Advances in the Discovery of Biomarkers for Alzheimer’s Disease.pdf
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1、 1 Advances in the Discovery of Biomarkers for Alzheimers Disease Opportunities presented by “omics” and imaging technologies for the development of diagnostic tests Reference Code: BI00041-004 Publication Date: December 2011 2 About the author Dr David Templeton has over 25 years experience in acad
2、emic and pharmaceutical industry research, including time in major pharma, innovative biotech, and generic drug development. His expertise spans discovery pharmacology, toxicology, and clinical pharmacology. He has held management positions in several organizations, including Xenova, Pfizer, GSK, an
3、d Eisai. His drug discovery expertise has been focused principally on neurodegeneration, including stroke, multiple sclerosis, and Alzheimers disease. He has also been responsible for the clinical introduction of novel therapeutics in Alzheimers disease. He graduated from the University of Glasgow w
4、ith an honors degree in pharmacology and also completed his PhD in the Department of Pharmacology at Glasgow. Disclaimer Copyright 2011 Business Insights Ltd This report is published by Business Insights (the Publisher). This report contains information from reputable sources and although reasonable
5、 efforts have been made to publish accurate information, you assume sole responsibility for the selection, suitability and use of this report and acknowledge that the Publisher makes no warranties (either express or implied) as to, nor accepts liability for, the accuracy or fitness for a particular
6、purpose of the information or advice contained herein. The Publisher wishes to make it clear that any views or opinions expressed in this report by individual authors or contributors are their personal views and opinions and do not necessarily reflect the views/opinions of the Publisher. 3 Table of
7、Contents About the author 2 Disclaimer 2 Executive summary 10 Introduction 10 Biomarkers in Alzheimers disease 10 A and tau as biomarkers 11 Genomics and non-genomic factors 12 Transcriptomics 12 Proteomics 13 Biomarkers in saliva and urine 14 Metabonomics 14 Imaging 15 Use of cognitive testing to d
8、etect preclinical Alzheimers disease 16 Chapter 1 Introduction 17 Summary 17 Introduction 17 Phases of AD: model of preclinical, MCI, and dementia 19 Chapter 2 Biomarkers in Alzheimers disease 26 Summary 26 Introduction 26 Biomarker definitions 28 4 Chapter 3 A and tau as biomarkers 30 Summary 30 In
9、troduction 30 Amyloid 31 Background 31 Developments in understanding of the toxic species of A 33 Tau 34 A/tau as biomarkers in CSF and plasma 35 CSF amyloid and tau 35 A and tau aids differentiation of AD from other dementias 37 Plasma A as a biomarker in AD 39 Plasma tau as a biomarker in AD 42 Ot
10、her CSF biomarkers 42 A oligomers 46 ALZAS protein 47 BACE1 47 Clusterin 49 Isoprostanes 49 Proteomic 15/17 panel 50 Ubiquitin 51 Chapter 4 Genomics and non-genomic factors 53 Summary 53 Introduction 53 Genetic factors in FAD 54 Genetic risk factors in sporadic AD 55 Apolipoprotein E 57 5 TOMM40 58
11、Other AD genes 59 Non-genetic risk factors 59 Age 59 Homocysteine 59 Chapter 5 Transcriptomics 61 Summary 61 Introduction 62 Non-coding RNA 62 miRNA 62 Long ncRNA 67 BACE1 antisense 67 RNA splice variants 68 38A/17A 70 Exonhit 71 DiaGenic 72 Epigenetic control of RNA in AD 73 Summary 77 Chapter 6 Pr
12、oteomics 79 Summary 79 Introduction 79 Plasma proteomic screen in AD 79 Chapter 7 Biomarkers in saliva and urine 85 Summary 85 Introduction 85 Saliva 86 6 Urine 88 Chapter 8 Metabonomics 90 Summary 90 Introduction 90 Key developments 91 Chapter 9 Imaging 93 Summary 93 Introduction 94 Volumetric MRI
13、as a neurodegeneration marker 94 FDG-PET detects functional changes in AD 96 11C-PiB amyloid imaging 98 Chapter 10 Use of cognitive testing to detect preclinical Alzheimers disease 102 Summary 102 Introduction 102 Cognitive testing in AD 103 Chapter 11 Conclusion 108 Conclusion 108 Appendix 112 Meth
14、odology 112 Primary research 112 Secondary research 112 Scope 112 7 Abbreviations 113 References 119 8 Table of figures Figure 1: Hypothetical model of the phases of AD 22 Figure 2: Detailed description of the preclinical phase of AD 23 Figure 3: A production from APP 32 Figure 4: Stages of neurotox
15、icity 35 Figure 5: Regulation of BACE1 by miRNA 66 Figure 6: Regulation of homocysteine metabolism 75 Figure 7: Chemical structures of Thioflavin-T, PiB, and GE-067 100 9 Table of tables Table 1: Tau and A in the differentiation of AD from other dementias 37 Table 2: Potential CSF protein biomarkers
16、 (part 1) 44 Table 3: Potential CSF protein biomarkers (part 2) 45 Table 4: Potential CSF protein biomarkers (part 3) 46 Table 5: Genetic associations in FAD 55 Table 6: Genetic associations in sporadic AD (part 1) 56 Table 7: Genetic associations in sporadic AD (part 2) 57 Table 8: NextGen Sciences
17、 human CSF AD 37-plex screen (part 1) 81 Table 9: NextGen Sciences human CSF AD 37-plex screen (part 2) 82 Table 10: NextGen Sciences 15-plex plasma screen 83 Table 11: Summary of AD biomarker technologies by company 111 10 Executive summary Introduction ? Alzheimers disease (AD) is the major unmet
18、clinical need in the neurosciences, with the number of patients doubling every 20 years to reach 115.4 million by 2050. The global cost was estimated to be in excess of $600m in 2010. Disease-modifying drugs are urgently required to prevent AD or slow progression. Disease-modifying drugs would have
19、a major impact on both total numbers and the socio- economic cost. ? AD occurs as two forms, namely early-onset or familial AD (FAD) and late-onset or sporadic AD. The gene mutations responsible for FAD have been identified, but in sporadic AD there is no equivalent genetic abnormality. Sporadic AD
20、occurs later in life than FAD. ? FAD is accompanied by increased levels of amyloid beta (A) in the brain, which results in neurotoxicity and neurodegeneration. The “amyloid cascade hypothesis” has been behind most of the research in AD for decades. Several drugs targeting A have reached late-phase c
21、linical trials but unfortunately with disappointing results. ? It is now accepted that AD may occur in three phases. There is an initial preclinical asymptomatic phase in which pathological changes are occurring without visible signs. This is followed by mild cognitive impairment (MCI) and eventuall
22、y increasing loss of function and dementia. ? The preclinical phase may last for decades and if it can be identified with the use of validated biomarkers offers the best opportunity for therapeutic intervention. Biomarkers in Alzheimers disease ? The term biomarker includes data sets acquired based
23、on imaging technology, cognitive assessments, and data from genomics, transcriptomics, proteomics, and metabonomics based on body fluids, including blood, CSF, saliva, and urine. 11 ? Differing definitions of biomarkers have been proposed, including diagnostic, prognostic, and pharmacological versio
24、ns. ? Alternative terms include trait, rate, and state biomarkers. Trait biomarkers identify those at risk; state biomarkers correlate with severity of disease; rate biomarkers require repeated measurement and can follow the rate of decline or improvement in disease progression. ? Surrogate biomarke
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