Yan Ji

Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease A meta-analysis

Objective: To perform a meta-analysis on the effect of lowering homocysteine levels via B vitamin supplementation on cerebrovascular disease risk. Methods: Using clinical trials published before August 2012 to assess stroke events, we used relative risks (RRs) with 95% confidence intervals (95% CIs) to measure the association between B vitamin supplementation and endpoint events using a fixed-effects model and χ2 tests. We included 14 randomized controlled trials with 54,913 participants in this analysis. Results: We observed a reduction in overall stroke events resulting from reduction in homocysteine levels following B vitamin supplementation (RR 0.93; 95% CI 0.86–1.00; p = 0.04) but not in subgroups divided according to primary or secondary prevention measures, ischemic vs hemorrhagic stroke, or occurrence of fatal stroke. There were beneficial effects in reducing stroke events in subgroups with ≥3 years follow-up time, and without background of cereal folate fortification or chronic kidney disease (CKD). Some trials that included CKD patients reported decreased glomerular filtration rate with B vitamin supplementation. We conducted detailed subgroup analyses for cyanocobalamin (vitamin B12) but did not find a significant benefit regarding intervention dose of vitamin B12 or baseline blood B12 concentration. Stratified analysis for blood pressure and baseline participant medication use showed benefits with >130 mm Hg systolic blood pressure and lower antiplatelet drug use in reducing stroke risk. Conclusions: B vitamin supplementation for homocysteine reduction significantly reduced stroke events, especially in subjects with certain characteristics who received appropriate intervention measures.

CHCHD2 gene mutations in familial and sporadic Parkinson's disease

Mutations in CHCHD2 gene have been reported in autosomal dominant Parkinsons disease (ADPD). However, there is still lack of evidence supported CHCHD2 mutations lead to ADPD in other populations. We performed whole exome sequencing, positron emission tomography (PET), and haplotype analyses in an ADPD pedigree and then comprehensively screened for CHCHD2 gene mutations in additional 18 familial parkinsonism pedigrees, 364 sporadic PD patients, and 384 healthy controls to assess the frequencies of known and novel rare nonsynonymous CHCHD2 mutations. We identified a heterozygous variant (c.182C>T; p.Thr61Ile) in the CHCHD2 gene in the ADPD pedigree. PET revealed a significant reduction in dopamine transporter binding in the putamen and caudate nucleus of the proband, similar to idiopathic PD. The single nucleotide variant 5C>T (Pro2Leu) in CHCHD2 was confirmed to have a significantly higher frequency among sporadic PD patients than controls. Our results confirm that ADPD can be caused by CHCHD2 mutations and show that the Pro2Leu variant in CHCHD2 may be a risk factor for sporadic PD in Chinese populations.

Transplantation of human neuro-epithelial-like stem cells derived from induced pluripotent stem cells improves neurological function in rats with experimental intracerebral hemorrhage

Specific targeted therapy for intracerebral hemorrhage (ICH), which has high disability and case-fatality rate, is currently not available. Induced pluripotent stem cells (iPSCs) generated from somatic cells of ICH patients have therapeutic potential for individualized cerebral protection. While, whether ICH patient-originated iPSCs could differentiate into neuro-epithelial-like stem (NES) cells and whether such NES cells could improve functional recovery in the hemorrhage-injured brain are unclear. Here, we showed that fibroblasts from an ICH patient can be efficiently reprogrammed to iPSCs by lentiviral vectors carrying defined transcription factors (OCT4, SOX2, KLF4, and c-MYC). These iPSCs have the typical morphology, surface antigens, capability of self-renewal and differentiating into cell types of all three embryonic germ layers that are similar to human embryonic stem cells (hESCs). Using defined serum-free neural differentiation medium, we induced the iPSCs differentiate into NES cells. Subsequently, the NES cells from ICH patient-originated iPSCs were transplanted into the perihematoma of rats with experimental ICH injury. Intriguingly, recovery of neurological dysfunction in experimental ICH rats was observed post-NES cells graftage. Transplanted NES cells migrated to the surrounding area of hematoma, survived and differentiated into neuron-like cells. Our study demonstrates that the transplantation of human iPS-originated NES cells is an effective approach of treating ICH injury and the improvement of neural function is partially due to neuronal replacement and regeneration.

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.

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.

Prognostic Significance of Homocysteine Levels in Acute Ischemic Stroke: A Prospective Cohort Study.

Associations between hyperhomocysteinemia and prognosis of stroke were seldom explored and always indefinite. We therefore performed a study to elucidate the relationship between homocysteine levels and stroke prognosis. Between 2008 and 2013, baseline data and blood samples of acute ischemic stroke patients were collected from the Henan Province Stroke Registry. Using a prospective cohort, scheduled follow-up, and multivariable logistic regression analysis, associations among the blood homocysteine level and acute neurological impairment and outcomes, stroke recurrence, and all-cause death were investigated. Relevant cutoff homocysteine levels were determined using the area under the receiver operating characteristics curve. Of 1,460 patients, 1,342 completed the 12-month follow-up. We observed higher homocysteine levels in males, those with an advanced age, concomitant hyperlipidemia, a smoking habit, and excessive alcohol consumption. The homocysteine level was an independent risk factor for severe neurological impairment (adjusted relative risk [RR]: 1.021, 95% confidence interval [CI]: 1.004-1.037), a poor functional outcome (adjusted RR with 95% CI: 3-month, 1.029, 1.018-1.039; 6-month, 1.029, 1.018-1.039; and 12-month, 1.038, 1.027-1.049), and stroke recurrence in the large artery atherosclerosis subtype (adjusted RR: 1.025, 1.006-1.045). The optimal cutoff for severe neurological impairment was 17.64 µmol/L, and the cutoffs for poor functional outcomes were 17.28 µmol/L, 17.28 µmol/L, and 14.78 µmol/L at 3, 6, and 12 months, respectively. We found an elevated homocysteine level independently predicted severe neurological impairment, a poor functional outcome, and stroke recurrence in the large artery atherosclerosis stroke subtype. The relevant cutoff homocysteine levels also provide a reference for future clinical work.

Homocysteine Level Is Associated with White Matter Hyperintensity Locations in Patients with Acute Ischemic Stroke.

Background and Purpose The relationship between plasma level of total homocysteine (tHcy) and white matter hyperintensities (WMHs), especially in patients with acute ischemic stroke (AIS), is controversial. The present study investigated the association between these two as well as WMH locations in a large cohort of patients with AIS. Methods Consecutive patients were reviewed from a prospective ischemic stroke database. Clinical data, including tHcy level and WMHs, were assessed. WMHs were assessed using the Fazekas scale and Age-Related White Matter Changes (ARWMC) visual grading scale. The association between tHcy and WMH locations was investigated by using multivariate logistic regression analyses. Results A total of 923 out of 1,205 patients were examined. The average age was 58.9 ± 11.9 years; 31.6% were female. Elevated tHcy level was significantly associated with WMHs. For the highest tHcy quartile, the odds ratio (OR) (95% confidence interval; CI) was 1.891 (1.257; 2.843) according to the Fazekas scale and 1.781 (1.185; 2.767) according to the ARWMC scale when compared to the lowest quartile. However, in a subgroup analysis, only WMHs in the periventricular area and left or right frontal areas were found to be independently associated with tHcy level. For the highest tHcy quartile, the OR (95% CI) was 1.761 (1.172; 2.648) for the periventricular WMHs, 1.768 (1.134; 2.756)for the left frontal WMHs, and 1.890 (1.206; 2.960)for the right frontal WMHs. Conclusions In patients with AIS, plasma tHcy level is related to WMHs, especially WMHs distributed within the periventricular and frontal areas.

Vascular Lesion Thickness in the Lenticulostriate Artery Region Serves as a Biomarker for Early Neurological Deterioration.

BACKGROUND Early neurological deterioration (END) was common in single small subcortical infarction (SSSI). Distal type of SSSI (dSSSI) was reported to have a lower risk of END than proximal type of SSSI (pSSSI) in lenticulostriate artery(LSA) territory. However, dSSSIs with different lesion thickness might have different risks of END. OBJECTIVE In this prospective cohort study, we aimed to investigate whether dSSSIs visible on ≥3 serial axial diffusion weighted imaging (DWI) slices were also imaging markers for END. METHODS Patients of SSSIs in the LSA territory admitted within 72 hours from the onset were selected in a prospective stroke database. Clinical characteristics including the occurrence of END after admission were recorded. The lowest slice (LS), total number of slices (TNS) involved and the maximum axial diameter were evaluated for lesion location and size on axial plane of DWI images. Lesion patterns were categorized according to LS and TNS. Multivariate logistic analysis was performed to determine the imaging pattern that associated with END. RESULTS A total of 201 out of 1,158 patients were analyzed. END occurred in 32(15.9%) patients after admission. SSSI was categorized to pSSSI (LS≤2), distal and large SSSI (dl-SSSI, LS>2, TNS≥3), distal and small SSSI (ds-SSSI, LS>2, TNS<3) respectively. Multivariate logistic analysis showed that ds-SSSI patients had a significantly lower rate of END(OR 0.20, 95% CI 0.06-0.71, P=0.013) comparing to dl-SSSI patients; pSSSI patients, however, had a similar rate of END (OR 1.27, 95% CI 0.50-3.21, P=0.611) to dl-SSSI patients. CONCLUSION Except for pSSSI, dl-SSSI was also an imaging marker for END in the territory of LSA.