A comparative analysis of 375 patients with lateral and medial medullary infarction.

BACKGROUND: Few studies have compared the etiology and clinical features between pure lateral medullary infarction (LMI) and pure medial medullary infarction (MMI). METHODS: All patients included were hospitalized at The First Affiliated Hospital and The Second Affiliated Hospital of Wenzhou Medical University from January 2015 to July 2020. Their risk factors, clinical manifestation, stroke mechanisms and short-term prognosis were analyzed retrospectively. RESULTS: Among the 387 patients enrolled, 266 (68.7%) had LMI, 109 (28.2%) had MMI, and 12 (3.1%) (nine men and three women) had LMI plus MMI. We analyzed the 375 patients of LMI and MMI. The average ages of LMI and MMI were 59.4 years and 62.69 years, respectively. Univariate analysis and multivariable logistic regression was used to investigate the existing risk factors of MMI relative to LMI. Prior infarction, poor glycemic control, and atherosclerosis were more frequently associated with MMI than with LMI. The clinical manifestation was significantly different between LMI and MMI. We used modified Rankin Scale (mRS) score as the short-term prognostic evaluation criteria, and MMI appeared worse than LMI. CONCLUSIONS: This study reveals that: (1) patients with MMI are older than those with LMI; (2) prior infarction, poor glycemic control, and atherosclerosis are independent risk factors of MMI than that of LMI; (3) the clinical manifestations of LMI and MMI are heterogeneous; (4) short-term prognosis of MMI is worse than LMI.

A homozygous mutation of alanyl-transfer RNA synthetase 2 in a patient of adult-onset leukodystrophy: A case report and literature review.

INTRODUCTION: Leukodystrophy is a group of hereditary leukoencephalopathies predominantly affecting the white matter. Multiple genes and mutations have been reported to be associated with this disorder. Identification of pathogenic genes can facilitate diagnosis of leukodystrophy and development of therapeutic strategies. METHODS: A case was presented with clinical examinations. Exome sequencing was applied to identify potential mutations. Sanger sequencing of blood DNA was applied to confirm the mutation and to examine additional members. RESULTS: We reported a Chinese male patient of adult-onset leukodystrophy. Genetic examinations identified a homozygous mutation, c. 452T>C (p. M151T), in alanyl-tRNA synthetase 2 (AARS2) in the patient. The disease was autosomal recessive as suggested by the genotypic analyses of his family members. We also reviewed phenotypic spectra of AARS2 mutation-associated leukodystrophies from a total of 16 reported cases. CONCLUSIONS: Our data provide further evidence that mutations of AARS2 are implicated in adult-onset leukodystrophy.

Mitochondrial DNA variants modulate genetic susceptibility to Parkinson's disease in Han Chinese.

It is well recognized that mitochondrial dysfunction is involved in the pathogenesis of Parkinson's disease (PD). The mtDNA displacement loop (D-loop) region is known to accumulate structural alterations and mutations. To understand how mtDNA variants contribute to the susceptibility to sporadic PD in Chinese, a total of 500 PD patients and 505 controls were recruited from East China, and their D-loop regions were sequenced. A total of 389 variants were detected out of the 1005 subjects. There were 91 variants with frequencies >1%, which included 88 single nucleotide polymorphisms (SNPs), 2 deletions and 1 insertion. Amongst, 6 SNPs were significantly associated with sporadic PD. Specifically, the SNPs 151T/C, 189G/A, 16086C/T and 16271C/T contributed to increased susceptibility, while 318C/T and 16134T/C were associated with reduced risk for PD. Further analyses of mtDNA haplogroups and their risk for PD occurrence showed that subjects carrying haplogroup A5 were susceptible while haplogroup B5 carriers were more resistant to the disease. In summary, our study for the first time systematically analyzed mtDNA variants by sequencing the D-loop region in a Chinese population to understand their associations with PD. These results demonstrate that mtDNA variants modulate risk for sporadic PD.

Meta-analysis of brain iron levels of Parkinson's disease patients determined by postmortem and MRI measurements.

Brain iron levels in patients of Parkinson's disease (PD) are usually measured in postmortem samples or by MRI imaging including R2* and SWI. In this study we performed a meta-analysis to understand PD-associated iron changes in various brain regions, and to evaluate the accuracy of MRI detections comparing with postmortem results. Databases including Medline, Web of Science, CENTRAL and Embase were searched up to 19th November 2015. Ten brain regions were identified for analysis based on data extracted from thirty-three-articles. An increase in iron levels in substantia nigra of PD patients by postmortem, R2* or SWI measurements was observed. The postmortem and SWI measurements also suggested significant iron accumulation in putamen. Increased iron deposition was found in red nucleus as determined by both R2* and SWI, whereas no data were available in postmortem samples. Based on SWI, iron levels were increased significantly in the nucleus caudatus and globus pallidus. Of note, the analysis might be biased towards advanced disease and that the precise stage at which regions become involved could not be ascertained. Our analysis provides an overview of iron deposition in multiple brain regions of PD patients, and a comparison of outcomes from different methods detecting levels of iron.

Selenotranscriptomic Analyses Identify Signature Selenoproteins in Brain Regions in a Mouse Model of Parkinson's Disease.

Genes of selenoproteome have been increasingly implicated in various aspects of neurobiology and neurological disorders, but remain largely elusive in Parkinson's disease (PD). In this study, we investigated the selenotranscriptome (24 selenoproteins in total) in five brain regions (cerebellum, substantia nigra, cortex, pons and hippocampus) by real time qPCR in a two-phase manner using a mouse model of chronic PD. A wide range of changes in selenotranscriptome was observed in a manner depending on selenoproteins and brain regions. While Selv mRNA was not detectable and Dio1& 3 mRNA levels were not affected, 1, 11 and 9 selenoproteins displayed patterns of increase only, decrease only, and mixed response, respectively, in these brain regions of PD mice. In particular, the mRNA expression of Gpx1-4 showed only a decreased trend in the PD mouse brains. In substantia nigra, levels of 17 selenoprotein mRNAs were significantly decreased whereas no selenoprotein was up-regulated in the PD mice. In contrast, the majority of selenotranscriptome did not change and a few selenoprotein mRNAs that respond displayed a mixed pattern of up- and down-regulation in cerebellum, cortex, hippocampus, and/or pons of the PD mice. Gpx4, Sep15, Selm, Sepw1, and Sepp1 mRNAs were most abundant across all these five brain regions. Our results showed differential responses of selenoproteins in various brain regions of the PD mouse model, providing critical selenotranscriptomic profiling for future functional investigation of individual selenoprotein in PD etiology.

Paroxetine ameliorates lipopolysaccharide-induced microglia activation via differential regulation of MAPK signaling.

BACKGROUND: Paroxetine, a selective serotonin reuptake inhibitor for counteracting depression, has been recently suggested as having a role in prevention of dopaminergic neuronal degeneration in substantia nigra, a hallmark of Parkinson's disease (PD). The pathogenesis of this type of neurological disorders often involves the activation of microglia and associated inflammatory processes. Thus in this study we aimed to understand the role of paroxetine in microglia activation and to elucidate the underlying mechanism(s). METHODS: BV2 and primary microglial cells were pretreated with paroxetine and stimulated with lipopolysaccharide (LPS). Cells were assessed for the responses of pro-inflammatory mediator and cytokines, and the related signaling pathways were evaluated and analyzed in BV2 cells. RESULTS: Paroxetine significantly inhibited LPS-induced production of nitric oxide (NO) and pro-inflammatory cytokines such as TNF-α and IL-1ß. Further analysis showed inducible nitric oxide synthase (iNOS) and mRNA expression of TNF-α and IL-1ß were attenuated by paroxetine pretreatment. Analyses in signaling pathways demonstrated that paroxetine led to suppression of LPS-induced JNK1/2 activation and baseline ERK1/2 activity, but had little effect on the activation of p38 and p65/NF-κB. Interference with specific inhibitors revealed that paroxetine-mediated suppression of NO production was via JNK1/2 pathway while the cytokine suppression was via both JNK1/2 and ERK1/2 pathways. Furthermore, conditioned media culture showed that paroxetine suppressed the microglia-mediated neurotoxicity. CONCLUSIONS: Paroxetine inhibits LPS-stimulated microglia activation through collective regulation of JNK1/2 and ERK1/2 signaling. Our results indicate a potential role of paroxetine in neuroprotection via its anti-neuroinflammatory effect besides targeting for depression.

CCDC62 variant rs12817488 is associated with the risk of Parkinson's disease in a Han Chinese population.

It has been recently proposed by a genome-wide association study (GWAS) meta-analysis that the CCDC62 variant rs12817488 is a new risk locus associated with Parkinson's disease (PD). In this study, we aimed to investigate the association between rs12817488 and PD in a Chinese cohort. A total of 341 PD patients and 423 matched controls were recruited in Eastern China. Our results showed that the A allele of rs12817488 was significantly associated with an aggravated risk of PD (p = 0.006) and represented a major allele in contrast to a minor one in Caucasians. Genotype distributions also differed between PD patients and controls (p = 0.011 for AA/AG/GG). Further analysis showed that the association of rs12817488 with PD only existed in females. We also investigated the protein level of CCDC62 in peripheral blood mononuclear cells from 41 AA or GG carriers and found an apparently higher expression in PD patients carrying the AA genotype. A potential interaction was found between two estrogen-related loci, i.e. rs12817488/CCDC62 and rs2697962/PRDM2, particularly in the female stratum. In conclusion, our study demonstrated for the first time a significant association between the rs12817488 polymorphism and PD predisposition in a Chinese population with gender variations and provides new insight regarding the variant's protein expression and estrogen-related genetic interaction.

[Effects of chronic hypoxic hypercapnia on spatial learning-memory and expression of NMDAR1 in rats].

AIM: To explore the effect of chronic hypoxic hypercapnia on learning-memory and the possible mechanisms involved. METHODS: Fifty-eight male SD rats were randomly divided into three groups: Normal control group (NC, n=18), 2-week (2HH, n=18), and 4-week hypoxic hypercapnia (4HH, n=20) group. The rats, spatial learning-memory tasks were assessed by the Morris water maze. The expression of NMDAR1mRNA was determined by hybridization in situ. RESULTS: Compared with NC group, rats exposed to chronic hypoxic hypercapnia displayed significant impairment in their performance assessed by two measures: mean escape latencies (2HH: 38.59 +/- 8.35 s, 4HH: 60.59 +/- 17.28 s) and swim path distances(2HH: 9893.45 +/- 1958.16 mm, 4HH: 18077.57 +/- 6878.85 mm). The expression level of NMDAR1mRNA in the hippocampus and cortex were lower than those in the NC group, especially, the NMDAR1mRNA expression of hippocampus CA1 in 4HH decreased by 21.4% (P < 0.01). CONCLUSION: Chronic hypoxic hypercapnia could impair the rat spatial learning-memory and the decrease in expression of NMDAR1mRNA might be involved in.