Adult hippocampal neurogenesis impairment at preplaque stage in a transgenic rat model of Alzheimer like amyloid pathology

The contribution of adult hippocampal neurogenesis (AHN) impairment on cognitive decline in early Alzheimer disease (AD) remains poorly understood. This can be ascribed to the technical difficulties to measure AHN in postmortem brains and patients. Furthermore, most animal models of AD exhibit an aggressive neuropathology at early age and harbor gene mutations and express transgenes that disrupts AHN by pathways not directly involved in AD pathology. To overcome some of these limitations, we studied AHN at preplaque stage (6 month old) in hemizygous (Tg+/-) and homozygous (Tg+/+) McGill-R-Thy1-APP transgenic rats. This model exhibits a much less aggressive neuropathology that nevertheless is associated with a marked cognitive impairment from early age. Our results revealed that Tg+/+ rats showed a reduced number of PCNA+ cells, DCX+ immature neurons and BrdU+/NeuN+ colabed neurons in dorsal and ventral dentate gyrus. Moreover, dendritic arborization was less developed. AHN was not impaired in Tg+/- rats, although dendritic arborization was slightly decreased. On the other hand, both hemizygous and homozygous rats exhibited spatial memory impairments in the Morris water maze. These results suggest that 1) AHN is dysregulated from the preplaque stage in homozygous rats, 2) AHN impairment is dependent on APP transgene copy numbers since hemizygous rats did not show it, 3) Dysregulation of AHN is not directly associated with spatial memory impairments since hemizygous rats exhibited spared neurogenesis despite showing spatial memory deficits. Funding: International Society for Neurochemistry CAEN Grant and Andalucia TECH-ICE (PG), and PICT-2015-0285 (LM).Fil: Galeano, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Dalmasso, María Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Prestia, Federico Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Cuello, Augusto Claudio. McGill University; CanadáFil: Santín Nuñez, Luis Javier. Universidad de Málaga; EspañaFil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaThe International Society for Neurochemistry and the American Society for Neurochemistry MeetingMontrealCanadáInternational Society for NeurochemistryAmerican Society for Neurochemistr

A prognostic model integrating PET-derived metrics and image texture analyses with clinical risk factors from GOYA

Image texture analysis (radiomics) uses radiographic images to quantify characteristics that may identify tumour heterogeneity and associated patient outcomes. Using fluoro‐deoxy‐glucose positron emission tomography/computed tomography (FDG‐PET/CT)‐derived data, including quantitative metrics, image texture analysis and other clinical risk factors, we aimed to develop a prognostic model that predicts survival in patients with previously untreated diffuse large B‐cell lymphoma (DLBCL) from GOYA (NCT01287741). Image texture features and clinical risk factors were combined into a random forest model and compared with the international prognostic index (IPI) for DLBCL based on progression‐free survival (PFS) and overall survival (OS) predictions. Baseline FDG‐PET scans were available for 1263 patients, 832 patients of these were cell‐of‐origin (COO)‐evaluable. Patients were stratified by IPI or radiomics features plus clinical risk factors into low‐, intermediate‐ and high‐risk groups. The random forest model with COO subgroups identified a clearer high‐risk population (45% 2‐year PFS [95% confidence interval (CI) 40%–52%]; 65% 2‐year OS [95% CI 59%–71%]) than the IPI (58% 2‐year PFS [95% CI 50%–67%]; 69% 2‐year OS [95% CI 62%–77%]). This study confirms that standard clinical risk factors can be combined with PET‐derived image texture features to provide an improved prognostic model predicting survival in untreated DLBCL

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