Characteristics and Mechanism of Acute Ischemic Stroke in NAVF Patients With Prior Oral Anticoagulant Therapy.

OBJECTIVES: We aimed to analyze the characteristics and mechanisms of acute ischemic stroke (AIS) in patients with nonvalvular atrial fibrillation (NVAF) who received prior anticoagulant therapy. METHODS: We retrospectively analyzed the data of patients with NVAF and AIS between January 2016 and December 2021. Patients were divided into non-anticoagulant, adequate anticoagulant, and insufficient anticoagulant groups according to their prior anticoagulant status. Patients with prior anticoagulant therapy were further divided into warfarin and direct oral anticoagulant groups. RESULTS: A total of 749 patients (661 without anticoagulants, 33 with adequate anticoagulants, and 55 with insufficient anticoagulants) were included. Patients with adequate anticoagulant had a milder National Institute of Health Stroke Scale at presentation ( P =0.001) and discharge ( P =0.003), a higher proportion of Modified Rankin Scale (mRS) ≤2 at discharge ( P =0.011), and lower rates of massive infarction ( P =0.008) than patients without anticoagulant. Compared with the non-anticoagulant group, the proportion of intravenous thrombolysis was significantly lower in the adequate anticoagulant ( P <0.001) and insufficient anticoagulant ( P =0.009) groups. Patients in the adequate anticoagulant group had higher rates of responsible cerebral atherosclerotic stenosis ( P =0.001 and 0.006, respectively) and competing large artery atherosclerotic mechanisms ( P =0.006 and 0.009, respectively) than those in the other 2 groups. Compared with warfarin, direct oral anticoagulant was associated with higher rates of Modified Rankin Scale ≤2 at discharge ( P =0.003). CONCLUSIONS: Adequate anticoagulant therapy may be associated with milder stroke severity and better outcomes at discharge in patients with NVAF. Competing large artery atherosclerotic mechanisms may be associated with anticoagulant failure in patients with NAVF with prior adequate anticoagulant therapy.

Changing trends and factors influencing anticoagulant use in patients with acute ischemic stroke and NVAF at discharge in the NOACs era.

OBJECTIVES: We sought to explore the trends and influencing factors of the use of anticoagulants in patients with acute ischemic stroke and non-valvular atrial fibrillation (NVAF) at discharge in the era of novel oral anticoagulants (NOACs). METHODS: We recruited consecutive inpatients with acute ischemic stroke and NVAF in a registered study (NCT04080830) from January 2016 to December 2021. The relevant data of patients were collected. We compared the proportions of anticoagulant treatment at discharge before and after NOACs entered China's medical insurance system. The proportion of each antithrombotic status as well as anticoagulant agents at discharge in every year were calculated, and the trends during the study period were analyzed. The relevant factors affecting anticoagulant use at discharge were further analyzed. RESULTS: The proportion of anticoagulation at discharge increased significantly after NOACs entered China's medical insurance system in 2018 versus before (χ2 = 42.828, P < 0.001). There were statistically significant differences in antithrombotic status (χ2 = 69.954, P < 0.001) and in the proportion of different anticoagulant drugs (χ2 = 63.049, P<0.001) by year. Anticoagulant therapy (χ2 = 1.55, P = 0.671) and NOACs (χ2 = .178, P = 0.243) increased over 2016-2018 but was relatively stable during 2018-2021. Multivariate logistic regression analysis showed that age ≥75 years, coexisting cerebral artery stenosis, massive cerebral infarction and hemorrhagic transformation were independent risk factors affecting anticoagulants use (all P < 0.05). CONCLUSION: NOACs have indeed improved anticoagulants use in patients with acute ischemic stroke and NVAF at discharge. However, some specific factors affect anticoagulation therapy use at discharge and hinder further improvement even in the NOACs era.

Bow Hunter's syndrome combined with ipsilateral vertebral artery dissection/pseudoaneurysm: case study and literature review.

BACKGROUND: Bow hunter's syndrome (BHS), also known as rotational vertebral artery occlusion syndrome, is rare. Occasionally, it combines with dissection/pseudoaneurysm of the ipsilateral VA. METHODS: We report a case of BHS combined with ipsilateral VA dissection/pseudoaneurysm and review eight similar cases reported in the literature. Their aetiology, clinical and imaging features, treatment, and prognosis were analysed. RESULTS: Nine patients (seven male, two female; average age 22.0 ± 4.5 years) were enrolled. Visual symptoms comprised the most common clinical finding (66.7%, 7/9). Clinical symptoms were not related to neck rotation in seven patients (77.8%). Eight patients (88.9%) had multiple, scattered, new and old infarctions of the posterior circulation revealed on computed tomography/magnetic resonance imaging (CT/MRI) scans. Dissection/pseudoaneurysm was found in the ipsilateral VA - usually subtle and localised in the atlas, axis, and occipital bone - in all nine patients. Seven patients (66.7%) had special causes for the syndrome (i.e. congenital bone dysplasia). Altogether, 87.5% (7/8) experienced recurrence with cerebral infarction after antithrombotic therapy alone. Aetiologically targeted treatment, including surgical decompression or vertebral fixation, was performed in seven patients (77.8%). CONCLUSION: Young patients presenting with cryptogenic stroke in the posterior circulation and localised, subtle dissection/pseudoaneurysm of the ipsilateral VA around the atlanto-axial joint should undergo carotid ultrasonography with a neck rotation test or dynamic CT angiography/MR angiography/digital subtraction angiography, if necessary, to rule out/diagnose BHS.

A Whole-Scope Evaluation of Cervicocephalic Atherosclerotic Burden is Essential to Predict 90-Day Functional Outcome in Large-Artery Atherosclerotic Stroke.

AIM: Cervicocephalic atherosclerosis (AS) of patients with large-artery atherosclerotic (LAA) stroke might be more closely correlated to the functional outcome than patients with stroke of other etiologies. We aimed to investigate whether a whole-scope evaluation of cervicocephalic AS condition was better at predicting the 90-day functional outcome of LAA stroke than evaluation of intracranial or cervical AS condition alone. METHODS: Patients with LAA stroke were consecutively enrolled in this study. Computed tomography angiography was performed to evaluate AS condition of various cervicocephalic arterial segments. AS conditions ranging from no AS plaque to complete arterial occlusion scored 0-4 points. Intracranial atherosclerotic burden (IAB) and cervical atherosclerotic burden (CAB) were in respective the sums of AS scores of all intracranial arterial segments and all cervical arterial segments. And the sum of them was intracranial and cervical atherosclerotic burden (ICAB). Relationships of these three scores with the 90-day unfavorable functional outcome (modified Rankin Scale[mRS] score ＞2 points) were compared. RESULTS: Of 172 patients who finished 90-day follow-up, only ICAB (adjusted odds ratio[OR]=1.10, 95% confidence interval[CI]:1.00-1.21, p=0.044) predicted 90-day unfavorable functional outcome independently of clinical factors, National Institutes of Health Stroke Scale (NIHSS) and mRS scores at admission. ICAB (adjusted hazard ratio[HR]=1.16, 95%CI:1.02-1.32, p=0.029) was related to 90-day recurrent ischemic stroke/death independently of clinical factors and was independently, positively correlated with NIHSS score at admission (r=0.16, p=0.047), whereas IAB and CAB were not. CONCLUSION: A whole-scope evaluation of cervicocephalic AS condition using ICAB outperformed evaluation of intracranial or cervical AS condition alone in predicting 90-day functional outcome of patients with LAA stroke.

Prognosis and Predictors of Symptomatic Intracranial Hemorrhage After Endovascular Treatment of Large Vessel Occlusion Stroke.

BACKGROUND: Symptomatic intracranial hemorrhage (sICH) is a devastating complication of endovascular treatment (EVT) in patients with acute ischemic stroke (AIS) and is associated with high risk of disability and mortality. This study intended to evaluate the predictors of sICH after EVT in patients with large vessel occlusion (LVO)-induced AIS. METHODS: We conducted a retrospective review on consecutive AIS patients who underwent EVT in our University hospital between January 2019 and August 2020. The patients were classified into two groups based upon the occurrence of sICH. The main outcomes were the occurrence of sICH using the Heidelberg Bleeding Classification and functional condition at 90 days. Multivariate logistic regression analysis and receiver operating characteristics (ROC) curves were used to identify independent predictors of sICH after EVT. RESULTS: Three hundred and 69 patients were enrolled in the study, of which 16.8% (n = 62) developed sICH. Favorable neurological outcome was lower in patients with sICH than in patients without sICH (6.5 vs. 43.3%; P < 0.001), with the overall mortality being 112 (30.4%) at 90 days post- EVT. Results from univariate analysis showed significant differences between the two groups in the prevalence of diabetes, initial Alberta Stroke Program Early CT Score (ASPECTS) score, National Institutes of Health Stroke Scale (NIHSS) score after operation, the levels of fasting blood glucose (FBG), neutrophil to lymphocyte ratio (NLR), platelets (PLT), and thrombin time (TT) at admission. Multivariate logistic regression analysis showed that FBG ≥ 7.54 mmol/L (OR: 2.765; 95% confidence interval [CI]: 1.513-5.054), NLR ≥ 5.48 (OR: 2.711; 95% CI: 1.433-5.128), TT at admission ≥ 16.25 s (OR: 2.022; 95% CI: 1.115-3.667), and NIHSS score within 24 h after the operation ≥ 10 (OR: 3.728; 95% CI: 1.516-9.170) were independent predictors of sICH. The combination of NLR ≥ 5.48, FBG ≥ 7.54 mmol/L, TT at admission ≥ 16.25 s, and NIHSS score within 24 h after the operation ≥ 10 generated an optimal prediction model (AUC: 0.723). CONCLUSION: Higher levels of FDG, NLR, TT at admission, and NIHSS score after operation were associated with sICH after EVT in patients with LVO-induced AIS.

Preventing Ischemic Cerebrovascular Events in High-Risk Patients With Non-disabling Ischemic Cerebrovascular Events Using Remote Ischemic Conditioning: A Single-Arm Study.

Background: Secondary stroke prevention after a high-risk, non-disabling ischemic cerebrovascular event needs to be enhanced. The study was conducted to investigate whether remote ischemic conditioning (RIC) is effective in preventing recurrent ischemic events within 3 months. Methods: This was a four-center, single-arm, open-label Phase IIa futility trial (PICNIC-One Study). Adult patients (≥18 years of age) who had an acute minor ischemic stroke (AMIS) with a National Institutes of Health Stroke Scale score ≤ 3 or a transient ischemic attack (TIA) with moderate-to-high risk of stroke recurrence (ABCD score ≥ 4) within 14 days of symptom onset were recruited. Patients received RIC as adjunctive therapy to routine secondary stroke prevention regimen. RIC consisted of five cycles of 5-min inflation (200 mmHg) and 5-min deflation of cuffs (45 min) on bilateral upper limbs twice a day for 90 days. Results: A total of 285 patients met the study criteria, of which 167 provided signed informed consent and were enrolled. Data from 162 were analyzed with five subjects excluded. Recurrent AIS/TIA occurred in 6/162 (3.7%) patients within 3 months, with no occurrence of hemorrhagic stroke. The top three adverse events were upper limb pain (44/162, 27.2%), petechia (26/162, 16.0%), and heart palpitation (5/162, 3.1%). About 68 (42.0%) subjects completed ≥ 50% of 45-min RIC sessions. Conclusions: RIC is a safe add-on procedure and it has a potential benefit in reducing recurrent cerebrovascular events in patients with high-risk, non-disabling ischemic cerebrovascular events as the risk of stroke/TIA events is lower than expected; however, its compliance needs to be improved. Our study provides critical preliminary data to plan a large sample size, randomized controlled clinical study to systematically investigate the safety and efficacy of RIC in this population.

Profiles of Vertebral Artery Dissection with Congenital Craniovertebral Junction Malformation: Four New Cases and a Literature Review.

OBJECTIVE: Vertebral artery dissection (VAD) combined with congenital craniovertebral junction malformation (CVJM) is rare. This study aimed to analyze the etiology, clinical and imaging features, treatment, and prognosis of VAD with CVJM. METHODS: Four new cases of VAD with congenital CVJM and 28 similar cases found in the literature were included. Detailed clinical data from all cases were retrospectively analyzed. RESULTS: A total of 32 patients (28 men, four women; mean age 19.01±12.53 years) were included. Seventeen of 32 cases (53.1%) had had multiple ischemic episodes. The most common neurological symptoms were limb numbness/weakness (20/32), ataxia (15/32), and dizziness/vertigo (12/32). In sum, 31 of 32 cases had multiple infarcts scattered throughout the posterior circulation area on cranial computed tomography or resonance imaging. Dissection had occurred in the V3 segment of the VA in 29/31 cases (93.5%). The most common congenital CVJMs were atlantoaxial dislocation and atlantoaxial subluxation (found in 20/32 cases [62.5%]), while 27/32 cases (84.3%) had multiple combined abnormalities. Seven of eleven cases (63.6%) with initial antiplatelet treatment and one of eleven (9.1%) with initial anticoagulation treatment experienced stoke recurrence. Fusion or vertebral fixation was performed in 16 patients and aneurysm resection in one patient. There was no reported recurrence after surgery in 13 patients with follow-up data. CONCLUSION: Underlying CVJM is a rare but overlooked etiology in VAD, and is prone to induce recurrent ischemic stroke. Patients with VAD, especially that localized in the V3 segment, should be examined for CVJM. Timely assessment is critical for determining the specific cause and to provide targeted intervention.

The efficacy of transcranial alternating current stimulation for treating post-stroke depression: Study Protocol Clinical Trial (SPIRIT Compliant).

BACKGROUND: The treatment of post-stroke depression (PSD) with anti-depressant drugs is partly practical. Transcranial alternating current stimulation (tACS) offers the potential for a novel treatment modality for adult patients with PSD. In this study, we will assess the efficacy and safety of tACS for treating PSD and explore its effect on gamma and beta-oscillations involving in emotional regulation. METHODS: The prospective study is an 8-week, double-blind, randomized, placebo-controlled trial. Seventy eligible participants with mild to moderate PSD aged between 18 years and 70 years will be recruited and randomly assigned to either active tACS intervention group or sham group. Daily 40-minute, 77.5-Hz, 15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas on weekdays for 4 consecutive weeks (week 4), and an additional 4-week observational period (week 8) will be followed up. The primary outcome is the proportion of participants having an improvement at week 8 according to the Hamilton Depression Rating Scale 17-Item (HAMD-17) score, including the proportion of participants having a decrease of ≥ 50% in HAMD-17 score or clinical recovery (HAMD-17 score ≤ 7). Secondary outcomes include neurological function, independence level, activities of daily living, disease severity, anxiety, and cognitive function. The exploratory outcomes are gamma and beta-oscillations assessed at baseline, week 4, and week 8. Data will be analyzed by logistical regression analyses and mixed-effects models. DISCUSSION: The study will be the first randomized controlled trial to evaluate the efficacy and safety of tACS at a 77.5-Hz frequency and 15-mA current in reducing depressive severity in patients with PSD. The results of the study will present a base for future studies on the tACS in PSD and its possible mechanism. TRIAL REGISTRATION NUMBER: NCT03903068, pre-results.

The Clinical and Vascular Characteristics of RNF213 c.14576G>A Variant-Related Intracranial Major Artery Disease in China.

BACKGROUND AND PURPOSE: Recently, several studies indicated the c.14576G>A variant on the ring finger protein 213 (RNF213), a founder variant of moyamoya diseases (MMD), was associated with non-MMD intracranial major artery stenosis/occlusion (non-MMD ICASO). We proposed that RNF213 variant-related ICASO including MMD might be a special entity with its own characteristics based on a genetic background. The aim of the study was to learn the clinical and vascular features of RNF213 variant-related ICASO. Moreover, we tried to explore the clinical significance of a testing variant in ICASO patients in China. METHODS: Clinical material and routine image data were collected in 160 Chinese patients with ICASO, including 41 verified MMD and 119 non-MMD. DNA samples were extracted, and the c.14576G>A variant on RNF213 was genotyped. Then, the clinical and vascular features were compared between the patients with and without a relevant variant. Furthermore, the patients with RNF213 mutation were performed with high resolution magnetic resonance imaging (HR-MRI) examination to conclude features of the artery wall. RESULTS: There were 16 (10%) patients (including 9 MMD and 7 non-MMD ICASO) presenting a heterozygous c.14576G>A variant while none of homozygote was found. Compared to the patients without the c.14576G>A variant, the variant group had more female, less symptomatic patients, and more possibility of having collateral vessels in vascular imaging. In the symptomatic subgroup, there is no significant difference in clinical presentation (p > 0.05) between two groups. However, RNF213 variant-related ICASO had lower scores in NIHSS (1.0 ± 3.0 vs. 3.9 ± 5.0, p < 0.05) but not in mRS. In the symptomatic subgroup, in addition, most of the HR-MRI images of variant ICASO (77.8%, 7 of 9) were characterized by a shrunken outer diameter, concentric thickening vessel wall, and collateral vessel structures on the stenotic portion, which was prone to be diagnosed as HR-MMD (a MMD diagnosis diagnosed by HR-MRI). The rest of the two variants showed a relatively eccentric luminal narrow, normal outer diameter without collateral vessel findings, identified as HR-ICAD (intracranial atherosclerotic disease diagnosed by HR-MRI). CONCLUSIONS: Our study demonstrated that the c.14576G>A variant on RNF213 may be a biomarker to good outcome of ICASO in Chinese. The variant-related ICASO was characterized by both features of MMD and ICAD diagnosed by HR-MRI.

The association between the ring finger protein 213 gene R4810K variant and intracranial major artery stenosis/occlusion in the Han Chinese population and high-resolution magnetic resonance imaging findings.

BACKGROUND AND PURPOSE: The ring finger protein 213 (RNF213) gene R4810K variant, a susceptibility locus for moyamoya disease (MMD), has recently been identified to be associated with intracranial major artery stenosis/occlusion (ICASO) without satisfying the diagnostic criteria of MMD in the Japanese population. However, further studies are needed to determine whether this variant is associated with ICASO in other populations and whether R4810K variant-related ICASO could be categorized as MMD. The aim of this study is to elucidate whether the R4810K variant was associated with ICASO among the Han Chinese population and potential histopathology of R4810K variant-related ICASO. MATERIALS AND METHODS: We conducted a case-control study to evaluate association and performed high-resolution (HR) magnetic resonance imaging (MRI) to investigate arterial wall feature of ICASO. The R4810K variant was genotyped in 114 ICASO patients and 268 controls. Then, patients with R4810K variant-related ICASO were subjected to HR MRI examination and presumptively diagnosed based on the characteristics thus observed. STATISTICAL ANALYSIS: The relationship between R4810K variant and ICASO was evaluated by Fisher's exact test with odds ratios (OR) and 95% confidence interval (CI). RESULTS: The R4810K variant was associated with ICASO and increased the risk for ICASO (P < 0.01; OR: 20.2; 95% CI: 2.5-163.11). Presumptive MMD was diagnosed in all female patients with R4810K variant. However, presumptive intracranial atherosclerotic stenosis was diagnosed in one of three males harboring this variant. CONCLUSIONS: The R4810K variant is a genetic risk factor for ICASO among the Han Chinese population and that R4810K variant-related ICASO should be identified as MMD in female but not uncertain in male patients.

Screening for Fabry's disease in young patients with ischemic stroke in a Chinese population.

PURPOSE: Fabry disease is an X-linked lysosomal storage disorder frequently associated with cerebrovascular disease. Data regarding Fabry disease and ischemic stroke has been lacking in China. In this study, we investigated the prevalence of Fabry disease and the distribution of the alpha-galactosidase A (α-GalA) gene - GLA mutations in young stroke patients in the Chinese population and its association with stroke subtypes. METHODS: A total of 357 ischemic stroke patients admitted to Xuanwu Hospital of Capital Medical University, aged 18-55 years old, including 293 patients with cerebral infarction and 64 patients with transient ischemic attack, were enrolled in this study. Mutations in the GLA gene were screened by Sanger sequencing. Enzyme levels were measured to further confirm the disease in patients with the gene mutation. The mutation frequency was compared among different stroke subtypes and further compared with the control group individually. RESULTS: No pathogenic mutations in the coding regions of the GLA gene were identified in this group of patients and thus no Fabry disease was found in our study. However, the frequency of an intronic polymorphism c.-10C>T was significantly different among different Trial of Org 10172 in Acute Stroke Treatment subtypes (p < 0.01). The frequency of the c.-10C>T polymorphism in patients with stroke due to other causes and undetermined causes was much higher than that in the control group (OR = 3.18, 95% CI: 1.29-7.83, p < 0.01). CONCLUSIONS: Fabry disease is a rare disease, and it will not benefit to screen all stroke patients. In addition, our results suggested that the c.-10C>T polymorphism may be a risk factor for ischemic stroke of other and undetermined causes. Further study is required to confirm our findings.

Isolated symptomatic middle cerebral artery stenosis in young adults: clinical prognosis and vascular change.

BACKGROUND AND PURPOSE: To investigate the clinical prognosis and vascular outcome of ischemic stroke patients with isolated symptomatic middle cerebral artery stenosis, and further analysis of the predictors associated with the results. METHODS: Ischemic stroke patients aged 18-55 years old with isolated symptomatic middle cerebral artery stenosis were evaluated and followed up prospectively for six months. Logistic regression was used to detect predictors of ipsilateral stroke recurrence, and factors associated with the dynamic changes of lesion vascular were analyzed. RESULTS: Eighty patients were included, with a mean age of 41.8 ± 8.3 years old. Males predominated in this cohort at a proportion of 78.8% (63/80). Twenty percent of patients presented with ipsilateral ischemic stroke recurrence during this time but mostly with a good outcome (70% mRS ≤ 1); multiple logistic regression indicated that diabetes mellitus is an independent predictor for stroke recurrence; 38.6% patients presented with significant vascular changes during the follow-up, with progression in 12 (17.1%) and regression in 15 (21.4%) patients individually. No variables were detected as predictors of cerebral vascular progression. CONCLUSION: Isolated symptomatic middle cerebral artery stenosis in young adults had unaccepted high rates of recurrence but comparatively good prognosis; despite the dramatic change of lesion artery in the short period after stroke, no factors were detected as the probable factors associated with the dynamic process.

Diagnosis and treatment of dementia in neurology outpatient departments of general hospitals in China.

INTRODUCTION: The status of dementia diagnosis and treatment of neurology outpatients in general hospitals in China remains unclear. METHODS: From neurology outpatients at 36 randomly selected hospitals, we first collected baseline data concerning the number of dementia doctors, memory clinics, and patients diagnosed with dementia. In stage 2, we intervened based on drawbacks discovered in stage 1, implementing a dementia initiative program. In stage 3, we reinvestigated the outpatients to determine the effects of intervention. RESULTS: After intervention, all 36 hospitals had established memory clinics (205 dementia doctors) compared with only 6 (47 dementia doctors) before intervention. The percentage of patients diagnosed with dementia significantly increased from 0.10% (536 dementia patients of 553,986 outpatients) in stage 1 to 0.41% (2482 dementia patients of 599,214 outpatients) in stage 3. DISCUSSION: Proper diagnosis and treatment are unavailable to many dementia patients because of a lack of dementia doctors and memory clinics in China.

[Prevalence of ischemic stroke in young adults and Fabry disease].

OBJECTIVE: To investigate the prevalence of Fabry disease and GLA gene mutations in young patients with ischemic stroke. METHODS: A total of 269 consecutive hospitalized patients of ischemic stroke, aged between 18-55 years, were recruited. DNA was extracted from peripheral blood. And 7 exons and flanking introns of α-galactosidase gene (GLA) were sequenced. RESULTS: The cases were cerebral infarction (n = 239, 88.8%) transient ischemic attack and posterior circulation ischemia (n = 30, 11.2%). There were 216 males and 53 females with a mean age of 44 ± 8years.Large artery atherosclerosis was predominant at 55.4% according to the TOAST classifications. Among them, there were c.-12G> A point mutation (n = 12) and c.-10C> T mutation (n = 20). These two sites were located in the 5 'end of non-untranslated region in exon 1. Both loci were polymorphic loci.No disease-causing mutations were detected. CONCLUSION: The prevalence of Fabry disease in young stroke patients is not high as in Western countries;there has some difference in TOAST types between patients with c.-10C> T mutation and without, further studies are needed to testing the significance.

Association of polymorphisms in the LRP1 and A2M genes with Alzheimer's disease in the northern Chinese Han population.

Low-density lipoprotein receptor-related protein1 (LRP1) and alpha-2-macroglobulin (A2M) are candidate genes for sporadic Alzheimer's disease (SAD). It is not clear whether the LRP1 exon 3 and A2M exon 24 polymorphisms are associated with SAD. In the present study, we used direct sequencing to genotype the LRP1 C766T (rs1799986) polymorphism in exon 3 and the A2M I1000V (rs669) polymorphism in exon 24 in 364 patients with SAD and 291 healthy control subjects from the Northern Chinese Han population. The distributions of LRP1 genotypes (chi-squared [χ(2)]=7.25, degrees of freedom [d.f.]=2, p=0.027) and alleles (χ(2)=8.154, d.f.=1, p=0.004) were significantly different between patients and controls who were apolipoprotein E (APOE) ε4 positive. The T allele and TT+TC genotype were associated with a reduced risk of developing SAD (T allele: odds ratio [OR]=0.541, 95% confidence interval [CI]=0.368-0.859, p=0.005; TT+TC genotype: OR=0.613, 95% CI=0.315-0.725, p=0.012). There was no statistically significant difference in allele and genotype frequencies between patients with SAD and control subjects for the A2M I1000V polymorphism, even after stratification by age of onset, gender, and APOE ε4 status. We found an interaction between LRP1 and APOE genotypes (p=0.001), but no interaction between LRP1 and A2M genotypes. Our results suggest that the T allele of the LRP1 C766T polymorphism is associated with a decreased risk of SAD in APOE ε4 carriers from the Northern Han Chinese population.

Stable knockdown of MYCN by lentivirus-based RNAi inhibits human neuroblastoma cells growth in vitro and in vivo.

Neuroblastoma is the most common childhood solid tumor, yet current treatment approaches have not been able to effectively control this cancer. Amplification and overexpression of MYCN have been shown to be closely related with high risk and poor prognosis in neuroblastoma. This suggests that MYCN is an important target for the antitumor therapy. Recently, vector-based RNA interference (RNAi) systems have been successfully used to eliminate gene expression, but knockdown of MYCN by vector-based RNAi as a therapeutic model for neuroblastoma has not been fully established. In this study, we used a lentivirus vector-based RNAi approach which expresses short hairpin RNA (shRNA) to knockdown MYCN in neuroblastoma cell lines IMR-32 and LAN-1. Western blotting analysis showed that expressions of MYCN were efficiently downregulated after infection with MYCN shRNA expression vector. The stable suppression of MYCN expression induced differentiation and apoptosis in neuroblastoma cell lines. Furthermore, we demonstrated that these changes were associated with caspase-3 activation, p27 upregulation as well as Bcl-2 and MDM2 downregulation. Finally, we demonstrated that downregulation of MYCN expression significantly reduced colony formation in vitro and tumor growth in nude mice. Our data indicate that lentivirus vector-mediated silencing of MYCN in neuroblastoma cells could efficiently and significantly inhibit tumor growth both in vitro and in vivo. Therefore we demonstrate the therapeutic potential of lentivirus-delivered shRNA as a novel approach for treatment of neuroblastoma and other malignant tumors with MYCN overexpression.

Association between somatostatin gene polymorphisms and sporadic Alzheimer's disease in Chinese population.

Recent evidence has suggested that down-regulation of somatostatin (SST) expression in the human brain during early stages of aging leads to an elevation in the steady-state levels of Abeta and therefore may be involved in Alzheimer's disease (AD) progression. We hypothesized that alterations in the SST gene might alter its expression or function and also play a role in the pathogenesis of sporadic AD (SAD). First, we sequenced the entire SST gene in 25 randomly selected controls and 25 SAD patients and then screened for C/T polymorphisms (rs4988514) in the 3' un-translated region. We genotyped rs4988514 polymorphisms as well as apolipoprotein epsilon4 (APOE epsilon4) status in 309 SAD patients and 276 normal controls with restriction fragment length polymorphism (RFLP) analysis. Results showed that the C allele of the rs4988514 polymorphism had an increased incidence in the SAD group compared to the control group (p=0.042). In subjects with the APOE epsilon4 allele, the presence of both the CC genotype and the C allele of this polymorphism were elevated in the SAD group compared to the control group (genotype p=0.027, allele p=0.011). In the whole study group, the age, sex, and APOE epsilon4 adjusted OR for the risk of AD in C allele carriers was 1.313 (95%CI=1.068-2.234, p=0.027) whereas within only APOE epsilon4 allele carriers, the adjusted OR increased to 2.734 (95%CI=1.236-5.862, p=0.012). Our results supported the notion that the C allele of the rs4988514 polymorphism may increase the risk for AD in the Chinese population and possibly have additive effect with the APOE epsilon4 allele.

Cerebral diffusion tensor imaging in tuberous sclerosis.

PURPOSE: The purpose of this study was to investigate the features of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in cortical tubers and white-matter lesions in patients with tuberous sclerosis (TS) using diffusion tensor imaging (DTI). MATERIALS AND METHODS: Conventional magnetic resonance imaging (MRI) and DTI were performed in 14 patients with clinically established TS. Based on these DT images, ADC and FA maps were generated. The ADC values in 32 cortical tubers, and the ADC and FA values in 18 white-matter lesions were measured and compared with those of the corresponding contralateral regions. RESULTS: Compared with the corresponding contralateral regions, cortical tubers of TS patients had significantly higher ADC values (P<0.001); white-matter lesions had significantly higher ADC values (P<0.001) and significantly lower FA values (P<0.001). CONCLUSION: DTI is a useful tool for demonstrating changes in cortical tubers and white-matter lesions resulting from TS.

Whole-brain voxel-based morphometry of white matter in medial temporal lobe epilepsy.

PURPOSE: The purpose of this study was to analyze whole-brain white matter changes in medial temporal lobe epilepsy (MTLE). MATERIALS AND METHODS: We studied 23 patients with MTLE and 13 age- and sex-matched healthy control subjects using voxel-based morphometry (VBM) on T1-weighted 3D datasets. The seizure focus was right sided in 11 patients and left sided in 12. The data were collected on a 1.5 T MR system and analyzed by SPM 99 to generate white matter density maps. RESULTS: Voxel-based morphometry revealed diffusively reduced white matter in MTLE prominently including bilateral frontal lobes, bilateral temporal lobes and corpus callosum. White matter reduction was also found in the bilateral cerebellar hemispheres in the left MTLE group. CONCLUSION: VBM is a simple and automated approach that is able to identify diffuse whole-brain white matter reduction in MTLE.