Beijing Key Laboratory for Parkinsons Disease

Beijing, China

Beijing Key Laboratory for Parkinsons Disease

Beijing, China
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Xiu S.,Capital Medical University | Zheng Z.,Capital Medical University | Zheng Z.,Key Laboratory on Neurodegenerative Disease of Ministry of Education | Zheng Z.,Beijing Key Laboratory for Parkinsons Disease | And 6 more authors.
Neuroscience Letters | Year: 2017

The relationship between serum uric acid (sUA) and cognitive function is contradictory. This study assessed the association between sUA and cognitive impairment in 10,039 community–dwelling subjects aged ≥55 years living in Beijing, China. Participants underwent determination of sUA and an evaluation of cognitive function using the scholarship-adjusted Mini-Mental State Examination (MMSE): MMSE ≤17 for illiterates; MMSE ≤ 20 for primary school graduates (≥6 years of education); and MMSE ≤ 24 for junior school graduates or above (≥9 years of education). Among the 10016 persons with valid MMSE scores, the prevalence of cognitive impairment was 9.14%. A multivariate logistic regression model including demographic, clinical and genetic parameters was performed to assess the relationship between sUA and cognitive impairment. Persons with cognitive impairment had lower sUA levels than those with normal cognitive function: (302.30 ± 82.80 vs. 312.20 ± 84.01 μmol/L, p = 0.001). After adjusting for age, sex, lifestyle, relevant diseases and the apolipoprotein E (APOE) ε4 allele, stepwise logistic regression showed that participants with higher levels of sUA had a lower risk of cognitive impairment (hazard ratio (HR): 0.78; 95% confidence interval (CI): 0.62–0.96; p = 0.022). In this baseline cross-sectional population-based sample, high levels of sUA were associated with a decreased risk of cognitive impairment. © 2016 Elsevier Ireland Ltd

Zheng Z.,Capital Medical University | Zheng Z.,Beijing Institute for Brain Disorders | Zheng Z.,Key Laboratory on Neurodegenerative Disease | Zheng Z.,Beijing Key Laboratory for Parkinsons Disease | And 13 more authors.
Journal of the American Geriatrics Society | Year: 2016

Objectives: To estimate the prevalence and incidence of frailty and evaluate the effect of frailty on adverse outcomes in Chinese elderly adults. Design: Secondary analysis of prospective cohort study. Setting: Community in Beijing, China. Participants: Individuals aged 55 and older (N = 10,039). Measurements: A Frailty Index (FI) was derived from 34 items using Rockwood's cumulative deficits method. A FI of 0.25 or greater indicated frailty. The clinical outcome was evaluated using a composite variable of any of the following adverse events: falls, hospitalization, activity of daily living disability, and death. Results: The overall crude prevalence of frailty was 12.3% (95% confidence interval (CI) = 11.7–13.0%), and the standardized prevalence was 9.1% (95% CI = 8.6–9.7%). The crude incidence was 13.0% (95% CI = 12.2–13.9%), and the standardized incidence 10.8% (95% CI = 10.0–11.6%). Prevalence and incidence were significantly greater with age (P for trend <.001) and greater in women (P < .001) and urban residents (P < .001). Participants with lower education and having three or more diseases and taking four or more medications daily were more likely to develop frailty over follow-up (all P < .05). After adjusting for age, number of diseases, and smoking at baseline, the risk of any adverse event in 1 year in the frail group was 58% higher than in the nonfrail group (adjusted odds ratio = 1.58, 95% CI = 1.30–1.93, P < .001). Conclusion: A feasible FI that can be used in routine medical evaluation in a primary care setting was developed, and a 12.3% prevalence and a 13% incidence of frailty was demonstrated in community-dwelling Chinese older adults. Frailty is more common for urban and female residents in the oldest old group. Being frail significantly predicts geriatric adverse outcomes, indicating the importance of early screening and intervention in frail individuals in primary care. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

Chen M.,Capital Medical University | Chen M.,Beijing Institute for Brain Disorders | Yang W.,Capital Medical University | Yang W.,Beijing Institute for Brain Disorders | And 14 more authors.
Oncotarget | Year: 2016

We previously reported that the levels of α-syn oligomers, which play pivotal pathogenic roles in age-related Parkinson's disease (PD) and dementia with Lewy bodies, increase heterogeneously in the aging brain. Here, we show that exogenous α-syn incubated with brain extracts from older cynomolgus monkeys and in Lewy body pathology (LBP)-susceptible brain regions (striatum and hippocampus) forms higher amounts of phosphorylated and oligomeric α-syn than that in extracts from younger monkeys and LBP-insusceptible brain regions (cerebellum and occipital cortex). The increased α-syn phosphorylation and oligomerization in the brain extracts from older monkeys and in LBP-susceptible brain regions were associated with higher levels of polo-like kinase 2 (PLK2), an enzyme promoting α-syn phosphorylation, and lower activity of protein phosphatase 2A (PP2A), an enzyme inhibiting α-syn phosphorylation, in these brain extracts. Further, the extent of the age- and braindependent increase in α-syn phosphorylation and oligomerization was reduced by inhibition of PLK2 and activation of PP2A. Inversely, phosphorylated α-syn oligomers reduced the activity of PP2A and showed potent cytotoxicity. In addition, the activity of GCase and the levels of ceramide, a product of GCase shown to activate PP2A, were lower in brain extracts from older monkeys and in LBP-susceptible brain regions. Our results suggest a role for altered intrinsic metabolic enzymes in age- and brain region-dependent α-syn oligomerization in aging brains.

Yang W.,Capital Medical University | Yang W.,Beijing Key Laboratory for Parkinsons Disease | Li X.,Capital Medical University | Li X.,Beijing Key Laboratory for Parkinsons Disease | And 3 more authors.
Oncotarget | Year: 2016

Neuronal hemoglobin (nHb) plays a critical role in maintaining normal mitochondrial functioning in the brain. However, in aging and Parkinson's disease (PD) brains, mitochondrial nHb levels are greatly reduced in neurons that accumulate a-synuclein (a-syn), suggesting a link between the two proteins. In this study, we demonstrate that a-syn and Hb can form a complex in both brain tissue and peripheral red blood cells (RBCs) in aging cynomolgus monkeys. nHb-a-syn complex levels in the mitochondrial fraction of the striatum decreased with age; this was negatively correlated with levels in the cytoplasmic fraction and in RBCs and was accompanied by a reduction in mitochondrial free nHb. In contrast, no changes in nHb-a-syn complex formation or free nHb levels were detected in the cerebellum. In vitro studies using a cultured dopaminergic cell line showed that intracellular accumulation of a-syn caused an elevation in nHb-a-syn complex levels in both mitochondrial and cytoplasmic fractions as well as a reduction in mitochondrial free nHb. nHb overexpression increased free nHb levels in mitochondria, stabilized mitochondrial membrane potential, and reduced a-syn-induced apoptosis. The above results suggest that a-syn forms a complex with nHb in selected regions of the aging brain, thereby decreasing mitochondrial function and increasing the risk of PD.

Liu S.,Soochow University of China | Cheng X.-Y.,Soochow University of China | Wang F.,Soochow University of China | Liu C.-F.,Soochow University of China | Liu C.-F.,Beijing Key Laboratory for Parkinsons Disease
Translational Neurodegeneration | Year: 2015

Maintaining the physiological pH of interstitial fluid is crucial for normal cellular functions. In disease states, tissue acidosis is a common pathologic change causing abnormal activation of acid-sensing ion channels (ASICs), which according to cumulative evidence, significantly contributes to inflammation, mitochondrial dysfunction, and other pathologic mechanisms (i.e., pain, stroke, and psychiatric conditions). Thus, it has become increasingly clear that ASICs are critical in the progression of neurologic diseases. This review is focused on the importance of ASICs as potential therapeutic targets in combating neurologic diseases. © 2015 Liu et al.; licensee BioMed Central.

Wang Y.,Soochow University of China | Li S.,Soochow University of China | Liu W.,Soochow University of China | Wang F.,Soochow University of China | And 5 more authors.
Biochemical and Biophysical Research Communications | Year: 2016

Vesicular monoamine transporter 2 (Vmat2) is widely distributed in the central nervous system, and responsible for uptaking transmitters into the vesicles. However, whether Vmat2-deficiency is related to the anxiety is rarely investigated, especially in zebrafish. Here, we reported Vmat2 heterzygous mutant zebrafish displayed anxiety-like behavior. The mutants spent less time in the top area and took longer latency to the top in the novel tank test. Consistently, they showed dark avoidance in the light/dark box test, with longer duration in the light zone and increased number of crossing between the two zones. Monoamine concentration analysis showed that the levels of monoamine neurotransmitters including dopamine (DA), 5-hydroxy tryptamine (5-HT) and norepinephrine (NE), as well as their metabolites were decreased in VMAT mutants. Taken together, these findings suggest that Vmat2 heterzygous mutant zebrafish may serve as a new model of anxiety, which may be related with the low level of DA, 5-HT and NE. © 2016 Elsevier Inc. All rights reserved.

Du H.-P.,Soochow University of China | Li J.,Soochow University of China | You S.-J.,Soochow University of China | Wang Y.-L.,Soochow University of China | And 5 more authors.
Biochemical and Biophysical Research Communications | Year: 2016

Recent studies suggest that epigenetic alterations such as DNA methylation control many aspects of monocytes/macrophages and participate in the pathogenesis of atherosclerosis, a lipid-driven inflammatory disorder. Our and other groups demonstrated that dysregulation of cystathionine γ-lyase (CSE) -hydrogen sulfide (H2S) pathway was involved in monocyte/macrophages-mediated inflammation and atherosclerosis. However, it remains unknown whether altered cse methylation in macrophages may play a role in linking CSE-H2S dysregulation and atherosclerosis. In the present study, we showed that plasma H2S and H2S production in the peritoneal macrophages of apolipoprotein knockout (apoE-/-) mice gradually decreased with ages, and were also lower than that in control mice at 12 weeks older. Moreover, CSE mRNA expressions decreased while DNA methyltransferase (DNMT) expressions increased in the peritoneal macrophages isolated from apoE-/- mice, compared to age-matched wildtype mice. Similar observations were obtained in an in vitro study. In oxidized low-density lipoprotein (ox-LDL)-treated raw264.7 macrophages, cse transcription was down-regulated while the expression and activity of DNMT was up-regulated, associated with enhanced DNA methylation in cse promoter. Suppression of DNMT with its inhibitor or siRNA reversed the decrease of CSE mRNA. Therefore, our data suggest that DNA hypermethylation of CpG rich region in cse promoter might contribute to the decrease of cse transcription and H2S production in macrophages, and thus contribute to atherosclerosis development. © 2015 Elsevier Inc. All rights reserved.

Zhang J.-R.,Soochow University of China | Chen J.,Soochow University of China | Yang Z.-J.,Soochow University of China | Zhang H.-J.,Soochow University of China | And 6 more authors.
Chinese Medical Journal | Year: 2016

Background: Rapid eye movement (REM) sleep behavior disorder (RBD) may be a risk factor for cognitive impairment in patients with Parkinson’s disease (PD). However, little is known regarding the relation between the severity of RBD and the different domains of cognitive impairment. The aim of this study was: (1) to investigate the domains of cognitive impairment in patients with PD and RBD, and (2) to explore risk factors for PD‑mild cognitive impairment (PD‑MCI) and the relationship between RBD severity and impairment in different cognitive domains in PD. Methods: The participants were grouped as follows: PD without RBD (PD‑RBD; n = 42), PD with RBD (PD + RBD; n = 32), idiopathic RBD (iRBD; n = 15), and healthy controls (HCs; n = 36). All participants completed a battery of neuropsychological assessment of attention and working memory, executive function, language, memory, and visuospatial function. The information of basic demographics, diseases and medication history, and motor and nonmotor manifestations was obtained and compared between PD‑RBD and PD + RBD groups. Particular attention was paid to the severity of RBD assessed by the RBD Questionnaire‑Hong Kong (RBDQ‑HK) and the RBD Screening Questionnaire (RBDSQ), then we further examined associations between the severity of RBD symptoms and cognitive levels via correlation analysis. Results: Compared to PD‑RBD subjects, PD + RBD patients were more likely to have olfactory dysfunction and their Epworth Sleepiness Scale scores were higher (P < 0.05). During neuropsychological testing, PD + RBD patients performed worse than PD‑RBD patients, including delayed memory function, especially. The MCI rates were 33%, 63%, 33%, and 8% for PD‑RBD, PD + RBD, iRBD, and HC groups, respectively. RBD was an important factor for the PD‑MCI variance (odds ratio = 5.204, P = 0.018). During correlation analysis, higher RBDSQ and RBDQ‑HK scores were significantly associated with poorer performance on the Trail Making Test‑B (errors) and Auditory Verbal Learning Test (delayed recall) and higher RBD‑HK scores were also associated with Rey–Osterrieth complex figure (copy) results. Conclusions: When PD‑RBD and PD + RBD patients have equivalent motor symptoms, PD + RBD patients still have more olfactory dysfunction and worse daytime somnolence. RBD is an important risk factor for MCI, including delayed memory. Deficits in executive function, verbal delayed memory, and visuospatial function were consistently associated with more severe RBD symptoms. © 2016 Chinese Medical Journal.

Wang M.-X.,Soochow University of China | Cheng X.-Y.,Soochow University of China | Jin M.,Soochow University of China | Cao Y.-L.,Soochow University of China | And 8 more authors.
Experimental Neurology | Year: 2015

Tumor necrosis factor-α (TNF) is increasingly implicated as a critical pro-inflammatory cytokine involved in chronic inflammation and neurodegeneration of Parkinson's disease (PD). However, the cellular and molecular events that lead to dopaminergic neuron degeneration are not fully understood. In this study, we demonstrated that microglia-released and recombinant TNF disrupted α-synuclein (α-SYN) degradation and caused its accumulation in PC12 cells and midbrain neurons. At subtoxic doses, recombinant TNF was found to increase the number of LC3 puncta dots and LC3II protein level, associated with the increases of P62 protein level. Inhibition of lysosomal degradation with Bafilomycin A1 pretreatment abrogated the TNF-induced elevation in LC3II protein level whereas autophagy inhibitor 3-methyladenine did not affect it. Moreover, TNF led to a marked increase in the number of yellow LC3 dots with a marginal elevation in red-only dots in RFP-GFP-tandem fluorescent LC3 (tf-LC3) transfected PC12 cells, implying the impairment in autophagic flux. Furthermore, TNF treatment reduced lysosomal acidification, as LysoTracker Red fluorescence and LysoSensor fluorescence shift from blue to yellow was markedly decreased in TNF-treated PC12 cells. Co-treatment with mammalian target of rapamycin kinase complex 1 (mTORC1) inhibitor PP242, which activated transcription factor EB (TFEB) signaling and lysosome biogenesis, partially rescued the accumulation of α-SYN in PC12 cells and midbrain neurons. Taken together, our results demonstrated that at subtoxic levels, TNF was able to impair autophagic flux and result in α-SYN accumulation by compromising lysosomal acidification in dopaminergic cells. This may represent a novel mechanism for TNF-induced dopaminergic neuron degeneration in PD. © 2015 Elsevier Inc.

Chen Y.,Soochow University of China | Mao C.-J.,Soochow University of China | Li S.-J.,Soochow University of China | Wang F.,Soochow University of China | And 8 more authors.
Parkinsonism and Related Disorders | Year: 2015

Introduction: Pain and sensory disturbances affect many patients with Parkinson's disease (PD). The present study aimed to evaluate the pain and sensory sensitivity of each class of afferent fibers in PD patients and determine the effects of dopaminergic therapy on pain and sensory sensitivity. Methods: Current perception threshold (CPT) and pain tolerance thresholds (PTT) at three frequencies, 2000Hz, 250Hz, and 5Hz, to stimulate Aβ fibers, Aδ fibers, and small C-polymodal fibers, respectively, were measured in 72 PD patients and 35 healthy controls. Results: CPT was higher at all three frequencies and PTT was lower at 2000Hz and 250Hz in PD patients with pain versus healthy controls (P<0.05). CPT was higher at 2000Hz and 250Hz and PTT was lower at 2000Hz and 250Hz in PD patients without pain versus healthy controls (P<0.05). PD patients with pain exhibited higher CPT at 5Hz and 250Hz than PD patients without pain (P<0.05). Dopaminergic therapy did not affect CPT or PPT in PD patients (P>0.05). Conclusions: Abnormal Aδ fiber- and Aβ fiber-dependent sensory inputs may exist in PD. Abnormal sensory inputs via C fibers and Aδ fibers might be associated with the presence of pain in PD. Because dopaminergic therapy failed to mitigate these sensory and pain dysfunctions, mechanisms not involving the dopaminergic pathway are likely to be implicated. © 2015 Elsevier Ltd.

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