Sporadic cerebral amyloid angiopathy is a common small vessel disease that preferentially involves small cortical and leptomeningeal arteries due to progressive amyloid-β deposition in their walls. Cerebral amyloid angiopathy occurs frequently in elderly people, and is a common and important cause of symptomatic lobar intracerebral haemorrhage and cognitive impairment. There is currently a growing interest in cerebral amyloid angiopathy, at least partly thanks neuroimaging, which now allows an unprecedented ability to investigate the disease dynamics in vivo using MRI to reveal complex patterns of cerebral bleeding and ischaemia. The detection of CAA during life is becoming an increasingly important challenge, since approaches of prevention or treatment (disease-modification) are now emerging as realistic possibilities. Determining the most promising treatments requires development of reliable biomarkers, the goal of my research. The main objective of this PhD thesis is to provide new insights into potential clinical and applied clinical neuroimaging biomarkers in patients with cerebral amyloid angiopathy. This is accomplished by a portfolio of research studies investigating: (a) the clinical and radiological spectrum of transient focal neurological episodes as a potential clinical clue for cerebral amyloid angiopathy; (b) cortical superficial siderosis, a distinct pattern on bleeding in the brain, as both a diagnostic and a prognostic marker of cerebral amyloid angiopathy; (c) MRI-visible perivascular spaces topography, as a new marker of small vessel disease and cerebral amyloid angiopathy; (d) potential pathological, neuroimaging and genetic differences in patients with pathology-proven CAA with and without intracerebral haemorrhage and presents evidence for different disease phenotypes; (e) the evidence whether the presence and burden of cerebral microbleeds on MRI scans is associated with an increased risk of recurrent spontaneous ICH, and if this risk is different according to MRI-defined microangiopathy subtype, in a meta-analysis.

This thesis will examine monogenetic forms of primary dystonia related to TOR1A, THAP1 and GCH1 genes with a focus on genetic and neuropathological investigation. Further, this thesis discusses the neuropathology of genetic disorders under the neurodegeneration with brain iron accumulation (NB IA) spectrum , B eta - propeller protein associated neurodegeneration (B PAN ) and neuroacanthocytosis. The genetics of spinocerebellar ataxia 8 will be discussed. This thesis also discusses the possibility of a common pathology for the lysosomal storage disorders (LSDs) impinging on ceram ide pathway.

A dominant view in current memory research is that there are distinct implicit (unconscious) and explicit (conscious) memory systems. The present thesis proposes an alternative, single-system signal-detection model of priming (a traditional implicit memory phenomenon) and recognition (a traditional explicit memory phenomenon). The model has two core assumptions: 1) priming and recognition are driven by the same memory strength signal, and 2) this signal is subjected to independent sources of random noise for priming and recognition tasks (the variance of which is typically greater for priming tasks). The model is shown to account for numerous results: 1) the sensitivity of priming tasks does not typically exceed that of recognition tasks, and priming therefore does not occur when recognition is at chance (Experiments 1-8) 2) the magnitude of the effect produced by manipulations of attention at encoding is greater on recognition than priming (Experiments 5-8), and this can give rise to single dissociations (Appendix 1) 3) priming and recognition can be very weakly correlated, even though they are driven by the same memory signal 4) priming can occur for items that are not recognised (Experiment 9 Simulation Study 2) 5) the relationship between the identification latencies to misses and false alarms can change as a function of overall memory strength (Simulation Study 3) 6) priming and fluency are relatively intact in amnesics, despite severe impairments in recognition (Simulation Study 4). Thus, contrary to previous interpretation, (2)-(6) are not inconsistent with a single-system view (1) suggests that the contents of the memory driving priming are accessible to consciousness. Finally, the predictions of the model were tested in a novel paradigm, the CID-2AFC task (Experiments 10-12 Simulation Study 5). Limitations of the model (and a dual-system version) were revealed, suggesting directions for future research.

Genome-wide association study (GWAS) is an effective method for mapping genetic variants underlying common and complex diseases. This thesis describes the investigation of the disorders, frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). FTD affects the frontal/temporal lobes and presents behavioural changes (bvFTD), cognitive decline or language dysfunction (primary progressive aphasia [PPA]), whilst PSP affects predominantly the brain stem resulting in loss of balance, falls, and parkinsonian signatures. Beside recent advancements in the understanding of the clinical and neuropathological characteristics as well as the genetics associated with these diseases, their underlying pathogenic mechanisms are still unclear. The main aims of the work in this thesis were to perform a complete GWAS on clinical FTD and a follow up targeted study of new loci identified in the recent PSP-GWAS in a cohort of ~100 pathologically confirmed PSP cases. By completing these projects the main expected outcomes were to: 1 – Identify novel risk loci associated with FTD, and; 2 – Identify SNPs and haplotypes associated with increased risk of developing PSP and genetic variants possibly affecting expression and/or splicing of transcription elements relevant to PSP.

Background: In vestibular schwannoma (VS) important clinical questions such as whether balance symptom severity and loss of mobility affect quality of life, or whether surgery worsens balance function remain inadequately answered. The relationship between an objective balance deficit and subjective balance dysfunction is unclear. Factors affecting vestibular compensation like anxiety and stress have yet to be clearly defined as relevant in symptom exacerbation. Studies are often hampered by the limitations of retrospective series, poor controls and the inadequate use of validated standardised assessment tools. In this study standardised validated tools were used to prospectively measure subjective, objective and functional balance outcomes in VS. Aims: To investigate balance dysfunction and the factors responsible for poor compensation in the VS population using validated assessment tools. Methods: Patients were recruited from the National Hospital for Neurology and Neurosurgery and Guy’s Hospital. Balance was assessed using an objective vestibular test battery and questionnaires. Psychological symptoms were assessed using questionnaires and the stress response was measured in relation to vestibular testing. Results: Balance symptom severity, ambulant posture, and anxiety were significant contributors to balance related handicap. While symptoms were not as severe as in other neuro-otological cohorts they were nonetheless worse than in healthy controls. There was little correlation between the presence of an objective balance deficit and the severity of balance dysfunction. Anxiety and stress may be important factors in vestibular compensation. Surgery was not found to be a significant predictor of balance related outcomes. Conclusions: This study has identified and measured factors that contribute to balance dysfunction in VS patients using validated standardised tools and provides information that could inform vestibular rehabilitation strategies. Attention is drawn to the relative roles of the severity of balance symptoms, objective vestibular deficits, dysfunction of posture and mobility, and anxiety and stress in balance related handicap.

Emerging evidence suggests that p53, a tumour suppressor protein thought to be primarily involved in cancer biology, also coordinates a diverse variety of novel functions in the CNS including mediating pathways underlying neurodegenerative disease pathogenesis. Moreover, an evolving concept in cell and molecular neuroscience is that glial cells may be far more fundamental to disease progression than previously thought, which may occur via a non-cell-autonomous mechanism that is also heavily dependent on p53 activities. As a crucial hub connecting many intracellular control pathways, including cell-cycle control and apoptosis, p53 is ideally placed to coordinate the cellular response to a range of stresses. The data reported in this thesis demonstrates crucial roles for p53 in mediating microglial activation. This behavior occurs via a transcription-dependent mechanism, with the subsequent inhibition of microglial p53 leading to reductions in neuronal cell death. Furthermore, the loss of synapses represents a key early feature in numerous neurological disorders, with mounting evidence implicating microglia as causal agents in this process, via a phenomenon known as synaptic stripping. We reveal evidence suggesting that microglial p53 is detrimental to synaptic properties, prior to any visible signs of neuronal cell death, and that such behaviour correlates with changes in neuronal exocytosis, microglial cytokine production, and phosphorylated p53 activity in microglia. Although neurodegenerative diseases each display a distinct and diverse molecular pathology, the multimodal capacity of the p53 system to orchestrate apoptosis and microglial cell behaviour highlights this protein as a potential unifying target for therapeutic intervention.

Understanding the functional architecture of the brain has long been a challenge in neuroscience with a variety of techniques having been developed to explore this structure-function relationship. However, in order to be able to accurately identify the underlying system we require techniques that have the capabilities of describing the complexities therein. In order to perform lesion-function studies a cohort of brain scans with the location of the lesion identified must be collected. Utilising diffusion weighted magnetic resonance imaging, normally collected in the clinical setting, I propose a new unsupervised lesion segmentation routine. The cohort of brain scans also need to be spatially normalised such that homologous regions of the brain are brought into register with each other. However, this process can be perturbed by the presence of a lesion within the scan. Though a series of simulations I evaluate the performance of 12 different spatial normalisation routines on brains scans that possess a lesion. Historically lesion-function mapping studies have tended to use a univariate statistical approach, where different locations within the brain are treated as being spatially independent from each other. Here I show that biases within the structure of the data have the potential to distort the lesion-function inferences we draw. Though a series of simulations, I show that a mass univariate technique is vulnerable to these biases and assess three different multivariate methods (Support Vector Machines, Relevance Vector Machines and Flexible Bayesian Modelling) as potential solutions to this problem. Asides from making lesion-function inferences, these multivariate models can be used to predict future events. Using a data set of paired admission diffusion weighted magnetic resonance imaging scans and functional outcome scores I apply these techniques to the clinical scenario of predicting the functional outcome of patients after a cerebral vascular event.

The skeletal muscle channelopathies are a group of inherited disorders due to the dysfunction of voltage gated channels in the sarcolemma resulting in abnormal membrane excitability. Simplistically they are broadly divided into those that result froman “over excited” membrane (the non-dystrophic myotonias) and those due to an inexcitable one (the periodic paralyses). Skeletal muscle channelopathies were describedclinically long before they were genotyped or hypotheses regarding pathogenesis fullyevolved. This thesis explores all three, the phenotype, the genotype and recent insightsinto the pathogenesis. Detailed clinical and neurophysiologic examination of a large group of patients identifiednew aspects of the phenotype including neonatal presentations with importantimplications for early life care. Morphological findings are also expanded with thepresence of inflammatory infiltrates, not previously described in the channelopathies. Extensive DNA sequencing of causative genes was undertaken in a carefully genotypedcohort. In hypokalaemic periodic paralysis an exclusive relationship between mutationsand the channel voltage sensor emerged which relates closely to recentelectrophysiological evidence of a “gating pore” disease mechanism. A small butsignificant minority of cases remain however where no mutation is found. The implication of other potential genetic mechanisms or even undescribed genes in thesecases is discussed. Current drug therapies are also examined in three separate cohorts and evidence suggests acetazolamide, a commonly prescribed treatment, may only be effective in 50-60% of those with hypokalaemic periodic paralysis. A tentative relationship between efficacy and genotype also emerges. Patch clamp studies show significant loss of function of the main alpha pore of the sodium channel in periodic paralysis but the implications of this in light of the “gating pore” hypothesis are discussed. Tentative explorations are made as to the viability of performing future studies in myoctes as opposed to the traditional HEK cell model with early experiments illustrating limitations.

Inherited neuropathies are a clinically and genetically heterogeneous group of diseases affecting the peripheral nervous system (PNS). More than 70 causative genes have been recognised, however, there are still patients whose disease-causing genes have not been identified, particularly those presenting with complex phenotypes which also involve the central nervous system (CNS) and other organs. The main objective of my PhD was to establish the genetic diagnosis in these patients through an integrated approach combining conventional Sanger sequencing and the next generation sequencing (NGS) technologies which include whole exome sequencing (WES) and targeted resequencing. Based on this integrated approach, mutations in several genes for inherited neuropathies and related disorders have been identified. My thesis focuses on: (1) screening studies in large cohorts of patients conducted by Sanger sequencing to define the frequency of the mutations in the NEFL gene in Charcot-Marie-Tooth disease (CMT), in the SPTLC2 gene in hereditary sensory neuropathy type I and in the PDYN gene in autosomal dominant cerebellar ataxia (ADCA) in British population; (2) WES studies to identify mutations in patients with inherited neuropathies or autosomal recessive cerebellar ataxia (ARCA), including a novel ADCK3 mutation in ARCA and two novel genes causing CMT, MARS and C12orf65; (3) the development of two targeted resequencing panels for CMT and hereditary spastic paraplegia (HSP) with axonal neuropathy to identify disease-causing mutations in two cohorts; (4) the broadening of the phenotypic spectrum of KIF5A in patients with HSP and CMT type 2. In this thesis functional studies for some of the identified mutations were also performed such as the impairment of the mitochondrial respiratory enzymes in the lymphoblasts of patients with the C12orf65 mutation and in fibroblasts of patients with the ADCK3 mutation. The challenges faced by the use of NGS in genetic diagnosis and how to address these challenges in the future are discussed.

Epilepsy is a common disorder with significant associated morbidity and mortality. Despite advances in treatment, there remain a minority of people with pharmacoresistant focal epilepsy for whom surgery may be beneficial. It has been suggested that not enough people are offered surgical treatment, partly owing to the fact that current non-invasive techniques do not always adequately identify the seizure onset zone so that invasive EEG is required. EEG-fMRI is an imaging technique, developed in the 1990s (Ives, Warach et al. 1993) which identifies regions of interictal epileptiform discharge associated haemodynamic changes, that are concordant with the seizure onset zone in some patients (Salek-Haddadi, Diehl et al. 2006). To date there has been no large scale prospective comparison with icEEG and postoperative outcome. This thesis presents a series of experiments, carried out in a cohort of patients scanned using EEG-fMRI as part of a multi-centre programme, designed to investigate the relationship between EEG-fMRI and intracranial EEG and to assess its potential role in pre-surgical evaluation of patients with focal epilepsy. The results suggested that positive, localised IED-related BOLD signal changes were sensitive for the seizure onset zone, as determined on icEEG, both in patients neocortical epilepsies, but were not predictive of outcome. Widespread regions of positive IEDrelated BOLD signal change were associated with widespread or multifocal abnormalities on icEEG and poor outcome. Patterns of haemodynamic change, identified using both data driven and EEG derived modeling approaches, correspond to regions of seizure onset on icEEG, but improvements for modeling seizures are required. A study of a single seizure in a patient who underwent simultaneous icEEGfMRI, showed similar findings. An exploratory investigation of fMRI-DCM in EEG-fMRI, suggested it can provide information about seizure propagation and this opens new avenues for the non-invasive study of the epileptic network and interactions with function.