Dataset Information

Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource.

ABSTRACT: Given the central role of genetic factors in the pathogenesis of common neurodegenerative disorders, it is critical that mechanistic studies in human tissue are interpreted in a genetically enlightened context. To address this, we performed exome sequencing and copy number variant analysis on 1511 frozen human brains with a diagnosis of Alzheimer's disease (AD, n = 289), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS, n = 252), Creutzfeldt-Jakob disease (CJD, n = 239), Parkinson's disease (PD, n = 39), dementia with Lewy bodies (DLB, n = 58), other neurodegenerative, vascular, or neurogenetic disorders (n = 266), and controls with no significant neuropathology (n = 368). Genomic DNA was extracted from brain tissue in all cases before exome sequencing (Illumina Nextera 62 Mb capture) with variants called by FreeBayes; copy number variant (CNV) analysis (Illumina HumanOmniExpress-12 BeadChip); C9orf72 repeat expansion detection; and APOE genotyping. Established or likely pathogenic heterozygous, compound heterozygous, or homozygous variants, together with the C9orf72 hexanucleotide repeat expansions and a copy number gain of APP, were found in 61 brains. In addition to known risk alleles in 349 brains (23.9% of 1461 undergoing exome sequencing), we saw an association between rare variants in GRN and DLB. Rare CNVs were found in <1.5% of brains, including copy number gains of PRPH that were overrepresented in AD. Clinical, pathological, and genetic data are available, enabling the retrieval of specific frozen brains through the UK Medical Research Council Brain Banks Network. This allows direct access to pathological and control human brain tissue based on an individual's genetic architecture, thus enabling the functional validation of known genetic risk factors and potentially pathogenic alleles identified in future studies.

SUBMITTER: Keogh MJ

PROVIDER: S-EPMC5204341 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource.

Keogh Michael J MJ Wei Wei W Wilson Ian I Coxhead Jon J Ryan Sarah S Rollinson Sara S Griffin Helen H Kurzawa-Akanbi Marzena M Santibanez-Koref Mauro M Talbot Kevin K Turner Martin R MR McKenzie Chris-Anne CA Troakes Claire C Attems Johannes J Smith Colin C Al Sarraj Safa S Morris Chris M CM Ansorge Olaf O Pickering-Brown Stuart S Ironside James W JW Chinnery Patrick F PF

Genome research 20161221 1

Given the central role of genetic factors in the pathogenesis of common neurodegenerative disorders, it is critical that mechanistic studies in human tissue are interpreted in a genetically enlightened context. To address this, we performed exome sequencing and copy number variant analysis on 1511 frozen human brains with a diagnosis of Alzheimer's disease (AD, n = 289), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS, n = 252), Creutzfeldt-Jakob disease (CJD, n = 239), Parkinson' ...[more]

PMID: 28003435

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Project description:The Medical Research Council grading system has served through decades for the evaluation of muscle strength and has been recognized as a cardinal feature of daily neurological, rehabilitation and general medicine examination of patients, despite being respectfully criticized due to the unequal width of its response options. No study has systematically examined, through modern psychometric approach, whether physicians are able to properly use the Medical Research Council grades. The objectives of this study were: (i) to investigate physicians' ability to discriminate among the Medical Research Council categories in patients with different neuromuscular disorders and with various degrees of weakness through thresholds examination using Rasch analysis as a modern psychometric method; (ii) to examine possible factors influencing physicians' ability to apply the Medical Research Council categories through differential item function analyses; and (iii) to examine whether the widely used Medical Research Council 12 muscles sum score in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy would meet Rasch model's expectations. A total of 1065 patients were included from nine cohorts with the following diseases: Guillain-Barré syndrome (n = 480); myotonic dystrophy type-1 (n = 169); chronic inflammatory demyelinating polyradiculoneuropathy (n = 139); limb-girdle muscular dystrophy (n = 105); multifocal motor neuropathy (n = 102); Pompe's disease (n = 62) and monoclonal gammopathy of undetermined related polyneuropathy (n = 8). Medical Research Council data of 72 muscles were collected. Rasch analyses were performed on Medical Research Council data for each cohort separately and after pooling data at the muscle level to increase category frequencies, and on the Medical Research Council sum score in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. Disordered thresholds were demonstrated in 74-79% of the muscles examined, indicating physicians' inability to discriminate between most Medical Research Council categories. Factors such as physicians' experience or illness type did not influence these findings. Thresholds were restored after rescoring the Medical Research Council grades from six to four options (0, paralysis; 1, severe weakness; 2, slight weakness; 3, normal strength). The Medical Research Council sum score acceptably fulfilled Rasch model expectations after rescoring the response options and creating subsets to resolve local dependency and item bias on diagnosis. In conclusion, a modified, Rasch-built four response category Medical Research Council grading system is proposed, resolving clinicians' inability to differentiate among its original response categories and improving clinical applicability. A modified Medical Research Council sum score at the interval level is presented and is recommended for future studies in Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy.

Project description:BackgroundChronic Kidney Disease (CKD) is a growing global health issue with a complex symptom phenotype. It negatively impacts patients' health-related quality of life and increases healthcare utilization. While digital health interventions offer promising avenues for improving symptom management in CKD, understanding their development, validation, and effectiveness is crucial for clinical application.ObjectiveTo comprehensively map the existing literature on digital health interventions designed to manage symptoms in patients with Chronic Kidney Disease (CKD), using the UK Medical Research Council's complex intervention framework as a guiding lens. This scoping review aims to: (1) catalogue digital health interventions utilized in CKD symptom management; (2) detail the range of outcome measures assessing intervention effectiveness, including clinical efficacy, patient adherence, and quality of life; (3) examine the methodologies and frameworks employed in the creation of these interventions; (4) assess the pilot testing and effectiveness evaluations; and (5) categorize and analyze the barriers to implementation.MethodsA scoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Databases searched included PubMed, Scopus, Embase, and others, covering literature up to December 2023. Studies were selected based on predefined eligibility criteria for digital health interventions for CKD symptom management.ResultsThe search yielded 31 studies, with a mix of development and validation studies, predominantly from developed countries. The review highlights the potential of digital interventions in enhancing symptom management, quality of life, and patient engagement in CKD care. However, gaps were identified as follows: (1) Iterative refinement cycles involving multidisciplinary stakeholders enhanced intervention acceptability and usability should be guaranteed, (2) Theory-driven and evidence-based approaches were underutilized in current intervention development, (3) Long-term implementation outcomes and process evaluations were rarely assessed. This review maps an evolving landscape where digital health interventions offer patient-centric solutions for CKD symptom management while highlighting opportunities for methodological advancements.ConclusionDigital health interventions hold promise for improving symptom management in CKD, yet more research is needed to overcome current limitations and fully realize their potential. Future studies should focus on patient-centred designs, comprehensive validation processes, exploring the underlying mechanism using process evaluation and the integration of these technologies into routine clinical practice.

Dataset Information

Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource.

Publications

Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource.

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