Approaches to disease progression modelling for identifying predictors of future cognitive decline in dementia

Dementia progression is characterised by a lengthy pre-symptomatic phase, where pathology may be accumulating, followed by a more rapid decline evidenced by onset of clinical symptoms and eventually functional impairment. The rate of decline in symptoms from cognitive impairment to dementia greatly varies between individuals, complicating prognosis and the assessment of much needed disease-modifying drugs. As a result there is a huge demand for greater understanding of the between-subject variability in progression and a need to understand biomarkers and risk factors for predicting future cognitive decline. In cohorts derived from two of the largest NHS foundation trust mental health service providers in the UK and multiple Alzheimer’s cohorts, this thesis explores methods for modelling disease progression and investigates the relationship between blood based proteins, genetic variants, health indicators and potential repurposing medications with cognitive decline. Through applying approaches that tackle three areas that require consideration for modelling of cognitive decline and disease progression, this thesis identified associations of antidepressant medication and psychotic symptoms associated with faster cognitive decline in dementia, in two separate cohorts. Acknowledgements I would like to thank my supervisors Professor Richard Dobson, Dr Stephen Newhouse and Dr Mizanir Khondoker for all of the support, opportunities and advice given throughout my PhD. I would like to thank Dr Steven Kiddle for the opportunity to collaborate and exchange ideas. I gratefully acknowledge the financial support received from Janssen Pharmaceuticals studentship. I would like to thank my family for their endless love and support. To my brother for always looking out for me, my grandparents for the wisdom, my mother for showing me true determination and to my father for providing the wine. Finally, I would like to thank Edward for your infinite patience, love and encouragement. Statement of Authorship All work in this thesis have been conducted by Elizabeth Baker. This included the design and collection of the two health record based retrospective cohorts (Chapters 5 to 7) and pre-processing, statistical analysis and interpretation of all thesis chapters. A few exceptions include: • the pre-processing of the LC-MS/MS proteomics samples within Chapter 3 which was conducted by Nicholas Ashton. • The processing of genetic data and calculation of polygenic risk scores for Chapter 4 was carried out by Hamel Patel. • The published paper in Chapter 5 was circulated for co-author review and subject to peer review prior to publication. • The idea to apply methodology in Chapter 6 to electronic health records came about through a collaboration between Elizabeth Baker, Dr Steven Kiddle and Professor Richard Dobson. • In Chapter 7 the extraction of the EHR cohort from Camden and Islington CRIS was implemented by Kenneth Lui. This thesis was written by Elizabeth Baker and supervised by Professor Richard Dobson, Dr Stephen Newhouse and Dr Mizanur Khondoker. Elizabeth Baker received a studentship from Janssen Pharmaceuticals to complete this work. Elizabeth Baker February 2018 Abbreviations Abbreviation Description χ2 chi-squared statistic A4 Anti-Amyloid treatment in Asymptomatic Alzheimer’s Disease trial Aβ Amyloid-β protein ABCA6 ATP binding cascade subfamily A member 6 transporter gene AD Alzheimer’s disease ADAS-cog Alzheimer’s disease Assessment Scale cognitive sub-scale ADL Activities of Daily Living ADNI Alzheimer’s disease Neuroimaging Initiative AChE Achetylcholinesterase inhibitors AIBL Australian Imaging, Biomarker and Lifestyle Study of Ageing AIC Akaike Information Criterion ANM AddNeuroMed cohort study ANOVA Analysis of Variance Analysis APOE ε4 Apolipoprotein E ε4 variant APP Amyloid-β Precursor Protein ARI Adjusted Rand Index AUC Area Under the Curve BDNF Brain Derived Neurotropic Factor BIC Bayesian Information Criterion BIN1 Bridging integrator 1 BLRT Bootstrap Likelihood Ratio Test BRC Biomedical Research Centre CD2AP CD2-associated protein CD33 Sialic acid-binding immunoglobulin-like lectin CDR Clinical Dementia Rating scale C&I Camden and Islington NHS Foundation Trust CI Confidence Interval CLU Clusterin CPRD Clinical Practice Research Database CR1 Complement Receptor 1 gene CRIS Clinical Record Interactive Search System CSF Cerebrospinal fluid CTAP111 Connective tissue-activating peptide III DCR Dementia Case Register df degrees of freedom DIAN Dominantly Inherited Alzheimer’s Disease Network EHR Electronic health records EIC Entropy Information Criterion EMIF European Medical Information Framework EPHA1 Ephrin type-A receptor 1 precursor gene FDG Fluorodeoxyglucose FDR False Discovery Rate FTD Frontotemporal dementia FUS Tumour associated protein fused in sarcoma GATE General Architecture for Text Engineering GenADA Genetics AD Association GMM Growth Mixture Model GWAS Genome-wide association study HES Hospital Episode Statistics HoNOS Health of the Nation outcome scales IWG-2 International Working Group-2 IALSA Integrative Analysis of Longitudinal Studies of Aging and Dementia ICAM Intracellular adhesion molecule ICD-10 International Classification of Disease 10 IL Interleukin IMI Innovative Medicines Initiative IQR Inter-quartile range KCL King’s College London KHP King’s Health partners kNN k-nearest neighbour K-W Kruskal-Wallis test LBD Lewy body dementia LCGA Latent Class Growth Analysis LC-MS/MS Liquid Chromatography tandem Mass spectrometry LD Linkage-Disequilibrium LMR-LRT Lo-Mendal-Rubin Likelihood Ratio Test lqmm Linear quantile mixed model LR Likelihood ratio MAPT Microtubule associated protein Tau MCI Mild Cognitive Impairment MHOA Mental Health for Older Adults services MMSE Mini-Mental State Examination MRI Magnetic Resonance Imaging MS4A4E Membrane-spanning 4 domains A4E MS4A6A Membrane-spanning 4 domains A6A NAP-2 Neutrophil-activating peptide-2 NCAM Neural cell adhesion molecule NHS National Health Service NIA-AA National Institute of Aging and Alzheimer’s Association NICE National Institute for Clinical Excellence NSAIDs Non-steroidal anti-inflammatory drugs ONS Office for National Statistics OR Odds Ratio p-tau181p Tau phosphorylated at threnonine PAQUID Personnes Agees QUID cohort study PBP Platelet Binding Protein PET Positron Emission Tomography PiB Pittsburgh Compound B PiB-SUVR 11C-Pittsburgh Compound B solute volume uptake ratio PICALM Phosphatidylinositol Binding Clathrin Assembly Protein gene PJS Patient Journey System PRS Polygenic risk score PSEN1 Presilin 1 PSEN2 Presilin 2 RFU Relative Fluorescent Unit RRR Relative Risk Ratio SD Standard Deviation SE Standard Error SLAM South London and the Maudsley NHS Foundation Trust SNPs Single Nucleotide Polymorphism SOMAmer Slow Off-rate Modified Aptamer SOMAscan Slow Off-rate Modified Aptamer – based capture array SPON1 Spondin 1 gene SQL Structured Query Language sRAGE soluble receptor for advanced glycation end products SUVR Solute uptake volume ratio SVM Support Vector Machine t-tau total tau TDP transactive response DNA-binding protein TMT Tandem Mass Tag TOMM Translocator of outer mitochondrial membrane complex gene TREM2 Triggering receptor expressed on myeloid cells 2 gene VD Vascular dementia WHP World Health Organisation Table of contents Dedication 2 Abstract 3 Acknowledgements 4 Statement of Authorship 5 Abbreviations 6 Table of contents 9 List of figures 16 List of tables 17