GBA Variants Influence Motor and Non-Motor Features of Parkinson’s Disease.

The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson’s disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson’s patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021), earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013), as well as more prevalent motor and non-motor symptoms in patients carrying dele- terious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complica- tions could be influenced by GBA variants.Ministerio de Economı́a y Competitividad SAF2007-60700.Instituto de Salud Carlos III PI10/01674, PI13/01461, PI14/01823.Consejerı́a de Economı́a, Innovación, Ciencia y Empleo CVI-02526, CTS- 7685Consejería de Igualdad, Salud y Políticas Sociales PI-0377/2007, PI-0741/2010, PI-0437-2012, PI-0471-201

GDNF gene is associated with tourette syndrome in a family study

Huertas-Fernández, Ismael et al.[Background] Tourette syndrome is a disorder characterized by persistent motor and vocal tics, and frequently accompanied by the comorbidities attention deficit hyperactivity disorder and obsessive-compulsive disorder. Impaired synaptic neurotransmission has been implicated in its pathogenesis. Our aim was to investigate the association of 28 candidate genes, including genes related to synaptic neurotransmission and neurotrophic factors, with Tourette syndrome.[Methods] We genotyped 506 polymorphisms in a discovery cohort from the United States composed of 112 families and 47 unrelated singletons with Tourette syndrome (201 cases and 253 controls). Genes containing significant polymorphisms were imputed to fine-map the signal(s) to potential causal variants. Allelic analyses in Tourette syndrome cases were performed to check the role in attention deficit hyperactivity disorder and obsessive-compulsive disorder comorbidities. Target polymorphisms were further studied in a replication cohort from southern Spain composed of 37 families and three unrelated singletons (44 cases and 73 controls).[Results] The polymorphism rs3096140 in glial cell line–derived neurotrophic factor gene (GDNF) was significant in the discovery cohort after correction (P = 1.5 × 10−4). No linkage disequilibrium was found between rs3096140 and other functional variants in the gene. We selected rs3096140 as target polymorphism, and the association was confirmed in the replication cohort (P = 0.01). No association with any comorbidity was found.[Conclusions] As a conclusion, a common genetic variant in GDNF is associated with Tourette syndrome. A defect in the production of GDNF could compromise the survival of parvalbumin interneurons, thus altering the excitatory/inhibitory balance in the corticostriatal circuitry. Validation of this variant in other family cohorts is necessary. © 2015 International Parkinson and Movement Disorder SocietyThis study was supported by New Jersey Center for Tourette Syndrome and Associated Disorders (NJCTS), the National Institute of Mental Health (R01MH092293), the Instituto de Salud Carlos III (PI10/01674, PI13/01461, PI14/01823), the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0741/2010, PI-0437-2012, PI-0471-2013), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña and the Jaques and Gloria Gossweiler Foundation. Ismael Huertas Fernández was supported by the “PFIS” program, Pilar Gómez Garre was supported by the “Miguel Servet” program, and Juan Francisco Martín Rodríguez was supported by the “Sara Borrell” program, all 3 from the Instituto de Salud Carlos III.Peer Reviewe

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

SHARDS frontier fields: physical properties of a low-mass Lyα emitter at z = 5.75

We analyze the properties of a multiply-imaged Lyman-alpha (Lya) emitter at z=5.75 identified through SHARDS Frontier Fields intermediate-band imaging of the Hubble Frontier Fields (HFF) cluster Abell 370. The source, A370-L57, has low intrinsic luminosity (M_UV~-16.5), steep UV spectral index (\beta=-2.4+/-0.1), and extreme rest-frame equivalent width of Lya (EW(Lya)=420+180-120 \AA). Two different gravitational lens models predict high magnification (\mu~10--16) for the two detected counter-images, separated by 7", while a predicted third counter-image (\mu~3--4) is undetected. We find differences of ~50% in magnification between the two lens models, quantifying our current systematic uncertainties. Integral field spectroscopy of A370-L57 with MUSE shows a narrow (FWHM=204+/-10 km/s) and asymmetric Lya profile with an integrated luminosity L(Lya)~10^42 erg/s. The morphology in the HST bands comprises a compact clump (r_e<100 pc) that dominates the Lya and continuum emission and several fainter clumps at projected distances <1 kpc that coincide with an extension of the Lya emission in the SHARDS F823W17 and MUSE observations. The latter could be part of the same galaxy or an interacting companion. We find no evidence of contribution from AGN to the Lya emission. Fitting of the spectral energy distribution with stellar population models favors a very young (t<10 Myr), low mass (M*~10^6.5 Msun), and metal poor (Z<4x10^-3) stellar population. Its modest star formation rate (SFR~1.0 Msun/yr) implies high specific SFR (sSFR~2.5x10^-7 yr^-1) and SFR density (Sigma_SFR ~ 7-35 Msun/yr/kpc^2). The properties of A370-L57 make it a good representative of the population of galaxies responsible for cosmic reionization.Comment: 14 pages, 8 figures, 4 tables. Accepted for publication in Ap

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

The Seventeenth Data Release of the Sloan Digital Sky Surveys: Complete Release of MaNGA, MaStar and APOGEE-2 Data

This paper documents the seventeenth data release (DR17) from the Sloan Digital Sky Surveys; the fifth and final release from the fourth phase (SDSS-IV). DR17 contains the complete release of the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey, which reached its goal of surveying over 10,000 nearby galaxies. The complete release of the MaNGA Stellar Library (MaStar) accompanies this data, providing observations of almost 30,000 stars through the MaNGA instrument during bright time. DR17 also contains the complete release of the Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) survey which publicly releases infra-red spectra of over 650,000 stars. The main sample from the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), as well as the sub-survey Time Domain Spectroscopic Survey (TDSS) data were fully released in DR16. New single-fiber optical spectroscopy released in DR17 is from the SPectroscipic IDentification of ERosita Survey (SPIDERS) sub-survey and the eBOSS-RM program. Along with the primary data sets, DR17 includes 25 new or updated Value Added Catalogs (VACs). This paper concludes the release of SDSS-IV survey data. SDSS continues into its fifth phase with observations already underway for the Milky Way Mapper (MWM), Local Volume Mapper (LVM) and Black Hole Mapper (BHM) surveys

Sensitivity Analysis of a Default Time Model for Credit Risk Portfolio Management

Depto. de Análisis Matemático y Matemática AplicadaFac. de Ciencias MatemáticasFALSEMinisterio de Ciencia e Innovación (España). Plan Nacional de I+D+i 2008-2011Comunidad de MadridBanco de SantanderUniversidad Complutensesubmitte