4-year PhD Programme (Clinical and Non-clinical)
These students are funded by generous donations from the Wolfson Foundation and Eisai. This prestigious programme is for clinical and non-clinical fellows and includes an initial training year with lab rotations.
|Dr Rubika Balendra|
Molecular mechanisms and therapeutic strategies in amyotrophic lateral sclerosis (ALS) caused by mutations in the C9orf72 gene
Supervisors: Prof Adrian Isaacs, Prof Linda Partridge, and Dr Rickie Patani
Mutations in the C9orf72 gene are a frequent genetic cause of both ALS and frontotemporal dementia (FTD). I integrated two pre-clinical C9orf72-ALS disease models to study pathogenic mechanisms and potential disease therapies: human induced pluripotent stem cell derived motor neurons and a Drosophila in-vivo model. I was an LWENC Clinical Research Training Fellow and was also funded by a Wellcome Trust Research Training Fellowship. I have successfully completed my PhD and returned to clinical training.
Dr Balendra's complete publication list can be found on her ResearchGate page.
|Dr David Lynch|
Understanding white matter disorders: focus on genetics and mitochondrial health
Supervisors: Prof Henry Houlden and Dr Helene Plun-Favreau
My research focused on the genetics and cell biology of hereditary leukodystrophies and Hereditary Spastic Paraplegia. Advances in genetics have led to an explosion in the number of genes recognised to cause these diseases. I used a variety of approaches including whole exome sequencing to genetically characterise one of the largest cohorts of adult onset leukodystrophy in Europe. In addition to genetic work, I used cell biology techniques to help to understand the pathobiology of these disorders, with a particular focus on nuclear encoded mitochondrial gene defects and how these affect mitochondrial and cellular health. I have successfully completed my PhD and returned to clinical training.
Dr Lynch's complete publication list can be found on his ResearchGate page.
|Dr Stephen Mullin|
Glucocerebrosidase mutations in the pathogenesis of Parkinson’s disease: opportunities for drug intervention
Supervisors: Prof Tony Schapira and Prof Sandip Patel
My research project had three areas of focus. First, I looked at the early clinical features of Parkinson’s caused by the GBA gene and have developed an internet based portal (RAPSODI), which screens for these features amongst a large cohort of GBA carriers. The aim of this study was to tackle some of the issues related to the variable penetrance of GBA Parkinson’s and to develop clinical, genetic and chemical biomarkers to allow identification of at risk carriers. I am also a co-investigator on the AiM PD study, a phase IIa clinical trial of ambroxol, a putative neuroprotective treatment for GBA Parkinson’s disease. Finally, I examined the cell biology of GBA and specifically in aberrant calcium signalling as a cause for the selective vulnerability of dopaminergic neurons in Parkinson’s. I have successfully completed my PhD and taken up an academic clinical lectureship at the University of Plymouth.
Dr Mullin's complete publication list can be found on his UCL Iris page.
|Dr Ross Nortley|
The role of capillary pericytes in cerebral blood flow changes in early Alzheimer’s disease
Recent work has suggested that vascular compromise is an early event in Alzheimer’s disease and other dementias, and Aβ has been shown to reduce cerebral blood flow. This may partly reflect constriction of penetrating arterioles, but in the brain vasculature most resistance is in capillaries, suggesting that Aβ might primarily act on pericytes, the contractile cells on capillary walls. I investigated the role that capillary pericytes play in controlling cerebral blood flow in early Alzheimer’s dementia. I have successfully completed my PhD and taken up a clinical post.
Dr Nortley's complete publication list can be found on his ReserachGate page.
Identification and Validation of Novel Synaptic Markers
My research project was on validating and identifying synaptic biomarkers for Alzheimer’s disease. We aimed to combine clinical and basic science to identify and better understand the regulation of release of synaptic biomarkers as well as disease aetiology. I have successfully completed my PhD and taken up a postdoctoral position within the Eisai funded TIG collaboration and am currently a postdoctoral research associate in Prof Zetterberg's lab within the UK Dementia Research Institute.
Dr Wellington's complete publication list can be found on her UCL Iris page.
Investigating structural brain connectivity in multiple sclerosis
DNA methylation and neurodegeneration in prion and prion-like diseases
This project’s aim is to compare DNA methylation profiles between sporadic Creutzfeldt-Jakob Disease (CJD) and either variant CJD or Alzheimer’s disease with a view to delineating novel and/or shared epigenetic mechanisms in prion/prion-like diseases. Methylation landscapes of blood and post-mortem brain tissue derived DNA from patients with prion diseases will be profiled. Genes in differentially methylated regions will be considered within the context of pathology and previously characterised functions; poorly characterised genes will be investigated biochemically. Oxidative bisulphite processing and locus-specific polymerase chain reactions (PCR) or pyrosequencing will be used to distinguish between methylation and hydroxymethylation. The effect of these locus-specific modifications on the disease mechanism will be modelled in vitro using DNA methyltransferase (DNMT) inhibitors and the established cell-scrapie assay protocol; any modulatory effects can be further investigated in vivo using DMNT knock-down mice or other relevant models.
Deficits in axonal transport as a target for pharmacological intervention in Amyotrophic lateral sclerosis
Supervisors: Prof Giampietro Schiavo and Prof Linda Greensmith
Growing evidence suggests that alterations in retrograde axonal transport occur early in the pathogenesis of ALS. One target that has been shown to effect retrograde axonal transport is the Insulin-like growth factor receptor 1 (IGF1R). The main aims of my project will be to analyse the ability if IGF1R to influence retrograde transport both in vitro and in vivo using both ALS mouse models and human iPSCs, hopefully leading to pharmacological interventions for ALS.
Manipulation of C9orf72 dipeptide repeat proteins
The accumulation of misfolded and aggregated protein is strongly implicated in the pathogenesis of many neurodegenerative diseases. New approaches to reduce protein misfolding, enhance protein quality control or reduce aggregation to restore proteostasis therefore represent potentially important therapeutic advances for these diseases. My research project involves investigating the potential of molecular chaperones to modify the consequences of expression of neurotoxic dipeptide repeat proteins produced as a result of the hexanucleotide repeat expansion of the C9orf72 gene, the most common genetic cause of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. I am using a cellular model of C9ALS/FTD to investigate the molecular mechanisms and consequences of DPR aggregation, and exploring how the molecular chaperone machinery can manipulate this to reduce cellular toxicity.
|Dr Carolin Koriath|
Seeking new genetic causes of HD-lookalike disorders and other dementias
Supervisors: Prof Sarah Tabrizi and Prof Simon Mead
Carolin is a Leonard Wolfson clinical fellow at UCL Institute of Neurology and an Honorary Specialist Registrar in Neurology at the National Hospital for Neurology and Neurosurgery. She studied Medicine at Ludwig-Maximilians-University Munich and worked as a Neurology registrar at the University Hospital of Munich with a focus on vertigo and oculomotor disorders. Carolin joined the team in 2015 and has a special interest in the genetics of dementia and Huntington’s Disease phenocopy syndromes, carrying out research with next-generation sequencing techniques in a collaboration project between Prof Sarah Tabrizi and Prof Simon Mead.
Dr Koriath's complete publication list can be found on her UCL Iris page.
|Dr Charles Marshall|
Physiological phenotyping of network dysfunction in frontotemporal dementia
Supervisors: Prof Jason Warren and Prof James Kilner
I explored autonomic, visceral and motor signatures of perceptual changes in frontotemporal dementia to develop a paradigm of FTD as a disease that selectively affects networks involved in complex perceptual and affective valuations, which are based on the binding of visceral afferent, semantic and motoric information in the insula. I have successfully completed my PhD and have taken up a clinical lectureship at Barts & the London, Queen Mary University.
Dr Marshall's complete publication list can be found on his QMUL page.
Evaluation of positron emission tomography (PET) tracers for imaging of neurodegenerative diseases
Supervisors: Prof Erik Arstad, Prof Henrik Zetterberg, Dr Tammaryn Lashley, Dr Kerstin Sander
Molecular imaging using tau positron emission tomography (PET) tracers may allow for the early diagnosis and treatment monitoring in patients with tau-based dementias. The binding of novel tracers to native pathological tau aggregates is yet to be comprehensively validated and characterised. The major aim of my project is to use prospective tau PET tracers and analyse their binding behaviour in human post-mortem brain tissue. My research integrates work with the Institute of Nuclear Medicine and the Queen Square Brain Bank at the Institute of Neurology, where I can combine radiochemical expertise with the precious resource of human dementia samples and knowledge regarding neurodegenerative pathology.
Investigating the effect of ALS-causing FUS mutations on the axonal transcriptome of motor neurons
Supervisors: Prof Giampietro Schiavo, Prof Elizabeth Fisher, Dr Pietro Fratta, and Dr Rickie Patani
C-terminal mutations in the gene FUS can lead to familial, early-onset forms of the motor neuron disease amyotrophic lateral sclerosis (ALS). FUS is an RNA-binding protein implicated in a wide range of cellular processes, including the localisation and transport of RNA. I am investigating the effect of these mutations on the transcriptome of motor neuron axons using primary neuron culture, embryonic stem cell and human induced-pluripotent stem cell models. In addition, I am studying sensory neurons, which are comparatively unaffected in ALS.
|Dr Ashvini Keshavan|
Blood and cerebrospinal fluid based biomarkers for neurodegenerative disease
Supervisors: Prof Jonathan Schott, Prof Henrik Zetterberg, and Dr Amanda Heslegrave
Developing blood based biomarkers for dementia has proved a significant challenge for more than twenty years. In this project I tackle this challenge by bringing together the following resources at UCL:
(1) SimoaTM HD-1 analyser which provides a robust means of measuring proteins down to femtomolar concentrations
Starting with the DRC prospective cohort I will take promising markers and assess them as tools for differential diagnosis (Alzheimer’s disease vs controls and other diseases) and for understanding disease heterogeneity (Alzheimer’s disease subtypes).
Serum neurofilament light chain, plasma tau and other promising candidates emerging from the SimoaTM, or mass spectrometry analyses, will then be measured in the Insight 46 cohort. This will allow for correlations with amyloid status, markers of neurodegeneration (atrophy), white matter burden, cognitive performance, life course measures of cognitive decline, and the influence of Alzheimer’s disease-related genetic risk factors. It is hoped that this will provide new insight into if/how blood based biomarkers may be used as part of the diagnostic evaluation of early or presymptomatic neurodegeneration.
Dr Keshavan's complete publication list can be found on her UCL Iris page.
|Donald Iain MacDonald|
Cellular subpopulations and mechanisms of neuropathic pain after peripheral neurodegeneration
Supervisors: Prof John N Wood and Prof Robert Brownstone
In neuropathic pain, afferent peripheral nerves carrying noxious sensory input die off, yet patients live in excruciating pain. Aberrant activity in distinct subsets of primary sensory neurons in the dorsal root ganglia (DRG) may cause the hyperalgesia, allodynia and spontaneous pain experienced by these patients. Yet which subpopulations of cells degenerate and go awry – and by what mechanisms – remain unknown. I am implementing and using a combination of in vivo calcium imaging, chemogenetics, electrophysiology, behaviour and molecular analysis to define the sets of cells and ion channels engaged in these pain states associated with degeneration. By investigating how altered nociceptor activity results in pain in different mouse models of neuropathy, this work can inform the development of new, rational and disease-specific analgesics.
|Dr Akshay Nair|
Modelling and modulation of apathy in Huntington’s disease
Supervisors: Prof Sarah Tabrizi, Prof Geraint Rees, Dr Robb Rutledge
Neuropsychiatric symptoms associated with dementia cause significant distress and disability. Apathy is a common, disabling and poorly understood symptom of many neuropsychiatric and neurodegenerative diseases. Reduction in goal-directed behaviour and motivation seen in apathetic patients with neurodegenerative diseases severely impacts on quality of life and accelerates the loss of independence. In Huntington’s disease (HD), a genetic form of dementia with marked striatal pathology, apathy is highly prevalent and tracks closely with the stage of illness.
In my PhD I have three main aims:
I joined the Wolfson Fellowship after completing an Academic Clinical Fellowship at the Institute of Psychiatry and in the first year of my Wolfson Fellowship I completed rotations with Prof. Jason Warren, Prof. Sarah Tabrizi and Prof. Nick Fox.
Dr Nair's complete publication list can be found on his UCL Iris page.
Generation of an accurate transcriptome map of brain-relevant cell types
Supervisors: Dr Mina Ryten and Prof John Hardy
Understanding the biological implications of a genome sequence is fundamental to our interpretation of genetic variation and its effect on phenotype and disease risk. Transcriptome profiling has contributed significantly to this understanding; however, it remains incomplete in complex tissues such as the brain, with its high level of alternative splicing and cellular heterogeneity. Importantly, this heterogeneity is not limited to our current understanding of cell type, but also includes cell state. Cell state is determined by genotype and environment, and interactions between the two; the latter is particularly understudied in the brain. The aim of this PhD is to address this gap, via two main strategies:
1. Integrating in-house RNA-sequencing, publicly available -omics data, and novel methods of analysis to understand the effect of cell type and state on the brain transcriptome in health and disease.
2. Exposing healthy iPSC-derived brain-relevant cell types to disease-relevant environmental conditions to investigate the effect of such conditions on their transcriptomic profile. This will involve use of bulk and single-cell RNA-sequencing, and annotation-agnostic quantification pipelines.
|Dr Harri Sivasathiaseelan||Dr Sivasathiaseelan's full publication list can be found on his ResearchGate page.|
Post-transcriptional modifications of RNA in neurodegeneration
Supervisors: Prof Jernej Ule, Dr Pietro Fratta
Mutations within RNA Binding Proteins (RBPs) are causative of many neurodegenerative diseases, notably the motor neurone disease Amyotrophic Lateral Sclerosis (ALS). This gives a strong indication that there exists an overarching paradigm, at the level of protein-RNA interactions, to explain the onset of this disease spectrum. Whilst much focus has been given to the aggregation propensity of ALS-linked proteins containing disease mutations, what seeds the initial aggregation when no mutations are present is unclear. In recent years post-transcriptional modifications to RNA (collectively known as the ‘epitranscriptome’) have gained attention as potentially important regulators of RNA metabolism at the level of splicing, structure, degradation and protein binding (none of which are necessarily mutually exclusive). I am interested in how such modifications may function to modify the behaviour of RNA and RNA binding proteins, linked to neurodegenerative disease.
White matter hyperintensities in sporadic and familial Alzheimer's disease: investigations into their pathological basis and biomarker potential
Phoebe's complete publication list can be found on her ResearchGate page.
Zebrafish to study genes associated with Alzheimer’s disease
Variants in dozens of genes increase or decrease your lifetime risk of developing Alzheimer’s disease, but little is known about how. Could they do so by impacting development? An unbiased approach to pick up interesting phenotypes is to look at the behaviour of an animal carrying a loss-of-function mutation in the gene of interest. Zebrafish are ideal for such a genetic screen: more than 75% of human genes are present in the zebrafish genome and the behaviour of hundreds of larvae can be quantified during several days. However, generating a zebrafish knockout line typically takes half a year and hundreds of animals. To tackle this bottleneck, I developed a method to rapidly generate zebrafish knockouts suitable for behavioural experiments, effectively compressing the time needed to obtain knockout animals from months to hours. Next, I will use this method to investigate genes associated with Alzheimer’s disease using the zebrafish.
|Dr Wei Zhang|
Engineering RNA granules in Neurodegenerative diseases
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with no cure. TDP-43 cytoplasmic aggregation is a common histopathological hallmark of ALS. Recently, there’s been a plethora of RNA binding protein (RBP) encoding genes being associated with familial ALS. However, the precise sequence of events from aberrant RBP, to neuronal cell death remains elusive. Many lines of evidence point towards the disturbance in the dynamics of liquid-liquid phase separation pathway as a key driver in pathology.
The role of hnRNP K in the pathogenesis of frontotemporal lobar degeneration
Supervisors: Prof Tammaryn Lashley, Prof Pietro Fratta
My research aims to better understand the role of hnRNP K mislocalisation in health and disease with the aid of pathological analysis and stem cell (iPSC) models of hnRNP K depletion. By comparing the neuronal profiles of hnRNP K pathology in control (n = 28) and FTD (n = 50) subjects, we hope to establish how much hnRNP K mislocalisation can be attributed to the natural aging process and the extent to which it is accelerated by neurodegenerative disease. Additionally, as with many hnRNPs hnRNP K is predicted to repress the activation of non-evolutionary conserved cryptic exons on target mRNA which only resemble bona fide splice sites. An iPSC model of hnRNP K knockdown utilising CRISPR-interference technology will allow us to assess the impact hnRNP K depletion has on cryptic exon inclusion events. I then hope to be able to validate any potential cryptic hits in brain tissue using fluorescent in situ (fish) hybridisation.
|Dr Zhongbo Chen||Dr Chen's full publication list can be found on her UCL Iris profile.|
Investigating mechanisms behind novel heat shock proteins in Amyotrophic lateral sclerosis and
Supervisors: Prof Adrian Isaacs, Prof Pietro Fratta
Investigating the role of the non-specific lethal (NSL) complex in modifying mitophagy and other Parkinson’s disease-related genes and pathways
Supervisors: Prof Mina Ryten, Prof Helene Plun-Favreau, Dr Claudia Manzoni
Mitochondrial dysfunction is implicated in both sporadic and familial Parkinson’s disease and disruption of nuclear-mitochondrial coordination may be a driver of neurodegeneration. The non-specific lethal (NSL) complex has the capability to contribute to this coordination and has recently been implicated in PD. The most notable of its nine members is acetyl transferase, KAT8 which influences gene expression mainly by acetylating lysine 16 on histone 4. As well as its role in chromatin regulation, the NSL complex has demonstrated effects on mitochondrial quality control: a screen of sporadic PD GWAS genes detecting modifiers of PINK1-mediated mitophagy identified KAT8 and regulatory NSL complex subunit, KANSL1. Furthermore, reduced PINK1 and PRKN expression in KAT8 and KANSL1 knockdown cells highlighted a close transcriptional relationship. My project aims to identify gene regulatory relationships between NSL complex and PD-relevant genes, and assess tissue or cell type specificity. These relationships will be validated using in vitro cell models, investigating the expression of regulated genes and their effect on PD-relevant pathways, as well as by generating new multi-omic data to assess the global genomic effects of NSL complex perturbation.
Dysfunction of a key lysosomal pathway is a critical cellular mechanism that drives neurodegenerative disease
Supervisors: Prof Sonia Gandhi, Prof Selina Wray, Prof Helene Plun-Favreau
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder worldwide. Heterozygous mutations in GBA, which encodes the lysosomal enzyme GCase, are the greatest numerical risk factor for PD. Lysosomal dysfunction is a hallmark of PD pathology, and may contribute to alpha-synculein proteinopathy. In addition to GCase, numerous other lysosomal proteins have been implicated in PD pathogenesis, including progranulin (GRN), prosaposin (PSAP), cathepsin D (CTSD) and cathepsin B (CTSB). These four proteins in particular are thought to make up a lysosomal pathway that is both capable of modifying GCase activity and is integral for lysosomal health.
My research aims to investigate this potential pathway in iPSC-derived models of PD-GBA, in particular midbrain dopaminergic neurons and microglia. In these cells I aim to unpick the sequential order of this pathway by genetic and pharmacological manipulation. I aim to support my in vitro findings by investigating post-mortem human brain tissue from PD patients with GBA mutations. I hope to improve our knowledge of lysosomal dysfunction in PD pathogenesis.
Joy Bunker Scholar
This student is funded by a generous donation from the Bunker family who wish to support dementia research.
Investigating tau pathology in familial Alzheimer's Disease caused by APP mutations
Supervisors: Prof Selina Wray, Prof Tammaryn Lashley, Prof Henrik Zetterberg
Affiliated with the Leonard Wolfson Experimental Neurology Centre and Queen Square Brain Bank
My project focuses on the characterisation of post-translational modifications to tau in iPSC-neurons and post-mortem brain tissue from patients with familial Alzheimer’s Disease and other tauopathies. Using proteomics to investigate post-translational modifications to tau in iPSC-neurons, post-mortem brain tissue and CSF, we aim to understand the full diversity of modifications to tau (phosphorylation, acetylation, ubiquitination etc) and the sequence of pathological changes that occurs during disease onset and progression. Modifications to tau that are present only in disease samples will be further investigated in cells and tissue from other tauopathies to determine disease specificity. We will use our proteomics data to identify candidate enzymes and pathways that can be manipulated in iPSC-neurons pharmacologically, to understand whether specific modifications to tau increase toxicity and are associated with both familial and sporadic disease.
LWBL-funded Wolfson PhD Students
These students are funded by the Wolfson Foundation and form part of our CSF Biomarkers service within the Biomarkers Programme (LWBL).
Amyloidogenic processing of amyloid beta (A4) precursor protein in an induced pluripotent stem cell derived neuronal model
Supervisors: Prof John Hardy, Prof Henrik Zetterberg, Prof Selina Wray, Dr Amanda Heslegrave
The generation of amyloid beta (Abeta) peptides from amyloid beta (A4) precursor protein (APP) plays an important role in Alzheimer’s disease, but the exact mechanism of neurodegeneration is, as yet, insufficiently understood. My project seeks to better characterise the amyloidogenic process, and provide a platform for future work on Abeta-related neurodegeneration.
Work will involve two phases: 1. To investigate aspects of cerebrospinal fluid (CSF) and cell culture media (CCM) sample collection, handling and storage practices that influence measurement of Abeta, and establish methods to control factors identified. 2. To incorporate these control methods to explore the mechanisms of amyloidogenic APP processing in paired patient induced pluripotent stem cell (IPSC) derived neurons and CSF, using a combination of ELISA, mass-spectrometry, and live cell imaging. Of particular interest are the questions ‘what dictates differential cleavage by secretase activity?’ and ‘can IPSC derived neurons reflect processes that contribute to a patient’s CSF Abeta profile?’
|Martha Foiani||Identification of novel biofluid markers of tauopathies|
Supervisors: Prof Henrik Zetterberg, Dr Jonathan Rohrer, Dr Amanda Heslegrave, Prof Tammaryn Lashley and Prof Selina Wray
Tauopathies are clinically, pathologically and biochemically heterogeneous diseases characterised by dysfunction of the tau protein in the brain. The objective of this project will be to look into tau fragments or tau associated proteins as possible biomarker species to distinguish the tauopathies from TDP-43opathies, and to differentiate between the various tauopathies, which include: MAPT mutations, Pick’s Disease, CBD, PSP, GGT, AGD and PART.
Joint Wolfson-Engineering PhD Students
Computational modelling of protein accumulation and spread in the brain
Supervisors: Dr Marc Modat, Prof Jason Warren, Prof Sebastien Ourselin
My research project involves the creation of a computational model to improve our understanding of misfolded protein accumulation and spread within the brain. Neurodegenerative diseases, such as Alzheimer’s disease, are caused by the accumulation of specific misfolded (abnormally shaped) proteins. Due to their misfolded state, the brain is unable to eliminate them. Neuroscientists hypothesise that these proteins are able to misfold normally folded proteins of the same type when they come in close proximity, yielding their toxic accumulating. I use computational modelling to create simulations of the impact of misfolded proteins (or "molecular nexopathies") on neural networks. The model I created to date embeds formulation that governs misfolded protein spawning rate, misfolding of normally folded protein, intra-cellular and trans-synaptic spread as well as the toxicity of misfolded proteins on neuronal cells. Using such a model, I am able to rapidly simulate processes that otherwise take several decades in-vivo and thus test clinical hypotheses to gain a better understanding of the molecular nexopathies.
Analysis of rs-fMRI in dementia
Supevisors: Prof Sebastien Ourselin, Dr Jonathan Rohrer
In my current research, I build biophysical models of the underlying origins of resting-state fMRI time courses. I am especially interested in how individual parameters of these models are influenced by morphology and pathology, and their change during disease progression.
Previous research has already shown that the disruption of the Default Mode Network (DMN) has potential to be the most prevalent functional biomarker for Alzheimer's disease. Multiple imaging modalities including measurement of glucose metabolism (PIB-PET), intrinsic/task-evoked brain activity (fMRI) and structural atrophy (MRI) revealed disruptions in the DMN in Alzheimer patients. Amyloid beta depositions overlap to a great extent with the DMN. Great scientific inside will thus be enabled by PET-MR devices that allow for simultaneously tracking neuro-chemical changes (PET) and invoked brain activity (BOLD-fMRI). My research focuses on the functional organization of the human brain by looking at its characteristics from an engineering perspective, enabling me to study the disrupted functional organization of the human brain when challenged by neurodegenerative diseases. My focus is hereby the development of new functional multi-modal biomarkers and their translation into the clinical landscape.
Optimal acquisition schemes for ASL in dementia
Supervisors: Prof Sebastien Ourselin, Dr Jonathan Rohrer
My work explores how non-invasive perfusion measurement in the brain, using Arterial Spin Labelling, might be used as a biomarker for neurodegenerative diseases. In particular, there is hope that perfusion (and related phenomena) can be used for early detection and classification of dementias. My work over
the past year consisted in two related strands. First, I studied the quality and reproducibility of existing ASL acquisition strategies. Motivated by these results and previous work in the literature, I sought to create a novel, optimised multiple inversion time ASL acquisition protocol using the theoretical framework of Bayesian experimental design. Initial results are promising; generally showing a significant improvement compared to a representative "reference" ASL acquisition. Future work will develop this further by characterising the design's improved performance more fully, and by making the design process more suitable for multi-parametric estimation.
Quantification and correction of partial volume effects for dynamic Amyloid PET kinetic modelling
Supervisors: Sebastien Ourselin, Brian Hutton, Jonathan Schott
Positron Emission Tomography (PET) using an amyloid targeting radiotracer has shown promise in the detection of amyloid plaques, which are of interest in the study of Alzheimer's disease. However, quantitative measures of the tracer kinetics are biased by the partial volume effect (PVE), caused by the
limited resolution of this imaging modality. In this work, a pipeline has been developed to generate a realistic spatio-temporal tracer distribution as the ground truth, to simulate the corresponding detected PET data using a Monte Carlo approach, and to perform kinetic modelling on both datasets. To ensure that analysis is not influenced by the data synthesis, different software implementations were used for the two stages. This framework makes it possible to evaluate the efficacy of state of the art correction techniques, which could improve the accuracy of quantitative biomarkers.
Automated white matter lesion segmentation
Supervisors: Prof Sebastien Ourselin, Prof Nick Fox, Dr Jorge Cardoso
With ageing, changes occur in the brain. Among them, white matter hyper intensities observed as hyper intense signal in specific MRI modalities (FLAIR, T2-weighted, PD-weighted) are common and reflect damage to the fibres of the brain. These damages have been related to speed processing and executive function impairment. Vascular deficiencies such as partial ischemia or defects in the blood brain barrier have been put forward as potential pathophysiological explanations for such lesions. Other types of vascular related lesions associated with age, such as lacunes or perivascular spaces can also been observed in ageing brains. Our work consists in first locating then characterising the various abnormalities of the brain using probabilistic models in a robust, accurate and reproducible manner. It then enables us to quantify the brain abnormalities and potentially allows us to draw relationships between this imaging-derived information and other clinical assessments, such as genetic status or cognitive scores.
MSc Dementia (Neuroscience) Leonard Wolfson scholars
- Rachel Hughes
- Denise So
- Katie Kelly
- Alicja Mrzygold