Biomarkers for Alzheimer’s Disease Drug Development (Methods in Molecular Biology, 2785)

Preface
Contents
Contributors
Part I: Strategies to Improve Alzheimer´s Disease Biomarkers
	Chapter 1: Blood-Based Biomarkers for Early Alzheimer´s Disease Diagnosis in Real-World Settings
		1 A Global Dementia Pandemic
		2 A Paradigm Shift Toward Early Disease Detection
		3 Targeting the Early Diagnostic Window with Therapies
		4 The Benefits of Digital Cognitive Testing
		5 Complementary Digital and Fluid Biomarkers
		6 Defining Appropriate Reference Ranges for Blood Biomarkers
		7 Lessons from Familial Alzheimer´s Disease
		8 Performance of Blood Biomarkers Across the Alzheimer´s Continuum
		9 Outlook and Next Steps Required
		References
	Chapter 2: Alzheimer´s Disease Prevention and Treatment Based on Population-Based Approaches
		1 Introduction
			1.1 A Multicausal Model of Alzheimer´s Disease
		2 Epidemiological Approaches to Alzheimer´s Disease Research
			2.1 The Value of Established Global Infrastructures
		3 Gene-Environment Interaction Analyses
			3.1 Diet and Nutrition
			3.2 Physical Activity and Other Active Lifestyles
			3.3 Psychosocial Factors
			3.4 Cardiometabolic Factors
		4 Conclusions
		References
Part II: Innovative Fluid Biomarkers
	Chapter 3: CSF N-Glycomics Using High-Throughput UPLC-ESI Techniques in Alzheimer´s Disease
		1 Introduction
		2 Materials
			2.1 Rapid Deglycosylation of Proteins: GlycoWorks Deglycosylation Module
			2.2 Rapid Labeling of Glycosylamines
			2.3 HILIC SPE Clean-up of Labeled Glycosylamines
			2.4 HILIC-UPLC-ESI-MS Analysis for GlycoWorks RapiFluor-MS-Labeled N-Glycans
		3 Methods
			3.1 Rapid Deglycosylation of Proteins: GlycoWorks Deglycosylation Module
			3.2 Rapid Labeling of Glycosylamines
			3.3 HILIC SPE Clean-up of Labeled Glycosylamines
			3.4 HILIC-UPLC-ESI-MS Analysis for GlycoWorks RapiFluor-MS-Labeled N-Glycans
		4 Notes
		References
	Chapter 4: CSF N-Glycomics Using MALDI MS Techniques
		1 Introduction
		2 Materials
			2.1 Denaturation of Proteins by Reduction and Alkylation
			2.2 PNGase F Digestion
			2.3 C18 Sep-Pak Purification of the Released N-Glycans
			2.4 Solid Phase Extraction of the Released N-Glycans
			2.5 Glycan Permethylation
			2.6 MALDI MS Analysis of Permethylated Glycans
			2.7 MALDI TOF/TOF MS/MS Differential Analysis of Bisected/Triantennary Glycans
		3 Methods
			3.1 Denaturation of Proteins by Reduction and Alkylation
			3.2 PNGase F Digestion
			3.3 C18 Sep-Pak Purification of the Released N-Glycans
			3.4 Solid Phase Extraction of the Released N-Glycans
			3.5 Glycan Permethylation
			3.6 MALDI MS Analysis of Permethylated Glycans
			3.7 MALDI TOF/TOF MS/MS Differential Analysis of Bisected/Triantennary Glycans
			3.8 Assignments of Molecular Ions of Native and Permethylated Glycans
		4 Notes
		References
	Chapter 5: Optimized Pre-analytical Handling Protocol for Blood-Based Biomarkers of Alzheimer´s Disease
		1 Introduction
		2 Materials
		3 Methods
		4 Notes
		References
	Chapter 6: Mass Spectrometry-Based Metabolomics Multi-platform for Alzheimer´s Disease Research
		1 Introduction
		2 Materials
			2.1 Collection and Extraction of Biological Samples
			2.2 Sample Derivatization
			2.3 Metabolomics Analyses
		3 Methods
			3.1 Collection of Biological Samples
				3.1.1 Human Blood Samples
				3.1.2 Blood and Tissue Samples from APP x PS1 Transgenic  Mice
			3.2 Extraction of Biological Samples
				3.2.1 Extraction of Serum Samples
				3.2.2 Extraction of Tissue Samples
				3.2.3 Quality Control Samples
			3.3 Sample Derivatization
			3.4 Metabolomics Fingerprinting: Direct MS Analysis
				3.4.1 Analysis by Direct Infusion Electrospray Mass Spectrometry (DI-ESI-MS)
				3.4.2 Analysis by Flow Injection Atmospheric Pressure Photoionization Mass Spectrometry (FI-APPI-MS)
			3.5 Metabolomics Profiling: Hyphenated MS-Based Approaches
				3.5.1 Analysis by Ultrahigh-Performance Liquid Chromatography-Mass Spectrometry (UHPLC-MS)
				3.5.2 Analysis by Gas Chromatography-Mass Spectrometry (GC-MS)
		4 Notes
		References
Part III: Magnetic Resonance Imaging Methods
	Chapter 7: Analysis of Resting-State Functional Magnetic Resonance Imaging in Alzheimer´s Disease
		1 Introduction
		2 The Brain Connectivity in Resting State
		3 Image Preparation
			3.1 Image Processing: Preprocessing, Denoising, and Postprocessing
				3.1.1 Preprocessing
				3.1.2 Denoising
				3.1.3 Postprocessing and Statistical Analysis
		4 Analytic Approaches: Measures
			4.1 Intrinsic Connectivity Networks
			4.2 Node Connectivity
			4.3 Other Approaches to Analyze Functional Connectivity
		5 Current and Potential Implications
		6 Conclusion
		References
	Chapter 8: Diffusion Tensor Imaging in Alzheimer´s Studies
		1 Introduction
		2 Materials
		3 Methods
		4 Notes
		References
	Chapter 9: Magnetic Resonance Spectroscopy (MRS) in Alzheimer´s Disease
		1 Basics
		2 Signal Detection
		3 Methods
			3.1 Techniques of MRS Acquisition
				3.1.1 Localization
				3.1.2 Acquisition Methods
				3.1.3 Adiabatic Localization
			3.2 Post Processing
			3.3 Quantification
			3.4 Main Limitations
				3.4.1 Chemical Shift Displacement
				3.4.2 Metabolite Concentration and Macromolecules
			3.5 Advancements
				3.5.1 Higher Magnetic Fields
			3.6 Additional Spectroscopy Techniques
			3.7 New Processing Techniques
		4 Results
			4.1 Common Metabolites in MRS and Their Roles in Alzheimer´s Disease
				4.1.1 N-acetylaspartate (NAA)
					NAA and  AD
					NAA and MCI
					NAA and Other AD Pathology Biomarkers
				4.1.2 Myo-inositol (mI)
					mI Changes and  AD
				4.1.3 Choline (Chol)
				4.1.4 Glutamate + Glutamine (Glx)
			4.2 Novel MRS Metabolites and Their Roles in  AD
				4.2.1 GABA
				4.2.2 Glutathione
				4.2.3 Ascorbate
				4.2.4 Glucose
		References
	Chapter 10: Neuroimaging Methods for MRI Analysis in CSF Biomarkers Studies
		1 Introduction
		2 Materials
			2.1 Magnetic Resonance Imaging Modalities
				2.1.1 Three-Dimensional T1-Weighted (3dT1w) Images
				2.1.2 Blood Oxygenation Level-Dependent (BOLD) Contrast Imaging
				2.1.3 Diffusion Tensor Imaging (DTI)
			2.2 Fundamental Neuroimaging Processing Tools
				2.2.1 Segmentation
				2.2.2 Coregistration and Spatial Normalization
				2.2.3 Smoothing and Denoising
		3 Methods
			3.1 Region of Interest (ROI)-Based Volumetric Analysis
				3.1.1 ROI-Based Analysis Using an Atlas
				3.1.2 Alternatives
			3.2 Voxel-Based Morphology (VBM)
				3.2.1 Cross-Sectional VBM Processing Pipeline
				3.2.2 Longitudinal Studies Processing Pipeline
				3.2.3 Getting Statistical Mappings
				3.2.4 Alternatives
			3.3 Parametric Diffusion Tensor Imaging (DTI) Analysis
				3.3.1 Preprocessing and Generation of Parametric Maps from DTI Data
				3.3.2 Spatial Normalization Through Anatomical Images and Statistical Analyses
			3.4 Structural Connectivity
			3.5 Functional Connectivity (fMRI)
				3.5.1 Processing fMRI
				3.5.2 Processing of rs-fMRI
				3.5.3 Second-Order Statistics, Group Comparison
				3.5.4 Functional Connectivity
				3.5.5 Alternatives
			3.6 Conclusions
		4 Notes
		References
Part IV: Molecular Imaging Approaches
	Chapter 11: Amyloid PET Imaging: Standard Procedures and Semiquantification
		1 Introduction
		2 Materials
			2.1 Patients´ Preparation and Tracer Injection
			2.2 Scan Acquisition
			2.3 Early Perfusion Amyloid PET and Dual Point Dynamic Imaging
			2.4 Dynamic Acquisition
			2.5 Aβ Radiotracers
				2.5.1 11C-PiB
				2.5.2 18F-Florbetaben
				2.5.3 18F-Florbetapir
				2.5.4 18F-Flutemetamol
		3 Methods
			3.1 Visual/Qualitative Images Evaluation
			3.2 Semiquantitative Approaches
			3.3 Integration Between Amyloid PET Data and Other AD Biomarkers
		References
	Chapter 12: PET Imaging to Measure Neuroinflammation In Vivo
		1 Introduction
		2 TSPO PET Tracers
			2.1 TSPO PET in Alzheimer´s Disease
			2.2 TSPO PET in Preclinical Models of Alzheimer´s Disease
			2.3 TSPO PET in Non-Alzheimer´s Tauopathies
		3 Alternative Targets for Microglia Activation
		4 PET Imaging of Reactive Astrogliosis
		5 Conclusions
		References
	Chapter 13: Imaging Neuroinflammation: Quantification of Astrocytosis in a Multitracer PET Approach
		1 Introduction
			1.1 Current Status of PET Imaging Tracers for Astrocytosis
			1.2 PET Imaging of Astrocytosis Using 11C-Deuterium-L-Deprenyl
			1.3 Association of 11C-Deuterium-L-Deprenyl PET with Aβ, Tau, Glucose Metabolism, and Brain Structure: Review of Multitracer S...
			1.4 Relationship of 11C-Deuterium-L-Deprenyl PET with Plasma Glial Fibrillary Protein (GFAP)
			1.5 Summary
		2 Materials
			2.1 MRI Scanners
			2.2 PET Scanners
			2.3 Image Analysis Software
		3 Methods
			3.1 Participants
			3.2 MRI
			3.3 Radiotracer Synthesis and Preparation
			3.4 PET Image Acquisition
			3.5 PET Image Reconstruction
			3.6 Within-Subject Realignment and Summation of PET Images
			3.7 Within-Subject Co-Registration Procedures
			3.8 Subject-Specific Gray Matter Atlas for PET Image Quantification
			3.9 Model for Quantification of 11C-DED PET Image  Data
			3.10 Semiquantitative Method for 11C-PiB and 18F-FDG PET Image  Data
			3.11 Statistical Approaches for Comparison of PET Uptake Between Diagnostic Groups
			3.12 Region-of-Interest (ROI) Based Analyses
			3.13 Voxel-Wise Analyses
		4 Notes
		References
Part V: Neuropathology
	Chapter 14: High-Throughput Lipidomic and Metabolomic Profiling for Brain Tissue and Biofluid Samples in Neurodegenerative Dis...
		1 Introduction
		2 Materials
			2.1 Equipment
			2.2 Solvents and Chemicals
			2.3 Supplies
			2.4 Internal Standard Mixtures
		3 Methods
			3.1 Collection of Brain Tissue
			3.2 Collection of Biofluids: Plasma, Urine, and CSF
			3.3 Sample Preparation: Lipid and Metabolite Extraction from Brain Tissue
			3.4 Sample Preparation: Lipid and Metabolite Extraction from Biofluids
			3.5 Multiplexed Lipidomics Assay in Positive Ionization Mode
			3.6 Multiplexed Lipidomics Assay in Negative Ionization Mode
			3.7 Multiplexed Metabolomics Assay
			3.8 Multiplexed Glucosyl- and Galactosyl-Sphingolipids Assay
		4 Notes
		References
	Chapter 15: Neuropathological Assessment as an Endpoint in Clinical Trial Design
		1 Introduction
		2 Materials
		3 Methods
			3.1 Macroscopic Dissection (Fresh Tissue)
			3.2 Macroscopic Dissection (Fixed Tissue)
			3.3 Tissue Sampling and Preparation
			3.4 Histological Staining
			3.5 Immunocytochemistry
			3.6 Pathology Staging
		References
	16: Noninvasive Visualization of Amyloid-Beta Deposits in Alzheimer´s Amyloidosis Mice via Fluorescence Molecular Tomography U...
		1 Introduction
		2 Materials
			2.1 Animal Models
			2.2 Anesthesia
			2.3 Materials for Animal Preparation
			2.4 Aβ Targeting Fluorescent Contrast Agent (See Note 2)
			2.5 Fluorescent Molecular Tomography
		3 Methods
			3.1 Animal Preparation, Inhalational Anesthesia, and Physiological Monitoring
			3.2 Data Acquisition
			3.3 Data Analysis
		4 Notes
		References
	Chapter 17: Brain Banking in Dementia Studies
		1 Introduction
		2 Materials and Methods
			2.1 Clinical Assessment
			2.2 Radiological Assessment
			2.3 Neuropathological Evaluation
				2.3.1 During the Performance of the Autopsy
				2.3.2 In Practice
				2.3.3 A Basic Panel of Histochemical and Immunohistochemical Stains Are Utilized
		3 Discussion
		References
Part VI: Digital Biomarkers and In Silico Methods
	Chapter 18: Speech-Based Digital Biomarkers for Alzheimer´s Research
		1 Introduction
		2 Materials
			2.1 Components
			2.2 Environment
		3 Methods
			3.1 Selection of Speech Tasks
			3.2 Practical Implications for the Assessment
			3.3 Speech Analysis
		4 Notes
		References
	Chapter 19: cCOG Web-Based Cognitive Assessment Tool
		1 Introduction
		2 Materials
			2.1 Test Subjects
			2.2 Healthcare Specialists
		3 Methods
		4 Notes
		References
	Chapter 20: In Silico Models to Validate Novel Blood-Based Biomarkers
		1 Introduction
		2 Materials
			2.1 Computational Requirements
			2.2 Programs Used
			2.3 R Packages
			2.4 Cytoscape App
		3 Methods
			3.1 Experimental Design
			3.2 Genetic Landscape
			3.3 Blood-Based Biomarker Expression in the Brain
			3.4 Functional Enrichment Analysis
			3.5 Network Analysis
				3.5.1 Style
				3.5.2 Layout and Network Density
				3.5.3 Clustering into Biological Functions
			3.6 Final Remarks
		4 Notes
		References
Index