Shilei Sun

Validation of the ABCD3-I Score to Predict Stroke Risk After Transient Ischemic Attack

Background and Purpose— The Age, Blood Pressure, Clinical Features, Duration, and Diabetes plus Dual TIA (ABCD3-I) score is recommended to predict the risk of early stroke after transient ischemic attack. The aim of this study was to validate the predictive value of the ABCD3-I score and compare the accuracy of the Age, Blood Pressure, Clinical Features, Duration, and Diabetes (ABCD2) and ABCD3-I scores in a Chinese population. Methods— Data were prospectively collected from patients who had transient ischemic attack, as defined by the World Health Organization time-based criteria. ABCD2 and ABCD3-I scores were available within 7 days of the index transient ischemic attack. The predictive outcome was stroke occurrence at 90 days. The receiver-operating characteristic curves were plotted, and the C statistics were calculated as a measure of predictive ability. The comparison of the area under the receiver-operating characteristic curve (area under the curve) was performed by Z test. Results— Among 239 eligible patients, the mean age was 57.4±13.32 years, and 40.2% of the patients were women. The incidence of stroke at 90 days was 12.1%, which ranged from 0% in patients with lower ABCD3-I scores (0–3) to 40.91% in those with higher scores of 8 to 13 (P for trend <0.0001). Moreover, the C statistic of ABCD3-I scores (0.825; 95% confidence interval, 0.752–0.898) was statistically higher than that of ABCD2 scores (0.694; 95% confidence interval, 0.601–0.786; P<0.001). Conclusions— The ABCD3-I score had a higher predictive value than the ABCD2 score for assessing the risk of early stroke after transient ischemic attack in a Chinese population.

Transplantation of Induced Pluripotent Stem Cells Alleviates Cerebral Inflammation and Neural Damage in Hemorrhagic Stroke

Background Little is known about the effects of induced pluripotent stem cell (iPSC) treatment on acute cerebral inflammation and injuries after intracerebral hemorrhage (ICH), though they have shown promising therapeutic potentials in ischemic stoke. Methods An ICH model was established by stereotactic injection of collagenase VII into the left striatum of male Sprague-Dawley (SD) rats. Six hours later, ICH rats were randomly divided into two groups and received intracerebrally 10 μl of PBS with or without 1×106 of iPSCs. Subsequently, neural function of all ICH rats was assessed at days 1, 3, 7, 14, 28 and 42 after ICH. Inflammatory cells, cytokines and neural apoptosis in the rats’ perihematomal regions, and brain water content were determined on day 2 or 3 post ICH. iPSC differentiation was determined on day 28 post ICH. Nissl+ cells and glial fibrillary acidic protein (GFAP)+ cells in the perihematoma and the survival rates of rats in two groups were determined on post-ICH day 42. Results Compared with control animals, iPSCs treatment not only improved neurological function and survival rate, but also resulted in fewer intracephalic infiltrations of neutrophils and microglia, along with decreased interleukin (IL)-1β, IL-6 and tumour necrosis factor-alpha (TNF-α), and increased IL-10 in the perihematomal tissues of ICH rats. Furthermore, brain oedema formation, apoptosis, injured neurons and glial scar formation were decreased in iPSCs-transplanted rats. Conclusions Our findings indicate that iPSCs transplantation attenuate cerebral inflammatory reactions and neural injuries after ICH, and suggests that multiple mechanisms including inflammation modulation, neuroprotection and functional recovery might be involved simultaneously in the therapeutic benefit of iPSC treatment against hemorrhagic stroke.

Interleukin 2 Receptor α Gene Polymorphism and Risk of Multiple Sclerosis: a Meta-analysis

This meta-analysis studied the association between interleukin 2 receptor a (IL2RA) gene polymorphisms rs2104286 and rs12722489 and susceptibility to multiple sclerosis (MS). Case-control genetic association studies published before January 2011 were retrieved from the PubMed and EMBASE databases and the Cochrane Library. Eight studies comprising 13 569 patients and 23 435 controls met the selection criteria for meta-analysis of the IL2RA rs2104286 polymorphism. Using a fixed-effects model, the T allele and the TT and TT + TC genotypes of the IL2RA rs2104286 polymorphism were found to be associated with MS. Five studies comprising 5643 patients and 6415 controls met the selection criteria for meta-analysis of the IL2RA rs12722489 polymorphism. Using a fixed-effects model, the C allele and the CC genotype of the IL2RA rs12722489 polymorphism were found to be associated with MS but the CC + CT genotype was not. It was concluded that both of the IL2RA gene polymorphisms, rs2104286 and rs12722489, were associated with increased susceptibility to MS.

Functional recovery after transplantation of induced pluripotent stem cells in a rat hemorrhagic stroke model.

Transplantation of induced pluripotent stem cells (iPSCs) has shown promising therapeutic effects for ischemic stroke. However, it is not clear if this treatment would promote recovery after intracerebral hemorrhage (ICH). In this study, we investigated the functional outcome of iPSCs transplantation in experimental ICH in rats. IPSCs were derived from an ICH patients fibroblasts and were injected into the ipsilateral side of ICH in rats. IPSCs transplantation significantly improved the neurological functions after ICH as compared to vehicle and fibroblast injection. The grafted iPSCs migrated into brain tissue around the hematoma, survived after 4 weeks of transplantation, and exhibited the neural cell-specific biomarkers nestin, β-tubulin, and GFAP. Immunohistochemical staining showed that the densities of brain derived neurophic factors (BDNF)-positive cells and vascular endothelial growth factor (VEGF)-positive cells were significantly increased around the hemorrhagic brain tissues of iPSCs-treated rats. In addition, iPSCs treatment increased the protein expression of BDNF and VEGF in the surrounding region of hematoma. These findings demonstrate that the transplantation of ICH patient-derived iPSCs contributes toward the improved neurological function in experimental ICH rats. The mechanisms are possibly due to neuronal replacement and enhanced secretion of neurophic factors. Our data suggest that transplantation of ICH patient-derived iPSCs may be a therapeutic strategy for hemorrhagic stroke.

Genotype-phenotype correlation in a cohort of paroxysmal kinesigenic dyskinesia cases☆

BACKGROUND Recently, PRRT2 gene mutations have been identified as a causative factor of paroxysmal kinesigenic dyskinesia (PKD). However, evidence is still lacking with respect to the genotype to phenotype correlation in PKD patients. METHODS We recruited a cohort of PKD patients with or without PRRT2 mutations for the study, and followed them for 6 months to observe the response to carbamazepine treatment. RESULTS Thirty-four participants were included in this study; 16 patients were positive for a hot-spot p.R217Pfs 8 heterozygous PRRT2 gene mutation, while the other 18 patients were negative for PRRT2 gene mutations. PRRT2 mutations were found to be associated with a younger age of onset, bilateral presence and a higher frequency of attacks. Furthermore, the follow-up study revealed that p.R217Pfs 8-positive patients showed dramatic improvement with complete abolition of dyskinetic episodes with carbamazepine treatment, while only 7 of the 18 patients without PRRT2 mutations showed a response to the antiepileptic drug. CONCLUSIONS Our study indicated that positivity for PRRT2 mutation is a predictor of younger age of onset and more frequent of attacks in PKD patients. Interestingly, the presence of PRRT2 mutations also predicted a good response to carbamazepine therapy, especially at low dose. Therefore, genetic testing shows potential clinical significance for guiding the choice of medication for individual PKD cases.

Calcium Intake and the Risk of Stroke: An Up-dated Meta-analysis of Prospective Studies

BACKGROUND AND PURPOSE Calcium intake has been associated with stroke risk in a prior meta-analysis, however, newly published results are inconsistent. Dairy food benefits on stroke incidence may involve a calcium-related mechanism. We have therefore updated this meta-analysis with particular references to any possibility of a calcium-mediated dairy food risk reduction of stroke risk. METHODS We searched multiple databases and bibliographies for prospective cohort studies. Reports with multivariate-adjusted relative risk (RR) and corresponding 95% confidence intervals (CI) for the association of calcium intake with stroke incidence were considered. RESULTS Ten studies with 371,495 participants and 10,408 stroke events were analyzed. The pooled analysis showed no statistically significant association of the risk of total stroke (RR=0.96; 95% CI: 0.89-1.04) and stroke subtypes with the highest and lowest calcium intake quantiles. Nevertheless, high dairy calcium intake was significantly associated with an approximately 24% reduction of stroke risk. (RR=0.76; 95% CI: 0.66-0.86). Furthermore, a long-term follow-up (>=14 years) was helpful to reduce the risk of stroke (RR=0.67; 95% CI: 0.51-0.88). Additionally, a non-linear dose-response relationship was predicted between calcium intake and stroke risk. CONCLUSIONS Dairy calcium intake is inversely associated with stroke incidence. There is a non-linear dose-response relationship between calcium intake and stroke risk. However, when the follow-up time is long enough, the inverse relationship is independent of dose. Additional large cohort studies are required to illustrate this relationship in detail.

PRRT2 gene mutations in familial and sporadic paroxysmal kinesigenic dyskinesia cases.

Thus, the presence or absence of neuropsychiatric features is not a reliable way of discriminating neuroferritinopathy from Huntington’s disease, in which psychiatric symptoms usually precede involuntary movements. Our results also showed the defects in verbal fluency on ACE-R, and verbal learning and language with neuropsychometry were similar to other neurodegenerative movement disorders such as progressive supranuclear palsy and corticobasal degeneration, demonstrating the importance of an accurate assessment of motor and cognitive symptoms to reach a diagnosis. These findings redefine the phenotype of neuroferritinopathy and highlight the importance of assessing and monitoring nonmotor symptoms in patients following diagnosis.

Recessive hereditary motor and sensory neuropathy caused by IGHMBP2 gene mutation

Hereditary motor and sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth disease (CMT), is a genetically heterogeneous disorder that affects both sensory and motor peripheral nerves. HMSN is characterized by distal and symmetric muscle atrophy in the lower limbs and hands, foot abnormalities, and distal sensory loss. It is associated with more than 50 causative genes or loci; however, the genetic cause remains undetermined in almost 50% of HMSN cases.1,2

Nerve growth factor for the treatment of spinocerebellar ataxia type 3: an open-label study.

Background: Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCA worldwide, and runs a slowly progressive and unremitting disease course. There is currently no curable treatment available. Growing evidence has suggested that nerve growth factor (NGF) may have therapeutic effects in neurodegenerative diseases, and possibly also in SCA3. The objective of this study was to test the efficacy of NGF in SCA3 patients. Methods: We performed an open-label prospective study in genetically confirmed adult (>18 years old) SCA3 patients. NGF was administered by intramuscular injection (18 &mgr;g once daily) for 28 days consecutively. All the patients were evaluated at baseline and 2 and 4 weeks after treatment using the Chinese version of the scale for assessment and rating of ataxia (SARA). Results: Twenty-one SCA3 patients (10 men and 11 women, mean age 39.14 ± 7.81 years, mean disease duration 4.14 ± 1.90 years, mean CAG repeats number 77.57 ± 2.27) were enrolled. After 28 days of NGF treatment, the mean total SARA score decreased significantly from a baseline of 8.48 ± 2.40 to 6.30 ± 1.87 (P < 0.001). Subsections SARA scores also showed significant improvements in stance (P = 0.003), speech (P = 0.023), finger chase (P = 0.015), fast alternating hand movements (P = 0.009), and heel-shin slide (P = 0.001). Conclusions: Our preliminary data suggest that NGF may be effective in treating patients with SCA3.

Exome sequencing reveals novel SPG11 mutation in hereditary spastic paraplegia with complicated phenotypes

We used a combined approach of whole-exome sequencing and candidate mutation validation to identify the disease-causing gene in a hereditary spastic paraplegia (HSP) patient with lower motor neuron involvement, mild cerebellar signs and dysgenesis of the corpus callosum. HSP is a clinically and genetically heterogeneous neurodegenerative disorder characterized by degeneration of the corticospinal tract motor neurons and resulting in progressive lower limb spasticity, often with a complicated phenotype. We identified novel compound heterozygous mutations in the SPG11 gene in this patient as follows: a mutation in exon 32, c.6194C > G transition (p.S2056X) and a novel c.5121+1C > T splicing mutation. Our finding suggests that these novel compound heterozygous mutations in SPG11 are associated with HSP and lower motor neuron involvement, mild cerebellar signs and dysgenesis of the corpus callosum. This study also demonstrates that exome sequencing is an efficient and rapid diagnostic tool for identifying the causes of some complex and genetically heterogeneous neurodegenerative diseases.