOD: We divided 86 patients with acute non-cardiogenic mild to moderate cerebral infarction into DIPC and control groups. RESULT: After 7 days of using different pressure DIPC therapies, the National Institutes of Health Stroke Scale (NIHSS) scores on the eighth day significantly decreased, and modified Rankin scale significantly increased in the DIPC group, compared to that before treatment. On the eight day of admission, the decrease in the NIHSS scores significantly differed between the two groups. However, there was no change in the early neurological deterioration and platelet aggregation rates between the two groups on the eighth day. CONCLUSION: These results demonstrate that DIPC can safely and effectively improve neurological deficits in acute stages of mild to moderate cerebral infarction without affecting the efficacy of antiplatelet drugs.

A case of CADASIL caused by NOTCH3 c.512_605delinsA heterozygous mutation.

BACKGROUND: Autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebrovascular disease closely related to the NOTCH3 gene. More than 200 mutations in this gene have been reported to be associated with this disease. METHODS: The NOTCH3 gene from CADASIL patient was screened for mutations by whole-exome sequencing (WES). PCR amplification and direct Sanger sequencing were used to verify the suspicious gene mutation sites detected by WES. RESULTS: We performed second-generation sequencing on a sample of the patient's genome and found a heterozygous deletion-insertion mutation c.512_605delinsA in exon 4 of NOTCH3, which resulted in amino acid changes p.G171_A202delinsE. This variation was confirmed by the direct Sanger sequencing. It may be rated as a CADASIL clinical variation. CONCLUSION: Discovery of this mutation site provides an important theoretical basis for specific gene-based diagnosis and treatment of CADASIL.

Emodin relieves hypoxia-triggered injury via elevation of microRNA-25 in PC-12 cells.

Emodin (EMO) possesses extensive pharmacological activities, which has been proven to exert the protective impact in diverse nervous system diseases. Nonetheless, whether EMO emerges a neuro-protective activity in hypoxic-evoked ischemic brain injury is still further probed. The intention of the research is to disclose whether EMO emerges neuro-protective activity in hypoxic-evoked ischemic brain injury. PC-12 received hypoxia administration, and then cell viability, apoptosis and autophagy were estimated. After EMO disposition, the above-involved cellular processes were evaluated again. MiR-25 functions in EMO-affected cells were also estimated. The interrelation between miR-25 and neurofilament light-chain polypeptide gene (NEFL) and the conceivable roles of NEFL in hypoxia-disposed cells were investigated. The latent mechanism was uncovered by mTOR and Notch pathways determination. Hypoxia triumphantly triggered apoptosis and autophagy, but EMO repressed these functions in PC-12 cells. Increased miR-25 was induced by EMO, and inhibited miR-25 abated the impacts of EMO on hypoxia-disposed PC-12 cells. NEFL as a neoteric target gene of miR-25 was predicated, and overexpressed NEFL annulled the functions of EMO in hypoxia-injured cells. EMO activated mTOR and Notch pathways through repressing NEFL. The investigations corroborated that EMO weakened hypoxia-triggered injury via elevating miR-25 by targeting NEFL in PC-12 cells.

Neuroprotective effects and dynamic expressions of MMP9 and TIMP1 associated with atorvastatin pretreatment in ischemia-reperfusion rats.

Atorvastatin has been reported to ameliorate ischemic brain damage after stroke, but the underlying mechanisms are not clear. This study investigated the effect of atorvastatin on dynamic expressions of MMP9 and TIMP1 in rats after cerebral ischemia reperfusion (I/R). Atorvastatin (5 mgkg(-1)d(-1)) or vehicle was administered orally to rats for 21d before middle cerebral artery occlusion (MCAo) for 2h, with perfusion at 3-, 12-, 24-, 48-, or 96-h thereafter. To evaluate functional outcome, a 5-point behavioral rating scale was performed. Ischemic lesion volume was assessed via triphenyl tetrazolium chloride (TTC) staining. mRNA levels of MMP-9 and TIMP-1 were detected by reverse transcription-PCR, and protein levels of MMP-9 and TIMP-1 were measured by immunohistochemical SABC method. At all reperfusion time points, atorvastatin pretreatment was associated with significantly (P<0.05) improved neurological function and reduced brain infarct sizes compared with vehicle treatment, and MMP9 levels were significantly (P<0.05) lower and TIMP1 levels were significantly (P<0.05) higher in both mRNA and protein levels. In conclusion, Oral administration of atorvastatin before stroke may reduce the severity in I/R injury and improve neurological outcome by lowering MMP9 levels and elevating TIMP1 levels.

Inactivition of CDKL3 mildly inhibits proliferation of cells at VZ/SVZ in brain.

CDKL3 has an important role in regulating cell growth and/or differentiation, and its inactivation is recently reported to be related to non-syndromic mild mental retardation (MR). MR is a common neurological disorder, predominantly characterized by impaired cognitive function. Though genetic factors play a very important role in the pathogenesis of MR, to date, only few genes linked to MR have been characterized and understood very well. Here, we investigated the role of the CDKL3 in the proliferation of cells surrounding the brain ventricle, and the results showed down-regulating CDKL3 by the method of RNAi in the cells surrounding the brain ventricle of the mouse embryo at E15 may inhibit their proliferation. As our previous study had shown that Cdkl3 mRNA expression is developmentally regulated in the central nervous system, peaking during late embryonic and early postnatal stages which are the key stages of neurite formation and maturation, furtherly, the present findings indicated that CDKL3 may be involved in proliferation of cells surrounding the brain ventricle where neuronal progenitor cells are enriched during the late embryo stage, supporting the notion that CDKL3 inactivation contributes to non-syndromic mild MR.

The relationship between serum insulin-like growth factor I levels and ischemic stroke risk.

OBJECTIVE: The aim of the study was to assess the relationship between insulin-like growth factor I (IGF-I) serum levels and acute ischemic stroke (AIS) in a Chinese population. METHODS: All consecutive patients with first-ever AIS from August 1, 2011 to July 31, 2013 were recruited to participate in the study. The control group comprised 200 subjects matched for age, gender, and conventional vascular risk factors. IGF-I serum levels were determined by chemiluminescence immunoassay. The National Institutes of Health Stroke Scale (NIHSS) score was assessed on admission blinded to serum IGF-I levels. RESULTS: The median serum IGF-1 levels were significantly (P = 0.011) lower in AIS patients (129; IQR, 109-153 ng/mL) compared with control cases (140; IQR, 125-159 ng/mL). We found that an increased risk of AIS was associated with IGF-I levels ≤135 ng/mL (unadjusted OR: 4.17; 95% CI: 2.52-6.89; P = 0.000). This relationship was confirmed in the dose-response model. In multivariate analysis, there was still an increased risk of AIS associated with IGF-I levels ≤135 ng/mL (OR: 2.16; 95% CI:1.33-3.52; P = 0.002) after adjusting for possible confounders. CONCLUSION: Lower IGF-I levels are significantly related to risk of stroke, independent from other traditional and emerging risk factors, suggesting that they may play a role in the pathogenesis of AIS. Thus, strokes were more likely to occur in patients with low serum IGF-I levels in the Chinese population; further, post-ischemic IGF-I therapy may be beneficial for stroke.

Association between genetic polymorphism of xrcc1 gene and risk of Glioma in ? Chinese population.

BACKGROUND: Gliomas are the most common type of primary brain tumor in adults, and the X-ray repair complementing group 1 gene (XRCC1) is an important candidate gene influencing its risk. The objective of this study was to detect the influence of XRCC1 genetic polymorphisms on glioma risk. MATERIALS AND METHODS: A total of 629 glioma patients and 641 cancer-free subjects were enrolled in this case-control study. The genotypes of the c.1471G>A genetic polymorphism were determined by created restriction site-polymerase chain reaction (CRS-PCR) and DNA sequencing methods. The influence of the XRCC1 genetic polymorphism on glioma risk was evaluated by association analysis. RESULTS: Our data indicated that the alleles/genotype of this genetic variant was statistically associated with glioma risk. The AA genotype was statistically associated with the increased risk of glioma compared to the GG wild genotype (odds ratios (OR) = 1.89, 95% CI 1.25-2.87, P = 0.003). The allele-A may contribute to increased the susceptibility to glioma (OR = 1.23, 95% CI 1.04-1.46, P = 0.017). CONCLUSIONS: These preliminary findings indicate that the c.1471G>A genetic polymorphism of XRCC1 has the potential to influence glioma susceptibility, and might be used as molecular marker for assessing glioma risk.

In vivo measurement of oxygenation changes after stroke using susceptibility weighted imaging filtered phase data.

BACKGROUND AND PURPOSE: Cerebral blood oxygenation level is critical for following the evolution of stroke patients. The purpose of this study was to investigate the feasibility of measuring changes in blood oxygen levels for patients with acute stroke using SWI and to compare these changes with the patient's recovery over time. MATERIALS AND METHODS: A total 30 MRI scans was performed on 10 acute ischemic stroke patients. Every patient was followed at three time points: less than 24 hours; 2-3 weeks after stroke and 2 months after stroke. Both MRI scan and NIH stroke scale (NIHSS) were acquired for each patient at all three time points. Oxygen saturation changes were derived from phase values differences (Δφ) measured over 10 veins from each hemisphere for all 10 patients over 3 time points. The correlation of oxygen saturation and NIHSS was further evaluated. RESULTS: The stroke affected side of the brain showed moderate (r = -0.62) to strong (r = -0.70) correlation between the oxygenation change and NIHSS change. The oxygen saturation change from the normal side of the brain had essentially no association with recovery (r = -0.02 and-0.31). The results suggest that increases in oxygen saturation correspond to improved outcome and reductions in oxygen saturation correspond to worse outcome. CONCLUSION: High resolution SWI provided a novel method to measure changes in oxygenation change of the human brain in vivo. By using the phase values from the veins, both spatial and temporal information can be found that relates to patient outcome post stroke.

Plasma copeptin levels in Chinese patients with acute ischemic stroke: a preliminary study.

Copeptin is a stable by-product of arginine-vasopressin synthesis and reflects its secretion. The objective of the study was to evaluate the predictive value of copeptine on functional outcome at 90-day follow-up from stroke onset. We conducted a prospective, observational cohort study in the emergency department of two hospitals and enrolled 125 patients with acute ischemic stroke. Plasma copeptin concentrations, determined by a CT-proAVP-luminescence-immunoassay, were measured. There was a good correlation between levels of plasma copeptin and NIHSS score (r = 0.733, P < 0.01). In the 41 patients (32.8 %) with a poor functional outcome, copeptin levels were higher compared with those in patients with a favorable outcome (27.3; IQR, 14.9-34.8 pmol/L vs. 12.9; IQR, 9.4-21.6 pmol/L; P < 0.0001). Copeptin levels in 18 patients who died were more than two times greater as compared to patients who survived (32.4; IQR, 18.7-38.5 pmol/L vs. 15.1; IQR, 12.4-24.6 pmol/L; P < 0.0001). After adjusting for all other significant outcome predictors, copeptin level remained an independent predictor for poor functional outcome and mortality with an odds ratio of 3.12 (95 % CI 1.54-6.46), 3.16 (95 % CI 0.92-6.15), respectively. Our study suggests that copeptin levels are a useful tool to predict outcome and mortality 3 months after acute ischemic stroke and have a potential to assist clinicians.