Increased Cerebrospinal Fluid Levels of Soluble Triggering Receptor Expressed on Myeloid Cells 2 and Chitinase-3-Like Protein 1 in Idiopathic Normal-Pressure Hydrocephalus.

BACKGROUND: Neurodegenerative disease pathology is associated with neuroinflammation, but evidence on idiopathic normal pressure hydrocephalus (iNPH) remains limited and cerebrospinal fluid (CSF) biomarker profiles need to be elucidated. OBJECTIVE: To investigate whether iNPH pathological mechanisms are associated with greater CSF markers of core Alzheimer's disease pathology (amyloid-ß42 (Aß42), phosphorylated tau (P-tau)), neurodegeneration (total tau (T-tau)), and neuroinflammation (soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase-3-like protein 1 (YKL-40)). METHODS: The study analyzed lumbar CSF samples from 63 patients with iNPH and 20 age-matched orthopedic surgery patients who had no preoperative gait or cognitive impairment (control group). Aß42, T-tau, P-tau, sTREM2, and YKL-40 in different subgroups were investigated. RESULTS: CSF sTREM2 levels were significantly higher in the iNPH group than in the control group, but no significant between-group difference was noted in YKL-40. Moreover, YKL-40 levels were significantly higher in the tap test non-responders than in the tap test responders (p = 0.021). At the 1-year follow-up after shunt surgery, the CSF P-tau levels were significantly lower (p = 0.020) in those with gait improvement and the CSF sTREM2 levels were significantly lower (p = 0.041) in those with cognitive improvement. In subgroup analysis, CSF sTREM2 levels were strongly correlated with CSF YKL-40 in the iNPH group (r = 0.443, p < 0.001), especially in the tap test non-responders (r = 0.653, p = 0.002). CONCLUSION: YKL-40 and sTREM2 are disease-specific markers of neuroinflammation, showing higher CSF levels in iNPH. In addition, sTREM2 is positively associated with YKL-40, indicating that interactions of glial cells play an important role in iNPH pathogenesis.

White matter hyperintensity mediating gait disorders in iNPH patients via neurofilament light chain.

Purpose: This study aimed to analyze the differences in regional white matter hyperintensities (WMH) volume and cerebrospinal fluid biomarker levels between idiopathic normal pressure hydrocephalus (iNPH) patients with or without gait disorder. Methods: Forty-eight iNPH patients undergoing bypass surgery and 20 normal senile individuals were included. The LST toolkit was used to segment all MRI fluid attenuation inversion images and quantify the WMH volume in each brain region. Cerebrospinal fluid was collected from all individuals and measured for concentrations of Aß, t-tau, p-tau, and neurofilament light chain (NfL). Patients with iNPH were followed up for 1 year and divided categorized into a gait disorder improvement group and no improvement group according to the 3 m round-trip test time parameter improvement by more than 10%. Results: We found that WMH in all areas of iNPH patients was higher than that in the control group. CSF levels of Aß, t-tau, and p-tau were lower than those in the control group, while NfL levels were higher than those in the control group. The gait (+) group NfL level was higher than that in gait (-), and there were no statistical differences in Aß, t-tau, and p-tau levels. The gait (+) group of frontal and parietal lobe WMH volume PVH above the gait (-) group. The mediating effect model analysis showed that PVH might affect the gait disorder of iNPH patients through NfL. A 1-year follow-up of the patients after the bypass surgery found that 24 of the 35 patients in the gait (+) group had improvements, while 11 had no significant improvements. The comparison of CSF marker levels between the two groups showed that the CSF NfL level in the improved group was lower than that in the non-improved group. The WMH volume and PVH in the frontal-parietal lobe of the improved group were lower than those of the non-improved group. Conclusion: iNPH patients have more serious frontoparietal and periventricular white matter lesions, and WMH volume in the frontoparietal may mediate the occurrence of gait disorder in iNPH patients through the increase of NfL level.

Thromboxane A2 receptor antagonist SQ29548 attenuates SH­SY5Y neuroblastoma cell impairments induced by oxidative stress.

Thromboxane A2 receptor (TXA2R) serves a vital role in numerous neurological disorders. Our previous study indicated that SQ29548, an antagonist of TXA2R, attenuated the induced neuron damage in cerebral infarction animals; however, the underlying mechanism remains unknown. Certain studies revealed a new role of TXA2R in the regulation of oxidative stress, which is one of the basic pathological processes in neurological disorders. Thus, the present study attempted to examine whether the inhibition of TXA2R with SQ29548 helped to protect the nerve cells against oxidative stress. SQ29548 was utilized as a TXA2R antagonist, and relevant assays were performed to detect the cell viability, cellular reactive oxygen species (ROS) level, cell apoptosis, expression levels of superoxide dismutase­2 (SOD2), catalase and caspases, and activation of mitogen­activated protein kinase (MAPK) pathways. It was observed that hydrogen peroxide (H2O2) dose­dependently reduced the viability of SH­SY5Y cells. In addition, H2O2 raised the level of ROS in cells, inhibited the expression levels of SOD2 and catalase, and potentially enhanced cell apoptosis and the expression of caspases via activating the MAPK pathways. Pretreatment with SQ29548 not only rescued the viability of SH­SY5Y cells, but also ameliorated the intracellular ROS level and the expression levels of SOD2 and catalase. Furthermore, it decreased the cell apoptosis and the expression of caspases, possibly via the inhibition of MAPK pathways. In conclusion, SQ29548, an antagonist of TXA2R, improved the antioxidant capacities of SH­SY5Y cells and reduced the cell apoptosis through the inhibition of MAPK pathways.

Genetic analysis and clinical assessment of four patients with Glycogen Storage Disease Type IIIa in China.

BACKGROUND: Glycogen Storage Disease Type III (GSD III) is a rare autosomal recessive metabolic disorder caused by AGL gene mutation. There is significant heterogeneity between the clinical manifestations and the gene mutation of AGL among different ethnic groups. However, GSD III is rarely reported in Chinese population. CASE PRESENTATION: In this study, we aimed to study the genetic and clinical characteristics of four patients with GSD IIIa from China, especially the neurological manifestations. Meanwhile, we conducted a literature review of GSD IIIa cases reported in Chinese population to investigate the relationship between genotype and phenotype. CONCLUSIONS: Three different AGL gene mutations were identified in our patients: c.206dupA, c.1735 + 1G > T and c.2590 C>T. Moreover, progressive myopathy accompanied by elevated creatine kinase level was the main manifestation of our patients in adolescents. Our results showed that AGL c.206dupA was a novel mutation and caused severe clinical manifestations. AGL c.1735 + 1G > T might be a recurrent mutation in the Chinese population. Genetic analysis of AGL gene mutation combined with muscle magnetic resonance imaging (MRI) might provide greater benefit to the patient in diagnosing GSD IIIa, rather than an invasive diagnostic procedure of biopsy.

Adjudin-preconditioned neural stem cells enhance neuroprotection after ischemia reperfusion in mice.

BACKGROUND: Transplantation of neural stem cells (NSCs) has been proposed as a promising therapeutic strategy for the treatment of ischemia/reperfusion (I/R)-induced brain injury. However, existing evidence has also challenged this therapy on its limitations, such as the difficulty for stem cells to survive after transplantation due to the unfavorable microenvironment in the ischemic brain. Herein, we have investigated whether preconditioning of NSCs with adjudin, a small molecule compound, could enhance their survivability and further improve the therapeutic effect for NSC-based stroke therapy. METHOD: We aimed to examine the effect of adjudin pretreatment on NSCs by measuring a panel of parameters after their transplantation into the infarct area of ipsilateral striatum 24 hours after I/R in mice. RESULTS: We found that pretreatment of NSCs with adjudin could enhance the viability of NSCs after their transplantation into the stroke-induced infarct area. Compared with the untreated NSC group, the adjudin-preconditioned group showed decreased infarct volume and neurobehavioral deficiency through ameliorating blood-brain barrier disruption and promoting the expression and secretion of brain-derived neurotrophic factor. We also employed H2O2-induced cell death model in vitro and found that adjudin preconditioning could promote NSC survival through inhibition of oxidative stress and activation of Akt signaling pathway. CONCLUSION: This study showed that adjudin could be used to precondition NSCs to enhance their survivability and improve recovery in the stroke model, unveiling the value of adjudin for stem cell-based stroke therapy.

Thromboxane A2 receptor antagonist SQ29548 suppresses the LPS­induced release of inflammatory cytokines in BV2 microglia cells via suppressing MAPK and NF­κB signaling pathways.

Inflammation in the brain, characterized by the activation of microglia, is hypothesized to participate in the pathogenesis of neuronal disorders. It is proposed that thromboxane A2 receptor (TXA2R) activation is involved in thrombosis/hemostasis and inflammation responses. In the present study, the anti­inflammatory effects of SQ29548 on lipopolysaccharide (LPS)­stimulated BV2 microglial cells and its molecular mechanisms were investigated. In the BV2 cell line, LPS­stimulated nitric oxide (NO) and inflammatory cytokine release, and the phosphorylation of mitogen­activated protein kinases (MAPKs) and the nuclear factor (NF)­κB were assessed using an NO assay kit, reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. In vitro studies demonstrated that SQ29548 inhibited LPS­stimulated BV2 activation and reduced the mRNA expression levels of interleukin (IL)­1ß, IL­6, tumor necrosis factor­α and inducible NO synthase via inhibition of MAPKs and the NF­κB signaling pathway. SQ29548 inhibited the LPS­induced inflammatory response by blocking MAPKs and NF­κB activation in BV2 microglial cells.