This study aimed to define the most consistent white matter microarchitecture pattern in Parkinson’s disease (PD) reflected by fractional anisotropy (FA), addressing clinical profiles and methodology-related heterogeneity. Web-based publication databases were searched to conduct a meta-analysis of whole-brain diffusion tensor imaging studies comparing PD with healthy controls (HC) using the anisotropic effect size–signed differential mapping. A total of 808 patients with PD and 760 HC coming from 27 databases were finally included. Subgroup analyses were conducted considering heterogeneity with respect to medication status, disease stage, analysis methods, and the number of diffusion directions in acquisition. Compared with HC, patients with PD had decreased FA in the left middle cerebellar peduncle, corpus callosum (CC), left inferior fronto-occipital fasciculus, and right inferior longitudinal fasciculus. Most of the main results remained unchanged in subgroup meta-analyses of medicated patients, early stage patients, voxel-based analysis, and acquisition with ˂30 diffusion directions. The subgroup meta-analysis of medication-free patients showed FA decrease in the right olfactory cortex. The cerebellum and CC, associated with typical motor impairment, showed the most consistent FA decreases in PD. Medication status, analysis approaches, and the number of diffusion directions have an important impact on the findings, needing careful evaluation in future meta-analyses.

Mild cognitive impairment (MCI), a well-defined nonmotor manifestation of Parkinson's disease (PD), greatly impairs functioning and quality of life. However, the contribution of cerebral perfusion, quantified by arterial spin labeling (ASL), to MCI in PD remains poorly understood. The selection of an optimal delay time is difficult for single-delay ASL, a problem which is avoided by multidelay ASL. This study uses a multidelay multiparametric ASL to investigate cerebral perfusion including cerebral blood flow (CBF) and arterial transit time (ATT) in early stage PD patients exhibiting MCI using a voxel-based brain analysis. Magnetic resonance imaging data were acquired on a 3.0 T system at rest in 39 early stage PD patients either with MCI (PD-MCI, N = 22) or with normal cognition (PD-N, N = 17), and 36 age- and gender-matched healthy controls (HCs). CBF and ATT were compared among the three groups with SPM using analysis of variance followed by post hoc analyses to define regional differences and examine their relationship to clinical data. PD-MCI showed prolonged ATT in right thalamus compared to both PD-N and HC, and in right supramarginal gyrus compared to HC. PD-N showed shorter ATT in left superior frontal cortex compared to HC. Prolonged ATT in right thalamus was negatively correlated with the category fluency test (p = .027, r = -0.495) in the PD-MCI group. This study shows that ATT may be a more sensitive marker than CBF for the MCI, and highlights the potential role of thalamus and inferior parietal region for MCI in early stage PD.

Objectives: Studies at the genomewide level of Parkinson's disease (PD) suggested a significant association between the Hydroxy-delta-5-steroid dehydrogenase, 3 beta-and steroid delta isomerase 7 (HSD3B7) gene rs9938550 variant and a decreased risk for PD. But its effect has only been discussed in Caucasian populations, and no phenotypic characteristics were included. To investigate the novel variant for PD in Chinese Han populations, we performed an association analysis of rs9938550 variant in a large cohort. Methods: Using a case-control methodology, a total of 2,239 subjects (1,072 sporadic patients with PD and 1,167 control) were genotyped and the genetic association was analyzed. Results: No significant association was found between allele A of rs9938550 and PD in the entire cohort (p = .079). However, the frequency of allele A was lower in late-onset PD (LOPD) as compared with controls older than 50 years (OR = 0.62, 95% CI: 0.45-0.85, p(adjust) = .002). Relatively lower Unified Parkinson's Disease Rating Scale scores were demonstrated in mid-to late-stage PD with GA + AA genotypes than GG genotype (p(adjust) = .018), while other clinical features were similar between carriers and noncarriers. Conclusions: Our results support that the HSD3B7 rs9938550 variant, which is likely linked to bile acid biosynthesis, reduces the risk of LOPD in Chinese patients and might induce a benign clinical performance.

Recent several meta-analyses and certain case–control studies suggested that the Ras-like without CAAX 2 (RIT2) rs12456492 increased the risk of Parkinson’s disease (PD) in Asian and Caucasian populations. However, as so far, the association between RIT2 rs12456492 and PD is still controversial. We investigated genetic association of RIT2 rs12456492 with PD susceptibility in a Han Chinese population of 1747 ethnic Han Chinese subjects comprising 884 PD patients and 863 healthy controls. The minor allele frequency (MAF) of G at the RIT2 rs12456492 was not significantly different between the cases and the controls. Furthermore, no significant differences were observed in genotype distribution between PD patients and healthy controls for the RIT2 rs12456492, even after being stratified by age at onset and gender. In addition, we found that no significant differences were detected in the clinical manifestations for gender, age at onset, and onset symptoms between PD patients with AG + GG genotypes and those with AA genotypes. Our study from the mainland China demonstrates that RIT2 rs12456492 do not increase the risk of developing PD. Therefore, more replication studies in additional Chinese population and other cohorts are warranted to further clarify the role of RIT2 rs12456492 in PD susceptibility.

Sequence variants in fibroblast growth factor 20 (FGF20) have been reported to be associated with Parkinson’s disease (PD). We genotyped the rs591323 variant in a total of 2220 Han Chinese subjects, including 1051 patients with sporadic PD and 1169 controls, to investigate the association between rs591323 and the risk of PD. In addition, we also conducted a stratified analysis according to age at onset of PD and compared the clinical characteristics of AA + AG subjects with GG subjects. In this study, we confirmed that the A allele of rs591323 in FGF20 reduces the risk of developing sporadic PD (P = 0.013). Additionally, subjects with the AA + AG genotype have a reduced risk compared to individuals with the GG genotype (P = 0.024). This association was significant among females (P = 0.036), but was not significant among males (P = 0.266). Furthermore, no significant association was observed among either the early-onset PD group (P = 0.051) or the late-onset PD group (P = 0.187). Moreover, we demonstrated that the AA + AG subjects could not be distinguished from the GG subjects based on their clinical features. Our study is the first to demonstrate that FGF20 (rs591323) is associated with a lower risk of PD in a Southern Han Chinese population from mainland China.

Purpose To use resting-state functional magnetic resonance (MR) imaging and graph theory approaches to investigate the brain functional connectome and its potential relation to disease severity in Parkinson disease (PD). Materials and Methods This case-control study was approved by the local research ethics committee, and all participants provided informed consent. There were 153 right-handed patients with PD and 81 healthy control participants recruited who were matched for age, sex, and handedness to undergo a 3-T resting-state functional MR examination. The whole-brain functional connectome was constructed by thresholding the Pearson correlation matrices of 90 brain regions, and the topologic properties were analyzed by using graph theory approaches. Nonparametric permutation tests were used to compare topologic properties, and their relationship to disease severity was assessed. Results The functional connectome in PD showed abnormalities at the global level (ie, decrease in clustering coefficient, global efficiency, and local efficiency, and increase in characteristic path length) and at the nodal level (decreased nodal centralities in the sensorimotor cortex, default mode, and temporal-occipital regions; P < .001, false discovery rate corrected). Further, the nodal centralities in left postcentral gyrus and left superior temporal gyrus correlated negatively with Unified Parkinson's Disease Rating Scale III score (P = .038, false discovery rate corrected, r = -0.198; and P = .009, false discovery rate corrected, r = -0.270, respectively) and decreased with increasing Hoehn and Yahr stage in patients with PD. Conclusion The configurations of brain functional connectome in patients with PD were perturbed and correlated with disease severity, notably with those responsible for motor functions. These results provide topologic insights into understanding the neural functional changes in relation to disease severity of PD. © RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on September 11, 2017.

Previous studies identified that polymorphisms RAB7L1/NUCKS1 rs823118, MCCC1 rs12637471 and STK39 rs1955337 to be the risk loci for Parkinson’s disease (PD) in a Caucasian population. However, the characteristics of these three polymorphisms in a Han Chinese population from mainland China were unknown. We examined genetic associations of rs823118, rs12637471 and rs1955337 with PD susceptibility in a Han Chinese population of 1016 sporadic PD patients and 1069 controls. We also conducted further stratified analysis according to age at onset and compared the clinical characteristics between minor allele carriers and non-carriers for each locus. In this study, the minor allele frequency (MAF) was significantly different of RAB7L1/NUCKS1 rs823118 ( P = 0.003) and MCCC1 rs12637471 ( P = 0.008) between cases and controls. Subjects of RAB7L1/NUCKS1 rs823118 with CC+CT genotypes had a decreased risk compared to those with TT genotype ( P = 0.001) and this association also can be seen among younger population (<50 years, P = 0.011). For the MCCC1 rs12637471, subjects with GA+GG genotypes had an increased risk compared to those with AA genotype ( P = 0.017). However, we did not observe any significant difference in allele and genotype distribution between PD patients and controls for rs1955337 in STK39 . In addition, minor allele carriers cannot be distinguished from non-carriers based on their clinical features of the three loci. Our study provides strong support for the susceptibility role of rs823118 and rs12637471 in sporadic PD in a Han Chinese population.

Recently, mutations in the coiled‐coil‐helix–coiled‐coil‐helix domain containing 2 (CHCHD2) gene have been identified in Japanese families with autosomal dominant Parkinson's disease (PD) and two single nucleotide variants (rs10043 and Pro2Leu) increased risk of sporadic PD. The role of CHCHD2 in PD susceptibility in other Asian populations still remains to be clarified. In a large Chinese cohort from mainland China (31 familial PD patients, 1,027 sporadic PD patients, and 1,095 health controls), we examined the association of rs10043 and Pro2Leu variants in CHCHD2 with PD. All subjects were homozygous for rs10043. Moreover, we detected six patients (0.57%, one of the six patients has family history) and three controls (0.27%) with a heterozygous Pro2Leu variant. Though the frequency of Pro2Leu variant was two times higher in PD compared to controls, the difference did not reach significance in genotypic distribution (P = 0.47) or allelic distribution (P = 0.47). However, our meta‐analysis in Asian populations revealed that the frequency of Pro2Leu variant was significantly higher in PD patients than in controls (P = 0.0002). Our study suggests that Pro2Leu in CHCHD2 may be a risk factor for PD among Asians. © 2016 Wiley Periodicals, Inc.

PURPOSE:A genome-wide association study (GWAS) has recently identified a novel single nucleotide polymorphism (SNP) rs356182 at SNCA that can modulate the risk of Parkinson's disease (PD) in Caucasian ancestry. The present study was designed to clarify the strength of the association in ethnic Chinese population. METHODS:Using a case-control methodology, we genotyped the SNP rs356182 to investigate the association with risk of PD. A total of 2205 ethnic Han Chinese study subjects comprising 1053 sporadic PD patients (581 males, 472 females) and 1152 controls (604 males, 548 females) were recruited from Mainland China. Additionally, the SHEsis software platform was applied for linkage disequilibrium (LD) analysis between rs356182 and another PD-associated synuclein SNP rs356219 we previously reported. RESULTS:The frequency of SNCA rs356182-G allele was significantly higher in PD group than that in controls (odds ratio (OR)=1.470, 95% confidence interval (CI): 1.284-1.683, P=2.306E-8). Subjects carrying GG/AG genotype had an increased risk compared with the AA carriers (OR=1.162, 95% CI: 1.143-2.274, P=0.006). Among all the genotypes of rs356182, GG genotype showed the strongest association with risk of PD (GG vs. AG/AA, OR=1.620, 95% CI: 1.368-1.919, P=2.001E-8). However, the gender, onset age, disease duration, Hoehn-Yahr stage, UPDRS scores and other clinical features were similar between GG genotype carriers and non-carriers. No LD between rs356182 and rs356219 was found in our population (r(2)=0.016 and D'=0.163). CONCLUSION:Our study firstly demonstrates that SNCA rs356182 variant has an increased risk of susceptibility to PD in Han Chinese population. Further functional analysis is required to determine the role of this SNP in development of PD.

Sequence variants in SLC41A1 (solute carrier family 41 member 1) within the PARK16 locus have been reported to be associated with Parkinson's disease (PD). We performed direct DNA sequencing of the SLC41A1 gene in 100 early‐onset PD cases. A novel intron variant (NM_173854.5:c.993‐90delA) and a known synonymous‐coding variant (NM_173854.5:c.339 C>T, causing p.Thr113Thr, rs11240569) were identified in the SLC41A1 gene. Then we genotyped the rs11240569 variant in a total of 2237 Han Chinese comprising of 1063 sporadic PD and 1174 controls to investigate the association with risk of PD, we also conducted further stratified analysis according to age at onset and compared the clinical characteristics of CC + CT subjects with TT subjects. In this study, we confirmed that the C allele of SLC41A1 (rs11240569) polymorphism reduces the risk to develop sporadic PD (P = 0.018). Additionally, subjects with CC + CT genotypes have a reduced risk compared to those with TT genotype (P = 0.022), the association was modestly seen among the younger age group (P = 0.05), but was not significant among the older age group (P = 0.641). Besides, we demonstrated that CC + CT subjects cannot be distinguished from TT subjects based on their clinical features. Our study, the first demonstrates that SLC41A1 (rs11240569) is associated with a lower risk of PD in a Han Chinese population from mainland China. © 2015 Wiley Periodicals, Inc.

Large‐scale meta‐analysis of genome‐wide association data has identified six new risk loci (SIPA1L2, INPP5F, MIR4697, GCH1, VPS13C, and DDRGK1) for Parkinson's disease (PD). However, the characteristics of those loci in a Han Chinese population from mainland China are unknown. We examined genetic associations of VPS13C rs2414739, MIR4697 rs329648, GCH1 rs11158026, and SIPA1L2 rs10797576 with PD susceptibility in a Han Chinese population of 1028 sporadic PD patients and 1109 healthy controls. All subjects were genotyped for these loci using the Sequenom iPLEX Assay. We also conducted further stratified analysis according to age at onset and compared the clinical characteristics between minor allele carriers and non‐carriers for each locus. However, we did not observe any significant difference in genotype distribution between PD patients and controls for the four loci, even after being stratified by age at onset. Besides, minor allele carriers cannot be distinguished from non‐carriers based on their clinical features. Our findings first demonstrated that VPS13C rs2414739, MIR4697 rs329648, GCH1 rs11158026, and SIPA1L2 rs10797576 do not confer a significant risk for PD in Chinese population. Additional replication studies in other populations and functional studies are warranted to better validate the role of the four new loci in PD risk. © 2015 Wiley Periodicals, Inc.

PURPOSE:To investigate the antiepileptic and protective effects of intravenous levetiracetam (iv LEV) in the rhesus monkey model of acute status epilepticus (SE).METHODS:Thirty minutes before intraperitoneal induction of SE by Coriaria lactone (CL), rhesus monkeys were treated with LEV (15 or 150 mg/kg) delivered intravenously as a single bolus. CL dose and epileptic behavior were recorded. Electroencephalography (EEG) was performed before and during the experiment. All rhesus monkeys were killed after 1-month video monitoring and processed for pathological investigation of neuronal injury, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, and glial fibrillary acidic protein (GFAP) staining.RESULTS:No animal exhibited spontaneous seizures during 1-month video monitoring. Development of acute SE was significantly inhibited in the group given 150 mg/kg LEV, compared with controls and the 15 mg/kg LEV group. Delayed latency, reduction of SE duration, decreased cumulative time of tonic convulsions, slight severity of SE, and a high CL induction dose were observed in the high LEV dose group (p<0.05). The EEG showed less frequent epileptic discharges in the group administered with 150 mg/kg LEV. Hematoxylin and eosin (H&E) staining, ultrastructural examination, TUNEL and GFAP staining revealed serious damage, including neuron loss, swollen mitochondrion, and strong positivity for TUNEL in the hippocampus and thalamus of controls, whereas moderate damage in the group administered with 15 mg/kg LEV, and very mild damage in the 150 mg/kg LEV group. Gliosis was found in the hippocampus of controls, not in the LEV groups and normal rhesus monkey.CONCLUSION:The study supports the antiepileptic and protective effect of pretreatment with intravenous LEV in rhesus monkey model with SE.

Background The manganese superoxide dismutase (MnSOD) gene, which encodes a chief reactive oxygen species (ROS) scavenging enzyme, has been reported to be associated with the risk of developing sporadic Parkinson's disease (PD) in some Asian races and the synapsin III (SYN3) gene with some neuropsychiatric diseases. Objective: To explore the associations between the MnSOD and SYN III variations and PD in two Chinese populations from mainland China and Singapore. Methods We recruited 2342 subjects including 1200 sporadic PD patients and 1142 healthy controls from two independent Asian countries. Using a case-control methodology, we genotyped the single nucleotide polymorphisms (SNP) in MnSOD (rs4880) and SYN III (rs3788470, rs3827336, rs5998557) to explore the associations with risk of PD. Results The results showed the genotype distributions and minor allele frequencies (MAF) of MnSOD (rs4880) and SYN III (rs3788470, rs3827336, rs5998557) were not significantly different between PD patients and healthy controls in mainland China and Singapore, as well as in merged populations. Conclusions The variations of MnSOD (rs4880) and SYN III (rs3788470, rs3827336, rs5998557) were not major risk factors for PD among Chinese, at least in our study populations.