Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

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

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

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic 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

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

Estudio de las modificaciones hemodinámicas cerebrales tras la realización de angioplatía transluminal percutánea carotídea

La angioplastia transluminal percutánea (ATP) de la arteria carótida interna es una técnica desarrollada en las dos últimas décadas y que surge como alternativa a la endarterectomía carotídea. Ambos procedimientos se han demostrado efectivos en el tratamiento y prevención del ictus isquémico al eliminar la placa ateromatosa en el vaso estenosado. La enfermedad arteriosclerótica de los troncos supraaórticos es una causa importante de ictus isquémico, debido a embolización de ramas más distales, a partir de trombos formados en úlceras o estenosis, en la mayoría de los casos. Además una pequeña proporción de ictus se deben a isquemia hemodinámica distal secundaria a una estenosis severa u oclusión arterial. Un 20% de los ictus establecidos van precedidos de ictus isquémicos reversibles o infartos menores que se recuperan sin secuelas. Este hecho permite, una vez detectada la estenosis arterial, una intervención terapeútica mediante la ATP evitando así futuros ictus mayores con incapacidad permanente. Gracias al desarrollo de esta técnica, la incidencia de ictus y muerte ha disminuido de forma importante, pudiéndose aplicar sobre todo a pacientes con estenosis carotídea sintomática y un alto riesgo quirúrgico, no subsidiarios de cirugía carotídea. Si bien se han estudiado los beneficios y complicaciones que implica esta técnica y sus efectos a largo plazo, todavía existen puntos por esclarecer. Así se desconocen los cambios hemodinámicos inmediatos que tienen lugar en la circulación cerebral tras la realización de la ATP carotídea. Tampoco existen datos concluyentes en la literatura sobre la fisiopatología de complicaciones hemodinámicas que pueden producirse en estos momentos, tales como el Síndrome de Hiperperfusión. Por último un mejor conocimiento de los cambios hemodinámicos inducidos por la ATP carotídea y riesgos derivados podría contribuir a asentar las futuras indicaciones en pacientes con estenosis carotídeas graves no sintomáticas. Por todo ello, el propósito de esta tesis es afianzar nuestros conocimientos en los beneficios y complicaciones de la ATP carotídea, centrándonos en el estudio de las modificaciones hemodinámicas cerebrales inmediatas a la técnica. Para ello hemos utilizado el Doppler transcraneal (DTC), excelente prueba incruenta y fiable para el estudio del flujo sanguíneo cerebral. De fácil reproducibilidad y cómoda al poder realizarse en la cabecera del enfermo, analiza no sólo las velocidades medias de las principales arterias cerebrales, sino también las modificaciones que ocurren en el lecho capilar y las arteriolas de resistencia. Esto, junto con unos conocimientos básicos sobre fisiología y anatomía de la circulación encefálica, nos permite conocer los cambios hemodinámicos que tienen lugar en pacientes con estenosis grave u oclusiones arteriales carotídeas y su evolución, sin necesidad de medidas invasoras o uso de sustancias exógenas

TMA-93 for Diagnosing Amnestic Mild Cognitive Impairment: A Comparison With the Free and Cued Selective Reminding Test.

TMA-93 examines binding by images, an advantage for the less educated individuals. To compare the discriminative validity of TMA-93 against the picture version of Free and Cued Selective Reminding Test (FCSRT) to distinguish patients with amnestic mild cognitive impairment (aMCI) from normal controls (NCs) without excluding less educated individuals. Phase I diagnostic evaluation study. A total of 30 patients with aMCI and 30 NCs matched for sociodemographics variables. The diagnostic accuracy for each test was calculated by conducting receiver operating characteristic curve analysis. Hanley and McNeil method was used to compare diagnostic accuracy of different tests on the same sample. Up to 41.7% of the sample had less than a first grade of education. Both tests showed excellent diagnostic accuracy. The comparisons did not show significant differences. TMA-93 is so accurate as FCSRT to differentiate aMCI from controls including less educated individuals. The test could be considered as a choice in this sociodemographic context