期刊全称 | Biomarkers for Alzheimer’s Disease Drug Development | 影响因子2023 | Robert Perneczky | 视频video | http://file.papertrans.cn/188/187795/187795.mp4 | 发行地址 | Includes cutting-edge methods and protocols.Provides step-by-step detail essential for reproducible results.Contains key notes and implementation advice from the experts | 学科分类 | Methods in Molecular Biology | 图书封面 |  | 影响因子 | .This volume aims to build a new generation of experts with a broader understanding of key topics in the Alzheimer’s disease field. Chapters guide readers through innovative approaches to the discovery of novel biomarkers in cerebrospinal fluid, innovation in blood-based biomarkers, a comprehensive overview of magnetic resonance imaging and molecular imaging approaches and their value for developing drugs for Alzheimer’s disease, cutting-edge developments in neuropathology and their relevance for Alzheimer’s disease trials, novel genomic strategies for biomarker development, and related topics including neuropsychological testing and advanced analytical methods.Written in the highly successful .Methods in Molecular Biology .series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls... ..Authoritative and cutting-edge, .Biomarkers for Alzheimer‘s Disease Drug Development .aims to ensure successful results in the further study of this vital field. . | Pindex | Book 2018 |
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Epidemiology of Dementia: The Burden on Society, the Challenges for Research |
Frank J. Wolters,MA Ikram |
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Dementia is among the leading causes of death and disability. Due to the ageing population, its prevalence is expected to nearly triple worldwide by 2050, urging the development of preventive and curative interventions. Various modifiable risk factors have been identified in community-based cohort studies, but insight into the underlying pathophysiological mechanisms is lacking. Clinical trials have thus far failed in the development of disease-modifying therapy in patients with dementia, thereby triggering a shift of focus toward the presymptomatic phase of disease. The extensive preclinical disease course of Alzheimer’s disease warrants reliable, easily obtainable biomarkers to aid in timely application of preventive strategies, selecting participants for neuroprotective trials, and disease monitoring in trials and clinical practice. Biomarker and drug discovery may yield the fruits from technology-driven developments in the field of genomics, epigenetics, metabolomics, and brain imaging. In that context, bridging the gap between translational and population research may well prove a giant leap toward development of successful preventive and curative interventions against dementi
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Population-Based Approaches to Alzheimer’s Disease Prevention |
Robert Perneczky |
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Progress in prevention and treatment of Alzheimer’s disease (AD) and dementia is hampered by the restricted understanding of the biological and environmental causes underlying pathophysiology. It is widely accepted that certain genetic factors are associated with AD and a number of lifestyle and other environmental characteristics have also been linked to dementia risk. However, interactions between genes and the environment are not yet well understood, and coordinated global action is required to utilize existing cohorts and other resources effectively and efficiently to identify new avenues for dementia prevention. This chapter provides a brief summary of current research on risk and protective factors and opportunities and challenges in relation to population-based approaches are discussed.
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Systems Biology Methods for Alzheimer’s Disease Research Toward Molecular Signatures, Subtypes, and |
Juan I. Castrillo,Simone Lista,Harald Hampel,Craig W. Ritchie |
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Alzheimer’s disease (AD) is a complex multifactorial disease, involving a combination of genomic, interactome, and environmental factors, with essential participation of (a) intrinsic genomic susceptibility and (b) a constant dynamic interplay between impaired pathways and central homeostatic networks of nerve cells. The proper investigation of the complexity of AD requires new holistic systems-level approaches, at both the experimental and computational level. Systems biology methods offer the potential to unveil new fundamental insights, basic mechanisms, and networks and their interplay. These may lead to the characterization of mechanism-based molecular signatures, and AD hallmarks at the earliest molecular and cellular levels (and beyond), for characterization of AD subtypes and stages, toward targeted interventions according to the evolving precision medicine paradigm. In this work, an update on advanced systems biology methods and strategies for holistic studies of multifactorial diseases—particularly AD—is presented. This includes next-generation genomics, neuroimaging and multi-omics methods, experimental and computational approaches, relevant disease models, and latest ge
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CSF Lipidomics Analysis: High-Resolution Mass Spectrometry Analytical Platform |
Paul L. Wood,Randall L. Woltjer |
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High-resolution mass spectrometry provides the resolution required for direct infusion allowing detection and characterization of a vast array of lipids with a single injection. This chapter presents the methodology utilized for both unbiased and targeted lipidomics of cerebrospinal fluid.
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CSF N-Glycomics Using MALDI MS Techniques in Alzheimer’s Disease |
Angelo Palmigiano,Angela Messina,Rosaria Ornella Bua,Rita Barone,Luisa Sturiale,Mario Zappia,Domenic |
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In this chapter, we present the methodology currently applied in our laboratory for the structural elucidation of the cerebrospinal fluid (CSF) N-glycome. N-glycans are released from denatured carboxymethylated glycoproteins by digestion with peptide-N-glycosidase F (PNGase F) and purified using both C18 Sep-Pak. and porous graphitized carbon (PGC) HyperSep™ Hypercarb™ solid-phase extraction (SPE) cartridges. The glycan pool is subsequently permethylated to increase mass spectrometry sensitivity. Molecular assignments are performed through matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) analysis considering either the protein N-linked glycosylation pathway or MALDI TOF MS/MS data. Each stage has been optimized to obtain high-quality mass spectra in reflector mode with an optimal signal-to-noise ratio up to . 4800. This method has been successfully adopted to associate specific N-glycome profiles to the early and the advanced phases of Alzheimer’s disease.
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MicroRNA Profiling of Alzheimer’s Disease Cerebrospinal Fluid |
Johannes Denk,Holger Jahn |
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MicroRNAs (miRNAs) are a class of small, highly conserved, and noncoding RNAs that modulate gene expression by regulating the activity and stability of target mRNAs. MiRNAs play significant roles by controlling fundamental cellular processes and its deregulation is associated with various diseases. Ubiquitous expression and its release into circulation make them interesting biomarkers, which can be measured by different platforms. In this book chapter, we provide a specific protocol that describes the detection of circulating miRNAs in CSF by using RT-qPCR.
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Validation of a Chemiluminescence Immunoassay for Measuring Amyloid-β in Human Blood Plasma |
Jonathan Vogelgsang,Jens Wiltfang,Hans W. Klafki |
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The technical performance of immunological assays and their suitability for the intended use should be carefully validated before implementation in research, clinical studies or routine. We describe here the evaluation of a sandwich electrochemiluminescence immunoassay for measuring total Amyloid-β levels in human blood plasma as an example of a laboratory protocol for a partial “fit for purpose” assay performance validation. We tested two different assay protocols and addressed impact of sample dilution, parallelism, intra- and inter-assay variance, lower limit of quantification, lower limit of detection, and analytical spike recoveries.
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Mass Spectrometry-Based Metabolomic Multiplatform for Alzheimer’s Disease Research |
Raúl González-Domínguez,Álvaro González-Domínguez,Ana Sayago,Ángeles Fernández-Recamales |
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The integration of complementary analytical platforms has emerged as a suitable strategy to perform a comprehensive metabolomic characterization of complex biological systems. In this work, we describe the most important issues to be considered for the application of a mass spectrometry multiplatform in Alzheimer’s disease research, which combines direct analysis with electrospray and atmospheric pressure photoionization sources, as well as orthogonal hyphenated approaches based on reversed-phase ultrahigh-performance liquid chromatography and gas chromatography. These procedures have been optimized for the analysis of multiple biological samples from human patients and transgenic animal models, including blood serum, various brain regions (e.g., hippocampus, cortex, cerebellum, striatum, olfactory bulbs), and other peripheral organs (e.g., liver, kidney, spleen, thymus). It is noteworthy that the metabolomic pipeline here detailed has demonstrated a great potential for the investigation of metabolic perturbations underlying Alzheimer’s disease pathogenesis.
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Blood-Based Biomarker Screening with Agnostic Biological Definitions for an Accurate Diagnosis Withi |
Filippo Baldacci,Simone Lista,Sid E. O’Bryant,Roberto Ceravolo,Nicola Toschi,Harald Hampel,for the A |
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The discovery, development, and validation of novel candidate biomarkers in Alzheimer’s disease (AD) and other neurodegenerative diseases (NDs) are increasingly gaining .. As a result, evolving diagnostic research criteria of NDs are beginning to integrate biofluid and neuroimaging indicators of pathophysiological mechanisms. More than 10% of people aged over 65 suffer from NDs. There is an urgent need for a refined two-stage diagnostic model to first initiate an early, sensitive, and noninvasive process in primary care settings. Individuals that meet detection criteria will then be channeled to more specific, costly (positron-emission tomography), and invasive (cerebrospinal fluid) assessment methods for confirmatory biological characterization and diagnosis..A reliable and sensitive blood test for AD and other NDs is not yet established; however, it would provide the golden screening gate for an efficient primary care management. A limitation to the development of a large-scale blood-screening biomarker-based test is the traditional application of clinically descriptive criteria for the categorization of single late-stage ND constructs. These are genetically and biologically hete
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Functional Magnetic Resonance Imaging in Alzheimer’ Disease Drug Development |
Stefan Holiga,Ahmed Abdulkadir,Stefan Klöppel,Juergen Dukart |
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While now commonly applied for studying human brain function the value of functional magnetic resonance imaging in drug development has only recently been recognized. Here we describe the different functional magnetic resonance imaging techniques applied in Alzheimer’s disease drug development with their applications, implementation guidelines, and potential pitfalls.
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Neuroimaging Methods for MRI Analysis in CSF Biomarkers Studies |
Carles Falcon,Grégory Operto,José Luis Molinuevo,Juan Domingo Gispert |
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Among others, the existence of pathophysiological biomarkers such as cerebrospinal fluid (CSF) Aβ-42, t-tau, and p-tau preceding the onset of Alzheimer’s disease (AD) symptomatology have shifted the conceptualization of AD as a .. In addition, magnetic resonance imaging (MRI) enables the study of structural and functional cross-sectional correlates and longitudinal changes in vivo and, therefore, the combination of CSF data and imaging analyses emerges as a synergistic approach to understand the structural correlates related with specific AD-related biomarkers. In this chapter, we describe the methods used in neuroimaging that will allow researchers to combine data on CSF metabolites with imaging analyses.
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Hybrid PET-MRI in Alzheimer’s Disease Research |
Ismini C. Mainta,Maria I. Vargas,Sara Trombella,Giovanni B. Frisoni,Paul G. Unschuld,Valentina Garib |
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Multiple factors, namely amyloid, tau, inflammation, metabolic, and perfusion changes, contribute to the cascade of neurodegeneration and functional decline occurring in Alzheimer’s disease (AD). These molecular and cellular processes and related functional and morphological changes can be visualized in vivo by two imaging modalities, namely positron emission tomography (PET) and magnetic resonance imaging (MRI). These imaging biomarkers are now part of the diagnostic algorithm and of particular interest for patient stratification and targeted drug development..In this field the availability of hybrid PET/MR systems not only offers a comprehensive evaluation in a single imaging session, but also opens new possibilities for the integration of the two imaging information. Here, we cover the clinical protocols and practical details of FDG, amyloid, and tau PET/MR imaging as applied in our institutions.
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Amyloid PET Imaging: Standardization and Integration with Other Alzheimer’s Disease Biomarkers |
Silvia Morbelli,Matteo Bauckneht |
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Amyloid plaques are a neuropathologic hallmark of Alzheimer’s disease (AD), which can be imaged through positron emission tomography (PET) technology using radiopharmaceuticals that selectively bind to the fibrillar aggregates of amyloid-β plaques (Amy-PET). Several radiotracers for amyloid PET have been investigated, including .C-Pittsburgh compound B and the .F-labeled compounds such as .F-florbetaben, .F-florbetapir, and .F-flutemetamol. Besides the injected radiotracer, images can be interpreted by means of visual/qualitative, semiquantitative, and quantitative criteria. Here we summarize the main differences between the available radiotracers for Amy-PET, the proposed interpretation criteria, and analytical methods.
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The Use of 18F-FDG PET in the Diagnostic Workup of Alzheimer’s Dementia |
Marion M. Ortner |
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The diagnosis of dementia probably due to Alzheimer’s disease is still primarily a clinical one. In cases that remain clinically unclear, however, biomarkers for amyloid deposition and neuronal injury can help to identify the underlying cause. One biomarker even for early neuronal injury in the stage of mild cognitive impairment is cerebral glucose hypometabolism measured by .F-FDG PET. Distinct patterns of hypometabolism can be seen, for example, in dementia due to Alzheimer’s disease, frontotemporal lobar degeneration, and dementia with Lewy bodies. This makes it possible to distinguish between different neurodegenerative diseases as well as major depressive disorder. While the sensitivity of .F-FDG PET to detect Alzheimer’s disease is high, specificity is low and the additional use of biomarkers for amyloid deposition might be beneficial in some cases. In conclusion, .F-FDG PET is a useful tool when the cause for dementia remains unclear and different diagnosis would lead to different treatment approaches. Due to the lack of treatment options in pre-dementia stages, the use of .F-FDG PET is currently not recommended for these cases in a purely clinical setting.
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