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1.  A Randomized Trial of Chinese Diaoshi Jifa on Treatment of Dizziness in Meniere's Disease 
Background. Meniere's disease is characterized by refractory dizziness and hearing disturbance. We aimed to investigate the efficacy and tolerance of Diaoshi Jifa, a Chinese hand skill for treating dizziness in Meniere's disease. Methods. An open-labeled, randomized, controlled intervention trial was conducted. Twenty-seven patients diagnosed with Meniere's disease were randomly allocated to control group or experimental group. Both groups were assessed by DHI (dizziness handicap inventory (DHI)) questionnaire score before and within 24 hours of receiving treatment, respectively. Results. Twenty-six participants completed the study, and no adverse event was reported due to Diaoshi Jifa treatment. The difference in the DHI scores between baseline and posttreatment reached significant difference in both groups (63.88 ± 19.94 versus 10.25 ± 9.77 and 54.36 ± 17.97 versus 49.6 ± 20.50). Significant difference in DHI scores was observed between the two groups after treatment (10.25 ± 9.77 versus 49.6 ± 20.50). Further investigation of DHI subscales in the experimental group revealed significant improvement posttreatment in the physical domain, functional domain, and emotional domain. Although higher rate of improvement in the emotional domain compared to physical or functional domains was found, the difference was not statistically significant. Conclusions. Diaoshi Jifa might be a fast, effective, and well-tolerated method for alleviating dizziness in Meniere's disease.
PMCID: PMC4052476  PMID: 24955104
2.  Selective Changes of Resting-State Brain Oscillations in aMCI: An fMRI Study Using ALFF 
BioMed Research International  2014;2014:920902.
Mild cognitive impairment (MCI) refers to a transitional state between normal aging and dementia and is a syndrome with cognitive decline greater than expected for an individual's age and educational level. As a subtype of MCI, amnestic mild cognitive impairment (aMCI) most often leads to Alzheimer's disease. This study aims to elucidate the altered brain activation in patients with aMCI using resting-state functional magnetic resonance. We observed Frequency-dependent changes in the amplitude of low-frequency fluctuations in aMCI patients (n = 20), and normal subjects (n = 18). At the same time, we took gray matter volume as a covariate. We found that aMCI patients had decreased amplitude of low-frequency fluctuation signal in left superior temporal gyrus, right middle temporal gyrus, right inferior parietal lobe, and right postcentral gyrus compared to the control group. Specially, aMCI patients showed increased signal in left superior and middle frontal gyrus. Our results suggested that increased activation in frontal lobe of aMCI patients may indicate effective recruitment of compensatory brain resources. This finding and interpretation may lead to the better understanding of cognitive changes of aMCI.
PMCID: PMC4005061  PMID: 24822220
3.  Peroxiredoxin 2 battles PARP1- and p53-dependent pro-death pathways following ischemic injury 
Background and Purpose
Ischemic/reperfusion neuronal injury is characterized by accumulation of reactive oxygen species (ROS) and oxidative DNA damage, which can trigger cell death by various signaling pathways. Two of these modes of death include poly(ADP-ribose) polymerase 1 (PARP1)-mediated death or p53- and Bax-mediated apoptosis. The present study tested the hypothesis that peroxiredoxin2 (PRX2) attenuates DNA damage-mediated pro-death signaling using in vitro and in vivo models of ischemic injury. The impact of this peroxide scavenger on p53- and PARP1-mediated ischemic death is unknown.
Neuronal PRX2 overexpression in primary cortical cultures and transgenic mice was combined with the PARP1 inhibitor AG14361. AG14361 was also applied to p53 and Bax knockout cultures and mice and combined with the JNK inhibitor SP600125. DCF fluorescence, AP sites, single-strand breaks, Comet tail-length, NAD+ depletion, and viability were assessed in response to oxygen-glucose deprivation in cultures or transient focal cerebral ischemia in mice.
PRX2 attenuated ROS, DNA damage, NAD+ depletion, and cell death. PRX2 knockdown exacerbated neuronal death following OGD. PRX2 ameliorated PARP1, p53, Bax, and caspase activation following ischemia. AG14361 reduced ischemic cell death in wild-type and p53 or Bax knockout cultures and animals but had no additional effect in PRX2-overexpressing mice. AG14361 and p53 knockout elicited additive effects with SP600125 on viability in vitro. Our findings support the existence of multiple parallel pro-death pathways with some crosstalk.
The promising therapeutic candidate PRX2 can clamp upstream DNA damage and efficiently inhibit multiple pro-death cascades operating in both parallel and interactive fashions.
PMCID: PMC3891055  PMID: 23429506
PRX2; stroke; apoptosis; necrosis; p53; PARP1; Bax
4.  A Lifespan Observation of a Novel Mouse Model: In Vivo Evidence Supports Aβ Oligomer Hypothesis 
PLoS ONE  2014;9(1):e85885.
Transgenic mouse models are powerful tools in exploring the mechanisms of AD. Most current transgenic models of AD mimic the memory impairment and the main pathologic features, among which the formation of beta-amyloid (Aβ) plaques is considered a dominant pathologic event. Recently, Aβ oligomers have been identified as more neurotoxic than Aβ plaques. However, no ideal transgenic mouse model directly support Aβ oligomers as a neurotoxic species due to the puzzling effects of amyloid plaques in the more widely-used models. Here, we constructed a single-mutant transgenic (Tg) model harboring the PS1V97L mutation and used Non-Tg littermates as a control group. Employing the Morris water maze, electrophysiology, immunohistochemistry, biochemistry, and electron microscopy, we investigated behavioral changes and pathology progression in our single-mutant transgenic model. We discovered the pathological alteration of intraneuronal accumulation of Aβ oligomers without Aβ plaques in the PS1V97L-Tg mouse model, which might be the result of PS1 gene mutation. Following Aβ oligomers, we detected synaptic alteration, tau hyperphosphorylation and glial activation. This model supports an initial role for Aβ oligomers in the onset of AD and suggests that Aβ plaques may not be the only prerequisite. This model provides a useful tool for studying the role of Aβ oligomers in AD pathogenesis.
PMCID: PMC3897547  PMID: 24465766
5.  White Matter Changes in Patients with Amnestic Mild Cognitive Impairment Detected by Diffusion Tensor Imaging 
PLoS ONE  2013;8(3):e59440.
Compared to normal aging adults, individuals with amnestic mild cognitive impairment (aMCI) have significantly increased risk for progressing into Alzheimer’s disease (AD). Autopsy studies found that most of the brains of aMCI cases showed anatomical features associated with AD pathology. The recent development of non-invasive neuroimaging technique, such as diffusion tensor imaging (DTI), makes it possible to investigate the microstructures of the cerebral white matter in vivo. We hypothesized that disrupted white matter (WM) integrity existed in aMCI. So we used DTI technique, by measuring fractional anisotropy (FA) and mean diffusivity (MD), to test the brain structures involved in patients with aMCI. DTI scans were collected from 40 patients with aMCI, and 28 normal controls (NC). Tract-based spatial statistics (TBSS) analyses of whole-brain FA and MD images in each individual and group comparisons were carried out. Compared to NC, aMCI patients showed significant FA reduction bilaterally, in the association and projection fibers of frontal, parietal, and temporal lobes, corpus callosum, bilateral corona radiation, right posterior thalamic radiation and right sagittal stratum. aMCI patients also showed significantly increased MD widespreadly in the association and projection fibers of frontal, parietal and temporal lobes, and corpus callosum. Assessment of the WM integrity of the frontal, parietal, temporal lobes, and corpus callosum by using DTI measures may aid early diagnosis of aMCI.
PMCID: PMC3605411  PMID: 23555673
6.  Genetic association of urokinase-type plasminogen activator gene rs2227564 site polymorphism with sporadic Alzheimer's disease in the Han Chinese population☆ 
Neural Regeneration Research  2012;7(30):2377-2383.
A missense C/T polymorphism in exon 6 (the NCBI rsID is rs2227564) of the urokinase-type plasminogen activator gene has been identified as a possible hot spot for Alzheimer's disease risk. The present study analyzed urokinase-type plasminogen gene polymorphisms of rs2227564 with sporadic Alzheimer's disease by PCR-restriction fragment length polymorphism. Results showed that CC, CT and TT genotype distribution frequencies had significant differences between sporadic Alzheimer's disease patients and healthy controls. In-depth analysis of the association between urokinase-type plasminogen gene rs2227564 polymorphisms and sporadic Alzheimer's disease indicated that people with the C-positive genotype CC + CT were at a higher risk for developing sporadic Alzheimer's disease. These results support the contribution of the polymorphisms of rs2227564 in the urokinase-type plasminogen gene to the pathogenesis of sporadic Alzheimer's disease in the Han Chinese population.
PMCID: PMC4268744  PMID: 25538763
Alzheimer's disease; urokinase plasminogen activator; polymorphism; genetic testing; Han Chinese population; neural regeneration
7.  Dissociation between Brain Amyloid Deposition and Metabolism in Early Mild Cognitive Impairment 
PLoS ONE  2012;7(10):e47905.
The hypothetical model of dynamic biomarkers for Alzheimer’s disease (AD) describes high amyloid deposition and hypometabolism at the mild cognitive impairment (MCI) stage. However, it remains unknown whether brain amyloidosis and hypometabolism follow the same trajectories in MCI individuals. We used the concept of early MCI (EMCI) and late MCI (LMCI) as defined by the Alzheimer’s disease Neuroimaging Initiative (ADNI)-Go in order to compare the biomarker profile between EMCI and LMCI.
To examine the global and voxel-based neocortical amyloid burden and metabolism among individuals who are cognitively normal (CN), as well as those with EMCI, LMCI and mild AD.
In the present study, 354 participants, including CN (n = 109), EMCI (n = 157), LMCI (n = 39) and AD (n = 49), were enrolled between September 2009 and November 2011 through ADNI-GO and ADNI-2. Brain amyloid load and metabolism were estimated using [18F]AV45 and [18F]fluorodeoxyglucose ([18F]FDG) PET, respectively. Uptake ratio images of [18F]AV45 and [18F]FDG were calculated by dividing the summed PET image by the median counts of the grey matter of the cerebellum and pons, respectively. Group differences of global [18F]AV45 and [18F]FDG were analyzed using ANOVA, while the voxel-based group differences were estimated using statistic parametric mapping (SPM).
EMCI patients showed higher global [18F]AV45 retention compared to CN and lower uptake compared to LMCI. SPM detected higher [18F]AV45 uptake in EMCI compared to CN in the precuneus, posterior cingulate, medial and dorsal lateral prefrontal cortices, bilaterally. EMCI showed lower [18F]AV45 retention than LMCI in the superior temporal, inferior parietal, as well as dorsal lateral prefrontal cortices, bilaterally. Regarding to the global [18F]FDG, EMCI patients showed no significant difference from CN and a higher uptake ratio compared to LMCI. At the voxel level, EMCI showed higher metabolism in precuneus, hippocampus, entorhinal and inferior parietal cortices, as compared to LMCI.
The present results indicate that brain metabolism remains normal despite the presence of significant amyloid accumulation in EMCI. These results suggest a role for anti-amyloid interventions in EMCI aiming to delay or halt the deposition of amyloid and related metabolism impairment.
PMCID: PMC3480449  PMID: 23112868
8.  Structural and Functional Changes in Subcortical Vascular Mild Cognitive Impairment: A Combined Voxel-Based Morphometry and Resting-State fMRI Study 
PLoS ONE  2012;7(9):e44758.
The present study aimed to investigate changes in structural gray matter (GM) volume and functional amplitude of spontaneous low-frequency oscillations (LFO) and functional connectivity density in patients with subcortical vascular mild cognitive impairment (svMCI). Structural MRI and resting-sate functional MRI data were collected from 26 svMCI patients and 28 age- and gender-matched healthy controls. Structurally, widespread GM atrophy was found in the svMCI patients that resided primarily in frontal (e.g., the superior and middle frontal gyri and medial prefrontal cortex) and temporal (the superior and inferior temporal gyri) brain regions as well as several subcortical brain sites (e.g., the thalamus and the caudate). Functionally, svMCI-related changes were predominantly found in the default mode network (DMN). Compared with the healthy controls, the svMCI patients exhibited decreased LFO amplitudes in the anterior part of the DMN (e.g., the medial prefrontal cortex), whereas increased LFO amplitudes in the posterior part of the DMN (e.g., the posterior cingulate/precuneus). As for functional connectivity density, the DMN regions (e.g., the posterior cingulate/precuneus, the medial prefrontal cortex and the middle temporal gyrus) consistently exhibited decreased functional connectivity. Finally, the overall patterns of functional alterations in LFO amplitudes and functional connectivity density remained little changed after controlling for structural GM volume losses, which suggests that functional abnormalities can be only partly explained by morphological GM volume changes. Together, our results indicate that svMCI patients exhibit widespread abnormalities in both structural GM volume and functional intrinsic brain activity, which have important implications in understanding the pathophysiological mechanism of svMCI.
PMCID: PMC3446994  PMID: 23028606
9.  Intraocular pressure vs intracranial pressure in disease conditions: A prospective cohort study (Beijing iCOP study) 
BMC Neurology  2012;12:66.
The correlation between intracranial pressure (ICP) and intraocular pressure (IOP) is still controversial in literature and hence whether IOP can be used as a non-invasive surrogate of ICP remains unknown. The aim of the current study was to further clarify the potential correlation between ICP and IOP.
The IOP measured with Goldmann applanation tonometer was carried out on 130 patients whose ICP was determined via lumber puncture. The Pearson correlation coefficient between ICP and IOP was calculated, the fisher line discriminated analysis to evaluate the effectivity of using IOP to predict the ICP level.
A significant correlation between ICP and IOP was found. ICP was correlated significantly with IOP of the right eyes (p < 0.001) and IOP of the left eyes (p = 0.001) and mean IOP of both eyes (p < 0.001), respectively. However, using IOP as a measurement to predict ICP, the accuracy rate was found to be 65.4%.
Our data suggested that although a significant correlation exists between ICP and IOP, caution needs to be taken when using IOP readings by Goldmann applanation tonometer as a surrogate for direct cerebrospinal fluid pressure measurement of ICP.
PMCID: PMC3444958  PMID: 22862817
Intracranial pressure; Intraocular pressure; Lumber puncture; Tonometer
10.  Hashimoto’s encephalopathy cases: Chinese experience 
BMC Neurology  2012;12:60.
Hashimoto’s encephalopathy is a poorly understood syndrome consisting of heterogeneous neurological symptoms and high serum antithyroid antibody titers, typically responding to steroids. More clinical series studies are required to characterize the clinical, laboratory and imaging features, and outcomes, especially in the Chinese population.
We analyzed the clinical, laboratory, and imaging features and outcomes of thirteen consecutive patients with Hashimoto’s encephalopathy diagnosed in Xuan Wu Hospital, Beijing from 2005 to 2010 retrospectively.
Cognitive impairment (84.6%) and psychiatric symptoms (38.5%) were the most frequent symptoms. Seizures (30.8%) and myoclonus (7.7%) were less common than previously described. Three (23.1%) patients showed abnormal signals in hippocampus or temporal lobe, which were believed related to their memory disorders or seizures. MRI changes showed resolution paralleling clinical improvement in one patient. Among eight patients who received steroid therapy, five patients recovered, one patient improved with residual deficits, and two patients relapsed or had no effect. Among five non-steroid treated patients, three patients experienced stable remission with antiepileptic drugs or general neurotrophic therapy, and two patients experienced continuous deterioration.
Most patients with Hashimoto’s encephalopathy showed good response to steroids. Some patients improved without steroid therapy. Considering its reversible course, we recommend that Hashimoto’s encephalopathy should always be in the differential diagnosis while evaluating disorders of the central nervous system.
PMCID: PMC3439285  PMID: 22827897
11.  Prevention strategies for Alzheimer’s disease 
Symptomatic treatment during the dementia stage of Alzheimer’s disease(AD) cannot delay or halt the progression of this disease. Therefore, prevention in the preclinical stage is likely the most effective way to decrease the incidence of this age-associated neurodegenerative condition, and its associated burden for individuals and society. Age, gender, family history, ApoE4, systolic blood pressure, body mass index, total cholesterol level and physical activity are all used as component of dementia risk score. There have been numerous challenges in conducting primary prevention trials in AD. Enrichment strategies for prevention studies include studying those subjects with more risk factors for AD, such as older age, those with a positive family history of late onset AD, and those who are ApoE4 positive. Each of these strategies is designed to increase the probability of developing AD thereby decreasing the sample size or the duration of follow up. Another strategy would be to target directly the pathophysiology of AD in its preclinical stages and use the biomarkers in prevention trial as surrogate markers. This will be done first in carriers of dominantly inherited early onset AD. As this research takes place networks of memory clinics must prepare to transfer new knowledge to persons interested in a preventive approach to AD.
PMCID: PMC3514088  PMID: 23210473
Alzheimer disease; Risk factor; Prevention; Clinical trial; Clinical practice
12.  A Novel Autosomal Dominant Inclusion Body Myopathy Linked to 7q22.1-31.1 
PLoS ONE  2012;7(6):e39288.
We describe a novel autosomal dominant hereditary inclusion body myopathy (HIBM) that clinically mimics limb girdle muscular dystrophy in a Chinese family. We performed a detailed clinical assessment of 36 individuals spanning four generations. The age of onset ranged from the 30s to the 50s. Hip girdle, neck flexion and axial muscle weakness were involved at an early stage. This disease progressed slowly, and a shoulder girdle weakness appeared later in the disease course. Muscle biopsies showed necrotic, regenerating, and rimmed vacuolated fibers as well as congophilic inclusions in some of the fibers. Electron micrograph revealed cytoplasmic inclusions of 15–21 nm filaments. A genomewide scan and haplotype analyses were performed using an Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM), which traced the disease to a new locus on chromosome 7q22.1–31.1 with a maximum multi-point LOD score of 3.65. The critical locus for this unique disorder, which is currently referred to as hereditary inclusion body myopathy 4 (HIBM4), spans 8.78 Mb and contains 65 genes. This localization raises the possibility that one of the genes clustered within this region may be involved in this disorder.
PMCID: PMC3377676  PMID: 22723986
13.  Bickerstaff’s brainstem encephalitis, Miller Fisher syndrome and Guillain-Barré syndrome overlap in an asthma patient with negative anti-ganglioside antibodies 
BMC Research Notes  2012;5:295.
Bickerstaff’s brainstem encephalitis (BBE), together with Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) were considered to form a continuous clinical spectrum. An anti-GQ1b antibody syndrome has been proposed to underlie the common pathophysiology for the three disorders; however, other studies have found a positive anti-GM1 instead of anti-GQ1b antibody.
Case presentation
Here we report a 20-year-old male patient with overlapping BBE, MFS and GBS. The patient had a positive family history of bronchial asthma and had suffered from the condition for over 15 years. He developed BBE symptoms nine days after an asthma exacerbation. During the course of illness, he had significantly elevated IgE levels in both serum and cerebrospinal fluid. Serologic analysis of antibodies against ganglioside complexes (anti-GDIa, anti-GDIb, anti-GM1, anti-GM2, anti-GM3, anti-GQIb and anti-GTIb antibodies) showed negative results.
Since asthma has recently been related to autoimmune disease, our case supports an autoimmune mechanism underlying the clinical spectrum composed of BBE, MFS and GBS. However, contrary to a proposed anti-GQ1b antibody syndrome, we would suggest that pathogenesis of this clinical spectrum is not limited to anti-ganglioside antibodies.
PMCID: PMC3419076  PMID: 22698187
Asthma; Autoimmune; Bickerstaff’s brainstem encephalitis; Miller Fisher syndrome; Guillain-Barré syndrome
14.  Tumor necrosis factor-alpha regulates the Hypocretin system via mRNA degradation and ubiquitination 
Biochimica et biophysica acta  2010;1812(4):565-571.
Recent studies recognize that Hypocretin system (also known as Orexin) plays a critical role in sleep/wake disorders and feeding behaviors. However, little is known about the regulation of the Hypocretin system. It is also known that tumor necrosis factor alpha (TNF-α) is involved in regulation of sleep/wake cycle. Here, we test our hypothesis that the Hypocretin system is regulated by TNF-α. Prepro-Hypocretin and Hypocretin receptor 2 (HcrtR2) can be detected at a very low level in rat B35 neuroblastoma cells. In response to TNF-α, Prepro-Hypocretin mRNA and protein levels are down-regulated, and also HcrtR2 protein level is down-regulated in B35 cells. To investigate the mechanism, exogenous rat Prepro-Hypocretin and rat HcrtR2 were overexpressed in B35 cells. In response to TNF-α, protein and mRNA of Prepro-Hypocretin are significantly decreased (by 93% and 94%, respectively), and the half-life of Prepro-Hypocretin mRNA is decreased in a time- and dose-dependent manner. The level of HcrtR2 mRNA level is not affected by TNF-α treatment; however, HcrtR2 protein level is significantly decreased (by 86%) through ubiquitination in B35 cells treated with TNF-α. Downregulation of cellular inhibitor of apoptosis protein-1 and -2 (cIAP-1 and -2) abrogates the HcrtR2 ubiquitination induced by TNF-α. The control green fluorescent protein (GFP) expression is not affected by TNF-α treatment. These studies demonstrate that TNF-α can impair the function of the Hypocretin system by reducing the levels of both Prepro-Hypocretin and HcrtR2.
PMCID: PMC3042489  PMID: 21094253
Prepro-Hypocretin; Hypocretin; Orexin; Tumor necrosis factor; narcolepsy; sleep disorder; Hypocretin receptor; Orexin receptor; Prepro-Orexin
15.  Anatomical and Functional Deficits in Patients with Amnestic Mild Cognitive Impairment 
PLoS ONE  2012;7(2):e28664.
Anatomical and functional deficits have been studied in patients with amnestic mild cognitive impairment (MCI). However, it is unclear whether and how the anatomical deficits are related to the functional alterations. Present study aims to characterize the association between anatomical and functional deficits in MCI patients.
Seventeen amnestic MCI patients and 18 healthy aging controls were scanned using a T1 Weighted MPRAGE sequence and a gradient-echo echo-planar imaging sequence. Clinical severity of MCI patients was evaluated by using Clinical Dementia Rating, Mini Mental State Examination (MMSE), Clock Drawing Test, Auditory Verbal Learning Test and Activities of Daily Living. VBM with DARTEL was used to characterize the gray matter deficits in MCI. Regional amplitude of low-frequency (0.01–0.08 Hz) fluctuations (ALFF) was used to evaluate regional functional alteration in MCI and fractional ALFF(fALFF) in slow 4 (0.027–0.073 Hz) and slow 5 (0.01–0.027 Hz) were also calculated.
Significantly decreased gray matter volume (GMV) was observed in amnestic MCI group mainly in bilateral prefrontal, left temporal and posterior cingulate cortex. Significant positive correlation was observed between the GMV in left inferior frontal gyrus and MMSE scores. Interestingly, decreased ALFF/fALFF was revealed in MCI group compared to controls mainly in prefrontal, left parietal regions and right fusiform gyrus, while the increased ALFF/fALFF was found in limbic and midbrain. Furthermore, the changes of fALFF in MCI in the slow-5 band were greater than those in the slow-4. No significant correlation was found between the morphometric and functional results.
Findings from the study document that wide spread brain volume reduction accompanied with decreased and increased regional function in MCI, while the anatomical and functional changes were independently. Therefore, the combination of structural and functional MRI methods would provide complementary information and together advance our understanding of the pathophysiology underlying the symptoms of MCI.
PMCID: PMC3272002  PMID: 22319555
16.  Acute toxic leukoencephalopathy in migrant workers exposed to organic solvents in construction materials 
PMCID: PMC3664387  PMID: 23390197
organic solvent; toluene; 1, 2, 3-trichloropropan; acute toxic leukoencephalopathy; migrant workers

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