43 research outputs found
Pathogenic transformations of shape and function of 'amyloid proteins' (Poster)
No full textThis is the visual CC BY 4.0 interpretation and simplification by @Sparks4PD of the article by Malmberg, M., Malm, T., Gustafsson, O., Sturchio, A., Graff, C., Espay, A.J., Wright, A.P., El Andaloussi, S., Lindén, A., Ezzat, K. (2020) Disentangling the amyloid pathways: A mechanistic approach to etiology, Frontiers in Neuroscience, vol.14, p 256. https://doi.org/10.3389/fnins.2020.00256</p
Progressive Ataxia with Hemiplegic Migraines: a Phenotype of CACNA1A Missense Mutations, Not CAG Repeat Expansions
No full textWe report a 52-year-old woman presenting with autosomal dominant progressive cerebellar ataxia and familial hemiplegic migraine type 1 whose genetic evaluation, negative for spinocerebellar ataxia (SCA) types 1, 2, 3, and 6, revealed instead a heterozygous pathogenic missense mutation in CACNA1A (NM_001127221:c.1748G > A:p.Arg583Gln). A systematic literature review showed that Arg583Gln is associated predominantly with progressive ataxia combined with episodic disorders (overwhelmingly hemiplegic migraine) whereas Thr666Met, the other most common CACNA1A missense mutation, with a combination of progressive ataxia and episodic disorders in half the cases and episodic disorders only in the other half. While uncertainties remain in the genotype-phenotype correlation of all CACNA1A mutations, the accumulated evidence suggests that that the co-occurrence of hemiplegic migraine and autosomal dominant progressive cerebellar ataxia should guide the clinician to test for CACNA1A missense mutation rather than CAG expansions or truncating mutations.Fil: Duque, Kevin R.. University of Cincinnati; Estados UnidosFil: Marsili, Luca. University of Cincinnati; Estados UnidosFil: Sturchio, Andrea. University of Cincinnati; Estados UnidosFil: Mahajan, Abhimanyu. University of Cincinnati; Estados UnidosFil: Merola, Aristide. Ohio State University; Estados UnidosFil: Espay, Alberto J.. University of Cincinnati; Estados UnidosFil: Kauffman, Marcelo Andres. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Centro Universitario de Neurología "Dr. José María Ramos Mejía".; Argentin
Levodopa-responsive progressive encephalomyelitis with rigidity and myoclonus associated with glycine receptor antibodies
No full textMovement disorders associated with neuronal antibodies: a data-driven approach
No full textBACKGROUND
Movement disorders can be associated with anti-neuronal antibodies.
METHODS
We conducted a systematic review of cases with documented anti-neuronal antibodies in serum and/or cerebrospinal fluid published in PubMed before April 1, 2020. Only patients with at least one movement disorder were included. We used random forests for variable selection and recursive partitioning and regression trees for the creation of a data-driven decision algorithm, integrated with expert's clinical feedback.
RESULTS
Three hundred and seventy-seven studies met eligibility criteria, totaling 844 patients and 13 antibodies: amphiphysin, GAD, GlyR, mGluR1, ANNA-2/Ri, Yo/PCA-1, Caspr2, NMDAR, LGI-1, CRMP5/CV2, ANNA-1/Hu, IgLON5, and DPPX. Stiffness/rigidity/spasm spectrum symptoms were more frequently associated with amphiphysin, GAD, and GlyR; ataxia with mGluR1, ANNA-2/Ri, Yo/PCA-1, Caspr2, and ANNA-1/Hu; dyskinesia with NMDAR and paroxysmal movement with LGI1; chorea/choreoathetosis with CRMP5/CV2, IgLON5, and NMDAR; myoclonus with GlyR and DPPX; tremors with ANNA2/Ri and anti-DPPX; and parkinsonism with IgLON5 and NMDAR. Data-driven classification analysis determined the following diagnostic predictions (with probability selection): psychiatric symptoms and dyskinesia predicted NMDAR (71% and 87%, respectively); stiffness/rigidity/spasm and ataxia, GAD (67% and 47%, respectively); ataxia and opsoclonus, ANNA-2/Ri (68%); chorea/choreoathetosis, CRMP5/CV2 (41%). These symptoms remained the top predictors in random forests analysis. The integration with an expert opinion analysis refined the precision of the approach. Breast and lung tumors were the most common tumors. On neuroimaging, cerebellar involvement was associated with GAD and Yo/PCA-1; temporal involvement with Caspr2, LGI-1, ANNA-1/Hu.
CONCLUSION
Selected movement disorders are associated with specific anti-neuronal antibodies. The combination of data-driven and expert opinion approach to the diagnosis may assist early management efforts
Genetic parkinsonisms and cancer: A systematic review and meta-analysis
No full textGenes associated with parkinsonism may also be implicated in carcinogenesis, but their interplay remains unclear. We systematically reviewed studies (PubMed 1967-2019) reporting gene variants associated with both parkinsonism and cancer. Somatic variants were examined in cancer samples, whereas germline variants were examined in cancer patients with both symptomatic and asymptomatic (carriers) genetic parkinsonisms. Pooled proportions were calculated with random-effects meta-analyses. Out of 9,967 eligible articles, 60 were included. Of the 28 genetic variants associated with parkinsonism, six were also associated with cancer. In cancer samples, SNCA was predominantly associated with gastrointestinal cancers, UCHL1 with breast cancer, and PRKN with head-and-neck cancers. In asymptomatic carriers, LRRK2 was predominantly associated with gastrointestinal and prostate cancers, PRKN with prostate and genitourinary tract cancers, GBA with sarcoma, and 22q11.2 deletion with leukemia. In symptomatic genetic parkinsonism, LRRK2 was associated with nonmelanoma skin cancers and breast cancers, and PRKN with head-and-neck cancers. Cancer was more often manifested in genetic parkinsonisms compared to asymptomatic carriers. These results suggest that intraindividual genetic contributions may modify the co-occurrence of cancer and neurodegeneration.Fil: Sturchio, Andrea. University of Cincinnati; Estados UnidosFil: Dwivedi, Alok K.. Texas Tech University Health Sciences Center El Paso; Estados UnidosFil: Vizcarra, Joaquin A.. University of Cincinnati; Estados Unidos. University of Emory; Estados UnidosFil: Chirra, Martina. Università degli Studi di Siena; ItaliaFil: Keeling, Elizabeth G.. University of Cincinnati; Estados UnidosFil: Mata, Ignacio F.. Cleveland Clinic Foundation; Estados UnidosFil: Kauffman, Marcelo Andres. Universidad de Buenos Aires. Facultad de Medicina. Centro Universitario de Neurología "Dr. José María Ramos Mejía".; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pandey, Manoj K.. University of Cincinnati; Estados UnidosFil: Roviello, Giandomenico. Università degli Studi di Firenze; ItaliaFil: Comi, Cristoforo. Università Degli Studi del Piemonte Orientale "amedeo Avogadro"; ItaliaFil: Versino, Maurizio. Università Degli Studi Dell'insubria; ItaliaFil: Marsili, Luca. University of Cincinnati; Estados UnidosFil: Espay, Alberto J.. University of Cincinnati; Estados Unido
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Stable isotopic investigations of in situ bioremediation of chlorinated organic solvents. 1997 annual progress report
No full text'The author has made significant progress in developing innovative methods for investigating the mechanism and extent of in situ bioremediation of chlorinated organic solvents. These methods use precise isotopic ratio measurements of chlorine and carbon in reactant and product species in laboratory experiments and in materials from field demonstration sites. Specific tasks completed during FY 1997 include: (1) refinement and publication of a new analytical method for precise determination of chlorine and carbon isotope ratios in chlorinated volatile organic compounds; (2) laboratory experiments involving biological degradation of chlorinated solvents in liquid cultures and soil columns; and (3) use of chlorine and carbon isotope ratios to investigate natural attenuation of trichloroethene at the Paducah Gaseous Diffusion Plant. This work can have immediate impact because it will provide the fundamental basis for a new and cost-effective means of evaluating and monitoring the effectiveness of in situ bioremediation schemes for chlorinated organic solvents in soils, vadose horizons, and groundwater plumes.
SNAP25 Gene Polymorphisms Protect Against Parkinson’s Disease and Modulate Disease Severity in Patients
No full textParkinson’s disease (PD) is a α-synucleinopathy in which intracellular aggregates of α-synuclein (α-syn) result in neurodegeneration and in the impairment of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex-mediated release of neurotransmitters. SNAP25 is a SNARE complex component: its concentration is increased in the cerebrospinal fluid of PD patients and this is related to the severity of cognitive and motor symptoms. Five SNAP25 single-nucleotide polymorphisms (SNPs) that modulate gene expression and were described to play a role in neurologic conditions (rs363050, rs363039, rs363043, rs3746544, and rs1051312) were analyzed in a cohort of 412 sporadic Italian PD patients and 1103 healthy controls (HC) in order to identify possible correlation with the disease. The SNAP25 rs1051312 C allele and CC genotype confer protection against PD onset, in particular in males (p = 0.003, OR(95%CI) = 0.67(0.51–0.88)) (pc = 0.008, OR(95%CI) = 0.28(0.10–0.70)). Co-segregation analyses revealed that the rs1051312 effect was reinforced when present within the rs363043 C-rs3746544 T-rs1051312 C haplotype (p = 3.3 × 10−4, OR = 0.47, 95%CI = 0.31–0.72), once again in males. Finally, rs363039 influenced age at onset (p = 0.02) and MMSE (Mini-Mental State Examination) scores (p = 0.01). The SNAP25 SNPs analyzed herein modulate gene expression at different levels as they are involved in binding miRNA and transcription factors; this suggests a possible synergistic effect of SNAP25 SNPs in the pathogenesis of PD. A replication in a larger and independent sample will help to further explore this hypothesis
Parkinson's disease patients have a complex phenotypic and functional Th1 bias: Cross-sectional studies of CD4+ Th1/Th2/T17 and Treg in drug-naïve and drug-treated patients
No full textParkinson's disease (PD) affects an estimated 7 to 10 million people worldwide, and only symptomatic treatments are presently available to relieve the consequences of brain dopaminergic neurons loss. Neuronal degeneration in PD is the consequence of neuroinflammation in turn influenced by peripheral adaptive immunity, with CD4+ T lymphocytes playing a key role. CD4+ T cells may however acquire proinflammatory phenotypes, such as T helper (Th) 1 and Th17, as well as anti-inflammatory phenotypes, such as Th2 and the T regulatory (Treg) one, and to what extent the different CD4+ T cell subsets are imbalanced and their functions dysregulated in PD remains largely an unresolved issue.Background: Parkinson's disease (PD) affects an estimated 7 to 10 million people worldwide, and only symptomatic treatments are presently available to relieve the consequences of brain dopaminergic neurons loss. Neuronal degeneration in PD is the consequence of neuroinflammation in turn influenced by peripheral adaptive immunity, with CD4+ T lymphocytes playing a key role. CD4+ T cells may however acquire proinflammatory phenotypes, such as T helper (Th) 1 and Th17, as well as anti-inflammatory phenotypes, such as Th2 and the T regulatory (Treg) one, and to what extent the different CD4+ T cell subsets are imbalanced and their functions dysregulated in PD remains largely an unresolved issue. Methods: We performed two cross-sectional studies in antiparkinson drug-treated and drug-naïve PD patients, and in age- and sex-matched healthy subjects. In the first one, we examined circulating Th1, Th2, Th17, and in the second one circulating Treg. Number and frequency of CD4+ T cell subsets in peripheral blood were assessed by flow cytometry and their functions were studied in ex vivo assays. In both studies, complete clinical assessment, blood count and lineage-specific transcription factors mRNA levels in CD4+ T cells were independently assessed and thereafter compared for their consistency. Results: PD patients have reduced circulating CD4+ T lymphocytes, due to reduced Th2, Th17, and Treg. Naïve CD4+ T cells from peripheral blood of PD patients preferentially differentiate towards the Th1 lineage. Production of interferon-γ and tumor necrosis factor-α by CD4+ T cells from PD patients is increased and maintained in the presence of homologous Treg. This Th1-biased immune signature occurs in both drug-naïve patients and in patients on dopaminergic drugs, suggesting that current antiparkinson drugs do not affect peripheral adaptive immunity. Conclusions: The complex phenotypic and functional profile of CD4+ T cell subsets in PD patients strengthen the evidence that peripheral adaptive immunity is involved in PD, and represents a target for the preclinical and clinical assessment of novel immunomodulating therapeutics
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Stable isotopic investigations of in-situ bioremediation of chlorinated organic solvents. 1998 annual progress report
No full text'Contamination of soils and groundwaters with chlorinated aliphatic hydrocarbons (CAHs) is one of the most serious environmental problems in the DOE system and in the nation at large. These compounds are designated as priority pollutants by the US Environmental Protection Agency (EPA) and are known or suspected to be carcinogenic or mutagenic in humans. These compounds are readily transported by groundwater and are not reduced to acceptable concentrations for human consumption by most municipal water supply treatments; thus the compounds represent a significant hazard to a large portion of the human population. In situ bioremediation is an emerging technology that shows great promise for mitigation of CAH contamination at many sites. One of the most severe limitations of in-situ bioremediation is the difficulty of proving when it is working at a given site. The concentrations of CAHs and their degradation products in plumes may be difficult to relate to the efficiency of the remediation process because of dilution effects, but this problem is mitigated to a large extent by measuring isotope ratios. If there is a significant isotopic fractionation between CAHs and derivative chlorine-bearing products, then the fraction of CAH that is dechlorinated can be inferred from the {sup 37}Cl/{sup 35}Cl and {sup 13}C/{sup 12}C isotope ratios of the residual CAH. It is important to point out that there is currently no published information available on the magnitude of chlorine and carbon isotopic fractionation associated with biological degradation of CAHs. The authors plan to help eliminate this important gap in the knowledge with the work being performed here. This work is relevant to EMSP goals because it will provide a new and cost-effective means of evaluating and monitoring the effectiveness of in-situ bioremediation. It will employ newly developed techniques to characterize isotopic fractionation (of chlorine and carbon) associated with biotic and abiotic degradation of CAHs in laboratory microcosms. These techniques and the data acquired by using them in laboratory studies will form the fundamental basis for quantitative assessment of the mechanisms, rates, and efficiencies of various in-situ bioremediation schemes for CAHs. This report summarizes work as of 21 months into a 36-month project. First, the author has developed methods for precise measurement of stable carbon and chlorine isotope ratios of micromolar amounts of CAHs. He has also developed methods for quantitative extraction of CAHs from water and air. He has applied these methods in laboratory experiments, to investigate isotopic fractionation caused by microbial degradation and by abiotic processes such as evaporation and chemical reduction. He has also applied these methods to field investigations of contaminated groundwater aquifers at the Paducah Gaseous Diffusion Plant, Kentucky and at several manufacturing plants in the Chicago and Kansas City metropolitan areas. Results of much of this work have already been incorporated into four manuscripts that have been published, accepted for publication, or are in review.
CSF d18:1 sphingolipid species in Parkinson disease and dementia with Lewy bodies with and without GBA1 variants
No full textVariants in GBA1 result in dysregulated sphingolipids. We investigated five CSF d18:1 sphingolipid species in a longitudinal multicenter cohort comprising people with Parkinson’s Disease and Dementia with Lewy bodies with and without GBA1 variants and healthy controls. We found no increase of sphingolipid species in heterozygous GBA1 variant participants and no effect on development of cognitive impairment. Thus, CSF d18:1 sphingolipids are not suitable as state markers in Parkinson’s Disease
