Novel mitochondrial alanyl-tRNA synthetase 2 (AARS2) heterozygous mutations in a Chinese patient with adult-onset leukoencephalopathy.

BACKGROUND: Missense mutations in the mitochondrial alanyl-tRNA synthetase 2 (AARS2) gene are clinically associated with infantile mitochondrial cardiomyopathy or adult-onset leukoencephalopathy with early ovarian failure. To date, approximately 40 cases have been reported related to AARS2 mutations, while its genetic and phenotypic spectrum remains to be defined. CASE PRESENTATION: We identified a 24-year-old Chinese female patient with adult-onset leukoencephalopathy carrying novel compound heterozygous pathogenic mutations in the AARS2 gene (c.718C > T and c.1040 + 1G > A) using a whole-exome sequencing approach. CONCLUSIONS: Our findings further extend the mutational spectrum of AARS2-related leukoencephalopathy and highlight the importance of the whole-exome sequencing in precisely diagnosing adult-onset leukoencephalopathies.

Hypereosinophilic syndrome presenting as acute ischemic stroke, myocardial infarction, and arterial involvement: A case report.

BACKGROUND: Simultaneous cerebral and myocardial infarction with arterial involvement has not been reported in hypereosinophilic syndrome (HES). Here, we report a patient with HES that was also associated with acute ischemic stroke, myocardial infarction, and arterial involvement of the left common carotid artery, vertebral arteries, posterior cerebral artery, and coronary artery. CASE SUMMARY: A 64-year-old male patient was admitted with headache and right lower extremity weakness. Laboratory tests indicated eosinophilia. Brain magnetic resonance imaging (MRI) showed bilateral and multiple acute infarcts in the border zones. Electrocardiography revealed that T wave was inverted and that the concentration of troponin I was significantly elevated above normal levels. Cardiac echocardiography showed an ejection fraction of 69% with mitral and tricuspid mild regurgitation. Computed tomography angiography detected multiple and localized instances of mild stenosis in the left common carotid artery bifurcation, bilateral vertebral arteries (V5 segment), and the posterior cerebral artery (P2 segment). These were observed together with multiple non-calcified and mixed plaques as well as luminal stenosis in the left circumflex artery, left anterior descending artery, and right coronary artery. The patient was treated with oral methylprednisolone and clopidogrel, after which the absolute eosinophil count fell rapidly to a normal level. After one month, a second brain MRI showed a partial reduction in the size and number of the lesions. CONCLUSION: HES can masquerade as ischemic stroke, myocardial infarction, and arterial vascular involvement. The patient reported here recovered very quickly when his eosinophil blood count returned to normal. Early diagnosis and rapid reduction of eosinophils may lead to a good prognosis.

Aspirin Exerts Neuroprotective Effects by Reversing Lipopolysaccharide-Induced Secondary Brain Injury and Inhibiting Matrix Metalloproteinase-3 Gene Expression.

OBJECTIVE: This study is aimed at exploring the possible neuroprotective mechanism of aspirin and the effect of bacterial endotoxin lipopolysaccharide (LPS) during cerebral ischaemia-reperfusion (CIRP) injury. METHODS: We established three animal models: the CIRP, LPS, and CIRP+LPS models. Mortality, the injured brain area, and the beam walking test were used to estimate the degree of cerebral injury among the rats. Immunohistochemistry and immunofluorescence were used to detect activated microglia, matrix metalloproteinase-3 (MMP-3), and osteopontin (OPN). RESULTS: The injured brain area and mortality were dramatically reduced (p < 0.01), and the beam walking test scores were elevated (p < 0.01) in the acetylsalicylic acid (ASA) group compared to the control group. The number of microglia-, MMP-3-, and OPN-positive cells also increased. Furthermore, the number of GSI-B4, OPN, and MMP-3 cells decreased in the ASA group compared to the control group. After LPS stimulation, the number of microglia reached a peak at 24 h; at 7 d, these cells disappeared. In the ASA group, the number of microglia was significantly smaller (p < 0.05), especially at 24 h (p < 0.01), compared to the LPS group. Moreover, the injured brain area and the mortality were dramatically increased and the beam walking test scores were reduced (p < 0.01) after LPS simulation following CIRP. The degree of injury in the ASA group resembled that in the control group. However, the number of MMP-3-immunoreactive neurons or microglia was significantly larger than that of the control group (p < 0.05). In the ASA group, the MMP-3 expression was also considerably decreased (p < 0.05). CONCLUSIONS: After CIRP, microglia were rapidly activated and the expression of MMP-3 and OPN significantly increased. For rats injected with LPS at reperfusion, the injured brain area and mortality also dramatically increased and the neurologic impairment worsened. However, ASA exhibited a neuroprotective effect during CIRP injury. Furthermore, ASA can reverse LPS-induced cerebral injury and inhibit the inflammatory reaction after CIRP injury.

GAA compound heterozygous mutations associated with autophagic impairment cause cerebral infarction in Pompe disease.

Clinical manifestations of the late-onset adult Pompe disease (glycogen storage disease type II) are heterogeneous. To identify genetic defects of a special patient population with cerebrovascular involvement as the main symptom, we performed whole-genome sequencing (WGS) analysis on a consanguineous Chinese family of total eight members including two Pompe siblings both had cerebral infarction. Two novel compound heterozygous variants were found in GAA gene: c.2238G>C in exon 16 and c.1388_1406del19 in exon 9 in the two patients. We verified the function of the two mutations in leading to defects in GAA protein expression and enzyme activity that are associated with autophagic impairment. We further performed a gut microbiome metagenomics analysis, found that the child's gut microbiome metagenome is very similar to his mother. Our finding enriches the gene mutation spectrum of Pompe disease, and identified the association of the two new mutations with autophagy impairment. Our data also indicates that gut microbiome could be shared within Pompe patient and cohabiting family members, and the abnormal microbiome may affect the blood biochemical index. Our study also highlights the importance of deep DNA sequencing in potential clinical applications.

Postural sway in patients with early Parkinson's disease performing cognitive tasks while standing.

OBJECTIVES: We investigated postural sway in patients with early Parkinson's disease (PD) to test the hypothesis that the postural control system was affected already at an early stage of PD. Moreover, we identified cases of dysfunction of stereopsis in PD patients. METHODS: We examined 23 patients with early PD and 23 healthy, sex- and age-matched control subjects. Postural sway was measured with an accelerometer at the center of mass at the lower spine. Subjects were asked to stand quietly for 30 s under two usual conditions (eyes open and eyes closed) and two dual tasks conditions (eyes open with dual task, eyes closed with dual task). Stereopsis was assessed using the Titmus fly test. RESULTS: In the usual conditions, no differences were found between the control group and PD group. With increasing task difficulty, PD patients showed an increase of RMS values of sway acceleration, compared to control subjects. These differences reached significance during cognitive task performance. PD patients showed larger JERK values with increasing difficulty of the sway task which also reached significance during cognitive task performance. Relative to controls, PD patients showed decreased stereopsis function. But, there were no statistically significant correlations between log seconds of arc of the Titmus test and JERK, even during cognitive task performance. CONCLUSION: Our results indicate that patients with early PD have subtle signs of postural instability when their attention is diverted or reduced. In addition, deficits of stereopsis may be common in early PD patients. St Abbreviations: ACC: Accelerometers; ANOVA: Analysis of variance; AP: Antero-posterior; COP: Center of pressure; EC: Eyes closed; ECDT: eyes closed with dual task; EO: Eyes open; EODT: Eyes open with dual task; GDS: Geriatric depression scale; JERK: Jerkiness of sway; ML: Medio-lateral; MMSE: Mini mental state examination; MoCA: Montreal cognitive assessment; PD: Parkinson's disease; PDAbS: PD Patients with abnormal stereopsis; PDNrS: PD Patients with normal stereopsis; PIGD: Postural instability and gait disorder; RMS: Root mean square; UPDRS: Unified Parkinson's disease rating scale.

Identification of key genes and pathways in Parkinson's disease through integrated analysis.

Parkinson's disease (PD) is a progressive, degene-rative neurological disease, typically characterized by tremors and muscle rigidity. The present study aimed to identify differe-ntially expressed genes (DEGs) between patients with PD and healthy patients, and clarify their association with additional biological processes that may regulate factors that lead to PD. An integrated analysis of publicly available Gene Expression Omnibus datasets of PD was performed. DEGs were identified between PD and normal blood samples. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses, as well as protein­protein interaction (PPI) networks were used to predict the functions of identified DEGs. Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was performed to validate the predicted expression levels of identified DEGs in whole blood samples obtained from patients with PD and normal healthy controls. A total of 292DEGs were identified between the PD and normal blood samples. Of these, 156 genes were significantly upregulated and 136 genes were significantly downregulated in PD samples following integrated analysis of four PD expression datasets. The 10 most upregulated and downregulated genes were used to construct a PPI network, where ubiquitin C­terminal hydrolase L1 (UCHL1), 3­phosphoinositide dependent protein kinase 1 (PDPK1) and protein kinase cAMP­activated catalytic subunit ß (PRKACB) demonstrated the highest connectivity in the network. DEGs were significantly enriched in amoebiasis, vascular smooth muscle contraction, and the Wnt and calcium signaling pathways. The expression levels of significant DEGs, UCHL1, PDPK1 and PRKACB were validated using RT­qPCR analysis. The findings revealed that UCHL1 and PDPK1 were upregulated and PRKACB was downregulated in patients with PD when compared with normal healthy controls. In conclusion, the results indicate that the significant DEGs, including UCHL1, PDPK1 and PRKACB may be associated with the development of PD. In addition, these factors may be involved in various signaling pathways, including amoebiasis, vascular smooth muscle contraction and the Wnt and calcium signaling pathways.

miR-148b Regulates Proliferation and Differentiation of Neural Stem Cells via Wnt/ß-Catenin Signaling in Rat Ischemic Stroke Model.

Stroke is the second leading cause of death worldwide. Stroke induced proliferation and differentiation of neural stem cells (NSCs) that have been proven to participate in ischemic brain repair. However, molecular mechanisms that regulate neurogenesis have not been fully investigated. MicroRNAs play an important role in the neurological repairing process and impact stroke recovery outcome. MiRNA-148b has been reported to regulate cell proliferation in tumor cells, but its role in NSCs after ischemic stroke remains unknown. Here, we found an overexpression of MiRNA-148b in subventricular zone (SVZ) of rat ischemic brain. In original cultured ischemic NSCs, transfection of MiRNA-148b mimic or inhibitor could suppress or enhance the expression of Wnt-1, ß-catenin, and Cyclin D1, hence effected wnt/ß-catenin signaling. MiRNA-148b inhibitor promoted NSCs proliferation and differentiation into newborn neural and astrocytes, and this action could be silenced with knockdown of Wnt-1. In middle cerebral artery occlusion (MCAo) rats, injection of MiRNA-148b inhibitor could reduce ischemic lesion volume and improve neurological function outcome. Collectively, our data suggest that MiRNA-148b suppressed wnt/ß-catenin signaling attenuates proliferation and differentiation of neural stem cells, these findings shed new light on the role of MiRNA-148b in the recovery process during the stroke and contribute to the novel therapy strategy.

Disrupted pursuit compensation during self-motion perception in early Alzheimer's disease.

Our perception of the world is remarkably stable despite of distorted retinal input due to frequent eye movements. It is considered that the brain uses corollary discharge, efference copies of signals sent from motor to visual regions, to compensate for distortions and stabilize visual perception. In this study, we tested whether patients with Alzheimer's disease (AD) have impaired corollary discharge functions as evidenced by reduced compensation during the perception of optic flow that mimics self-motion in the environment. We asked a group of early-stage AD patients and age-matched healthy controls to indicate the perceived direction of self-motion based on optic flow while tracking a moving target with smooth pursuit eye movement, or keeping eye fixation at a stationary target. We first replicated the previous findings that healthy participants were able to compensate for distorted optic flow in the presence of eye movements, as indicated by similar performance of self-motion perception between pursuit and fixation conditions. In stark contrast, AD patients showed impaired self-motion perception when the optic flow was distorted by eye movements. Our results suggest that early-stage AD pathology is associated with disrupted eye movement compensation during self-motion perception.

Impaired Center-Surround Suppression in Patients with Alzheimer's Disease.

Alzheimer's disease (AD) is often associated with declined visual processing abilities. Here we tested whether the functions of center-surround suppression- a hallmark property in the visual system- are altered by AD. To this end, we recruited three groups of participants (AD, elderly, and young) in a motion direction discrimination task, in which we measured the temporal duration threshold of a  drifting Gabor with varying stimulus sizes. We first replicated the phenomena of center-surround suppression that the required duration for discriminating a high contrast grating decreases with increasing stimulus size. We then showed that the magnitudes of suppression varied among the three groups. There was progressive reduction of suppression in the elderly and AD groups compared with the young group. Interestingly, we found that the levels of suppression can predict the severity of dementia in the AD group. Our results suggest that AD is associated with impaired center-surround functions in the visual motion processing pathway.

Contribution of Pro-inflammatory Cytokine Signaling within Midbrain Periaqueductal Gray to Pain Sensitivity in Parkinson's Disease via GABAergic Pathway.

BACKGROUND/AIMS: Hypersensitive pain response is often observed in patients with Parkinson's disease (PD); however, the mechanisms responsible for hyperalgesia are not well understood. Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Since the midbrain periaqueductal gray (PAG) is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role for pro-inflammatory cytokines (PICs) system of PAG in regulating exaggerated pain evoked by PD. METHODS: We used a rat model of PD to perform the experimental protocols. PD was induced by microinjection of 6-hydroxydopamine to lesion the left medial forebrain bundle. Pain responses to mechanical and thermal stimulation were first examined in control rats and PD rats. Then, ELISA and Western Blot analysis were used to determine PIC levels and their receptors expression. RESULTS: Protein expression of IL-1ß, IL-6, and TNF-α receptors (namely, IL-1R, IL-6R, and TNFR subtype TNFR1) in the plasma membrane PAG of PD rats was upregulated, whereas the total expression of PIC receptors was not significantly altered. The ratio of membrane protein and total protein (IL-1R, IL-6R, and TNFR1) was 1.48 ± 0.15, 1.59 ± 0.18, and 1.67 ± 0.16 in PAG of PD rats (P < 0.05 vs. their respective controls). This was accompanied with increases of PICs of PAG and decreases of GABA (623 ± 21 ng/mg in control rats and 418 ± 18 ng/mg in PD rats; P < 0.05 vs. control rats) and withdrawal thresholds to mechanical and thermal stimuli. Our data further showed that the concentrations of GABA and withdrawal thresholds were largely restored by blocking those PIC receptors in PAG of PD rats. Stimulation of GABA receptors in PAG of PD rats also blunted a decrease in withdrawal thresholds. CONCLUSION: Our data suggest that upregulation of the membrane PIC receptor in the PAG of PD rats is likely to impair the descending inhibitory pathways in regulating pain transmission and thereby plays a role in the development of hypersensitive pain response in PD.

Local thrombolytic therapy in severe cerebral venous sinus thrombosis during puerperium.

This study is to explore and evaluate the efficacy and safety of local thrombolytic therapy in superior sagittal sinus in patients with severe cerebral venous sinus thrombosis during puerperium, as well as the efficacy and safety of anti-platelet aggregation treatment for preventing recurrence. Twelve patients during postpartum period with cerebral venous sinus thrombosis were received local thrombolytic therapy by placing a micro-catheter at the distal end of superior sagittal sinus from January 2008 to December 2013. All the patients accepted mechanical thrombus maceration before local intrasinus thrombolytic therapy, and were treated with low molecular weight heparin in the acute phase. After local thrombolytic therapy, anti-platelet aggregation treatment was performed for 6 months. Follow-up data included lumber puncture, fundus examination and magnetic resonance venography (MRV) once per half year for 6-70 months. At discharge, the intracranial pressure of 12 patients reduced to below 200 mmH2O. DSA or MRV confirmed that superior sagittal sinus of 9 patients were smooth. The cortex venous and deep venous were recovered to normal. Superior sagittal sinus of 3 patients recanalized partly. Cortex venous and deep venous was compensated. The follow-up study indicated that no thrombosis and new neurological symptoms occurred among all patients. Local thrombolytic treatment is safe and effective in patients with severe cerebral venous sinus thrombosis during puerperium. The collateral circulation compensation is the main recovery factor. And it is also safe and effective for anti-platelet aggregation treatment to prevent recurrence of cerebral venous sinus thrombosis.

Postural sway in idiopathic rapid eye movement sleep behavior disorder: a potential marker of prodromal Parkinson's disease.

There is compelling evidence that postural instability occurs at very early clinical stages of Parkinson's disease (PD), making it tempting to speculate that changes in postural sway may even occur at a prodromal phase. Studies estimate that approximately half of patients with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) will eventually develop PD, so RBD may be an indicator of prodromal PD. This study was undertaken to investigate postural sway and its relation to stereopsis function in patients with RBD. We examined 24 patients with polysomnography-confirmed RBD and 23 healthy, sex-and age-matched control subjects. Postural sway was measured with an accelerometer at the center of mass at the lower spine. Subjects were asked to stand quietly for 30s under two usual conditions (eyes open and eyes closed) and three challenging conditions (eyes open with dual task, eyes closed with dual task, and tandem standing). Stereopsis was assessed using the Titmus fly test. RBD patients showed an increased variability of trunk acceleration and a decrease of smoothness of sway, compared to control subjects. These differences reached significance in the challenging conditions. RBD patients demonstrated significant impairment in stereopsis. There were statistically significant correlations between log seconds of arc of the Titmus test and some sway parameters within the RBD group. RBD patients with abnormal stereopsis showed a significant increase of JERK values compared to patients with normal stereopsis in the challenging conditions. Our results indicate that idiopathic RBD patients, especially with abnormal stereopsis, have subtle signs of postural instability under challenging conditions. Postural sway performance may serve as a biological marker for prodromal PD.

Effect of dual-task interference on the hand flexibility of patients with Parkinson's disease carrying the leucine-rich repeat kinase 2 gene mutation.

The aim of the present study was to observe the changes in hand flexibility of patients with Parkinson's disease (PD) and the effect of dual-task interference. Patients with PD were distributed into two subgroups: the leucine-rich repeat kinase 2 (LRRK2) mutation PD (LRRK2+) and the LRRK2 mutation-free (LRRK2-) PD groups. The healthy controls were distributed into two subgroups: the LRRK2+ control and the LRRK2- control groups. The first task was the Purdue pegboard test. The second task was to perform serial seven subtractions. Single-task and dual-task tests were performed, respectively. The numbers of pegs inserted with the dominant hand, non-dominant hand and both hands in the pegboard test and the number of correct responses in the serial seven subtractions test within 30 sec were recorded. The United Parkinson's Disease Rating Scale (UPDRS) III score of examinees in the LRRK2+ PD group was significantly higher than that of examinees in the LRRK2- PD group (P<0.05). The number of pegs inserted within 30 sec by patients with PD was significantly lower than that by the controls (P<0.05). The indicators of patients with PD, including number of variation in the subtraction test score when the dominant-hand was used in the pegboard test (NVD), number of variation in the subtraction test score when the non-dominant hand was used in the pegboard test (NVND) and number of variation in the subtraction test score when the both-hand was used in the pegboard test (NVB), were significantly different compared with those of the control group (P<0.05). The difference in the number of correct responses within 30 sec of patients with PD was significantly correlated with the UPDRSIII score (P<0.05). In conclusion, the hand flexibility of patients with PD was markedly lower than that of the controls. When both tasks were performed, the ability markedly decreased in the second cognitive task, particularly in the LRRK2+ PD group.