Preclinical PET as translational tool for imaging Alzheimer's disease: small-animal PET imaging of beta-amyloid plaques with [11 C] PiB, its multi-modal validation and application to the evaluation and ranking of new AD tracers
Gespeichert in:
| 1. Verfasser: | |
|---|---|
| Format: | Abschlussarbeit Buch |
| Sprache: | English |
| Veröffentlicht: |
2012
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| Schlagworte: | |
| Online-Zugang: | Volltext https://nbn-resolving.org/urn:nbn:de:bvb:91-diss-20120327-1098557-0-7 Inhaltsverzeichnis |
| Beschreibung: | XX, 188 S. Ill., graph. Darst. |
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| 100 | 1 | |a Manook, André |e Verfasser |4 aut | |
| 245 | 1 | 0 | |a Preclinical PET as translational tool for imaging Alzheimer's disease |b small-animal PET imaging of beta-amyloid plaques with [11 C] PiB, its multi-modal validation and application to the evaluation and ranking of new AD tracers |c André Manook |
| 264 | 1 | |c 2012 | |
| 300 | |a XX, 188 S. |b Ill., graph. Darst. | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 502 | |a München, Techn. Univ., Diss., 2012 | ||
| 546 | |a Mit einer Zssfassung in dt. Sprache | ||
| 655 | 7 | |0 (DE-588)4113937-9 |a Hochschulschrift |2 gnd-content | |
| 776 | 0 | 8 | |i Erscheint auch als |n Online-Ausgabe |o urn:nbn:de:bvb:91-diss-20120327-1098557-0-7 |
| 856 | 4 | 1 | |u http://mediatum.ub.tum.de/node?id=1098557 |x Verlag |z kostenfrei |3 Volltext |
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| 912 | |a ebook | ||
| 999 | |a oai:aleph.bib-bvb.de:BVB01-027159717 | ||
Datensatz im Suchindex
| _version_ | 1804151985788682240 |
|---|---|
| adam_text | BRIEF CONTENTS
DECLARATION IV
ABSTRACT V
ZUSAMMENFASSUNG VII
ACKNOWLEDGEMENTS XI
BRIEF CONTENTS XV
CONTENTS XVII
THESIS OUTLINE 1
PART I. INTRODUCTION 3
1. INTRODUCTION 5
2. ALZHEIMER S DISEASE 7
3. AMYLOID-BETA 13
4. BRAIN PET IMAGING OF AP IN SMALL ANIMALS 21
PART II.
RESULTS 33
5. INTRODUCTION 35
6. PET IMAGING OF AP WITH [
11
C]PIB IN MOUSE BRAIN 39
7. QUANTITATIVE MULTI-MODAL VALIDATION OF PIB PET IMAGING IN AD MICE 61
8. EVALUATION AND RANKING OF NEW AD TRACERS 79
PART III. DISCUSSION 85
9. INTRODUCTION 87
10. SMALL-ANIMAL PET 89
11.
RESEARCH MODEL 97
12. VALIDATION EXPERIMENTS 99
13. NOVEL
IMAGING MARKERS 105
14. CONCLUSION 107
PART IV. MATERIAL AND METHODS 115
15.
INTRODUCTION 117
16. ANIMALS 119
17. RADIOSYNTHESIS 121
18. ANESTHESIA 125
XV
HTTP://D-NB.INFO/1050275810
BRIEF CONTENTS
19. SUBSTANCE ADMINISTRATION 127
20. SMALL-ANIMAL PET 129
21. MOUSE BRAIN MRI 133
22. PET DATA ANALYSIS 135
23. BIODISTRIBUTION 139
24. TISSUE PROCESSING 141
25. AUTORADIOGRAPHY 145
26. NEUROHISTOLOGICAL STAINING 147
27. MICROSCOPY 149
28. HISTOLOGICAL QUANTIFICATION OF RELATIVE A|3 PLAQUE BURDEN AND PLAQUE
SIZE DISTRIBUTION 151
29. AP PROTEIN QUANTIFICATION WITH ELISA 153
30. COMBINED MULTI-MODAL EXPERIMENT 155
31. STATISTICAL ANALYSIS 157
APPENDIX 159
32. LIST OF FIGURES 161
33. LIST OF TABLES 163
34. LIST OF ABBREVIATIONS 165
35. LINKS AND URLS 169
36. LIST OF PUBLICATIONS WITHIN SCOPE OF THESIS 171
37. BIBLIOGRAPHY 175
XVI
CONTENTS
DECLARATION IV
ABSTRACT V
ZUSAMMENFASSUNG VII
ACKNOWLEDGEMENTS XI
BRIEF CONTENTS XV
CONTENTS XVII
THESIS OUTLINE 1
PART I. INTRODUCTION 3
1. INTRODUCTION 5
2. ALZHEIMER S DISEASE 7
2.1 DEFINITION 7
2.2 EPIDEMIOLOGY AND ECONOMIC BURDEN 7
2.3 DIAGNOSIS 8
2.4 BIOMARKERS 9
2.5 THERAPEUTIC OPTIONS 10
2.6 DISEASE CONCEPTS 11
3. AMYLOID-BETA 13
3.1 AP PROTEIN * DISCOVERY, ORIGIN AND STRUCTURE 13
3.2 AMYLOID HYPOTHESIS 15
3.3 IMAGING TARGET FOR PET 17
4. BRAIN PET IMAGING OF AP IN SMALL ANIMALS 21
4.1 TRANSGENIC RESEARCH MODELS OF AMYLOIDOSIS 21
4.2 SMALL-ANIMAL PET SCANNERS 23
4.3 AP TRACERS IN THE PRECLINIC 24
4.4 PET STUDIES IN MOUSE MODELS OF AD 27
4.5 TRACER DEVELOPMENT PROGRAM AT TUM 30
4.5.1 [
11
C]IMIDAZO[2,1
-B]BENZOTHIAZOLE (IBT) - A NOVEL AMYLOID TRACER 30
4.5.2 _[
124
L]BRLMPY - A NOVEL 6-IODO-2-PHENYL-IMIDAZO[1,2-A]PYRIDINE (IMPY) 31
PART II. RESULTS 33
5. INTRODUCTION 35
5.1 SCOPE AND OBJECTIVES 35
5.2 DESCRIPTION OF PROJECTS 36
6. PET IMAGING OF AP WITH [
11
C]PIB IN MOUSE BRAIN 39
6.1 PREREQUISITES AND FOUNDATIONS 39
XVII
CONTENTS
6.1.1 PET AND MRI SCANNING 39
6.1.2 IMAGE CO-REGISTRATION OF PET TO MRI 40
6.1.2.1 SEMI-AUTOMATED MANUAL OVERLAY OF EARLY PET 40
6.1.2.2 SEQUENTIAL DUAL-TRACER PET WITH [
18
F]FDG 41
6.2 MEASURING SMALL-ANIMAL [
R,
C]PIB PET IMAGES 43
6.2.1 DEFINITION OF REGIONS 43
6.2.2 PET WITH MRI IN STUDY GROUPS 45
6.2.3 CHARACTERIZATION OF ARTE10 CEREBELLUM AS REFERENCE REGION 48
6.2.4 CALCULATING BINDING POTENTIALS AND PARAMETRIC IMAGES OF MOUSE
BRAIN 49
6.2.5 PET TEST-RETEST SCANS 52
6.3 SPECIFICITY AND LOCALITY OF [
11
C]PIB BINDING 53
6.3.1 SPECIFIC PIB BINDING IN THE MOUSE CNS 53
6.3.2 EXTRACEREBRAL TRACER RETENTION IN FRONTAL PROXIMITY TO BRAIN 56
7. QUANTITATIVE MULTI-MODAL VALIDATION OF PIB PET IMAGING IN AD MICE 61
7.1 STUDY DESIGN 61
7.2 CROSS-VALIDATION OF PET IN STUDY GROUPS 62
7.2.1 QUANTIFICATION OF [
N
C]PIB BINDING IN PET 63
7.2.1.1 GROUP BEHAVIOUR OF TIME-ACTIVITY CURVES 64
7.2.1.2 ANALYZING PET WITH DIFFERENT METHODS 64
7.2.2 REGIONAL BRAIN BIODISTRIBUTION OF [ CJPIB EX VIVO 65
7.2.3 AUTORADIOGRAPHY WITH [
3
H]PIB EX VIVO 67
7.2.4 HISTOLOGICAL PLAQUE QUANTIFICATION IN NEOCORTEX OF TRANSGENIC MICE
68
7.2.4.1 THIOFLAVIN S AND A|340/42 ANTIBODIES FOR PLAQUE QUANTIFICATION
68
7.2.4.2 RELATIVE AP PLAQUE AREA AND PLAQUE SIZE DISTRIBUTION 70
7.2.5 AP40 AND A|342 PROTEIN LEVELS (ELISA) 72
7.2.6 OVERVIEW OF CROSS-VALIDATION RESULTS 73
7.3 COMBINED MULTI-MODAL DUAL-LABEL EXPERIMENT 75
8. EVALUATION AND RANKING OF NEW AD TRACERS 79
8.1 COMBINED MULTI-MODAL EXPERIMENT WITH [ CJIBT AND [
3
H]PIB 79
8.2 MULTI-MODAL EX VIVO EXPERIMENT WITH [
124
L]BRLMPY 82
PART III. DISCUSSION 85
9. INTRODUCTION 87
10. SMALL-ANIMAL PET 89
10.1 OVERVIEW OF PET RESULTS 89
10.2 CO-REGISTRATION AND UNSPECIFIC BINDING 90
10.3 PREVIOUS PET STUDIES 91
10.4 QUANTIFICATION OF TRACER BINDING 93
10.4.1 STANDARDIZED UPTAKE VALUES AND SIMILAR MEASURES 93
10.4.2 REFERENCE TISSUE APPROACHES 93
11. RESEARCH MODEL 97
XVIII
CONTENTS
12. VALIDATION EXPERIMENTS 99
12.1 HISTOLOGICAL QUANTIFICATION 99
12.2 ELISA 101
12.3 DUAL-LABEL DIGITAL AUTORADIOGRAPHY 102
12.4 SPECIFICITY OF PET TRACER BINDING 103
13. NOVEL
IMAGING MARKERS 105
13.1 [
11
C]IBT 105
13.2 BRIMPY 106
14. CONCLUSION 107
14.1 SUMMARY 107
14.2 CONTRIBUTION 107
14.3 TRANSLATIONAL VALUE 109
PART IV. MATERIAL AND
METHODS 115
15.
INTRODUCTION 117
16. ANIMALS 119
17.
RADIOSYNTHESIS 121
17.1 GENERAL PROCEDURES FOR RADIOSYNTHESIS 121
17.2 GENERAL PROCEDURE FOR /V-^C-METHYLATION OF PRIMARY AND SECONDARY
AMINES 121
17.3 ADAPTATIONS FOR SUBSTANCE ADMINISTRATION IN MICE 122
17.3.1 ALCOHOL CONTENT 122
17.3.2 SPECIFIC ACTIVITY OF THE APPLIED TRACER 122
17.4 RADIOLIGANDS 122
17.4.1 / /-[
11
C-METHYL]-6-OH-BENZOTHIAZOLE ([
11
C]PIB) 122
17.4.2 2-(P-[
11
C]METHYLAMINOPHENYL)-7-METHOXYIMIDAZO[2,1 -B]BENZOTHIAZOLE
([
11
C]IBT) 122
17.4.3 2-(4 -BROMOPHENYL)-6-IODOIMIDAZO[1,2-A]PYRIDINE (F
24
1]BRIMPY) 123
18. ANESTHESIA 125
19. SUBSTANCE ADMINISTRATION 127
20. SMALL-ANIMAL PET 129
20.1 GENERAL PET SCANNING PROCEDURE 129
20.2 SEQUENTIAL DUAL-TRACER PET SCANS WITH [ CJPIB AND [
18
F]FDG 131
20.3 CNS REMOVAL DURING PET 131
21. MOUSE
BRAIN MRI 133
22. PET DATA
ANALYSIS 135
22.1 GENERAL IMAGE DATA PREPROCESSING 135
22.2 IMAGE CO-REGISTRATION AND QUALITY CONTROL 135
22.3 VOLUME-OF-INTEREST (VOI) DEFINITION 136
22.4 QUANTIFICATION OF DYNAMIC [
N
C]PIB PET DATA 137
23. BIODISTRIBUTION 139
XIX
CONTENTS
23.1 REGIONAL BRAIN BIODISTRIBUTION 139
23.2 CRANIAL BIODISTRIBUTION OF [
11
C]PIB 139
24. TISSUE PROCESSING 141
24.1 GENE EXPRESSION ANALYSIS (QUANTITATIVE RT-PCR) 141
24.2 MOUSE BRAIN FOR HISTOLOGY AND AUTORADIOGRAPHY 142
24.3 MOUSE BRAIN TISSUE FOR QUANTITATION OF AP PROTEIN LEVELS 142
24.4 MOUSE CRANIUM FOR PH]PIB EX VIVO AUTORADIOGRAPHY 142
25. AUTORADIOGRAPHY 145
25.1 DIGITAL AUTORADIOGRAPHY 145
25.2 TRITIUM PLATE AUTORADIOGRAPHY 146
25.3 QUANTIFICATION OF TRACER RETENTION ON AUTORADIOGRAPHS 146
26. NEUROHISTOLOGICAL STAINING 147
26.1 THIONIN FAST NUCLEAR STAIN (NISSL) 147
26.2 THIOFLAVIN S STAINING 147
26.3 AFJ40 AND AP42 IMMUNOHISTOCHEMISTRY 147
27. MICROSCOPY 149
28. HISTOLOGICAL QUANTIFICATION OF RELATIVE AP PLAQUE BURDEN AND PLAQUE
SIZE DISTRIBUTION 151
29. AP PROTEIN QUANTIFICATION WITH ELISA 153
30. COMBINED MULTI-MODAL EXPERIMENT 155
31. STATISTICAL ANALYSIS 157
APPENDIX 159
32. LIST OF FIGURES 161
33. LIST OF TABLES 163
34. LIST OF ABBREVIATIONS 165
35. LINKS AND URLS 169
36. LIST OF PUBLICATIONS WITHIN SCOPE OF THESIS 171
36.1 INTERNATIONAL PEER-REVIEWED JOURNALS 171
36.2 INTERNATIONAL CONFERENCES 172
36.3 NATIONAL CONFERENCES 173
36.4 OTHER PUBLICATIONS 173
37. BIBLIOGRAPHY 175
XX
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| spelling | Manook, André Verfasser aut Preclinical PET as translational tool for imaging Alzheimer's disease small-animal PET imaging of beta-amyloid plaques with [11 C] PiB, its multi-modal validation and application to the evaluation and ranking of new AD tracers André Manook 2012 XX, 188 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier München, Techn. Univ., Diss., 2012 Mit einer Zssfassung in dt. Sprache (DE-588)4113937-9 Hochschulschrift gnd-content Erscheint auch als Online-Ausgabe urn:nbn:de:bvb:91-diss-20120327-1098557-0-7 http://mediatum.ub.tum.de/node?id=1098557 Verlag kostenfrei Volltext https://nbn-resolving.org/urn:nbn:de:bvb:91-diss-20120327-1098557-0-7 Resolving-System DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027159717&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Manook, André Preclinical PET as translational tool for imaging Alzheimer's disease small-animal PET imaging of beta-amyloid plaques with [11 C] PiB, its multi-modal validation and application to the evaluation and ranking of new AD tracers |
| subject_GND | (DE-588)4113937-9 |
| title | Preclinical PET as translational tool for imaging Alzheimer's disease small-animal PET imaging of beta-amyloid plaques with [11 C] PiB, its multi-modal validation and application to the evaluation and ranking of new AD tracers |
| title_auth | Preclinical PET as translational tool for imaging Alzheimer's disease small-animal PET imaging of beta-amyloid plaques with [11 C] PiB, its multi-modal validation and application to the evaluation and ranking of new AD tracers |
| title_exact_search | Preclinical PET as translational tool for imaging Alzheimer's disease small-animal PET imaging of beta-amyloid plaques with [11 C] PiB, its multi-modal validation and application to the evaluation and ranking of new AD tracers |
| title_full | Preclinical PET as translational tool for imaging Alzheimer's disease small-animal PET imaging of beta-amyloid plaques with [11 C] PiB, its multi-modal validation and application to the evaluation and ranking of new AD tracers André Manook |
| title_fullStr | Preclinical PET as translational tool for imaging Alzheimer's disease small-animal PET imaging of beta-amyloid plaques with [11 C] PiB, its multi-modal validation and application to the evaluation and ranking of new AD tracers André Manook |
| title_full_unstemmed | Preclinical PET as translational tool for imaging Alzheimer's disease small-animal PET imaging of beta-amyloid plaques with [11 C] PiB, its multi-modal validation and application to the evaluation and ranking of new AD tracers André Manook |
| title_short | Preclinical PET as translational tool for imaging Alzheimer's disease |
| title_sort | preclinical pet as translational tool for imaging alzheimer s disease small animal pet imaging of beta amyloid plaques with 11 c pib its multi modal validation and application to the evaluation and ranking of new ad tracers |
| title_sub | small-animal PET imaging of beta-amyloid plaques with [11 C] PiB, its multi-modal validation and application to the evaluation and ranking of new AD tracers |
| topic_facet | Hochschulschrift |
| url | http://mediatum.ub.tum.de/node?id=1098557 https://nbn-resolving.org/urn:nbn:de:bvb:91-diss-20120327-1098557-0-7 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027159717&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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