The Department of Clinical Neurosciences are encouraging applications despite the Covid pandemic, and we look forward to welcoming our new arrivals. There are no changes to our admission process for all arrivals or applicants.
Communications between supervisors and students will depend on the project and arrangements for this will be implemented. Procedures have already been put in place for all buildings with clear guidelines to follow to ensure a safe working environment, and some of our students are already back to work.
Further updates can be found here
Applications for the Academic year October 2022- September 2023 open 2nd September, Funding deadlines are as follows:
Gates US: 13th October 2021
Postgraduate Funding Competition (all other funders including Gates Cambridge): 2nd December 2021
*Above funding is not available for LT22 or ET22, but from MT22 as the new academic year
IMPORTANT – this included applications from applicants who wish to be considered for Cambridge Trust funding (both inside and outside the EU).
Please note that ALL supporting documents (references, transcript, CV) must be uploaded within 7 days of the date of applying
(Applications for Lent 22 and Easter 22 are all being considered, but funding must already be secured, application deadlines available here)
For more information about a specific project please contact the individual supervisor using the e-mail address provided, it is recommended that applicants contact supervisors prior to applying. However, please do not submit an application to the individual supervisor. All applications must be submitted following the process detailed on our How to Apply page.
Development of Novel Molecular Imaging Probes for Neuroimaging by Positron Emission Tomography (PET) – MPhil or PhD
The overarching objective of these projects is to develop novel molecular imaging probes, including PET probes, for imaging neuropathological features associated with various disorders such as neurodegeneration, neuroinflammation, multiple sclerosis and mitochondrial disorders. The projects would involve organic synthesis and in vitro assays of compounds, combined with developing the radiosynthesis of the novel PET probes. Evaluation of the probes would involve in vitro radiographic methods and in vivo imaging of animal models using a high-resolution PET-CT scanner.
NOTE: these projects are particularly suited to graduates in chemistry.
Translational Research in Characterisation and Application of Novel Molecular Imaging Probes in Models of Disease
The objective of these projects consist of two aspects; i) characterising the binding profiles of molecular imaging probes, including positron emission tomography probes on animal and human tissue using various in vitro techniques, including autoradiography and immunohistochemistry and ii) the application of PET probes for translational in vivo PET imaging research in animal models of various disorders using a high-resolution PET-CT scanner. Central to these projects are research links to the human PET imaging programme at the Wolfson Brain Imaging Centre.
NOTE: this project is particularly suited to graduates in biology/pharmacology.
Novel Carbon-11 and Fluorine Radiochemistry for Manufacture of PET Radiopharmaceutical
This project is focused on developing novel radiosynthetic methods for carbon-11 and fluorine-18 to widen the scope of radiolabelling method and produce simpler, more robust methods for the manufacture of PET radiopharmaceuticals. Novel technologies will be applied include flow chemical/microfluidic methods and micro-capillary films. – MPhil or PhD
NOTE: this project is particularly suited to graduates in chemistry.
Apathy in Huntington’s disease -PhD only
Apathy is a common and disabling feature of Huntington’s disease (HD) with patients and families ranking it as one of the top three most impactful features of the disease. Currently, the understanding of apathy in HD is limited. Research has primarily focused on mapping the prevalence of apathy across the disease span, using standard assessment tools which are insensitive to the exact nature of the diminished motivation experienced by this patient group. Little attention has been directed towards the study of the multidimensional nature of apathy in HD and in particular, the study of “social apathy” which is an abstract form of apathy characterised by a reduced initiative to propose and engage in social activities or interactions.
The objective of this project is to define the profile of “social” apathy in HD, understand how it changes as the disease evolves and how it relates to the wider cognitive and functional abnormalities seen in HD. The project will link closely with ongoing work in the group which is investigating impairments in social cognition in this patient population and how this might be improved with medical interventions.
Brain Repair in Adults and Children with Multiple Sclerosis
We are interested in the process of remyelination in humans, especially in assessing how the rate of remyelination changes with age and how best to test drugs that potentially promote remyelination. So, we are using electrophysiological techniques [visual evoked potentials] and structural imaging [optical coherence tomography and magnetic resonance imaging]. We study children and adults with multiple sclerosis and other demyelinating conditions like neuromyelitis optica. This project is suitable for anyone interested in studying human physiology. Clinical training is not a requirement.
Developing Novel Treatments for Children with Inherited Neuromuscular Diseases
(co-supervised with Professor Patrick Chinnery)
Inherited neuromuscular disorders are disabling, progressive, often fatal conditions, representing an enormous unmet medical need with devastating impacts on affected families, the healthcare system, and the economy. There are no cures and the limited therapies available treat symptoms without addressing the underlying disease.
Next-generation sequencing has facilitated a molecular diagnosis for many inherited neurological disorders, such as mitochondrial diseases and other neuromuscular diseases, which are the focus of this research. The development of targeted therapies requires detailed laboratory investigation of molecular and mutational mechanisms, and a systematic evaluation of well-chosen agents as well as gene and transcript directed strategies using standardized experimental systems. Our research is focusing on understanding the molecular pathogenesis of childhood onset inherited neuromuscular diseases, such as mitochondrial disease and other neuromuscular diseases to develop targeted therapies.
Using a translational approach, we aim to
1. understand the clinical course of patients in relation to the underlying disease mechanism
2. delineate the mutational and molecular mechanisms of the molecular defect in the appropriate cell types by developing model systems such as induced neuronal progenitor cells (in vitro) and zebrafish (in vivo)
3. improve the treatment options for patients by developing novel therapies that are directed at these mechanisms, including directly at the genetic mutation or resulting transcript.
We use a combination of exome sequencing, genome sequencing, and other omics technologies to identify novel disease genes and disease mechanisms. By functional evaluation in vitro (induced neuronal progenitor cells) and in vivo (zebrafish) we confirm pathogenicity and uncover molecular mechanisms of disease. To address the mutational mechanisms, we use gene transfer, splice modulation, allele silencing and CRISPR/cas systems.
1. Thompson R, Spendiff S, Roos A, Bourque PR, Warman Chardon J, Kirschner J, Horvath R, Lochmüller H. Advances in the diagnosis of inherited neuromuscular diseases and implications for therapy development. Lancet Neurol. 2020 Jun;19(6):522-532.
2. Munro B, Horvath R, Müller JS. Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok-/- zebrafish. Hum Mol Genet 2019;28(5):796-803.
3. Burns DT, Donkervoort S, Müller JS, et al., Horvath R, Bönnemann CG. Variants in EXOSC9 disrupt the RNA exosome and result in cerebellar atrophy with spinal motor neuronopathy. Am J Hum Genet 2018:102(5):858-873.
4. Bansagi B, et al, Chinnery PF, Horvath R. Genetic heterogeneity of motor neuropathies. Neurology. 2017 Mar 28;88(13):1226-1234.
5. Taylor RW, Pyle A, Griffin H, et al., Horvath R, Chinnery PF. Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA. 2014;312(1):68-77.
Targeting the Cellular Metabolism to treat Tissue-Specific Mitochondrial Diseases
(Co-supervisors: Dr. Juliane Müller & Dr. Denisa Hathazi)
Although mitochondria are present in almost all eukaryotic cell types, mitochondrial diseases have distinct tissue-specific phenotypes that are poorly understood. Our project focuses on mitochondrial diseases characterised by impaired mitochondrial translation, which can be caused either by mtDNA mutations (often in mt-tRNAs) or in nuclear encoded proteins that play a role in mitochondrial translation. Mt-tRNA or nuclear gene mutations affect tRNA levels and structure directly or indirectly, leading to a defect of mitochondrial protein synthesis. These mutations can also lead to the presence of free tRNAs without their cognate amino acid (‘uncharged tRNA’), which constitutes a stress signal for cells.
We will investigate whether different tissues have different levels of uncharged tRNAs and whether this correlates with the vulnerability for mitochondrial defects. Uncharged tRNA activates the integrated stress response (ISR), a major signalling pathway that allows eukaryotic cells to sense stress and adapt to it. We obtained fibroblasts from patients with different mitochondrial translation defects to determine tRNA and ISR levels. We will reprogram the fibroblasts to iPSCs and differentiate those to neurons, muscle cells and cardiomyocytes. Next, we will examine what metabolic changes are induced by the activated ISR in these cells.
In one disease studied by our laboratory, reversible infantile respiratory chain deficiency (RIRCD), the metabolic changes induced by the ISR in the muscle of patients allowed a recovery of the patients from severe disease. Our results indicate that the ISR is protective to some cells and damaging to others. We would like to exploit the knowledge gained in RIRCD to induce similar metabolic changes in mitochondrial conditions that are currently not reversible. Modifying the ISR or manipulating key metabolic factors (amino acids, FGF21) may enable us to devise therapeutic options for mitochondrial translation defects in the future.
Hathazi D et al., Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency. Medxiv 2020
Boczonadi V, et al., Horvath R. Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons. Hum Mol Genet. 2018;27(12):2187-2204
Taylor RW, Pyle A, Griffin H, et al., Horvath R, Chinnery PF. Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA. 2014;312(1):68-77.
Boczonadi V, Jennings MJ, Horvath R. The role of tRNA synthetases in neurological and neuromuscular disorders. FEBS Lett. 2018;592(5):703-717
Richter U, et al. RNA modification landscape of the human mitochondrial tRNALys regulates protein synthesis. Nat Commun. 2018;9(1):3966.
Boczonadi V, Ricci G, Horvath R. Mitochondrial DNA transcription and translation: clinical syndromes. Essays Biochem. 2018;62(3):321-340.
Testing new Treatment Options in Zebrafish Models of Mitochondrial Diseases
(Co-supervisor: Dr. Juliane Müller)
Mitochondria contain multiple copies of their own genetic material (mtDNA) which is replicated independently from DNA in the nucleus. Numerous proteins are involved in the mtDNA replication and in providing the nucleotides for DNA synthesis. Defects in any of these proteins cause mtDNA depletion syndromes (MDDS) characterised by a low amount of mtDNA in the cells. Depletion of mtDNA results in mitochondria being unable to synthesise enough ATP to meet the demands of the cell. Organs with a high energy demand such as the central nervous system, skeletal muscle and liver are therefore most often affected. Patients can present with a wide range of symptoms including progressive external ophthalmoplegia, myopathy, hepatic failure, renal tubulopathy and encephalomyopathy. The clinical symptoms of MDDS are very severe and debilitating and typically manifest in early infancy. Currently there is no cure available for MDDS, treatment focuses only on symptomatic management and supportive care.
Research in cell models of MDDS has suggested that supplementing the cells with nucleosides, the precursor building blocks of DNA, can increase the mtDNA copy number in the cells. In our lab, we have generated zebrafish mutant lines modelling different forms of MDDS (dguok, rrm2b, polg). First, the phenotype and pathomechanisms in these fish models will be characterised with different imaging methods and mitochondrial analysis methods. The main aim of the project is to systematically test nucleoside supplementation in these zebrafish models of MDDS and to establish the optimal combination and concentration of nucleosides and refine treatment duration. For this project, we are also working with the pharmaceutical company Zogenix, which will provide modified nucleosides with an increased bioavailability for us to test in our zebrafish models.
If nucleoside supplementation will prove successful in the zebrafish models of MDDS, our long term goal will be to organise a clinical trial for patients with MDDS. The results of this project will form the basis of future translational applications for clinical trials in MDDS in partnership with Zogenix and international experts in the field.
Thompson R, Spendiff S, Roos A, Bourque PR, Warman Chardon J, Kirschner J, Horvath R, Lochmüller H. Advances in the diagnosis of inherited neuromuscular diseases and implications for therapy development. Lancet Neurol. 2020 Jun;19(6):522-532.
Munro B, Horvath R, and Muller JS. Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok -/- zebrafish. Hum Mol Genet. 2019;28(5):796-803.
Viscomi C, and Zeviani M. MtDNA-maintenance defects: syndromes and genes. J Inherit Metab Dis. 2017;40(4):587-99.
Bulst S, Abicht A, Holinski-Feder E, Muller-Ziermann S, Koehler U, Thirion C, et al. In vitro supplementation with dAMP/dGMP leads to partial restoration of mtDNA levels in mitochondrial depletion syndromes. Hum Mol Genet. 2009;18(9):1590-9.
Bulst S, Holinski-Feder E, Payne B, Abicht A, Krause S, Lochmuller H, et al. In vitro supplementation with deoxynucleoside monophosphates rescues mitochondrial DNA depletion. Mol Genet Metab. 2012;107(1-2):95-103.
Investigating the Immunological Basis of Inflammatory Neuropathies
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease in which the patient’s own immune system mistakenly attacks and destroys the protective fatty covering (myelin) of their peripheral nerves, leading to progressive proximal and distal weakness. CIDP (and its many variants) is estimated to affect ~ 1 in 10,000 individuals causing considerable disability. In contrast to multiple sclerosis (where myelin is stripped off nerves of the central rather than peripheral nervous system), very little is known about the immunological basis of CIDP.
By combining CITE-SEq with 5P/V(D)J 10X genomics – the student working on this project will simultaneously measure RNA, protein and perform TCR/BCR profiling of immune cells extracted from the blood and spinal fluid (and where available nerve biopsies) of newly diagnosed individuals with CIDP with the ultimate goal of shedding light on the immunological mechanisms driving this disease and identifying new therapeutic targets. This work will be done in close collaboration with Sarah Teichmann (Head of Cellular Genetics at the Wellcome Sanger Institute).
*This project is still subject to funding confirmation
Elucidation of Initiating Cell and Molecular Pathologies in Human CNS Organoid Models of Neurodegeneration
Several potential projects are available in the Lakatos Lab. Our overarching theme concerns investigations of the relationship between the genetic risks and early sequences of molecular dysfunction that lead to disturbances of genomic stability, transcriptional/signalling networks and proteostasis. In particular, we are addressing how primary changes in a major glial cell population, the astrocytes could influence the function of synapses and neuronal networks. For this, we developed novel human 3D organoid models that recapitulate CNS architecture and pathologies relevant to untreatable neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and to other neurological disorders. These human in vitro platforms are highly accessible for perturbation experiments, and such they provide an unprecedented opportunity to examine precise mechanisms in a 3D multicellular tissue environment that are more reliably mimic cell-interactions than 2D models. In addition to a broad range of tools in cell and molecular biology, we use single cell RNA-sequencing and systems biology approaches to interrogate the breakdown of cell-interactions. A detailed understanding of these fundamental processes and our human translational platform may help develop alternative neuroprotective therapeutic targets for a wide range of neurological conditions.
For further information and recent publications, please visit our Lab Websites (www.lakatoslab.co.uk; www.neuroscience.cam.ac.uk/directory/profile.php?lakand) or Lab Twitter (@LakatosLab). Queries regarding specific projects are also welcome (AL291@cam.ac.uk).
Professor Hugh Markus (email@example.com) – Neurology
All projects are PhD only and not suitable for MPhil
Using genetics to identify treatments for cerebral small vessel disease and vascular dementia
Cerebral small vessel disease (SVD) causes lacunar stroke which itself is the cause of a quarter of all strokes. It is also the most common pathology underlying vascular dementia. Despite its importance there are few treatments to prevent progression of SVD or to prevent onset of vascular dementia in those patients with SVD. Genetics offers a powerful technique to identify new therapeutic pathways which can be targeted, and also to test causality of associations with risk factors. This is vital as intervening for specific risk factors will only improve outcome if they are causally related. The Stroke Research Group has a longstanding international reputation in this area and has published a recent large scale GWAS on genetic risk factors for SVD. The project will involve using this, and further data available within our international collaborations, to both identify novel risk factors for SVD using technologies such as GWAS in combination with metabolomic and proteomic techniques and RNA transcription data, as well as downstream techniques such as Mendelian randomisation to identify and prioritise potential drug treatments. The PhD will involve application of genetic statistical techniques, and although previous experience in this area is not necessary, some statistical/mathematical background and experience of using packages such as R would be an advantage.
Traylor M, Persyn E, … Lewis CM, Markus HS; Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies. Lancet Neurol. 2021 May;20(5):351-361.
Immune cell reprogramming and neuroinflammation in cerebral small vessel disease
Cerebral small vessel disease (SVD) causes a quarter of all strokes and is the most common cause of vascular dementia. Despite its importance we have few treatments for SVD. Increasing evidence implicates inflammation, both systemic (in the blood vessels) and central nervous system, are risk factors in SVD, but which aspects of the dysregulated immune response relate to progression and could be targeted therapeutically remains undetermined. This study will build on existing projects in the Department including the MRC funded MINERVA trial to investigate this area. CNS immune responses will be measured using PK1195 positron emission tomography, as well as data previously acquired in cerebrospinal fluid examination. Systemic immune responses have been determined by a comprehensive blood phenotype programme including cytokine measurement, flow cytometry, cytokine production capacity and single cell RNA sequencing. The relationships between peripheral and central inflammation will be identified, and whether they predict future brain damage (as assessed by diffusion tensor MRI) determined. Much of the data will have been acquired for this study although there is an opportunity for involvement in further MRI and immune phenotyping data collection. A major part of the project will involve analysis of PET and MRI imaging data.
Walsh J, Tozer DJ, Sari H, Hong YT, Drazyk A, Williams G, Shah NJ, O’Brien JT, Aigbirhio FI, Rosenberg G, Fryer TD, Markus HS. Microglial activation and blood-brain barrier permeability in cerebral small vessel disease. Brain. 2021 Jun 22;144(5):1361-1371.
Inhibiting HDAC9 with sodium valproate: A new treatment to prevent stroke?
Large artery stroke caused by atherosclerosis (which causes for example carotid artery stenosis), accounts for about a quarter of all ischaemic strokes. Treatments such as statin reduce recurrent stroke risk but fail to prevent many strokes. Therefore we need better preventative treatments. One way of identifying potential treatments is using genetics. In a genome wide association study (GWAS) we identified the HDAC9 gene as a risk factor for large artery stroke.(1) Subsequent studies have suggested that the HDAC9 protein is over-expressed and that this over-expression could be reduced by sodium valproate, a widely used anti-epileptic drug.(2,3) We are now testing this hypothesis in a phase 2 clinical trial. We will randomise patients between sodium valproate and determine whether the sodium valproate is associated with reduced atherosclerosis (using CT carotid imaging), reduced inflammation within the carotid plaque (using positron emission tomography) and altered carotid plaque structure (using advanced MRI). The student would be involved in recruiting patients to the study from the stroke service, and analysing the imaging outcome data. The project would suit a student who wishes to work on a patient related project, and learn about clinical trial methodology, but also wishes to learn about image analysis.
- Wellcome Trust Case Control Consortium 2 (WTCCC2), Bellenguez C, Bevan S, …, Donnelly P, Markus HS. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet. 2012 Feb 5;44(3):328-33.
- Markus HS, Mäkelä KM, Bevan S, Raitoharju E, Oksala N, Bis JC, O’Donnell C, Hainsworth A, Lehtimäki T. Evidence HDAC9 genetic variant associated with ischemic stroke increases risk via promoting carotid atherosclerosis. Stroke. 2013 May;44(5):1220-5.
- Brookes RL, Crichton S, Wolfe CDA, Yi Q, Li L, Hankey GJ, Rothwell PM, Markus HS. Sodium Valproate, a Histone Deacetylase Inhibitor, Is Associated With Reduced Stroke Risk After Previous Ischemic Stroke or Transient Ischemic Attack. Stroke. 2018 Jan;49(1):54-61.
Multiparametric MRI and PET Biomarkers of Glioblastoma (Co-supervised by Dr Chao Li)
Glioblastoma is the most aggressive brain tumour in adults, characterised by remarkable heterogeneity and dismal outcome. Developing non-invasive imaging biomarkers promises to provide crucial clinical decision support and inform precision medicine. This project aims to identify novel MRI and PET biomarkers to characterise tumour heterogeneity and tumour invasion in glioblastoma, based on our multi-centre imaging clinical trials funded by the CRUK and NIHR. Multiparametric MRI, including perfusion and diffusion MRI and amino-acid PET, will be leveraged to better 1) stratify patients for risk assessment, 2) define invasive margin for more precise surgery and radiotherapy. The prognostic value of the biomarkers will be determined according to patient follow-up and clinical outcomes. Further, our infrastructure, which closely integrates the imaging facilities with clinical instruments, provides exciting opportunities to improve real-world practice.
Artificial Intelligence for Precision Neuro-Oncology (Co-supervised by Dr Chao Li & Prof Carola-Bibiane Schönlieb)
Artificial intelligence (AI) is emerging as a powerful tool for precision medicine and could transform healthcare. In clinical practice, it remains a challenge to monitor brain tumours and early predict progression efficiently. This project aims to develop AI tools for brain tumour monitoring based on longitudinal brain MRI and clinical variables. The algorithm will re-align heterogeneous MRI scans, segment the tumour, perform probabilistic tumour progression prediction with reliable uncertainty quantification. The project will be based on the resources provided by our NIHR AI grant, in collaboration with Cambridge Mathematics of Information in Healthcare (Prof Carola-Bibiane Schönlieb) and Department of Computer Science, University of Bath (Dr Xi Chen). We particularly welcome candidates from the background of medical image analysis, biomedical engineering, computer vision, or mathematics.
Multi-omics Integration for Disease Phenotyping (Co-supervised by Dr Chao Li & Dr Jia Wu)
Radiomics has shown utilities in characterising tumour heterogeneity and predict molecular markers, patient outcomes, etc. Other omics (e.g., genomics, proteomics) and imaging data (e.g., histology images) contain biologically rich information. Integrating multi-omics data is promising to characterise diseases and provide clinically relevant treatment guidance. This project aims to develop a multi-omics integration approach to 1) develop data fusion techniques to integrate radiological images with genetics data to characterise neurological diseases; 2) discover novel multi-omics biomarkers and infer tissue property based on histology images to understand tumour heterogeneity and invasion; 3) investigate the value of the biomarkers in precision medicine. We collaborate with MD Anderson Cancer Centre (Prof Jia Wu) and Wellcome Sanger Institute (Dr Jing Su). We particularly welcome candidates from the background of bioinformatics, biomedical engineering or computer vision.
Ultra-High Field (7T) Magnetic Resonance Imaging (MRI) Development
I lead the 7T MRI physics group in Cambridge. We create new methods to studying the human brain and body using Cambridge’s state-of-the-art Siemens Terra 7T MRI scanner. My group have active collaborations with clinicians in clinical neurosciences, psychiatry, oncology, and cardiology (Papworth), and with experts in cognitive neuroscience. I welcome PhD students to join the group. The following are areas of strong interest from our community, which would be suitable to develop a PhD project in discussion with me.
(i) Imaging glycolytic metabolism in humans by 2H deuterium metabolic imaging (DMI). This is a promising new technique that may compete with 18FDG-PET, but without radiation. We are developing this for use in humans at 7T in the brain and the heart. In the brain, we collaborate with scientists interested in assessing the response of brain tumours to therapy. In the heart, we believe that DMI could be a key method to probe the heart’s preference for fats vs sugars as an energy source, which is believed to play a governing role in heart failure.
(ii) Developing methods for multinuclear imaging in the brain or body. For example, using a new whole-body 31P and 1H coil built for us by Tesla Dynamic Contrast to probe heart and liver oxidative metabolism in collaboration with colleagues at Royal Papworth hospital and Addenbrooke’s. Or in a planned multi-site collaborative study of neuro-metabolism and its changes in disease.
(iii) Developing advanced neuroimaging methods. These include methods for imaging the structure of the cortical layers in neurodegenerative disease. We have an active interest using the parallel transmit capabilities of the 7T Terra scanner to enhance image quality.
(iv) Developing advanced methods to interpret images of blood flow in stroke patients using machine learning / neural network approaches in collaboration with colleagues in Computer Science and stroke physicians.
We look for students with strong maths skills and ideally programming experience in C/C++, python or Matlab (or a willingness to learn). Most of my group have a physical science or engineering background. You will receive extensive training in biomedical imaging.
If you are interested in these projects or other aspects of 7T MRI physics development, please email firstname.lastname@example.org and I will be happy to discuss the details with you.
The Genetic Analysis of Multiple Sclerosis
Through genome-wide association studies and related follow up efforts we have identified over 100 genetic variants that influence the risk of developing multiple sclerosis. These variants map almost exclusively to regulatory regions of the genome that are active in immune cells suggesting that these variants primarily exert their effects by altering the expression of otherwise normal genes in critically important immune cell sub-types. In order to try and understand more precisely how these associated variants influence the development of multiple sclerosis we are undertaking a range of projects.
1) In work already completed we have established that at least two of the associated variants influence the expression of key immune signalling genes in B cell sub-types. These data confirm the importance of B cells in pathogenesis which is in keeping with the latest clinical trial data showing the positive effects of anti-B cell therapies. This project will focus on fine mapping the causal variants underlying observed associations by exploring the expression of key immune genes in B cell subtypes. The work will involve mapping of transcription and chromatin architecture, as well as protein expression and cell function.
2) The highly significant overlap in the genetic architecture of immune mediated inflammatory diseases (IMID) suggests that there are key pathways in the immune system that influence the propensity to autoimmunity. This project will use data from UK Biobank (500,000 genotyped individuals) to dissect out the genetic architecture of these common pathways. The project will then use genomewide methylation mapping to fine map associated variants epigenetically and determine the functional effects of these variants.
3) As part of the Cambridge Single Cell Analysis Core Facility we are undertaking single cell expression profiling in cells from the cerebrospinal fluid and blood of patients and controls. This project will allow a transcriptional based taxonomy of immune cells and identify master transcriptional regulators of relevance in multiple sclerosis. The project will also explore the epigenetic signature and functional effects of identified regulators.
The successful student will work closely with colleagues at the McGill University Epigenomics Mapping which is a leading institution in the International Human Epigenome Consortium (IHEC), the project may include the opportunity for willing students to spend a period of their research in Montreal.
Functional MRI Imaging in Traumatic Brain Injury (PhD/MPhil)
CENTER-TBI is a large European project that aims to improve the care for patients with Traumatic Brain Injury (TBI). The work undertaken in Cambridge will examine the role of MRI in routine TBI imaging and this project will focus on the role of resting state functional MRI in TBI imaging. There is now abundant evidence from functional MRI suggesting that the resting brain is organised in coherent long range networks. The functionality of these networks is easily inferred since they typically track the functional anatomy of networks identified during activation studies. For this reason, the translational potential of resting networks, particularly in patients unable to participate in stimulus driven experiments (e.g. TBI), seems immense but is mostly unrealised. This project will evaluate the usefulness of resting state functional MRI imaging in TBI for understanding and tracking disease processes and prognosticating cognitive recovery. Additionally we will aim to relate functional connectivity patterns to cognitive measures, vulnerability for depression and to functional outcome in general. Experience in neuroimaging, in particular MRI analysis, is required for this project. Some programming experience (e.g, Linux, Matlab, Python) is desirable.
Biomarkers for Risk and Clinical Outcome Prediction of Postoperative Cognitive Dysfunction (PhD/MPhil)
Postoperative cognitive impairment is increasingly prevalent in our aging society. This condition often has an acute phase of Postoperative Delirium (POD) which may then be followed by a more chronic phase of Postoperative Cognitive Dysfunction (POCD), which tends to persist over time. BIOCOG, a European FP7 funded project, aims to establish biomarkers for risk and clinical outcome prediction of POD/POCD. The study population are patients aged 65 to 80 undergoing major elective surgery. The work undertaken in Cambridge will focus on MRI imaging and will investigate whether brain network properties obtained from MRI diffusion tensor imaging (DTI) measures, relate to those obtained from resting state functional MRI data. Structural and functional network properties will be related to neuropsychological and clinical measures. Experience in neuroimaging, in particular MRI analysis, is required for this project. Skills in scientific computing and programming (e.g., Linux, Matlab, Python) are desirable.
The Default Mode Network in Consciousness (PhD/MPhil)
Brain injury management has improved considerably in recent years with resulting significant improvements in outcome. Nevertheless, a small but significant number of survivors do not fully emerge after acute coma and remain in prolonged disorders of consciousness (DoC), including vegetative and minimally conscious states. Long range brain networks, such as the default mode network (DMN), have been shown to be disrupted in DoC, and are partially or fully restored when patients recover cognitive capacity. The functional role of the DMN remains unclear. Although it was initially considered to be a task negative network, recent studies from our group and others have revealed DMN activity/connectivity during a wide range of self-referential and memory-based tasks, as well as altered DMN integrity in a variety of neuropsychiatric disorders. Such data provide support for inferences on the role of the DMN in cognitive capacity and consciousness. An emerging theory is that the DMN acts as a global workspace integrating information from a variety of sources through associations, to make sense of the world at present. The major hubs of the DMN are multisynaptic and are connected to both cortical and subcortical regions rendering this network a suitable candidate for integrating information. Within this emerging theoretical framework this project will utilise fMRI/EEG to focus on the role of the DMN at rest but also importantly during tasks, in a cohort of DoC patients and healthy volunteers. Experience in neuroimaging and/or electrophysiology is required for this project. Skills in scientific computing and programming (e.g, Linux, Matlab, Python) are desirable.
Machine Learning Supported Application of Advanced Neuromonitoring for Individualised Guided Management of Acute Traumatic Brain Injury in Intensive Care
Traumatic brain injury is an extremely complex pathology with a highly dynamic time profile developing over the course of the very first days in a critical care unit. Secondary pathological processes occur resulting from the initial trauma, with severe and often fatal consequences. The key aspects of the patient treatment/management during this period are: prevention (if possible), detection and subsequent alleviation of those insults. Monitoring of various metrics, like pressures, flows and electrical activities from the body and the brain provides some indications for the onset and severity of those processes. However, interpretation of those measurements as presented by the patient monitors, as well as the electronic record systems, is still rather simplistic and largely based on trivial metrics, like hourly mean values of individual measurements. In addition, critical values for those individual measurements are population based, and thus do not reflect inter-individual differences and are not adjusted over the course of the patient stay in ICU. The aim of the project is to develop sensitive and robust metrics based on multi- parameter, continuous neuro-monitoring that would be better suited for guiding therapeutic interventions in traumatic brain injury patients in ICU. The project will involve application of cutting-edge time series analysis methods to a large number (1300+) of data sets (at full, waveform level, temporal resolution) collected by the group from neuro ICU in Cambridge over the last decades as well as the new, prospective, data set to be collected in the neuro intensive care unit. As part of the project, methods for detecting early onsets of adverse events will be developed and algorithms for real time calculation of dynamic management targets proposed and implemented in software, building on top of the flagship software developed by the group ICM+ (https://icmplus.neurosurg.cam.ac.uk) and extending it’s functions with Python plugins. Furthermore, development and implementation of methods for automated data curation/pre-processing based on machine learning approaches will also form part of this project to ensure high quality of the input data for the decision making support algorithms.
Development of New, Robust, Approaches for Continuous Monitoring of Vascular and Brain Tissue Physical Properties in Traumatic Brain Injury Patients
Dynamic, pathological, biochemical processes triggered by a severe traumatic brain injury lead to brain swelling, often with devastating, persistent consequences to the brain tissue, frequently culminating in the patient’s death. Various physical properties of the brain vasculature and cerebral tissue controlling the cerebral blood flow naturally reflect those processes but they are impossible to monitor directly using currently available technology.
Instead, one must rely on surrogate measurements, like pressures and flows in the brain, and analysis of patterns carried by the temporal changes in those measurements at various time scales. Many metrics have been proposed, with some more successful then others, each of them carrying certain assumptions and gross simplifications. The purpose of this project is to use mathematical (system) modelling as well as statistical learning approaches to build on previous discoveries but ultimately aiming to provide a simplified, robust, and readily interpretable set of complemental metrics reflecting the physical properties of the cerebral vasculature along with the accuracy indicators. The project will take advantage of a large number (1300+) of data sets (at full, waveform level, temporal resolution) collected by the group from the neuro ICU in Cambridge over the last decades. The new metrics will be ultimately implemented for real time use at the bedside using tools included in the brain monitoring software written by the group ICM+ (https://icmplus.neurosurg.ca m.ac.uk), and by extending its battery via Python plugins. Appropriate visualisation methods for presentation of those metrics to the clinician at the bed-side will also be developed.
*Note: These project would suit graduates in Biomedical Engineering, Physics, Mathematics, Signal Processing, Electrical Engineering, and Computer Science.
Mathematical Modelling of Brain Haemodynamics and Pressure-Volume Compensation (co-supervised by Prof Marek Czosnyka)
Dynamical properties of cerebral blood flow (CBF) and cerebrospinal fluid circulation (CSF) can be modelled by a structure of nonlinear differential equations (1). Models describe such phenomena as autoregulation of blood flow, brain venous blood outflow, compensatory role of CSF circulation, etc (2). They are relevant to understanding of pathophysiological mechanisms after traumatic brain injury, subarachnoid haemorrhage, stroke, in hydrocephalus and in idiopathic intracranial hypertension. Database of recorded clinical signals is available for verification or identification of successful modelling structures. Project will be focused on further refinement of the existing models, including their application for non-invasive assessment of intracranial pressure (3), asymmetry of CBF and phenomenon related to collapse of cerebral venous sinuses. Project suits neuroscientists with strong computer skills (including writing own codes, advanced Matlab, etc).
Further readings (4). 1. Czosnyka et al. J Neurol Neurosurg Psychiatry. 1997 Dec;63(6):721-31. 2. Piechnik et al. J Cereb Blood Flow Metab. 2001 Feb;21(2):182-92. 3 Kashif FM et al. Sci Transl Med. 2012;4(129):129ra44. 4.http://www.neurosurg.cam.ac.uk/pages/brainphys/index.php
Methodology of Clinical Tests for Assessment of Cerebral Autoregulation after Traumatic Head Injury (co-supervised by Prof Marek Czosnyka)
Various methods exist for assessment of autoregulation of Cerebral Blood Flow (CBF). They incorporate different modalities: arterial blood pressure, intracranial pressure, blood flow velocity, cerebral perfusion pressure, and brain tissue oxygenation (1). Dynamical tests of cerebral autoregulation include time series analysis, analysis of models based on transfer function, wavelet decomposition, non-linear decomposition, etc. The aim of the project is to compare various methodologies, various modalities and compare them from the point of view of clinical utility in a group of head injured patients. Strong emphasis will be put on feasibility studies of new and existing methodologies at the bedside: such as a concept of ‘optimal’ Cerebral Perfusion Pressure or individualized threshold of intracranial pressure. Also links between brain physics modalities and electrophysiology and biochemistry will be of interest Project is ideal for a person having medical or biological background with strong practical computer skills.
Further readings (4). 1. Czosnyka M et al. Neurocrit Care. 2009;10(3):373-86. 2. Aries MJ et al. Crit Care Med. 2012; 40(8):2456-63. 3. Lazaridis C et al. J Neurosurg. 2014 Apr;120(4):893-900. 4.http://www.neurosurg.cam.ac.uk/pages/brainphys/index.php
Mechanisms Controlling Cerebrospinal Fluid Dynamics (co-supervised by Prof Marek Czosnyka)
In various pathologies, reasons for intracranial hypertension may be different. In hydrocephalus: disturbed outflow of Cerebrospinal Fluid (CSF); in idiopathic intracranial hypertension (IIH): obstruction of venous blood outflow; in head injury and stroke: brain edema, increased vasogenic component of ICP, failing regulation of cerebral blood volume or all three factors together, etc. (1) This is an interdisciplinary project requiring good background in clinical neurosciences, brain physics and computational methods (time series analysis, dynamic modelling). Clinical applications are envisaged (but not limited to) mainly in area of hydrocephalus (2) and IIH . Vast database of recorded signals and clinical material (over 5000 cases) can be used for mastering new methodologies of processing and modelling (3). Strong knowledge of brain imaging techniques will be essential. Project is ideal for a person having medical or biological background with strong practical computer skills.
Further readings (4). 1. Czosnyka M, Pickard JD. J Neurol Neurosurg Psychiatry. 2004;75(6):813-21. 2. Weerakkody RA et al. Acta Neurol Scand. 2011;124(2):85-98. 3. Varsos GV et al.
(PhD or MPhil, PhD preferable)
Neural Stem Cell – Niche Interactions in Mitochondrial Disease
Mitochondrial diseases are caused by defects in genes required for energy production and oxidative phosphorylation (OxPhos). We find it intriguing that some patients with mitochondrial disease present late in life, with very tissue-specific phenotypes. It seems that not all cells and tissues are equally susceptible to mitochondrial disease.
The objective of this project is to study how specific cells respond to mitochondrial dysfunction within the context of a living organism. We plan to find out whether interactions between different cell types, may render cells and tissues more, or less, vulnerable to mitochondrial disease. The project will focus on the developing Drosophila brain and aims to investigate how neural stem cells interact with their surrounding glial cells in the stem cell niche. Possibility exists to translate findings from Drosophila into mouse or mammalian cell culture
We take advantage of the powerful genetics of Drosophila and combine targeted genetic manipulations with confocal and super-resolution imaging, biosensors to perform in vivo metabolite measurements and innovative sequencing approaches to study how different cell-types within the post-embryonic brain of a living organism interact and respond to mitochondrial dysfunction.
Impact of Mitochondrial Dysfunction on Nuclear Chromatin Dynamics during Brain Development
There is a constant interaction between mitochondria and the nucleus, with changes in each compartment affecting homeostasis in the other. DNA replication, histone modification and transcription all have specific metabolic requirements, and these may provide a direct link between gene expression and the metabolic status of the cell, tissue or organism.
The objective of this project is to uncover novel communication between mitochondria and the nucleus, and find mechanisms that buffer transcriptional output when confronted with cell- or tissue-wide changes in mitochondrial activity. Taking advantage of genetically encoded metabolite sensors, we will study nucleus/cytoplasm metabolite ratios in vivo in the Drosophila brain, and determine how these are affected by acute and chronic mitochondrial dysfunction. We next aim to profile the cell-type specific genome-wide impact of metabolic changes on transcription and histone modifications in vivo in NSCs and glia.
The project will rely mostly on confocal imaging, CRISPR/Cas9-mediated genome editing and novel cell-type specific DamID-seq technology that we previously developed.
– Mosteiro L, Hariri H, van den Ameele J. Metabolic decisions in development and disease. Development. 2021 Jun 1;148(11):dev199609.
– van den Ameele J, Hong YT, Manavaki R, et al. [11C]PK11195-PET brain imaging of the mitochondrial translocator protein in mitochondrial disease. Neurology. 2021;96(22):e2761-e2773.
– van den Ameele J, Li AYZ, Ma H, Chinnery PF. Mitochondrial heteroplasmy beyond the oocyte bottleneck. Semin Cell Dev Biol. 2020 Jan. 97:156-66.
– van den Ameele J, Brand AH. Neural stem cell temporal patterning and brain tumour growth rely on oxidative phosphorylation. eLife. 2019;8:e47887.
– Aloia L, McKie M, Vernaz G, et al. Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration. Nature Cell Biol. 2019 Nov;21(11):1321-33.
Modelling of Diffusion Weighted MRI
Recent methodological advances in diffusion weighted MRI allows for more complex modelling of anatomical parameters. There is interest in more pathologically meaningful metrics (such as axonal diameter measurements), those that more accurately reflect tissue complexity (such as kurtosis) and metrics that are robust and comparable across multi-centre studies. For such problems the optimal pulse sequences for such acquisitions are undetermined. This project will be to trial both different acquisition schemes and modelling, and apply these methods to clinically relevant research questions. The project will benefit from a research collaboration agreement with Siemens and access to both 3T and 7T field strength scanners for data acquisition. The project will be appropriate for a candidate with a background in Physics and strong mathematical skills, and an interest in translating methodology to provide novel and practical research tools.
Methods for Quantitative MRI
The contrast of magnetic resonance datasets is conventionally usually dimensionless; in order to derive meaningful quantitative measures (such as T1, T2, diffusion metrics etc) longer acquisitions and further modelling are required. However, for longitudinal studies and for multi-site studies (including different hardware platforms), repeatable and meaningful metrics are increasingly required (quantitative MRI; qMRI). This project is to study current strategies for robust qMRI including faster data acquisition and/or synthetic approaches. It will benefit from ongoing local longitudinal studies and the availability of multi-site datasets for comparison. The project will be appropriate for a candidate with a background in Physics and strong mathematical skills, and an interest in translating methodology to provide novel and practical research tools.
Alternative Analysis Strategies for Disorders of Consciousness Imaging Data
One of the most challenging clinical populations imaged within the Wolfson Brain Imaging Centre is that of patients with Disorders of Consciousness. The data from these participants is very valuable but also compromised by motion (for all data), and persistence of response (for functional data). Alternative methods are required to assess the information content of such datasets where participants cannot be assumed to follow task instructions.
This project will be to use previously acquired data, potentially correlating with behavioural data from outside of the scanner, in collaboration with the Cambridge Research into Consciousness (CRIC) group. The project will be appropriate for a candidate with a background in Physics/Maths/Statistics and strong mathematical/statistical skills.
All projects will benefit from strong links with the Cambridge Mathematics in Healthcare Hub (CMIH), and ongoing collaborative projects with disciplines including cognitive neuroscience, psychiatry, neurology, radiology and traumatic brain injury.
I am an academic neuro-ophthalmologist with a major research interest in mitochondrial genetics and inherited eye diseases. My research group is focused on new gene discovery and we are using a multipronged approach to dissect the disease pathways contributing to progressive neuronal loss and blindness, including zebrafish models and patient-derived induced pluripotent stem cells. I coordinate a specialist clinical service for patients with mitochondrial eye diseases in Cambridge and London. Over the past 20 years, we have established a national cohort of patients with inherited optic neuropathies, and we are using this unique resource for deep phenotyping, biomarker profiling and to push forward with an active translational research programme, including gene therapy.
I have long-standing collaborations with other principal investigators in the Cambridge Centre for Brain Repair, the Cambridge MRC Mitochondrial Biology Unit and the UCL Institute of Ophthalmology in London. This extensive research network will provide the student with access to a wide source of expertise, tailored supervision and the opportunity to develop a broad skill set as the project evolves.
- Elucidating the missing heritability in inherited optic neuropathies
- Dissecting disease mechanisms using iPSC-derived retinal ganglion cells
- Zebrafish models of Wolfram syndrome and therapeutics
- Gene therapy for inherited optic neuropathies