Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

INTRODUCTION: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. METHODS: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. RESULTS: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. DISCUSSION: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

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

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

New model for PET/CT image processing and radiotherapy planning based on dose painting

Resumen del póster presentado a la international conference on imaging techniques in subatomic physics, astrophysics, medicine, biology and industry; celebrada en Estocolmo (Suecia) del 13 al 16 de junio de 2016.-- et al.[Introduction]: Dose Painting (DP) is a radiotherapy treatment strategy for delivering a nonuniform dose distribution with a prescription based on the new concept of biological target volumes (BTVs) from medical images. Two approaches are being evaluated: threshold-based dose painting by contours (DPBC), and voxel-based dose painting by numbers (DPBN). The study of the impact of different developed PET image reconstruction protocols on the segmentation of the BTVs for DPBC, and the generation of the dose prescription maps for DPBN are topics under study in processing image for nuclear medicine and radiotherapy. [Purpose]: To present a new model for assessing the effect on the radiotherapy treatment planning of using different acquisition and reconstruction protocols for morpho-functional image from PET/CT before incorporating their use in the clinical routine. [Material and methods]: We used Siemens Biograph mCT PET/CT clinical scanner with Syngo V51C acquisition software. Acquisition and reconstruction methods for EARL (ResEARch for Life R , http://earl.eanm.org) [18F]FDG-PET/CT accreditation were carried out and a protocol for maximize Recovery Coefficient (RC) in Image Quality NEMA 2007 phantom was also implemented. The scanner and software apart from typical corrections allows Time of Flight correction, iterative OSEM reconstruction and application of Point Spread Function. Beyond the deviations already observed between dose prescriptions maps and the different reconstructed SUV images, in order to assess the impact of different reconstruction methods on the treatment planning algorithm, actual clinical cases should be also planned for both a dose painting by contours (DPBC) and a dose painting by numbers (DPBN) strategy. However, as far as we know, planning of DPBN is not supported by commercial treatment planning system. To make possible this evaluation, a novel algorithm has been developed for planning based on inverse planning, including an optimization method at the voxel level, so restriction of dose to volumes from a previous segmentation process in the image is not necessary. The software was implemented in our in-house platform CARMEN, based on Matlab (http://grupos.us.es/medicalphysics/) for radiotherapy research. New image processing methods for generating the previous maps to the optimization process and new metrics for the evaluation of results were implemented in CARMEN platform. The platform was developed for the easy implementation of new algorithms under evaluation and then, to be applied to imported clinical cases. [Results]: The different reconstruction methods for the generation of prescription dose maps for DPBN and different semiautomatic segmentation algorithms for DBPN showed relevant discrepancies in covering tumor and unwished doses in healthy tissue and organs at risk. These results evidenced the need to incorporate standard protocols in the processing of PET/CT images for radiotherapy planning. [Conclusions]: A new model was presented for the correct evaluation of the influence in the radiotherapy planning of the implementation of different reconstruction methods and thresholds of morpho-functional information by PET/CT image processing.Peer Reviewe

Application of EARL (ResEARch 4 Life®) approved and rejected protocols for [18F]FDG-PET/CT clinical and research studies

Resumen del trabajo presentado a la international conference on imaging techniques in subatomic physics, astrophysics, medicine, biology and industry; celebrada en Estocolmo (Suecia) del 13 al 16 de junio de 2016.In adjusting the available acquisition and reconstruction protocols to EARL (ResEARch 4 Life ®, http://earl.eanm.org) [18F]FDG-PET/CT accreditation we also tried to develop a protocol which maximises Recovery Coefficient (RC) for Image Quality NEMA 2007 phantom. We used Siemens Biograph mCT PET/CT clinical scanner with Syngo V51C acquisition software. The scanner and software apart from typical corrections allows Time of Flight correction, iterative OSEM reconstruction and application of Point Spread Function. The protocol fulfilling EARL requirements was developed and also the research protocol optimizing RC for mean Standard Uptake Value (SUV) and maximum SUV being as close to 1 as possible for both SUV types simultaneously and for NEMA 2007 phantom spheres of 17 mm diameter and larger. For all developed protocols we assessed the differences in mean and maximum SUV for small diameter and low metabolic rate tumours in several clinical cases. Additionally, we evaluated the differences in other tumour parameters derived from VOI and ROI delineation like dimensions and volume. An estimation of predictive value by using EARL accreditation protocol facing the research protocol is being carried out.Peer Reviewe

Application of EARL (ResEARch 4 Life®) protocols for [18F]FDG-PET/CT clinical and research studies. A roadmap towards exact recovery coefficient

Tumour uptake value is a critical result in [F]FDG-PET/CT ([F]fluorodeoxyglucose) quantitative scans such as the dose prescription for radiotherapy and oncology. The quantification is highly dependent on the protocol of acquisition and reconstruction of the image, especially in low activity tumours. During adjusting acquisition and reconstruction protocols available in our Siemens Biograph mCT scanner for EARL (ResEARch 4 Life®) [F]FDG-PET/CT accreditation requirements, we developed reconstruction protocols which will be used in PET based radiotherapy planning able to reduce inter-/intra-institute variability in Standard Uptake Value (SUV) results, and to bring Recovery Coefficient to 1 as close as possible for Image Quality NEMA 2007 phantom. Primary and secondary tumours from two patients were assessed by four independent evaluators. The influence of reconstruction protocols on tumour clinical assessment was presented. We proposed the improvement route for EARL accredited protocols so that they may be developed in classes to take advantage of scanner possibilities. The application of optimized reconstruction protocol eliminates the need of partial volume corrections.This work was in part supported by the Spanish regional government of Andalucía (Junta de Andalucía) within the project with reference CTS 2482 and the European Community funding (FEDER). “Acuerdo de colaboración en formación especializada entre el Hospital Universitario Virgen del Rocío y el Centro Nacional de Aceleradores” Spain is acknowledged for providing institutional and financial support.Peer Reviewe

Identification of the multimorbidity training needs of primary care professionals: Protocol of a survey

Background: Current epidemiological situation has prompted the consideration of multimorbility (MM) as a prevalent condition, influenced by age, educational level and social support, related to unfavorable social and health determinants. Primary Care (PC) has a key role in its approach but further training of professionals in MM is required. The evidence on the effectiveness of training interventions in MM is still limited. Knowing the experiences, opinions and training needs of professionals is essential to enhance training interventions. Objectives: Identify perceived training needs by PC health professionals (doctors and nurses) in MM and polypharmacy. Methods: Design: Cross-sectional study based on an online survey (anonymous-ad hoc questionnaire). Participants and recruitment: 384 doctors and nurses working in healthcare centers and out-of-hospital emergencies of the Spanish National Health System. Non-probabilistic convenience sampling via email addressed to Health Institutions, and social networks. Data: Demographic characteristics and professional profile data (close-ended and multiple-choice questions) will be collected. Open-ended questions will be used to identify training needs, difficulties and resources about MM; required skills to care patients with MM will be assessed using a 4-item ordinal scale. Analysis: Coding of data prior to analysis. Descriptive statistical analysis, participation and completion rates of the questionnaire and estimation of absolute and relative frequencies and 95% confidence intervals in close-ended questions. Content analysis with inductive methodology in open-ended questions. Ethics: Ethical approval, Online informed consent. Conclusions: The identification of training needs of health professionals who care for patients with MM will be necessary data for developing highly effective training activities

Cross-cultural adaptation and psychometric validation of a Spanish version of the revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire.

Successful deprescribing depends largely on factors related to the patient. The revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire was developed with the objective of evaluating the beliefs and attitudes of older adults and caregivers towards deprescribing. The present study was designed to validate a Spanish version of the rPATD questionnaire, both the versions for older adults and for caregivers, through a qualitative validation phase and the analysis of its psychometric properties. Cross-sectional validation study. Primary care settings in Málaga (Spain). A sample of 120 subjects (60 patients with polypharmacy and 60 caregivers of patients with polypharmacy) were enrolled in the study. In the qualitative validation stage, the rPATD questionnaire was translated/back-translated and subjected to a cross-cultural adaptation to evaluate its face validity and feasibility. Next, its psychometric properties were assessed. Confirmatory factor analysis was used to evaluate construct validity. Internal consistency was determined using Cronbach's alpha test. Criterion validity through pre-established hypotheses from the Beliefs about Medicines Questionnaire (BMQ) Specific-Concerns Scale, and test-retest reliability were analysed. Confirmatory factor analysis verified the four-factor structure of the original rPATD questionnaire, with items loading into four factors: involvement, burden, appropriateness and concerns about stopping. The Cronbach's alpha coefficient of the factors ranged from 0.683 to 0.879. The burden, appropriateness and concerns about stopping factors were significantly correlated with the BMQ Specific-Concerns Score, except for the concerns about stopping factor in the older adults' version. The consistency of the items between administration times (test-retest reliability) showed weighted Cohen's kappa values ranging from moderate (>0.4) to very good (>0.8). The Spanish version of the rPATD questionnaire is a feasible, valid and reliable instrument to evaluate attitudes towards deprescribing in Spanish-speaking patients and caregivers

Effectiveness of the MULTIPAP Plus intervention in youngest-old patients with multimorbidity and polypharmacy aimed at improving prescribing practices in primary care: study protocol of a cluster randomized trial

del Cura-Gonzalez I, Lopez-Rodriguez JA, Leiva-Fernandez F, et al. Effectiveness of the MULTIPAP Plus intervention in youngest-old patients with multimorbidity and polypharmacy aimed at improving prescribing practices in primary care: study protocol of a cluster randomized trial. Trials. 2022;23(1): 479.Background: The progressive ageing of the population is leading to an increase in multimorbidity and polypharmacy, which in turn may increase the risk of hospitalization and mortality. The enhancement of care with information and communications technology (ICT) can facilitate the use of prescription evaluation tools and support system for decision-making (DSS) with the potential of optimizing the healthcare delivery process. Objective: To assess the effectiveness and cost-effectiveness of the complex intervention MULTIPAP Plus, compared to usual care, in improving prescriptions for young-old patients (65-74 years old) with multimorbidity and polypharmacy in primary care. Methods/design: This is a pragmatic cluster-randomized clinical trial with a follow-up of 18 months in health centres of the Spanish National Health System. Unit of randomization: family physician. Unit of analysis: patient. Population: Patients aged 65-74 years with multimorbidity (>= 3 chronic diseases) and polypharmacy (>= 5 drugs) during the previous 3 months were included. Sample size: n = 1148 patients (574 per study arm). Intervention: Complex intervention based on the ARIADNE principles with three components: (1) family physician (FP) training, (2) FP-patient interview, and (3) decision-making support system. Outcomes: The primary outcome is a composite endpoint of hospital admission or death during the observation period measured as a binary outcome, and the secondary outcomes are number of hospital admission, all-cause mortality, use of health services, quality of life (EQ-5D-5L), functionality (WHODAS), falls, hip fractures, prescriptions and adherence to treatment. Clinical and sociodemographic factors will be explanatory variables. Statistical analysis: The main result is the difference in percentages in the final composite endpoint variable at 18 months, with its corresponding 95% CI. Adjustments by the main confounding and prognostic factors will be performed through a multilevel analysis. All analyses will be carried out in accordance to the intention-to-treat principle. Discussion: It is important to prevent the cascade of negative health and health care impacts attributable to the multimorbidity-polypharmacy binomial. ICT-enhanced routine clinical practice could improve the prescription process in patient care