Showing papers by "Bing Zhang published in 2017"

Subregional Structural Alterations in Hippocampus and Nucleus Accumbens Correlate with the Clinical Impairment in Patients with Alzheimer's Disease Clinical Spectrum: Parallel Combining Volume and Vertex-Based Approach.

Abstract: Deep grey matter structures are associated with memory and other important functions, which were typically impaired in Alzheimer’s disease (AD) and its preclinical stage of mild cognitive impairment (MCI). However, systemically characterizing the subregional atrophy and deformations in these structures in AD and MCI still need more investigations. In this paper, we combined complex volumetry- and vertex-based analysis to investigate the pattern of subregional morphological alterations in deep grey matter structures and its association with clinical assessment scores in AD (n = 30) and MCI patients (n = 30). Among all 7 pairs of structures, compared with normal controls, the bilateral hippocampi and nucleus accumbens (NAc) showed significant atrophy in AD (p 0.05). In conclusion, the degeneration of these four subregions in bilateral hippocampi and NAc resulted in severe cognition decline of patients, which might be potential target regions of treatment in preclinical AD. The surface analysis could provide additional information to volume comparison in finding the early pathological progress in deep grey matter structures.

The value of resting-state functional MRI in subacute ischemic stroke: comparison with dynamic susceptibility contrast-enhanced perfusion MRI.

Abstract: To evaluate the potential clinical value of the time-shift analysis (TSA) approach for resting-state fMRI (rs-fMRI) blood oxygenation level-dependent (BOLD) data in detecting hypoperfusion of subacute stroke patients through comparison with dynamic susceptibility contrast perfusion weighted imaging (DSC-PWI). Forty patients with subacute stroke (3-14 days after neurological symptom onset) underwent MRI examination. Cohort A: 31 patients had MRA, DSC-PWI and BOLD data. Cohort B: 9 patients had BOLD and MRA data. The time delay between the BOLD time course in each voxel and the mean signal of global and contralateral hemisphere was calculated using TSA. Time to peak (TTP) was employed to detect hypoperfusion. Among cohort A, 14 patients who had intracranial large-vessel occlusion/stenosis with sparse collaterals showed hypoperfusion by both of the two approaches, one with abundant collaterals showed neither TTP nor TSA time delay. The remaining 16 patients without obvious MRA lesions showed neither TTP nor TSA time delay. Among cohort B, eight patients showed time delay areas. The TSA approach was a promising alternative to DSC-PWI for detecting hypoperfusion in subacute stroke patients who had obvious MRA lesions with sparse collaterals, those with abundant collaterals would keep intact local perfusion.

The Contrast Enhancement of Intracranial Arterial Wall on High-resolution MRI and Its Clinical Relevance in Patients with Moyamoya Vasculopathy

Abstract: The purpose of this study is to investigate the characteristics of intracranial vessel wall enhancement and its relationship with ischemic infarction in patients with Moyamoya vasculopathy (MMV). Forty-seven patients with MMV confirmed by angiography were enrolled in this study. The vessel wall enhancement of the distal internal carotid artery, anterior cerebral artery and middle cerebral artery was classified into eccentric and concentric patterns, as well as divided into three grades: grade 0, grade 1 and grade 2. The relationship between ischemic infarction and vessel wall enhancement was also determined. Fifty-six enhanced lesions were found in patients with (n = 25) and without acute infarction (n = 22). The incidence of lesions with grade 2 enhancement in patients with acute infarction was greater than that in those without acute infarction (p = 0.011). In addition, grade 2 enhancement of the intracranial vessel wall was significantly associated with acute ischemic infarction (Odds ratio, 26.7; 95% confidence interval: 2.8–258.2; p = 0.005). Higher-grade enhancement of the intracranial vessel wall is independently associated with acute ischemic infarction in patients with MMV. The characteristics of intracranial vessel wall enhancement may serve as a marker of its stability and provide important insight into ischemic stroke risk factors.

Functional insights into aberrant brain responses and integration in patients with lifelong premature ejaculation.

Abstract: Even though lifelong premature ejaculation (PE) is highly prevalent, few studies have investigated the neural mechanisms underlying PE. The extent and pattern of brain activation can be determined through a version of functional magnetic resonance imaging (fMRI) with erotic picture stimuli (task fMRI) and a resting-state fMRI (rs fMRI). We showed that the brain activity in the left inferior frontal gyrus and left insula was decreased both during the task and in the resting state, while there was higher activation in the right middle temporal gyrus during the task. Higher functional connectivity was found in PE between those three brain areas and the bilateral middle cingulate cortex, right middle frontal gyrus and supplementary motor area. Moreover, the brain activity had positive correlation with clinical rating scales, such as intravaginal ejaculatory latency time (IELT) and the Chinese Index of Premature Ejaculation (CIPE). These findings revealed that brain responses and functional integration in certain brain areas are impaired in cases of PE, which was consistently supported by multiple measurements obtained using a task and rs fMRI approach.

An allosteric ligand-binding site in the extracellular cap of K2P channels

Abstract: Two-pore domain potassium (K2P) channels generate leak currents that are responsible for the maintenance of the resting membrane potential, and they are thus potential drug targets for treating diseases. Here, we identify N-(4-cholorphenyl)-N-(2-(3,4-dihydrosioquinolin-2(1H)-yl)-2-oxoethyl)methanesulfonamide (TKDC) as an inhibitor of the TREK subfamily, including TREK-1, TREK-2 and TRAAK channels. Using TKDC as a chemical probe, a study combining computations, mutagenesis and electrophysiology reveals a K2P allosteric ligand-binding site located in the extracellular cap of the channels. Molecular dynamics simulations suggest that ligand-induced allosteric conformational transitions lead to blockage of the ion conductive pathway. Using virtual screening approach, we identify other inhibitors targeting the extracellular allosteric ligand-binding site of these channels. Overall, our results suggest that the allosteric site at the extracellular cap of the K2P channels might be a promising drug target for these membrane proteins. TREKs are members of the two-pore domain potassium (K2P) channels, being important clinical targets. Here the authors identify inhibitors of K2P that bind to an allosteric site located in their extracellular cap, suggesting that it might be a promising drug target for these channels.

Emissions trading and technology adoption: An adaptive agent-based analysis of thermal power plants in China

Abstract: Market-based environmental policy can strongly affect both technological advancement and the diffusion of less pollution-intensive or less cost-intensive abatement technologies and facilities. This study applied an agent-based model to examine the effects of an emissions trading system on the NOx technology adoption of power plants in China. The results indicate that an emissions trading system influences obsolete technologies with lower removal levels, but it does not promote the adoption of the most advanced technology. Most power plants will adopt the best available technology under an emissions trading program. In addition, national emissions trading encourages power plants to adopt technologies with relatively higher removal rates compared with separate regional emissions trading systems, but a national program decreases the adoption of most advanced technology. Further, initial allowance allocations based on concentration standards rather than on generation performance standards may promote power plants to adopt the newest technologies more quickly.

Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD.

Abstract: Major depressive disorder (MDD) is a common neuropsychiatric disorder characterized by diverse symptoms. Although several antidepressants can influence dopamine system in the medial prefrontal cortex (mPFC), but the role of D1R or D2R subtypes of dopamine receptor during anti-depression process is still vague in PFC region. To address this question, we investigate the antidepressant effect of levo-stepholidine (l-SPD), an antipsychotic medication with unique pharmacological profile of D1R agonism and D2R antagonism, and clarified its molecular mechanisms in the mPFC. Our results showed that l-SPD exerted antidepressant-like effects on the Sprague-Dawley rat CMS model of depression. Mechanism studies revealed that l-SPD worked as a specific D1R agonist, rather than D2 antagonist, to activate downstream signaling of PKA/mTOR pathway, which resulted in increasing synaptogenesis-related proteins, such as PSD 95 and synapsin I. In addition, l-SPD triggered long-term synaptic potentiation (LTP) in the mPFC, which was blocked by the inhibition of D1R, PKA, and mTOR, supporting that selective activation of D1R enhanced excitatory synaptic transduction in PFC. Our findings suggest a critical role of D1R/PKA/mTOR signaling cascade in the mPFC during the l-SPD mediated antidepressant process, which may also provide new insights into the role of mesocortical dopaminergic system in antidepressant effects.

Spatial Navigation Impairment Is Associated with Alterations in Subcortical Intrinsic Activity in Mild Cognitive Impairment: A Resting-State fMRI Study.

Abstract: Impairment of spatial navigation (SN) skills is one of the features of the Alzheimer’s disease (AD) already at the stage of mild cognitive impairment (MCI). We used a computer-based battery of spatial navigation tests to measure the SN performance in 22 MCI patients as well as 21 normal controls (NC). In order to evaluate intrinsic activity in the subcortical regions that may play a role in SN, we measured ALFF, fALFF, and ReHo derived within 14 subcortical regions. We observed reductions of intrinsic activity in MCI patients. We also demonstrated that the MCI versus NC group difference can modulate activity-behavior relationship, that is, the correlation slopes between ReHo and allocentric SN task total errors were significantly different between NC and MCI groups in the right hippocampus (interaction , ), pallidum (, ), and thalamus (, ), which were negative in NC (right hippocampus, ; right pallidum, ; right thalamus, ; all ) but absent in MCI (right hippocampus, ; right pallidum, ; right thalamus ; all ). These findings may provide a novel insight of the brain mechanism associated with SN impairment in MCI and indicated a stage specificity of brain-behavior correlation in dementia. This trial is registered with ChiCTR-BRC-17011316.

Mitochondrial dysfunction and cerebral metabolic abnormalities in patients with mitochondrial encephalomyopathy subtypes: Evidence from proton MR spectroscopy and muscle biopsy.

Abstract: Aims Accumulated evidence indicates that cerebral metabolic features, evaluated by proton magnetic resonance spectroscopy (1 H-MRS), are sensitive to early mitochondrion dysfunction associated with mitochondrial encephalomyopathy (ME). The metabolite ratios of lactate (lac)/Cr, N-acetyl aspartate (NAA)/creatine (Cr), total choline (tCho)/Cr, and myoinositol (mI)/Cr are measured in the infarct-like lesions by 1 H-MRS and may reveal metabolic changes associated with ME. However, the application of this molecular imaging technique in the investigation of the pathology of ME subtypes is unknown. Methods In this study, cerebral metabolic features of pathologically diagnosed ME cases, that is, 19 mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); nine chronic progressive external ophthalmoplegia (CPEO); and 23 healthy controls, were investigated using 1 H-MRS. Receiver operating characteristics (ROC) analysis was used to evaluate the diagnostic power of the cerebral metabolites. Histochemical evaluation was carried out on muscle tissues derived from biopsy to assess the abnormal mitochondrial proliferation. The association between cerebral metabolic and mitochondrial cytopathy was examined by correlation analysis. Results Patients with MELAS or CPEO exhibited a significantly higher Lac/Cr ratio and a lower NAA/Cr ratio compared with controls. The ROC curve of Lac/Cr ratio indicated prominent discrimination between MELAS or CPEO and healthy control subjects, whereas the NAA/Cr ratio may present diagnostic power in the distinction of MELAS from CPEO. Lower NAA/Cr ratio was associated with higher Lac/Cr in MELAS, but not in CPEO. Furthermore, higher ragged-red fibers (RRFs) percentages were associated with elevated Lac/Cr and reduced NAA/Cr ratios, notably in MELAS. This association was not noted in the case of mI/Cr ratio. Conclusions Mitochondrial cytopathy (lactic acidosis and RRFs on muscle biopsy) was associated with neuronal viability but not glial proliferation, notably in MELAS. Mitochondrial neuronopathy and neuronal vulnerability are considered significant causes in the pathogenesis of MELAS, particularly with regard to stroke-like episodes.

Disrupted functional connectivity between perirhinal and parahippocampal cortices with hippocampal subfields in patients with mild cognitive impairment and Alzheimer’s disease

Abstract: Most patients with mild cognitive impairment and Alzheimer's disease can initially present memory loss. The medial temporal lobes are the brain regions most associated with declarative memory function. As sub-components of the MTL, the perirhinal cortex, parahippocampal cortex and hippocampus have also been identified as playing important roles in memory. The functional connectivity between hippocampus subfields and perirhnial cortices as well as parahippocampal cortices among normal cognition controls (NC group, n=33), mild cognitive impairment (MCI group, n=31) and Alzheimer's disease (AD group, n=27) was investigated in this study. The result shows significant differences of functional connectivity in 3 pairs of regions among NC group, MCI group and AD group: right perirhinal cortex with right hippocampus tail, left perirhinal cortex with right hippocampus tail, and right parahippocampal cortex with right hippocampus head. Clustering methods were used to classify NC group, MCI group and AD group (accuracy=100%) as well as different subtypes of mild cognitive impairment patients based on functional alterations. Functional connectivity disrupted between perirhinal and parahippocampal cortex with hippocampal subfields, which may provide a better understanding of the neurodegenerative progress of MCI and AD.

Balancing Development and the Environment in a Changing World: Expressways, GDP, and Pollution in China

Abstract: When productivity changes, how would an economy rebalance economic production and environmental preservation? We develop a conceptual framework to analyze the question, and predict that a productivity shock can have heterogeneous impacts on environmental quality and income. Exploiting a quasi-experiment provided by the dramatic expansion of China’s national expressway system, we find empirical evidence that is consistent with the model’s predictions: expressway access increases both pollution and GDP in initially poor counties, decreases pollution and GDP in initially rich counties, and decreases pollution while increasing GDP in counties with moderate levels of initial income. These findings cannot be fully explained by alternative theories such as the pollution haven hypothesis and home market effect.

Identification of Intracellular β-Barrel Residues Involved in Ion Selectivity in the Mechanosensitive Channel of Thermoanaerobacter tengcongensis.

Abstract: The mechanosensitive channel of small conductance (MscS) is a bacterial membrane pore that senses membrane tension and protects cells from lysis by releasing osmolytes. MscS is a homoheptameric channel with a cytoplasmic domain with seven portals and a β-barrel opening to the cytoplasm. TtMscS, an MscS channel from Thermoanaerobacter tengcongensis, is an anion-selective channel. A previous study from our laboratory has defined the crucial role of β-barrel in the anion selectivity of TtMscS (Zhang et al., 2012). However, the mechanistic details by which the β-barrel determines anion selectivity remain unclear. Here, using mutagenesis and patch-clamp recordings, we investigated the function and structural correlations between β-barrels and the anion selectivity of TtMscS at the atomic level. Our results indicated that mutation of V274, a residue at the centre of the inner wall of the β-barrel in TtMscS, caused the anion selectivity of TtMscS to reverse to cation selectivity. Moreover, the electrostatic potential (T272) and physical size (L276) of residues in the inner wall of β-barrel also determine the anion selectivity of TtMscS. In summary, the present study confirmed that the β-barrel region of TtMscS acts as a “selective filter” that renders TtMscS anion selective.

Olfactory processing is highly cognitively demanding: sensitive functional marker for cognitive deficits and dementia in ad

Abstract: Figure. 2. Olfactory andDMNs found during the odor stimulation paradigm in Healthy Controls (HC), MCI and AD subjects. The odor network encompasses the Primary olfactory cortex, amygdala and hippocampus. The DMN encompasses the posterior cingulate cortex, inferior parietal and ventral medial prefrontal cortex. Time courses for the odor networks are also shown. Poster Presentations: Tuesday, July 18, 2017 P1118

Response to Letter to the Editor: Can MR spectroscopy and muscle biopsy findings be correlated in MELAS and CPEO?

Abstract: 1. MELAS is not the most common subtype of mitochondrial dis‐ order (MID).Response: “Mitochondrial encephalomyopathy” (ME) is defined as a multisystem inherited disorder affecting tissues with high energy requirements, such as the muscle and central nervous systems.1 It is widely accepted that the subtypes of ME include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); myoclonic epilepsy and ragged red fiber disease (MERRF); chronic progressive external ophthal‐ moplegia (CPEO), Leigh syndrome, and others. MELAS is rec‐ ognized as one of the more common ME disorders.2 Thus, the definition of an MID given by Dr. Finsterer and Dr. ZarroukMahjoub is their own and not entirely applicable to our article. An extensive discussion of the function and genetics of MIDs is beyond the scope of this study. 2. CPEO results from single large-scale mtDNA depletion, as well as nDNA mutation.Response: Yes, we know that CPEO can result from both mtDNA and nDNA mutations (most commonly a 4977bp mtDNA deletion, as well as POLG, TWNK, RRM2B, and SLC25A4 nDNA mutations).3,4 The purpose of our study was to select CPEO patients and not to identify definite genetic mutations in CPEO. Hence, if patients had a history of chronic progressive external ophthalmoplegia, short stature, and mtDNA depletion, they satisfied the criteria for CPEO diagnosis, irrespective of the presence of nDNA mutations. 3. Leigh syndrome is not uncommon and is associated with specific cerebral abnormalities.Response: (i) Leigh syndrome occurs mostly between the ages of 3 and 12 months (childhood) and is reported to affect 1 in 40 000 live births.5 As most ME patients in our study were adolescents and adults, Leigh syndrome was relatively rare compared to MELAS, which is estimated to occur in as many as 60 in 100 000 individuals.6 (ii) Cerebral abnormalities in patients with Leigh syndrome include symmetric alterations to the basal ganglia or brain stem. However, these abnormalities are only suggestive of Leigh syndrome and are not diagnostic criteria, given their lack of specificity. Other pathological conditions such as hepatolenticular degeneration (Wilson’s disease) or carbon monoxide (CO) poison‐ ing demonstrate magnetic resonance imaging (MRI) characteristics similar to those of symmetric basal ganglia degeneration (Figure 1). 4. The disease durations were not mentioned.Response: In the pre‐ sent study, we focused on the peak period of the disease course rather than the entire disease duration of ME. Thus, the MRI exami‐ nations and muscle biopsies were performed at the peak clinical stage of disease, to avoid variations in lactate and N-acetylaspartate (NAA) values. Moreover, as the possibility of evaluating lactate lev‐ els by means of 1H-magnetic resonance spectroscopy (MRS) is re‐ lated to the concentration threshold of lactate methyl protons, the ideal time to perform MRS is the peak period of the disease course.7 5. There was unclear reasoning as to why only 13 of 19 MELAS pa‐ tients had cerebral involvement.Response: All of our patients had abnormal MRS imaging, with increased lactate levels or decreased NAA levels. However, these subtle metabolic changes may not be completely observed as clinical central nervous systems (CNS) manifestations, which include delayed development, skill loss, stroke-like episodes, migraines, seizures, myoclonus, cortical blind‐ ness, and others (Table S2 in our original article). The original