Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved under- standing of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, inter- rogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain tran- scriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/

Study of the near-barrier scattering of 8He on 208Pb

The structure and dynamics of 8He have been studied through the collision process with a 208Pb target at energies of 22 and 16 MeV, above and below the Coulomb barrier, respectively. The energy and angular distributions of the elastically scattered 8He and the 6,4He fragments were measured. In this paper, we discuss the method used to determine the effective position of the beam spot on the reaction target and the scattering and solid angles of each pixel of the detector array.Ministerio de Economía y Competitividad FPA2010-22131-C021-01, FPA2014-59954-C3-1-PMinistry of Science and Higher Education of Poland N202 033637European Science Foundation EUI2009-0416

Levodopa-Induced Dyskinesia in Parkinson Disease Specifically Associates with Dopaminergic Depletion in Sensorimotor-Related Functional Subregions of the Striatum

[Purpose] To determine whether the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) specifically relates to dopaminergic depletion in sensorimotor-related subregions of the striatum.[Methods] Our primary study sample consisted of 185 locally recruited PD patients, of which 73 (40%) developed LID. Retrospective 123I-FP-CIT SPECT data were used to quantify the specific dopamine transporter (DAT) binding ratio within distinct functionally defined striatal subregions related to limbic, executive, and sensorimotor systems. Regional DAT levels were contrasted between patients who developed LID (PD + LID) and those who did not (PD-LID) using analysis of covariance models controlled for demographic and clinical features. For validation of the findings and assessment of the evolution of LID-associated DAT changes from an early disease stage, we also studied serial 123I-FP-CIT SPECT data from 343 de novo PD patients enrolled in the Parkinson Progression Marker’s Initiative using mixed linear model analysis.[Results] Compared with PD-LID, DAT level reductions in PD + LID patients were most pronounced in the sensorimotor striatal subregion (F = 5.99, P = 0.016) and also significant in the executive-related subregion (F = 5.30, P = 0.023). In the Parkinson Progression Marker’s Initiative cohort, DAT levels in PD + LID (n = 161, 47%) were only significantly reduced compared with PD-LID in the sensorimotor striatal subregion (t = −2.05, P = 0.041), and this difference was already present at baseline and remained largely constant over time.[Conclusion] Measuring DAT depletion in functionally defined sensorimotor-related striatal regions of interest may provide a more sensitive tool to detect LID-associated dopaminergic changes at an early disease stage and could improve individual prognosis of this common clinical complication in PD.Peer reviewe

Fusion of 8He with 206Pb around Coulomb barrier energies

The experimental study of the fusion of light neutron-rich nucleus 8He with 206Pb is reported in this work. A fusion stack of 206Pb targets has been used for this study. The most prominent evaporation residue (210Po), which has half-life of 138 days and decays by alpha emission, is populated in the reaction. Radiochemical analysis technique is used to extract the yield of this evaporation residue.Ministerio de Ciencia e Innovavión FPA2007-63074European Union 21269

Glyphosate detection with ammonium nitrate and humic acids as potential interfering substances by pulsed voltammetry technique

Pulsed voltammetry has been used to detect and quantify glyphosate on buffered water in presence of ammonium nitrate and humic substances. Glyphosate is the most widely used herbicide active ingredient in the world. It is a non-selective broad spectrum herbicide but some of its health and environmental effects are still being discussed. Nowadays, glyphosate pollution in water is being monitored but quantification techniques are slow and expensive. Glyphosate wastes are often detected in countryside water bodies where organic substances and fertilizers (commonly based on ammonium nitrate) may also be present. Glyphosate also forms complexes with humic acids so these compounds have also been taken into consideration. The objective of this research is to study the interference of these common pollutants in glyphosate measurements by pulsed voltammetry. The statistical treatment of the voltammetric data obtained lets us discriminate glyphosate from the other studied compounds and a mathematical model has been built to quantify glyphosate concentrations in a buffer despite the presence of humic substances and ammonium nitrate. In this model, the coefficient of determination (R-2) is 0.977 and the RMSEP value is 2.96 x 10(-5) so the model is considered statistically valid. (C) 2013 Elsevier B.V. All rights reserved.Authors acknowledge financial support from the Universitat Polltecnica de Valencia and its Centre de Cooperacio al Desenvolupament (Programa ADSIDEO-COOPERACIO 2010) for the research fellowship. We also thank MICINN (MAT2012-38429-C04-04) and GVA (PPC/2011/019) for their respective research fellowships.Martínez Gil, P.; Laguarda Miró, N.; Soto Camino, J.; Masot Peris, R. (2013). Glyphosate detection with ammonium nitrate and humic acids as potential interfering substances by pulsed voltammetry technique. Talanta. (115):702-705. https://doi.org/10.1016/j.talanta.2013.06.030S70270511

Near barrier scattering of 8He on 208Pb

The exotic nucleus 8He is investigated by means of the measurement of the angular distributions of the elastic channel and the 6He and 4He fragment yields produced in the collision with a 208Pb target at two energies around the Coulomb barrier, 16 and 22 MeV. The experiment was performed at the GANIL-SPIRAL facility, with the aim of extracting information about the structure of 8He and the relevant reaction mechanisms. In this contribution, details of the experimental setup and preliminary data on elastic cross sections are reporte

In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: Imaging results from the COPPADIS study

COPPADIS Study Group.[Introduction] We aimed to assess associations between multimodal neuroimaging measures of cholinergic basal forebrain (CBF) integrity and cognition in Parkinson's disease (PD) without dementia.[Methods] The study included a total of 180 non-demented PD patients and 45 healthy controls, who underwent structural MRI acquisitions and standardized neurocognitive assessment through the PD-Cognitive Rating Scale (PD-CRS) within the multicentric COPPADIS-2015 study. A subset of 73 patients also had Diffusion Tensor Imaging (DTI) acquisitions. Volumetric and microstructural (mean diffusivity, MD) indices of CBF degeneration were automatically extracted using a stereotactic CBF atlas. For comparison, we also assessed multimodal indices of hippocampal degeneration. Associations between imaging measures and cognitive performance were assessed using linear models.[Results] Compared to controls, CBF volume was not significantly reduced in PD patients as a group. However, across PD patients lower CBF volume was significantly associated with lower global cognition (PD-CRStotal: r = 0.37, p < 0.001), and this association remained significant after controlling for several potential confounding variables (p = 0.004). Analysis of individual item scores showed that this association spanned executive and memory domains. No analogue cognition associations were observed for CBF MD. In covariate-controlled models, hippocampal volume was not associated with cognition in PD, but there was a significant association for hippocampal MD (p = 0.02).[Conclusions] Early cognitive deficits in PD without dementia are more closely related to structural MRI measures of CBF degeneration than hippocampal degeneration. In our multicentric imaging acquisitions, DTI-based diffusion measures in the CBF were inferior to standard volumetric assessments for capturing cognition-relevant changes in non-demented PD.This work was supported by the Alzheimer Forschung Initiative e.V. (AFI International Training Grant to MJG), the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER) [PI14/01823, PI16/01575, PI18/01898, PI19/01576, PI20/00613], the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI-0471-2013, PE-0210-2018, PI-0459-2018, PE-0186-2019], the Fundación Alicia Koplowitz and the Fundación “Curemos el Parkinson” (https://www.curemoselparkinson.org). MJG is supported by the “Miguel Servet” program [CP19/00031], MALE by the University of Seville [USE-20046-J], JFM by the “Sara Borrell” program [CD13/00229] and VI-PPIT-US from the University of Seville [USE-18817-A], SJ by the “Acción B-Clínicos-Investigadores” program [B-0007-2019], and DMG by the “Río Hortega” program [CM18/00142].Peer reviewe

In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: Imaging results from the COPPADIS study

Introduction: We aimed to assess associations between multimodal neuroimaging measures of cholinergic basal forebrain (CBF) integrity and cognition in Parkinson’s disease (PD) without dementia. Methods: The study included a total of 180 non-demented PD patients and 45 healthy controls, who underwent structural MRI acquisitions and standardized neurocognitive assessment through the PD-Cognitive Rating Scale (PD-CRS) within the multicentric COPPADIS-2015 study. A subset of 73 patients also had Diffusion Tensor Imaging (DTI) acquisitions. Volumetric and microstructural (mean diffusivity, MD) indices of CBF degeneration were automatically extracted using a stereotactic CBF atlas. For comparison, we also assessed multimodal indices of hippocampal degeneration. Associations between imaging measures and cognitive performance were assessed using linear models. Results: Compared to controls, CBF volume was not significantly reduced in PD patients as a group. However, across PD patients lower CBF volume was significantly associated with lower global cognition (PD-CRStotal: r =0.37, p <0.001), and this association remained significant after controlling for several potential confounding variables (p =0.004). Analysis of individual item scores showed that this association spanned executive and memory domains. No analogue cognition associations were observed for CBF MD. In covariate-controlled models, hippocampal volume was not associated with cognition in PD, but there was a significant association for hippocampal MD (p =0.02). Conclusions: Early cognitive deficits in PD without dementia are more closely related to structural MRI measures of CBF degeneration than hippocampal degeneration. In our multicentric imaging acquisitions, DTI-based diffusion measures in the CBF were inferior to standard volumetric assessments for capturing cognition- relevant changes in non-demented PD

Clinical and structural brain correlates of hypomimia in early-stage Parkinson's disease

Altres ajuts: acord transformatiu CRUE-CSICBackground and purpose: Reduced facial expression of emotions is a very frequent symptom of Parkinson's disease (PD) and has been considered part of the motor features of the disease. However, the neural correlates of hypomimia and the relationship between hypomimia and other non-motor symptoms of PD are poorly understood. Methods: The clinical and structural brain correlates of hypomimia were studied. For this purpose, cross-sectional data from the COPPADIS study database were used. Age, disease duration, levodopa equivalent daily dose, Unified Parkinson's Disease Rating Scale part III (UPDRS-III), severity of apathy and depression and global cognitive status were collected. At the imaging level, analyses based on gray matter volume and cortical thickness were used. Results: After controlling for multiple confounding variables such as age or disease duration, the severity of hypomimia was shown to be indissociable from the UPDRS-III speech and bradykinesia items and was significantly related to the severity of apathy (β = 0.595; p < 0.0001). At the level of neural correlates, hypomimia was related to motor regions brodmann area 8 (BA 8) and to multiple fronto-temporo-parietal regions involved in the decoding, recognition and production of facial expression of emotions. Conclusion: Reduced facial expressivity in PD is related to the severity of symptoms of apathy and is mediated by the dysfunction of brain systems involved in motor control and in the recognition, integration and expression of emotions. Therefore, hypomimia in PD may be conceptualized not exclusively as a motor symptom but as a consequence of a multidimensional deficit leading to a symptom where motor and non-motor aspects converge

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/