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Students and Projects

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. 

 
2013 Intake  
Dr Rubika Balendra 

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. 

  • Balendra, Rubika & M. Isaacs, Adrian. (2018). C9orf72-mediated ALS and FTD: multiple pathways to disease. Nature Reviews Neurology. 14. 10.1038/s41582-018-0047-2. 
  • Balendra, Rubika & Moens, Thomas & M Isaacs, Adrian. (2017). Specific biomarkers for C9orf72 FTD/ALS could expedite the journey towards effective therapies. EMBO molecular medicine. 9. 10.15252/emmm.201707848.
  • Balendra R, Patani R. Quo vadis motor neuron disease? Review published in World Journal of Methodology, March 2016
  • Balendra R, Uphill J, Collinson C, Druyeh R, Adamson G, Hummerich H, Zerr I, Gambetti P, Collinge J, Mead S. (2016) Variants of PLCXD3 are not associated with variant or sporadic Creutzfeldt-Jakob disease in a large international study. Bmc Medical Genetics. 17: 28. PMID 27055460 DOI: 10.1186/s12881-016-0278-2 
  • Balendra, R., Mizielinska, S., Moens, T., Niccoli, T., Ridler, C., Simone, R., Woodling, N., Parkinson, G., Neidle, S., Patani, R., et al. (2016). Molecular mechanisms and therapeutic strategies in amyotrophic lateral sclerosis caused by C9orf72 mutations. The Lancet 387, S13. (Oral Plenary abstract from Spring Meeting for Clinician Scientists in Training 2016) DOI: http://dx.doi.org/10.1016/S0140-6736(16)00400-1

Dr Balendra's complete publication list can be found on her ResearchGate page. 

    Dr David Lynch

    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. 

    • Lynch, David & Paiva, Anderson Rodrigues Brandão & Jia Zhang, Wei & Bugiardini, Enrico & Freua, Fernando & Lucato, Leandro & Inês Macedo-Souza, Lucia & Lakshmanan, Rahul & A Kinsella, Justin & Merwick, Aine & Rossor, Alexander & Bajaj, N & Herron, Brian & McMonagle, Paul & J Morrison, Patrick & Hughes, Deborah & Pittman, Alan & Laurà, Matilde & M Reilly, Mary & Houlden, Henry. (2017). Clinical and genetic characterization of leukoencephalopathies in adults. Brain : a journal of neurology. 140. 10.1093/brain/awx045. 
    • Lynch, D.S., Zhang, W.J., Lakshmanan, R., Kinsella, J.A., Uzun, G.A, Karbay, M., Tufekcioglu, Z., Hanagasi, H., Burke, G., Foulds, N., Hammans, S., Bhattacharjee, A., Wilson, H., Adams, M., Walker, M., Nicoll, J.A.R., Chataway, J., Fox, N., Davagnanam, I., Phadke, R., Houlden, H. Analysis of mutations in AARS2 in a Series of CSF1R-Negative Patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. JAMA Neurology. 73. 10.1001/jamaneurol.2016.2229. 
    • Lynch, D, et al. (2015) Hereditary leukoencephalopathy with axonal spheroids: a spectrum of phenotypes from CNS vasculitis to parkinsonism in an adult onset leukodystrophy series. J Neurol Neurosurg Psychiatry. doi:10.1136/jnnp-2015-310788
    • Lynch, D, et al. (2015) Hereditary spastic paraplegia in Greece: characterisation of a previously unexplored population using next-generation sequencing. European Journal of Human Genetics. doi:10.1038/ejhg.2015.200 

    Dr Lynch's complete publication list can be found on his ResearchGate page.

    Dr Stephen Mullin

    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. 

    • Mullin, S, & Schapira, A.  (2015) Pathogenic Mechanisms of Neurodegeneration in Parkinson Disease. Neurologic Clinics of NA, 33(1), 1–17. http://doi.org/10.1016/j.ncl.2014.09.010
    • Mullin, S., & Schapira, A. (2015) The genetics of Parkinson's disease. British Medical Bulletin, 114(1), 39–52. http://doi.org/10.1093/bmb/ldv022
    • Porcari, R, Proukakis, C, Waudby, CA, Bolognesi, B, Mangione, PP, Paton, JFS, Mullin, SW et al. (2015) The H50Q mutation induces a 10-fold decrease in the solubility of α-synuclein. Journal of Biological Chemistry, 290(4), 2395–2404. http://doi.org/10.1074/jbc.M114.610527

    Dr Mullin's complete publication list can be found on his UCL Iris page. 

    Dr Ross Nortley 

    Ross Nortley

    The role of capillary pericytes in cerebral blood flow changes in early Alzheimer’s disease

    Supervisors: Prof David Attwell and Prof Nick Wood

    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. 

    • Nortley, Ross & Mishra, Anusha & Jaunmuktane, Zane & Kyrargyri, Vasiliki & Madry, Christian & Gong, Hui & Richard-Loendt, Angela & Brandner, Sebastian & Sethi, Huma & Attwell, David. (2018). Amyloid beta oligomers constrict human capillaries in Alzheimer's disease via signalling to pericytes. 10.1101/357095. 
    • Nortley, Ross & Attwell, David. (2017). Control of brain energy supply by astrocytes. Current opinion in neurobiology. 47. 80-85. 10.1016/j.conb.2017.09.012. 

    Dr Nortley's complete publication list can be found on his ReserachGate page.

    Henny Wellington 

    Henny Wellington

    Identification and Validation of Novel Synaptic Markers
    Supervisors: Prof Henrik Zetterberg and Prof Jonathan Schott

    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. 

    • Wellington, H., Paterson, R., Suarez-Gonzalez, A., Poole, T., Frost, C., Sjobom, U., . . . Schott, J. (2018). CSF Neurogranin or Tau distinguish typical and atypical Alzheimer DiseaseAnnals of Clinical and Translational Neurology. doi:10.1002/acn3.518
    • Wellington, H., Paterson, R.W., Portelius, E., Törnqvist, U., Magdalinou, N., Fox, N.C., Blennow, K., Schott, J.M., and Zetterberg, H. (2016). Increased CSF neurogranin concentration is specific to Alzheimer disease. Neurology 86, 829–835.
    • Wellington, H, et al. Elevated cerebrospinal fluid neurogranin concentrations are specific to Alzheimer’s Disease – a cross-disease comparison* [Poster]*Student poster competition winner in the diagnosis and prognosis theme

    Dr Wellington's complete publication list can be found on her UCL Iris page

    2014 Intake  
    Thalis Charalambous

    Thalis Charalambous

    Investigating structural brain connectivity in multiple sclerosis

    Supervisors: Dr Ahmed Toosy, Prof Alan Thompson, Prof Claudia Wheeler-Kingshott, and Dr Jonathan Clayden

    Brain connectivity measures, functional and structural, are emerging as potential intermediate biomarkers for neurodegenerative disorders. My research sought to investigate how structural connectivity is altered in Multiple Sclerosis, how it changes over time and how it is related to clinical outcome using a variety of advanced image processing techniques on MRI patient data. I have successfully completed my PhD and am now studying medicine at St George's Medical School, Cyprus campus. 

    • Charalambous T. et al. (2018) Longitudinal Analysis Framework of DWI Data for Reconstructing Structural Brain Networks with Application to Multiple Sclerosis. In: Kaden E., Grussu F., Ning L., Tax C., Veraart J. (eds) Computational Diffusion MRI. Mathematics and Visualization. Springer, Cham
    Luke Dabin

    Luke Dabin

    DNA methylation and neurodegeneration in prion and prion-like diseases

    Supervisors: Prof Simon Mead and Dr Emmanuelle Vire 

    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. 

    Alex Fellows

    Alex Fellows

    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.

    Lauren Gittings

    Lauren Gittings

    Manipulation of C9orf72 dipeptide repeat proteins
    Supervisors: Dr Adrian Isaacs, Dr Tammaryn Lashley, Prof Mike Cheetham, and Dr Alison Hardcastle

    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 

    Caroline 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.

    • Koriath, C., Kenny, J., ADAMSON, G., Druyeh, R., Taylor, W., Quinn, L., . . . Mead, S. (2018). Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral seriesMolecular Psychiatry. doi:10.1038/s41380-018-0224-0
    • Koriath, C. A. M., Bocchetta, M., Brotherhood, E., Woollacott, I., Norsworthy, P., Simon-Sanchez, J., ...Rohrer, J. (2016). The clinical, neuroanatomical, and neuropathologic phenotype of TBK1-associated frontotemporal dementia: A longitudinal case report. Alzheimer's and Dementia. doi:10.1016/j.dadm.2016.10.003
    • Koriath, C. A.M., Moss, D.J.H., Tabrizi, S.J. (2016). C9orf72 expansions and HD phenocopies (Original Article: C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies). HD Insights Vol. 13, p. 4.

    Dr Koriath's complete publication list can be found on her UCL Iris page.

    Dr Charles Marshall

    Charlie 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. 

    • Marshall CR, Hardy CJD, Allen M et al. (2018). Cardiac responses to viewing facial emotion differentiate frontotemporal dementias. 10.1002/acn3.563 
    • Marshall CR, Hardy CJD, Volkmer A et al. (2018). Primary progressive aphasia: a clinical approach. 10.1007/s00415-018-8762-6
    • Marshall CR, Hardy CJD, Russell LL et al. (2018). Motor signatures of emotional reactivity in frontotemporal dementia. 10.1038/s41598-018-19528-2
    • Marshall CR, Hardy CJD, Russell LL et al. (2017). Impaired Interoceptive Accuracy in Semantic Variant Primary Progressive Aphasia. 10.3389/fneur.2017.00610 
    • Marshall CR, Hardy CJD, Rossor MN et al. (2016). Teaching NeuroImages: Nonfluent variant primary progressive aphasia: A distinctive clinico-anatomical syndrome. 

      10.1212/WNL.0000000000003408

    •  Marshall CR, Bocchetta M, Rohrer JD et al. (2016). C9orf72 mutations and the puzzle of cerebro-cerebellar network degeneration. 10.1093/brain/aww103

    • Marshall CR, Guerreiro R, Thust S et al. (2015). A Novel MAPT Mutation Causing Corticobasal Syndrome Led by Progressive Apraxia of Speech. 10.3233/JAD-150477

    Dr Marshall's complete publication list can be found on his QMUL page

    Melissa Wren 

    Melissa Wren

    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.

    • Wren MC, Sander K, Lashley T, Fox N, Arstad E (2017) 'Microscopic neuropathological evaluation of the binding profile of tau selective PET ligands in Alzheimer’s disease and primary tauopathies'. Oral presentation, Human Amyloid imaging (HAI) conference, Miami 11-13 January 2017. She was also selected for the HAI young investigator 2017 travel scholarship.
    • Wren, MC, et al. (2016) 'Sequential analysis of tau positron emission tomography tracer binding on human post-mortem brain tissue in Alzheimer’s disease and primary tauopathies'. This abstract was selected for an oral platform presentation at the British Neuropathological Society, 2-5 March 2016. [Oral abstract] 
    2015 Intake  
    Matthew Bentham

    Matthew Bentham

    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

    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
    (2) In collaboration with ICH, state-of-the-art mass spectrometry for biomarker discovery (3) Unique sample collections, including: • the DRC prospective clinical cohort, in which cerebrospinal fluid, urine and blood samples, neuropsychology and magnetic resonance imaging data are available from 300 patients recruited from the cognitive disorders clinics at the NHNN since 2013, with ongoing collection via a dedicated cerebrospinal fluid clinic that I manage; • blood collection as part of Insight 46, a prospective biomarker/amyloid PET/multimodal MRI/genetic and neuropsychology study of 500 members of the MRC NSHD 1946 birth cohort. 

    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

    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

    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:
    1) Working with the Rutledge lab at the Max Planck Centre, I will use computational modelling techniques and functional neuroimaging to develop a better understanding of the neural processes causing apathy in Huntington’s disease and ask whether these processes differ from apathy in other populations, including healthy controls.  2) Using the existing imaging datasets from large cohort studies with measures of apathy such as TRACK-HD and TRACK-ON, I will apply functional and structural connectivity techniques to assess the neuroimaging correlates of apathy in HD. 3) Finally, I will assess whether a non-invasive neurostimulation technique known as ‘real-time fMRI based neurofeedback’ can be used as a novel way to target apathy in a cohort of patients with HD. 

    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.

    2016 Intake  
    Regina Reynolds
    Regina Reynolds

    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  
    Patrick Toolan-Kerr
    Patrick Toolan-Kerr

    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.

    Phoebe Walsh   
    2017 Intake   
    Liam Kempthorne   
    Francois Kroll 
    Francois Kroll
     
    Dr Wei Zhang 
    Wei Zhang

    Engineering RNA granules in Neurodegenerative diseases 
    Supervisors: Prof Jernej Ule, Dr Sonia Gandhi, Dr Rickie Patani

    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. 
    I will investigate a novel RNA binding protein that has been identified in familial ALS families. I  will use various different cellular models, including human iPSC derived motor neurons as a  platform to further dissect the downstream aberrant biological phenotype and mechanistic pathways that have potential as therapeutic targets. 
     

    2018 Intake  
    Alex Bampton 
    Alex Bampton
    Rotation year 
    Dr Zhongbo Chen  Rotation year
    Louise Holland  Rotation year 

    Joy Bunker Scholar 

    This student is funded by a generous donation from the Bunker family who wish to support dementia research.  

    Chris Lovejoy 

    Investigating tau pathology in familial Alzheimer's Disease caused by APP mutations

    Supervisors: Dr Selina Wray, Dr 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.

    Public engagement
    Neuronal Disco at Southbank: https://www.southbankcentre.co.uk/whats-on/128414-neuronal-disco-2018
    Guardian article: https://www.theguardian.com/science/2018/mar/31/two-brains-better-than-one-stem-cells-transplant-organst

    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).  

    Jamie Toombs

    Jamie Toombs

    Amyloidogenic processing of amyloid beta (A4) precursor protein in an induced pluripotent stem cell derived neuronal model

    Supervisors: Prof John Hardy, Prof Henrik Zetterberg, Dr 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?’

    • Guerreiro R, Bras J, Toombs J, Heslegrave A, Hardy J, Zetterberg H. (2015) Genetic Variants and Related Biomarkers in Sporadic Alzheimer’s Disease. Curr Genet Med Rep 3:19–25. DOI 10.1007/s40142-014-0062-6
    • Toombs J, Paterson RW, Nicholas JM, Petzold A, Schott JM, Zetterberg H. (2015) The impact of Tween 20 on repeatability of amyloid β and tau measurements in cerebrospinal fluid. Clin Chem Lab Med. DOI 10.1515/cclm-2015-0414

     

    Martha Foiani  Identification of novel biofluid markers of tauopathies
    Supervisors: Prof Henrik Zetterberg, Dr Jonathan Rohrer, Dr Amanda Heslegrave, Dr Tammaryn Lashley and Dr 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 

    These students are joint-funded by the Wolfson Foundation and the Faculty of Engineering, with close ties to the EPSRC Centre for Doctoral Training

    Konstantinos Georgiadis 

    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.

    Michael Hutel 

    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.

     David Owen 

    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.

     Catherine Scott 

    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.

     Carole Sudre 

    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.

    Status: COMPLETED 

    • Carole H. Sudre, M. Jorge Cardoso, Willem H. Bouvy, Geert Jan Biessels, Josephine Barnes, and Sebastien Ourselin. Bayesian model selection for pathological neuroimaging data and application to white matter lesion segmentation. In Press IEEE TMI 2015

    MSc Dementia (Neuroscience) Leonard Wolfson scholars

    • Rachel Hughes
    • Denise So
    • Katie Kelly