An overview of the first 5 years of the ENIGMA obsessive–compulsive disorder working group: The power of worldwide collaboration

Abstract Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive?compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA

Problem-based learning in an on-line biotechnology course

Problem-based learning (PBL) is a pedagogical tool that uses a real world problem or situation as a context for learning. PBL encourages student development of critical thinking skills, a high professional competency, problem-solving ability, knowledge acquisition, the ability to work productively as a team member and make decisions in unfamiliar situations, and the acquisition of skills that support self-directed life-long learning, metacognition, and adaptation to change. However, little research has focused on the use of PBL in on-line virtual classes. We conducted two studies exploring the use of PBL in an on-line biotechnology course. In the first study, ethical, legal, social, and human issues were used as a motivation for learning about DNA testing technologies, applications, and bioethical issues. In the second study, we combined PBL pedagogy with a rich multimedia environment of streaming video interviews, physical artifacts, and extensive links to articles and databases to create a multidimensional immersive PBL environment called Robert\u27s World . In Robert\u27s World , a man is determining whether to undergo a pre-symptomatic DNA test for an untreatable, incurable, fatal genetic disease for which he has a family history. In both studies, design and implementation issues of the on-line PBL environment are discussed, as are differences between on-line PBL and face-to-face PBL. Both studies provide evidence to suggest that PBL stimulates higher-order learning in students. However, in both studies, student performance on an exam testing acquisition of lower-order factual learning was lower for PBL students than for students who learned the same material through a traditional lecture-based approach. Possible reasons for this lower level of performance are explored. Student feedback expressed engagement with the issues and material covered, with reservations about some aspects of the PBL format, such as the lack of flexibility provided in cooperative learning. We conclude that on-line PBL is a powerful tool in helping to develop higher-order learning in students. The reasons for the decrease in student understanding of factual information are unclear. However, there are certain circumstances unique to on-line classes to keep in mind when implementing on-line PBL. These are summarized in concluding recommendations

A precision medicine initiative for Alzheimer's disease: the road ahead to biomarker-guided integrative disease modeling

After intense scientific exploration and more than a decade of failed trials, Alzheimer’s disease (AD) remains a fatal global epidemic. A traditional research and drug development paradigm continues to target heterogeneous late-stage clinically phenotyped patients with single 'magic bullet' drugs. Here, we propose that it is time for a paradigm shift towards the implementation of precision medicine (PM) for enhanced risk screening, detection, treatment, and prevention of AD. The overarching structure of how PM for AD can be achieved will be provided through the convergence of breakthrough technological advances, including big data science, systems biology, genomic sequencing, blood-based biomarkers, integrated disease modeling and P4 medicine. It is hypothesized that deconstructing AD into multiple genetic and biological subsets existing within this heterogeneous target population will provide an effective PM strategy for treating individual patients with the specific agent(s) that are likely to work best based on the specific individual biological make-up. The Alzheimer’s Precision Medicine Initiative (APMI) is an international collaboration of leading interdisciplinary clinicians and scientists devoted towards the implementation of PM in Neurology, Psychiatry and Neuroscience. It is hypothesized that successful realization of PM in AD and other neurodegenerative diseases will result in breakthrough therapies, such as in oncology, with optimized safety profiles, better responder rates and treatment responses, particularly through biomarker-guided early preclinical disease-stage clinical trials

Relationship between explore to the environmental toxicant methylmercury and the transcriptional repressor rest in vitro model of amyotrophic lateral sclerosis

Since MeHg exposure hastens the onset of amyotrophic lateral sclerosis-like phenotype in SOD1G93A mice activating glutamate receptors and determined neuronal cell death by increasing REST expression, we invesigated the possible role of MeHg to accelerate reduction in cell survival in NSC-34 motor neuron like cells transiently transfected whit G93A-SOD1 construct via REST up regulation. Furthermore, we studied the trascriptional activators Sp1, Sp3, CREB and JunD. Additionally, we identified the epigenetic mechanism by which MeHg regulated REST gene. Since REST overexpression in neurons determined cell death by activating necroptosis, we investigated the role of MeHg to activate necroptosis in NSC34 cells overexpressing G93A-SOD1 construc

Identification of genetic factors underpinning phenotypic heterogeneity in Huntington's disease and other neurodegenerative disorders

Neurodegenerative diseases including Huntington’s disease (HD), the spinocerebellar ataxias and C9orf72 associated Amyotrophic Lateral Sclerosis / Frontotemporal dementia (ALS/FTD) do not present and progress in the same way in all patients. Instead there is phenotypic variability in age at onset, progression and symptoms. Understanding this variability is not only clinically valuable, but identification of the genetic factors underpinning this variability has the potential to highlight genes and pathways which may be amenable to therapeutic manipulation, hence help find drugs for these devastating and currently incurable diseases. Identification of genetic modifiers of neurodegenerative diseases is the overarching aim of this thesis. To identify genetic variants which modify disease progression it is first necessary to have a detailed characterization of the disease and its trajectory over time. In this thesis clinical data from the TRACK-HD studies, for which I collected data as a clinical fellow, was used to study disease progression over time in HD, and give subjects a progression score for subsequent analysis. In this thesis I show blood transcriptomic signatures of HD status and stage which parallel HD brain and overlap with Alzheimer’s disease brain. Using the Huntington’s disease progression score in a genome wide association study, both a locus on chromosome 5 tagging MSH3, and DNA handling pathways more broadly, are shown to modify HD progression: these results are explored. Transcriptomic signatures associated with HD progression rate are also investigated. In this thesis I show that DNA repair variants also modify age at onset in spinocerebellar ataxias (1, 2, 3, 6, 7 and 17), which are, like HD, caused by triplet repeat expansions, suggesting a common mechanism. Extending this thesis’ examination of the relationship between phenotype and genotype I show that the C9orf72 expansion, normally associated with ALS/FTD, is also the commonest cause of HD phenocopy presentations

Development of the Personal Genomics Industry

Today, numerous commercial services offer genetic testing, genotyping and genome sequencing services both to medical providers and directly to the public. Twenty-five years ago, such offerings would have been unthinkable, both in terms of cost and medical practice. This chapter describes the development of the personal genomics industry and its evolving business models and goals

The contribution of disease focused nonprofits to biomedical research and development

Thesis (S.M.)--Harvard-MIT Program in Health Sciences and Technology, 2013.Cataloged from PDF version of thesis.Includes bibliographical references (pages 88-92).Patient-centered, disease-focused nonprofits are playing an increasingly prominent role in accelerating the development of new diagnostics, drugs, and therapies. They are engaging in a variety of complex venture philanthropic activities as they seek to bridge the "valley of death" gap between basic and clinical research. Examples of such activities include developing preclinical research tools, supporting clinical trials infrastructure, and investing in private biotechnology companies. In this thesis, 1: 1) quantify the financial contribution of US-based nonprofits to biomedical research and development (R&D) and the allocation to therapeutic areas; and 2) propose a framework for understanding the core functions of biomedical venture philanthropies. I find that US-based nonprofits contributed $3.7 billion to biomedical R&D in 2011, and that within certain disease areas nonprofit spending is comparable to or exceeds spending by the National Institutes of Health (NIH). I catalogue nonprofit activities and place them in a framework of five core functions: bridging gaps, enabling research, directing pipelines, informing stakeholders, and shaping markets. I present several case studies via this framework, discuss opportunities, and point out challenges such as a lack of conflict of interest standards. Methods included recording and analyzing publically available financial data from over 400 biomedical nonprofits, and conducting a series of in depth interviews with nonprofit executives and other related professionals.by Jordanna Polis Schutz.S.M

Predictive testing and clinical genetic counselling services for Huntington disease in the Western Cape : an evaluation over eleven years

Includes bibliographical references (leaves 273-325)

Development of Translational Imaging Biomarkers in Mouse Models of Huntington's Disease

Huntington’s disease (HD) is a genetic neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene that results in movement disorders and cognitive and psychiatric decline. To better track disease onset and progression, biomarkers that precede irreversible structural changes are needed. Alterations in metabolic processes detectable using magnetic resonance imaging (MRI) and other MR approaches may provide such biomarkers but need characterisation in HD mouse models to improve their clinical translatability. The aim of this thesis was to develop imaging biomarkers in transgenic R6/2 and knock-in zQ175 mice, two commonly used HD mouse models. To undertake the most comprehensive time-course analyses of metabolite concentrations in these models so far, proton magnetic resonance spectroscopy (1H-MRS) was acquired in selected brain regions throughout disease progression. Significant metabolic alterations were observed in zQ175 and R6/2 mice, with fluctuations at early disease stages. These changes suggested diminished neuronal integrity and reactive gliosis, which were confirmed using histology. Brain regions also exhibited specific metabolic profiles, many of said profiles being observed across both mouse models (albeit with some discrepancies). Chemical Exchange Saturation Transfer (CEST), which ought to overcome the limited sensitivity of 1H-MRS, was also acquired. However, we show CEST is not sensitive to HD pathology and do not recommend it for biomarker development in HD. Lastly, we acquired diffusion-weighted MRS (DW-MRS) in zQ175 mice to assess the diffusion of metabolites confined to cell-specific compartments. We found no changes in metabolite diffusion properties, but given the experimental nature of the protocol we used, DW-MRS needs further investigation in the context of HD. Overall, we have moved the field of HD forward by evaluating in detail the metabolic consequences of the disease in two mouse models that are widely used to investigate HD pathogenesis and evaluate therapeutic targets