Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Anales de Edafología y Agrobiología Tomo 40 Número 3-4

Suelos. Mineralogenesis de arcillas de suelos forestales del Centro-oeste de España. 11. Sierra de Francia, por Mª A. Vicente Hernández y M. Sánchez Camazano.-- Suelos podsólicos y podsoles de la sierra de Urbasa. l. Morfología y datos analiticos, por Rosa Mana Val Legaz y Jaime Iñiguez Herrero.-- Suelos podsólicos y podsoles de la sierra de Urbasa. II. Mineralogía de arcillas, micromorfología y genesis, por Rosa María Val Legaz y Jaime Iñiguez Herrero.-- Consideraciones acerca de la acidificación de los suelos de la zona húmeda española a través de la vegetación, por R.M. Calvo de Anta y F. Díaz Fierros Viqueira.-- Suelos del valle de Ulzama (Navarra). Ultisoles. I Morfología, propiedades químicas y clasificación, por Elisa Barragan y Jaime Iñiguez.--Palexerolls de la provincia de Murcia, por L. J. Alias y C. Pérez Sirvent.-- Estudio de algunos calcixerolls de la provincia de Albacete, por L. J. Alias y C. Pérez Sirvent.-- Aplicación de los modelos de Gouy-Chapman y Stem a suelos con carga va- riable. Andosuelos, por Jaime Iñiguez Herrero y Rosa María Val Legaz.-- Nematodos encontrados en los suelos de la provincia de Guadalajara, por Mª Cristina Zancada y A. BellO.-- Mineralogía de la fracción arcilla en suelos de las sierras de Gredas y Gata. III. Grupo SpodosolOstalf, por M. T. García-González, J. García Vicente y M.P. Riesco.-- Mineralogía de la fracción arcilla en suelos de las sierras de Gredas y Gata. IV. Grupo Spodosol Orthod, por M. T. García-González, l. García Vicente y M.P. Riesco.-- Fertilidad de Suelos.-- Interferencias producidas por el Cl2 Ba-Tea en la determinación conjunta de sodio y potasio, por fotometría de Llama, por Ramón Madrid Vicente y Asunción Roig Garcra Ferrández.-- Fraccionamiento de Boro en suelos calizos, mediante un sistema de electroultrafiltración (EUF), por A. Gárate, C. Cadahía y O. Carpena.-- Acción de los insecticidas: Diazinon, Fention y Carbofuran sobre el "Nematodo de los dtricos" Tylenchulus Semipenetrans Cobb, 1913, por Elisa Valcarce.-- Susceptibilidad de las larvas del "Nematodo de los cítricos" Tylenchulus semipenetrans Cobb, 1913, a los herbicidas Limiron y Dapalon, por Elisa Valcarcel.-- Influencia del carbonato y contenido de arcilla sobre la relación Q/1 del P en suelos, por B. Eleizalde.-- Adsorción de fosfato en suelos calizos. l. Ajuste a distintas Isotermas: Parametros de adsorción, por M.C. Bolarin, F. Santa Cruz, F.G. Fernández y M. Romero.-- Adsorción de fosfato en suelos calizos. II. Correlaciones entre parametros de adsorción y algunas características del suelo, por F. Santa Cruz, M.C. Bolarin, M. Caro y M. Romero.-- Evoluciones, durante las etapas de la floración primaveral, del fósforo de diferentes fracciones orgánicas en flores de Citrus limonum fisiologicamente normales, por Mª Parra y A. Ortuño.-- Estudio de las evoluciones del fósforo de diferentes fracciones en flor de me- locotonero Jeronimo II, durante las distintas etapas de la floración, por Mª Parra.-- Simultaneous measurement of C02 and 0 2 evolution in plant respirometry, por A. J. Sánchez-Raya, M. Gómez y A. Leal.-- Estudio de algunos de los factores nutricionales que modifican la calidad de la proteína en el grano de trigo. l. Influencia de la cantidad de fertilización nitrogenada aplicada en cobertera y de la variedad empleada, por Luis Recalde Manrique y Julio López Gorgé.-- Estudio de algunos de los factores nutricionales que modifican la cantidad de la proteína en el grano de trigo. II. Interacción entre la fertilización nitrogenada aplicada en cobertera y las aplicaciones de azufre elemental por vía foliar, por Luis Recalde Manrique y Julio López Gorgé. Injerto en Hipocotilo de plántulas de castaño, por Mª Luisa Vieitez y Ana Mª Vieltez.-- 647 Efecto espeCÍfico de cloruros sobre la nutrición nitrogenada de plantas jovenes de tomate por Francisco García-Garda y Angel de Luque Escalona.-- Estudio de la fertilización diferenciada en la vid. I. Evolución del nitrogeno total, nitrogeno proteico, aminoacidos libres y prolina, por L. Catalina, R. Sarmiento, R. Romero, V. Valpuesta y C. Mazuelos.-- Predicción de temperaturas medias diarias, por María Dolores Menéndez Furones.-- Notas.-- BibliografíaPeer reviewe

Evaluation of the short- and long-term effectiveness and safety of fully covered self-expandable metal stents for drainage of pancreatic fluid collections: results of a Spanish nationwide registry

[Background and Aims]: Initial reports suggest that fully covered self-expandable metal stents (FCSEMSs) may be better suited for drainage of dense pancreatic fluid collections (PFCs), such as walled-off pancreatic necrosis. The primary aim was to analyze the effectiveness and safety of FCSEMSs for drainage of different types of PFCs in a large cohort. The secondary aim was to investigate which type of FCSEMS is superior.[Methods]:This was a retrospective, noncomparative review of a nationwide database involving all hospitals in Spain performing EUS-guided PFC drainage. From April 2008 to August 2013, all patients undergoing PFC drainage with an FCSEMS were included in a database. The main outcome measurements were technical success, short-term (2 weeks) and long-term (6 months) effectiveness, adverse events, and need for surgery.[Results]: The study included 211 patients (pseudocyst/walled-off pancreatic necrosis, 53%/47%). The FCSEMSs used were straight biliary (66%) or lumen-apposing (34%). Technical success was achieved in 97% of patients (95% confidence interval [CI], 93%-99%). Short-term- and long-term clinical success was obtained in 94% (95% CI, 89%-97%) and 85% (95% CI, 79%-89%) of patients, respectively. Adverse events occurred in 21% of patients (95% CI, 16%-27%): infection (11%), bleeding (7%), and stent migration and/or perforation (3%). By multivariate analysis, patient age (>58 years) and previous failed drainage were the most important factors associated with negative outcome.[Conclusions]: An FCSEMS is effective and safe for PFC drainage. Older patients with a history of unsuccessful drainage are more likely to fail EUS-guided drainage. The type of FCSEMS does not seem to influence patient outcome

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele