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PubMed | ADx NeuroSciences NV, University of Coimbra, Donders Institute for Brain, University of Perugia and 17 more.
Type: Journal Article | Journal: Neurobiology of aging | Year: 2015

Decreased levels of alpha-synuclein (aSyn) in cerebrospinal fluid (CSF) in Parkinsons disease and related synucleinopathies have been reported, however, not consistently in all cross-sectional studies. To test the performance of one recently released human-specific enzyme-linked immunosorbent assay (ELISA) for the quantification of aSyn in CSF, we carried out a round robin trial with 18 participating laboratories trained in CSF ELISA analyses within the BIOMARKAPD project in the EU Joint Program - Neurodegenerative Disease Research. CSF samples (homogeneous aliquots from pools) and ELISA kits (one lot) were provided centrally and data reported back to one laboratory for data analysis. Our study showed that although factors such as preanalytical sample handling and lot-to-lot variability were minimized by our study design, we identified high variation in absolute values of CSF aSyn even when the same samples and same lots of assays were applied. We further demonstrate that although absolute concentrations differ between laboratories the quantitative results are comparable. With further standardization this assay may become an attractive tool for comparing aSyn measurements in diverse settings. Recommendations for further validation experiments and improvement of the interlaboratory results obtained are given.


Albright J.W.,International Relief and Development Inc | Woo P.H.,Woos Comprehensive Restorative Dentistry Clinic | Ji S.,BioLegend Inc. | Sun B.,BioLegend Inc. | And 2 more authors.
Southeast Asian Journal of Tropical Medicine and Public Health | Year: 2013

We investigated associations between type 2 diabetes (DM) and several variables, including poor oral health and overweight/obesity, among a group of elderly Hmong subjects (60 years and older) who emigrated to the United States following the Vietnam conflict. Each subject was interviewed and their weight, height and waist circumference were measured. Each subject had an oral health examination. Each subject's saliva was analyzed for seven components related to inflammation. The presence of DM was correlated with poor oral health (POH) and overweight/obesity (OW) separately. There was a strong correlation between concurrent POH and OW and the presence of DM: all subjects with both POH and OW had DM. Logistic multivariate analysis of OW, POH, age, years of residence in California, and stress level revealed a significant association between the presence of DM and concurrent OW and POH. A change in diet after immigration was excluded as an explanatory variable. Subjects with DM and concurrent OW and POH had significantly elevated salivary levels of five analytes related to chronic inflammation. The association between POH and OW and the presence of DM needs further study.


Vilas D.,University of Barcelona | Shaw L.M.,University of Pennsylvania | Taylor P.,BioLegend Inc. | Berg D.,University of Tübingen | And 10 more authors.
Movement Disorders | Year: 2016

Background: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of inherited Parkinson's disease (PD). Nonmanifesting carriers of LRRK2 mutations are at high risk for developing PD. Information available on cerebrospinal fluid (CSF) biomarkers in LRRK2 carriers remains preliminary. Objectives: To measure CSF levels of α-synuclein, β amyloid1-42, total-tau, and phospho-tau181, in LRRK2-associated PD, idiopathic PD, nonmanifesting carriers, and first-degree relatives of LRRK2-associated PD patients without the mutation (nonmanifesting noncarriers). To correlate the clinical features and the integrity of the nigrostriatal pathway assessed by neuroimaging with the CSF biomarkers. Methods: 138 CSF samples provided by the Michael J. Fox Foundation LRRK2 Cohort Consortium were analyzed: 28 LRRK2-associated PD, 35 idiopathic PD, 41 nonmanifesting carriers, and 34 nonmanifesting noncarriers. All of the participants in the study were clinically assessed. Most of the participants underwent a dopamine transporter scan to assess the integrity of the nigrostriatal pathway. Results: CSF levels of α-synuclein were similar in LRRK2-associated PD, nonmanifesting carriers, and nonmanifesting noncarriers but significantly higher than in idiopathic PD (P=.041). No differences were found in the concentrations of β amyloid1-42, total-tau, or phospho-tau181 among study groups. CSF alpha-synuclein levels strongly correlated with total-tau and phospo-tau181 levels in all groups. No significant correlation was found between the CSF biomarkers and the striatal binding ratios for (123)I-FP-CIT in nonmanifesting carriers. Conclusion: The CSF protein profile differs in LRRK2-associated PD and idiopathic PD, suggesting that pathophysiological mechanisms different from IPD underlie LRRK2-associated PD. Cerebrospinal fluid biomarkers did not prove helpful in differentiating asymptomatic LRRK2 mutation carriers from noncarriers. © 2016 International Parkinson and Movement Disorder Society.


Zhu J.,Howard Hughes Medical Institute | Doan K.,Howard Hughes Medical Institute | Park J.,University of California at San Francisco | Park J.,University of California at Berkeley | And 5 more authors.
Immunity | Year: 2011

Neutrophils, critical innate immune effectors, use bacterial-derived chemoattractant-induced G protein-coupled receptor (GPCR) signaling for their pursuit of bacteria. Tyrosine phosphorylation pathways and receptor-like tyrosine phosphatases (RPTPs) are rarely considered in chemoattractant-mediated GPCR signaling. Here, we report that two RPTPs, CD45 and CD148, previously shown to share redundant roles in positively regulating Src family kinases (SFKs) in immunoreceptor signaling pathways in B cells and macrophages, are critical in the neutrophil response to S. aureus infection and, surprisingly, in chemoattractant-mediated chemotaxis. Remarkably, deficiency in either of these RPTPs influenced neutrophil GPCR responses in unique ways. Our results reveal that CD45 positively while CD148 positively and negatively regulate GPCR function and proximal signals including Ca 2+, phosphatidylinositol 3'OH kinase (PI3K), and phospho-extracellular regulated kinase (pERK) activity. Moreover, our results suggest that CD45 and CD148 preferentially target different SFK members (Hck and Fgr versus Lyn, respectively) to positively and negatively regulate GPCR pathways. © 2011 Elsevier Inc.


Song W.,University of Texas M. D. Anderson Cancer Center | Song W.,Shanghai Public Health Clinical Center | Delyria E.S.,University of Texas M. D. Anderson Cancer Center | Chen J.,University of Texas M. D. Anderson Cancer Center | And 18 more authors.
International Journal of Oncology | Year: 2012

Bioinformatic tools and databases for glycobiology and glycomics research are playing increasingly important roles in functional studies. However, to verify hypotheses generated by computational glycomics with empirical functional assays is only an emerging field. In this study, we predicted glycan epitopes expressed by a cancer-derived mucin, MUC1, by computational glycomics. MUC1 is expressed by tumor cells with a deficiency in glycosylation. Although numerous diagnostic reagents and cancer vaccines have been designed based on abnormally glycosylated MUC1 sequences, the glycan and peptide sequences responsible for immune responses in vivo are poorly understood. The immunogenicity of synthetic MUC1 glycopeptides bearing Tn or sialyl-Tn antigens have been studied in mouse models, while authentic glyco-epitopes expressed by tumor cells remain unclear. To examine the immunogenicit y of authentic cancer derived MUC1 glyco-epitopes, we expressed membrane bound forms of MUC1 tandem repeats in Jurkat, a mutant cancer cell line deficient of mucin-type core-1 β1-3 galactosyltransferase activity, and immunized mice with cancer cells expressing authentic MUC1 glyco-epitopes. Antibody responses to individual glyco-epitopes were determined by chemically synthesized candidate MUC1 glycopeptides predicted through computational glycomics. Monoclonal antibodies can be generated toward chemically synthesized glycopeptide sequences. With RPAPGS(Tn)TAPPAHG as an example, a monoclonal antibody 16A, showed 25-fold higher binding to glycosylated peptide (EC50=9.278±1.059 ng/ml) compared to its non-glycosylated form (EC50=247.3±16.29 ng/ml) as measured by ELISA experiments with plate-bound peptides. A library of monoclonal antibodies toward authentic MUC1 glycopeptide epitopes may be a valuable tool for studying glycan and peptide sequences in cancer, as well as reagents for diagnosis and therapy.


PubMed | University of Pennsylvania, University of Barcelona, Institute Dinvestigacions Biomediques Of Barcelona and BioLegend Inc.
Type: | Journal: Neurobiology of disease | Year: 2016

Mitochondrial DNA regulates mitochondrial function which is altered in both idiopathic and familial forms of Parkinsons disease. To investigate whether these two disease forms exhibit an altered regulation of mitochondrial DNA we measured cell free mitochondrial DNA content in cerebrospinal fluid (CSF) from idiopathic and LRRK2-related Parkinsons disease patients. The concentration of mitochondrial DNA was measured using a digital droplet polymerase chain reaction technique in a total of 98 CSF samples from a cohort of subjects including: 20 LRRK2(G2019S) mutation carriers with Parkinsons disease, 26 asymptomatic LRRK2(G2019S) mutation carriers, 31 patients with idiopathic Parkinsons disease and 21 first-degree relatives of LRRK2 Parkinsons disease patients without the mutation. Here we report that LRRK2(G2019S) mutation carriers with Parkinsons disease exhibit a high concentration of mitochondrial DNA in CSF compared with asymptomatic LRRK2(G2019S) mutation carriers and with idiopathic Parkinsons disease patients. In addition, idiopathic, but not LRRK2 Parkinsons disease is associated with low CSF concentration of -synuclein. These results show that high mitochondrial DNA content in CSF distinguishes idiopathic from LRRK2-related Parkinsons disease suggesting that different biochemical pathways underlie neurodegeneration in these two disorders.


PubMed | University of Tübingen, Institute for Neurodegenerative Disorders, University of Pennsylvania, Toronto Western Hospital and 4 more.
Type: Journal Article | Journal: Movement disorders : official journal of the Movement Disorder Society | Year: 2016

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of inherited Parkinsons disease (PD). Nonmanifesting carriers of LRRK2 mutations are at high risk for developing PD. Information available on cerebrospinal fluid (CSF) biomarkers in LRRK2 carriers remains preliminary.To measure CSF levels of -synuclein, amyloid1-42 , total-tau, and phospho-tau181 , in LRRK2-associated PD, idiopathic PD, nonmanifesting carriers, and first-degree relatives of LRRK2-associated PD patients without the mutation (nonmanifesting noncarriers). To correlate the clinical features and the integrity of the nigrostriatal pathway assessed by neuroimaging with the CSF biomarkers.138 CSF samples provided by the Michael J. Fox Foundation LRRK2 Cohort Consortium were analyzed: 28 LRRK2-associated PD, 35 idiopathic PD, 41 nonmanifesting carriers, and 34 nonmanifesting noncarriers. All of the participants in the study were clinically assessed. Most of the participants underwent a dopamine transporter scan to assess the integrity of the nigrostriatal pathway.CSF levels of -synuclein were similar in LRRK2-associated PD, nonmanifesting carriers, and nonmanifesting noncarriers but significantly higher than in idiopathic PD (P=.041). No differences were found in the concentrations of amyloid1-42 , total-tau, or phospho-tau181 among study groups. CSF alpha-synuclein levels strongly correlated with total-tau and phospo-tau181 levels in all groups. No significant correlation was found between the CSF biomarkers and the striatal binding ratios for (123)I-FP-CIT in nonmanifesting carriers.The CSF protein profile differs in LRRK2-associated PD and idiopathic PD, suggesting that pathophysiological mechanisms different from IPD underlie LRRK2-associated PD. Cerebrospinal fluid biomarkers did not prove helpful in differentiating asymptomatic LRRK2 mutation carriers from noncarriers. 2016 International Parkinson and Movement Disorder Society.

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