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This thesis comes within category D. □ This copy has been deposited in the Library of LA C t _ This copy has been deposited in the University of London Library, Senate □ House, Malet Street, London WC1E 7HU. •' * Clinical, pathological and biochemical diversity in progressive supranuclear palsy by David Williams Submitted to University College London For the degree of Doctor of Philosophy, Ph.D. 2006 Reta Lila Weston Institute of Neurological Studies University College London UMI Number: U592502 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U592502 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract This thesis examines the clinical, pathological and biochemical diversity of progressive supranuclear palsy (PSP). The material and patients used for these studies involved 23 clinically diagnosed living patients and 127 pathologically confirmed cases of PSP, archived at the Queen Square Brain Bank (QSBB). Differences between ‘classic’ PSP and ‘atypical’ PSP were identified, and a number of clinical features that separate them from other bradykinetic rigid syndromes were explored. • In addition to the clinical phenotype associated with PSP-tau pathology initially described by Richardson in 1963 (Richardson’s syndrome, RS) two other distinct clinical syndromes were identified: PSP-Parkinsonism (PSP-P) and pure akinesia with gait freezing (PAGF). • The following clinical features, in addition to the operational diagnostic criteria, were supportive of underlying PSP-tau pathology in patients presenting with Parkinsonism: an absence of drug induced dyskinesias, autonomic failure and visual hallucinations; the presence of falls within 6 years of disease onset; UPSIT scores above the 12th percentile for gender and age; and abnormalities in auditory startle response and auditory blink reflex. • PSP-tau pathology always involved the subthalamic nucleus (STN), globus pallidus (GP) and substantia nigra (SN), but involvement outside these structures was variable and could be sub-divided into at least three different patterns. • Severe tau pathology in PSP-P and PAGF was restricted to the GP, STN and SN. • Co-existent pathological diagnoses did not differ between RS, PSP-P and PAGF. • The ratio of pathological 4-repeat:3-repeat tau in PSP was variable. In RS the mean ratio was higher than in PSP-P (2.84 vs. 1.63 (p<0.003). • Mutations ofMAPT did not account for the diversity of clinical features The proposed clinical and pathological sub-classification of PSP will be helpful in clinical practice. Pathological and biochemical correlates raise the possibility that PSP-P 3 and PAGF may represent discrete nosological entities. Further research may ultimately lead to their absolute distinction from Richardson’s syndrome and related tauopathies. 4 Abstract 3 Tables 9 Figures 11 Abbreviations 13 Outline 14 1. Introduction 15 Progressive supranuclear palsy 16 What is PSP? 21 2. Tauopathies 26 Introduction 26 Molecular biology 27 Corticobasal degeneration 30 FTDP17 32 Parkinsonism dementia complex of Guam 32 Pick’s disease 34 Postencephalitic Parkinsonism 35 Alzheimer’s disease 36 Other tauopathies 37 3. Ambiguities in defining PSP 38 4. Hypothesis 41 5. Clinical heterogeneity in pathologically diagnosed PSP 44 6. Patterns of clinical presentation in pathologically diagnosed PSP 46 6.1. Analysis of clinical features in PSP 46 Aims 46 Materials and Methods 47 Results 49 Discussion 58 6.2. Post-hoc analysis of QSBB database - pure akinesia with gait freezing 62 Background 62 Aims 63 Patients and Methods 63 Results 64 Discussion 71 5 7. Pathological heterogeneity in pathologically diagnosed PSP 76 Introduction 76 Regional pathology in PSP 76 Regional analysis of tau isoform accumulation in PSP 79 Conclusion 80 8. Patterns of regional pathological involvement in PSP 81 Aims 82 Materials and Methods 82 Results 86 Discussion 96 Conclusion 102 9. Biochemical heterogeneity in PSP 104 Introduction 104 9.1. Comparison of methods for tau fractionation and dephosphorylation 108 Aims 108 Materials and methods 108 Results 110 Conclusion 111 9.2. Biochemical heterogeneity in PSP 112 Aims 112 Materials and methods 112 Results 113 Discussion 116 Conclusions 117 10. Genetics of progressive supranuclear palsy 118 Introduction 118 10.1. MAPT gene mutations in PSP 122 Aims 122 Methods 122 Results 123 Conclusions 123 10.2. Tau haplotype analysis in PSP 124 Aims 124 Methods 124 Results 124 Conclusions 125 6 103. Apolipoprotein E 126 Aims 126 Methods 126 Results 126 Conclusion 126 Overall conclusions 127 11. The diagnosis of PSP-P 128 11.1. Diagnostic experiments in clinically diagnosed patients 132 11.1.1. A visual hallucination inventory that differentiates PD from PSP 132 Background 132 Aims 132 Methods 133 Results 135 Discussion 138 11.1.2. Olfaction in PSP 141 Background 141 Aims 141 Methods 141 Results 142 Discussion 145 11.13. The auditory startle response in the diagnosis PSP 147 Background 147 Aims 148 Patients and methods 148 Results 150 Discussion 155 11.2. Retrospective studies in pathologically diagnosed patients 157 11.2.1. Clinical differences between RS, PSP-P & other Parkinsonism 157 Aims 157 Methods 157 Results 158 Conclusions 163 11.2.2. Falls in PSP 164 Background 164 Aims 164 Patients and methods 165 Results 166 Discussion 171 7 11.23. VH In pathologically diagnosed bradykinetic rigid syndromes 176 Aims 176 Patients and methods 176 Results 178 Discussion 181 Conclusions 184 12. Sample size calculations using clinical phenotypes 185 Introduction 185 Aims 185 Methods 185 Results 186 Discussion 188 13. Summary 190 Peer review publications related to this thesis 195 Acknowledgements 196 Appendix 197 Table of references 201 8 1.1 NINDS-SPSP clinical criteria for the diagnosis of PSP 2.1 Tauopathies 6.1 Clinical features in 103 pathologically confirmed cases of PSP 6.2 Cross tabulation of the number of characteristics from two sets 6.3 Early clinical features in cases with an incomplete data set 6.4 Patient profiles according to clinical group 6.5 Late clinical features in 89 cases separated into distinct groups 6.6 Diagnostic criteria for pure akinesia with gait freezing 6.7 Red flags for distinguishing PAGF from PD and VP 6.8 Demographics of patients with PAGF 6.9 Demographics of patients with PSP-P AGF vs. other diseases 8.1 Demographic details of patients included in pathology study 8.2 Additional pathological diagnoses 8.3 Demographics of cluster groups 10.1 ApoE genotype in PSP 10.2 ApoE allelic frequency in PSP 11.1 Visual hallucinations: Demographics in clinically diagnosed cases 11.2 Frequency of “yes” responses to QSVHI questions 11.3 QSVHI in PD and other bradykinetic rigid syndromes 11.4 Olfaction testing: Demographics of clinically diagnosed patients 11.5 Electrophysiology: Demographics in clinically diagnosed patients 11.6 EMG response according to clinical diagnosis 11.7 OO EMG responses according to clinical diagnosis 11.8 Scm EMG responses according to clinical diagnosis 11.9 Demographics of QSBB archives: PSP-P vs. non-PSP-P 11.10 Clinical features: PSP-P vs. PD 11.11 Clinical features: PSP-P vs. MSA 11.12 Clinical features: PSP-P vs. VP 11.13 Falls: Characteristics of patients according to pathological diagnosis 11.14 Clinical features in fallers and non-fallers 11.15 Factors affecting time to first fall in PSP, PSP and MSA 11.16 Disease duration in PSP fallers 11.17