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
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Applications for the Academic year October 2023- September 2024 open 15th September, Funding application deadlines are as follows:
Gates US: 12th October 2022 (now closed)
Postgraduate Funding Competition (all other funders including Gates Cambridge): 1st December 2022 (now closed)
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 Michaelmas 2023 are still 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.
Edward Avezov (ea347@medschl.cam.ac.uk) – UK Dementia Research Institute
(PhD or MPhil, PhD preferable)
Endoplasmic Reticulum Transport and Morphoregulation in Neuron (Patho) Physiology
The Endoplasmic Reticulum (ER) is a multifunctional organelle, shaped as a contiguous network of membranous pipes extending throughout the cell periphery. Its morphology benefits intercellular communication, allowing controlled distribution of ER luminal solutes (e.g. Ca2+ in muscular/neuronal signalling) and membrane-bound components to distant sites and adjoining organelles. Mounting data points to a critical role of ER morphology regulation in neuronal functioning. This is prominently exemplified by the direct association of ER morphogens (aka ER shaping proteins) with neuropathologies such as Hereditary Spastic Paraplegia and dementia-related diseases. We seek understanding of how ER’s network integrity, morphological regulation and luminal transport support neuronal cell functioning, with a view to identifying new intervention targets for prevention of neurodegenerative avalanche. The projects on this theme involve editing of candidate genes in cells with potential to differentiate to neurons/glia, and analysing the consequences of the targeted mutagenesis on structure/function of neuronal ER using live cell microscopy techniques such as super-resolution imaging and single-particle tracking and neuronal activity analyses e.g. calcium imaging (carried out in collaboration with optics physicists and computer scientists). Focused projects exploring benefits of modulation (e.g. induced degradation) of candidate ER-morphogens for neuronal health and axonal regeneration are also available.
Monitoring Protein Aggregation and Aggregates’ Handling by Neurons
Cells maintain dynamic protein homeostasis, ensuring a manageable load of unfolded proteins and adequate availability of the protein folding machinery. In healthy proteostasis nascent proteins are chaperoned through the functional folding route avoiding misfolding and aggregation. Dementia-related pathologies are associated with a disbalanced proteostasis manifested in the aggregation of several particularly aggregation-prone proteins (e.g. TAU, a-betta, a-synuclein etc.). In this project, we develop live-cell- imaging-compatible aggregation-sensing techniques to study cellular mechanisms and factors behind aggregation-predisposing cellular conditions, and those involved in aggregates’ turn-over. The aggregation monitoring techniques include biochemical assays and microscopy-based techniques such as Fluorescence Lifetime Imaging. The interplay between cellular stress, its response and protein aggregation handling is also explored.
Endoplasmic Reticulum Associated ROS and Redox Dynamics in Neurons
Reactive Oxygen Species (ROS) are utilised by cells as secondary messengers. Fine time-space regulation of ROS is vital to avoid their toxicity. Elevated ROS (oxidative stress) accompany dementia pathologies. Endoplasmic Reticulum (ER) and its insulated and regulated redox system emerges as key player in the physiological and controlled supply of certain ROS and may also act as a source of the pathological oxidative stress. The project aims to explore this notion and identify the factors endowing the ER with its ROS production, storage and supply capabilities. Work involves utilising (and further development) of genetically encoded probes for live-cell redox and ROS imaging in genetically and pharmacologically manipulated neurons.
Professor Roger Barker (rab46.cam.ac.uk ) – Neurology
Understanding Microglial Heterogeneity in Parkinson’s Disease (PhD only)
The role of microglia in Parkinson’s disease (PD) has gained a lot of traction in recent years. However, little is known about any underlying differences in the microglial profile of people with PD at different stages of disease. The project would entail deriving microglia from pre-existing patient induced pluripotent stem cell (iPSC) lines, or from patient peripheral blood mononuclear cells (PBMCs). The objective is to profile any underlying differences in microglia derived from PD patients at different stages throughout disease and what potential role these differences may play in neuroinflammation and compare these to control microglial lines.
The work will link closely with current ongoing projects trying to understand the immunogenicity of different cell types in stem cell therapies for PD.
Professor Patrick Chinnery pfc25@medschl.cam.ac.uk
Mitochondrial Mechanisms in Hereditary Spastic Paraplegia Type 7 (PhD only) fully funded project
(Joint supervision with Prof Evan Reid: Medical Genetics and the Cambridge Institute for Medical Research)
The Hazel Satchell Studentship – Home students only eligible to apply, deadline 1st December in line with funding deadlines. The studentship is fully funded and includes an annual stipend for 3.5 years at the MRC minimum rate (currently £17,688), University fees and research costs.
Hereditary spastic paraplegia (HSP) is a genetic disorder which causes progressive leg stiffness which ultimately prevents walking and has no cure. Autosomal recessive mutations in the gene SPG7 are a common cause of HSP, but it is not known how they cause the progressive disability. Preliminary evidence suggests that people with SPG7 collect mutations affecting their mitochondrial DNA (mtDNA) during life. This affects the function of nerve and muscle cells and contributes to the clinical problems that patients experience. This project aims to determine whether the loss of the SPG7 protein causes mtDNA mutations in human i3 neurons generated in the laboratory. The student will develop laboratory and computational skills to harness state-of-the-art single cell sequencing and transcriptomic analysis, and study the effects of the mutations on nerve cell function, and particularly whether the mutations cause nerve cells to die early. If this is the case, we will look for mechanisms that slow down the accumulation of the mutations by systematically removing (knocking out) genes that might be relevant by gene editing. This will lead to the identification of drug targets which we will test using panels of drugs (small molecule libraries). The ultimate aim is to find new treatments that slow down the progression of SPG7-HSP and may reverse the condition over time.
Applications must be made via the University online application portal here
Professor Michael Coleman mc469@cam.ac.uk
Axon Degeneration Mechanisms in Human Disease (PhD or MPhil)
Research in our laboratory showed that a preventable mechanism of axon degeneration, known as programmed axon death or Wallerian degeneration, is shared by injury and disease, and is regulated by NAD and related metabolites. Programmed axon death is executed by the NAD-degrading enzyme SARM1, whose activity in axons is kept at a low, safe level by the NAD-synthesising enzyme NMNAT2. When NMNAT2 activity is impaired, or its delivery into axons by axonal transport is blocked, SARM1 becomes activated and axons die. The human consequences include paralysis, gain- or loss of pain (sometimes leading to limb amputation), blindness, movement disorders and dysregulation of vital organs.
Recent studies show this pathway can be activated by loss- and gain-of-function (LoF, GoF) mutations in NMNAT2 and SARM1 respectively. These gene variants have already been associated with polyneuropathies and ALS, disorders of long human axons but animal data suggest much wider disease relevance, including in Parkinson’s disease, glaucoma, multiple sclerosis, and peripheral neuropathies due to diabetes, cancer chemotherapy, viruses and mutation of other genes. The pathway can also be activated by environmental risk factors, including certain toxins and viruses.
The Coleman Lab has several PhD and MPhil projects available to enhance understanding of how this pathway contributes to specific human neurological disorders. These studies will help indicate in which diseases, and in which specific patients, SARM1-blocking drugs currently under development can be most effectively targeted to prevent and treat human disease. They will also enhance our understanding of the function and regulation of NMNAT2 and SARM1.
Two projects will generate a comprehensive mutation map of SARM1 and NMNAT2 respectively, because the identification of more function-altering variants is one of the keys to establishing pathway involvement in further human disorders. We will identify protein sequences, and specific amino acids, whose alteration confers GoF or LoF, test whether such effects are dominant or recessive, and determine whether they are exerted by directly altering enzyme activity, changing how that enzyme activity is regulated, by altering protein stability, or by other mechanisms. Protein regions devoid of natural variants will also be studied using artificial mutations, in order to determine whether changing these regions is particularly pathogenic and thus selected against during human evolution.
A third project will study the activation of SARM1 by viruses in collaboration with virology groups in Cambridge and Glasgow. We aim to identify how specific viruses cause SARM1-dependent axon death, which amino acid changes alter the risk of viral-induced axon loss, and whether such mechanisms are drivers of viral neuropathies.
All three projects will provide extensive experience of molecular biology (DNA cloning, site-directed mutagenesis), cell culture (murine primary neuronal cultures and hiPSC-derived neurons), microscopy (fluorescent, phase contrast), enzyme and metabolite analysis (enzyme assays, NAD-Glo, collaborative use of HPLC and mass spectrometry), and bioinformatics (UK Biobank, 100,000 Genomes Project, etc). The results will be highly relevant to drug development for neurological disorders. Successful applicants will interact with collaborators in Italy, USA, UCL, KCL, Oxford, Glasgow and Cambridge, and work within a highly supportive team culture where valuing and developing our colleagues is seen as the best way to do great science.
Contact for enquiries: mc469@cam.ac.uk
Useful references
Coleman and Hoke (2020) Nat Rev Neurosci 21: 183-196
Coleman (2022) Neurotherapeutics In Press
Professor Alasdair Coles (ajc1020@medschl.cam.ac.uk ) – Neurology
Brain Repair in Adults and Children with Multiple Sclerosis
(co-supervised by Dr Nick Cunniffe)
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. We are using complimentary techniques to measure remyelination and neuroprotection: electrophysiological techniques (visual evoked potentials and eye tracking), blood markers of brain injury (such as neurofilament light) and structural imaging (optical coherence tomography and magnetic resonance imaging). We study children and adults with multiple sclerosis in the setting of both observational studies and clinical trials. We also research other demyelinating conditions like neuromyelitis optica. This project is suitable for anyone interested in studying human physiology. Clinical training is not a requirement.
Dr Rita Horvath (rh732@medschl.cam.ac.uk) – Neurology
Identifying Novel Genes and Developing 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.
References:
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. Jennings MJ, Kagiava A, Vendredy L, Spaulding EL, Stavrou M, Hathazi D, Grüneboom A, De Winter V, Gess B, Schara U, Pogoryelova O, Lochmüller H, Borchers CH, Roos A, Burgess RW, Timmerman V, Kleopa KA, Horvath R. NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice. Brain. 2022 Feb 10:awac055
3. Bansagi B, et al, Chinnery PF, Horvath R. Genetic heterogeneity of motor neuropathies. Neurology. 2017 Mar 28;88(13):1226-1234.
4. 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.
Unlocking mt-tRNA Synthetases: Impact on Neurodegeneration
(co-supervised with Dr Denisa Hathazi)
Making proteins is fundamental for energy production, fighting disease, growth and development. In a family of rare, neurodegenerative diseases, known as mitochondrial aminoacyl-tRNA synthetase (mt-aaRS) diseases, this process is disrupted at its most fundamental level: the attachment of amino acid ‘building blocks’ to the growing protein.
Mt-aaRS diseases affect the mitochondria of the cell, disrupting energy production. In each disease variant, it is the attachment of a different amino acid that is inhibited, resulting in a diverse array of problems affecting different organs in the body. For example, deficiency in the attachment of one amino acid might lead to heart failure, while deficiency in another to neurodegeneration, seizures, ataxia or spasticity. Research in mt-aaRS diseases has been largely focused on studying individual variants. This project will study neurodegenerative mt-aaRS diseases in the laboratory, to understand this disease family holistically.
Our aim is to build a comprehensive database including children afflicted worldwide and utilize cutting edge technologies including human brain organoids, single cell transcriptomics, zebrafish models, gene editing and advanced bioinformatics to identify the biological pathways and understand why the brain is more affected while other organs protected. Knowledge gained through each of these components will guide targeted therapies for patients with mt-aaRS and other neurodegenerative mitochondrial diseases affecting nearly 1.5 million worldwide.
References
1. D’Souza AR, Minczuk M. Mitochondrial transcription and translation: overview. Essays Biochem. 2018 Jul 20;62(3):309-320.
2.Boczonadi V, Ricci G, Horvath R. Mitochondrial DNA transcription and translation: clinical syndromes. Essays Biochem. 2018 Jul 20;62(3):321-340. Print 2018 Jul 20. Review.
3.Boczonadi V, Meyer K, Gonczarowska-Jorge H, Griffin H, Roos A, Bartsakoulia M, Bansagi B, Ricci G, Palinkas F, Zahedi RP, Bruni F, Kaspar B, Lochmüller H, Boycott KM, Müller JS, Horvath R. Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons. Hum Mol Genet. 2018 Jun 15;27(12):2187-2204.
4. Boczonadi V, Jennings MJ, Horvath R. The role of tRNA synthetases in neurological and neuromuscular disorders. FEBS Lett. 2018 Mar;592(5):703-717.
Targeting the Cellular Metabolism to Treat Tissue-Specific Mitochondrial Diseases (PhD only) Fully Funded
*The studentship is fully funded and includes an annual stipend for 4 years at the MRC minimum rate (currently £17,668), University fees and research costs.
(co-supervised with Dr Denisa Hathazi)
Mitochondria are specialised cell organelles which transform nutrients into energy. Mitochondria are made from proteins coded by DNA present inside mitochondria (mtDNA) and in the cell nucleus (nDNA), and mutations in either genome can cause mitochondrial diseases.1 Mitochondrial diseases affect the skeletal muscle, peripheral nerves, brain or other organs and there are no effective cures.2
We previously studied some ultra-rare reversible infantile mitochondrial diseases caused by abnormal synthesis of mtDNA-encoded proteins linked to a mutation in the mtDNA (m.14674T>C) or nuclear genes (TRMU, EARS2)3-4, characterised by severe muscle weakness in infants, followed by spontaneous recovery after 6 months of age.
We showed that affected individuals carry mutations in their mitochondrial or nuclear DNA impinging on the synthesis of mitochondrial proteins, associated with changes in metabolism of some amino acids (cysteine, glutamic acid) and activation of the integrated stress response (ISR).4 The ISR is a major signalling pathway that allows eukaryotic cells to sense stress and adapt to it. In a cascade of metabolic events in affected infants the availability of amino acids (cysteine, glutamic acid) is key for recovery.4 The factors identified in reversible mitochondrial diseases are probably of general importance for other mitochondrial and neuromuscular diseases.
This project will explore whether manipulating the ISR and some key amino acids can be used to treat non-reversible mitochondrial myopathies. We will study the effect of depletion and supplementation of amino acids in human cells and in a zebrafish model. In parallel, we will explore the effect of special diets in patients.
References:
1. Gorman, G.S., et al. Mitochondrial diseases. Nat Rev Dis Primers 2, 16080 (2016).
2. Boczonadi, V., Bansagi, B. & Horvath, R. Reversible infantile mitochondrial diseases. J Inherit Metab Dis 38, 427-435 (2015).
3. Horvath, R., et al. Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy. Brain 132, 3165-3174 (2009).
4. Hathazi, D., et al. Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency. EMBO J. 39(23):e105364. (2020)
Applications must be made by 1st December via the University online application portal here
Testing New Treatment Options in Zebrafish Models of Mitochondrial Diseases
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.
References:
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.
Trial Readiness in Ataxia Telangiectasia (AT)
(co-supervised with Dr Anke Hensiek)
Ataxia-telangiectasia (AT) is a rare incurable disorder caused by variants in the AT-mutated (ATM) gene. Early loss of ambulation due to neurodegeneration, immunodeficiency and malignancy, with average survival <30 years is seen in classic AT; individuals with the variant form have milder, more variable presentations. Current obstacles to evaluate novel treatments include the lack of validated outcome and progression disease biomarkers and a suitable disease model to assess therapeutic targets.
Antisense oligonucleotide (ASO) therapies present a promising disease-modifying treatment (e.g. SMA), and were recently applied to target single variants (“n-of-1” ASO trials). A deep intronic ATM splice-variant c.5763-1050A>G (present in 13 patients in our cohort) among others is an excellent ASO target, but the lack of validated outcome measures and biomarkers hampers clinical trial evaluation.
To evaluate therapeutic interventions, we will retrospectively and prospectively study AT patients to identify robust clinical outcome measures and biomarkers supporting clinical trials. Retrospective analysis will define clinical progression in 100 AT patients over 10 years, followed by 2 years of prospective, quantified run-in data in a trial-ready AT subpopulation carrying c.5763-1050A>G, amenable to splice modifying ASO therapy. Collection of biomaterials from a subpopulation of AT patients enables preclinical studies of novel therapeutics.
References:
1. Schon K, van Os NJH, Oscroft N, Baxendale H, Scoffings D, Ray J, et al. Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia. Ann Neurol. 2019;85(2):170–80.
2. Lee J-H, Paull TT. Cellular functions of the protein kinase ATM and their relevance to human disease. Nat Rev Mol Cell Biol. 2021;22(12):796-814..
3. Sutton IJ, Last JIK, Ritchie SJ, Harrington HJ, Byrd PJ, Taylor AMR. Adult-onset ataxia telangiectasia due to ATM 5762ins137 mutation homozygosity. Ann Neurol. 2004;55(6):891–5.
4. Tiet MY, Nannoni S, Scoffings D, Schon K, Horvath R, Markus HS, et al. White Matter Hyperintensities and Cerebral Microbleeds in Ataxia-Telangiectasia. Neurol Genet. 2021;7(6).
5. van Os NJ., Hensiek A, van Gaalen J, Taylor AMR, van Deuren M, Weemaes CMR, et al. Trajectories of motor abnormalities in milder phenotypes of Ataxia Telangiectasia. Neurology. 2018;92(1):e19–29.
6. Tiet MY, Horvath R, Hensiek AE. Ataxia telangiectasia: What the neurologist needs to know. Pract Neurol. 2020;20(5):404–14.
The Role of Mitochondrial Dysfunction in Ataxia Telangiectasia – (MPhil only)
(co-supervised with Dr Anke Hensiek)
One of the key features in Ataxia-Telangiectasia (A-T) is the neurological phenotype, however the mechanism by which altered DNA repair causes neurodegeneration is poorly understood. Our group and others have shown that there is extreme clinical variability in the phenotypic expression and neurological severity between some A-T patients which cannot be fully explained by ATM kinase levels alone (Schon et al., 2019). This indicates that factors other than ATM expression exist which modulate neurodegeneration in A-T.
Increasing evidence suggests that mitochondrial dysfunction influences the pathogenesis of A-T. We will study whether mtDNA repair mechanisms are also affected and contribute to neurodegeneration in A-T utilising patient fibroblasts and induced neuronal progenitor cells (iNPCs). This study will improve our understanding of the disease mechanism in A-T, the role of mitochondria in neurodegeneration and assist our search for novel therapeutic targets.
b) methods used/skills to be acquired
studying mtDNA maintenance and repair and mitochondrial function in fibroblasts and iNPCs (immunoblotting, Seahorse, blue-native PAGE)
References;
1. Schon, K. et al. (2019) ‘Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia’, Annals of Neurology, 85(2), pp. 170–180.
2. Munro, B., Horvath, R. and Müller, J. S. (2018) ‘ Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok −/− zebrafish ’, Human Molecular Genetics, 28(5), pp. 796–803.
3.Boczonadi, V. et al. (2018) ‘Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons’, Human Molecular Genetics, 27(12), pp. 2187–2204.
4. Bulst, S. et al. (2012) ‘In vitro supplementation with deoxynucleoside monophosphates rescues mitochondrial DNA depletion’, Mol Genet Metab, 107(0), pp. 95–103.
5. Bulst, S. et al. (2009) ‘In vitro supplementation with dAMP/dGMP leads to partial restoration of mtDNA levels in mitochondrial depletion syndromes’, Human Molecular Genetics, 18(9), pp. 1590–1599.
Dr Joanne Jones (jls53@medschl.cam.ac.uk) – Neurology
Investigating the Immunopathogenesis of Paediatric Acquired Demyelinating Syndromes (PhD only)
The term paediatric acquired demyelinating syndrome (ADS) encompasses a range of inflammatory demyelinating disorders of the central nervous system (CNS), including: acute disseminated encephalomyelitis (ADEM), transverse myelitis (TM), optic neuritis (ON) and neuromyelitis spectrum disorder (NMOSD).
In this project, single-cell sequencing technologies will be used to characterize the cellular composition of blood and cerebrospinal fluid (CSF) of patients and age-matched controls. Given that immune responses against myelin antigens, such as myelin oligodendrocyte glycoprotein (MOG), are believed to drive these disorders, we will also determine the antigen receptor repertoires binding to selected myelin antigens using state-of-the art dextramer technology. Our goals are (i) to shed light on the immune pathology of these understudied disorders and (ii) in the longer-term, identify reliable biomarkers, at the level of gene expression and/or TCR meta-clonotypes, which can be used to predict disease course, and enable improved monitoring and intervention strategies.
This project will be carried out in close collaboration with researchers at the Human Technopole and KAIST institute. As well as learning about single-cell sequencing and the analysis/interpretation of single cell data, the successful student will lead a parallel project aimed at characterising T regulatory cells in these disabling disorders of childhood.
*This project is still subject to funding confirmation (outcome of funding expected late October/early November) Applicants can still apply for this project.
Dr Maura Malpetti (mm2243@medschl.cam.ac.uk) – Neurology
Inflammation in frontotemporal Lobar Degeneration: A Multimodal Approach towards New Therapeutics (MPhil or PhD)
(Co-supervised with Professor James Rowe)
Neuroinflammation is an important driving mechanism in all diseases caused by frontotemporal lobar degeneration, and predicts clinical progression. Our research programme uses PET imaging and advanced blood analyses to quantify and characterise inflammation in people with frontotemporal dementia and progressive supranuclear palsy. Assessing how in vivo markers of inflammation relate to pathology and clinical outcomes is a crucial step to define their utility for clinical practice and future trials. PET imaging captures brain distribution and quantity of inflammation, while blood markers are more scalable and repeatable in large populations and in clinical trials. These tools can provide additive and complementary information on microglia-mediated inflammatory cascades. Your PhD studentship would be tailored according to your skills and interests, within our program’s aims to: (I) determine the diagnostic and prognostic utility of PET and blood markers of inflammation; (II) clarify the link between inflammation and other neuropathological processes, with a multimodal approach using in vivo markers for tau burden, atrophy, and synaptic loss; (III) validate these tools with post-mortem data.
For any queries regarding specific projects and further information, please email mm2243@medschl.cam.ac.uk .
Professor Hugh Markus (hsm32@medschl.cam.ac.uk) – 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.
Further reading:
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. The student will join on ongoing programme looking at the role of a dysregulated immune response and increased CNS inflammation in pathogenesis of SVD and cognitive decline. The programme uses advanced brain imaging to assess CNS inflammation (PK1195 positron emission tomography) and white matter damage (diffusion tensor imaging). It corelates this with detailed immunophenotyping of the blood and CSF, in collaboration with Prof Ziad Mallat in Cardiovascular Science. Systemic immune responses are being 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 but there is an opportunity for involvement in further MRI and immune phenotyping data collection.
Further reading:
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.
Why is the Disease Severity so Variable in Familial Causes of Stroke?
There are a number of familial causes of stroke, most of which cause the small disease type of stroke, in which strokes occur in the territory of the small perforating arteries supplying the deep structures within the brain. Such patients often also suffer migraine with aura, and can develop vascular dementia later in life. The most common of these conditions is CADASIL, but more recently a number of other similar conditions such as HTRA1 and COL4A1/2 execs have been described. We used to think such conditions were rare and such diseases were highly penetrant i.e. most patients with disease mutations had early onset stroke and dementia. However we now realise that the phenotype is much more variable with some patients suffering early-onset disease while others remaining healthy into later life. Emphasising this variability, much to our surprise, we have found disease-causing mutations are much more frequent in the general population (two in a thousand in UK biobank) compared with clinical prevalence of CADASIL which is reported as 4in 100,000. Why the disease is severe in some individuals and milder in others is a hot research topic, particularly as if we understood this we may be able to develop disease modifying strategies for this untreatable disease. In early studies we have identified that mutation site, cardiovascular risk factors, and other polygenic influences may affect disease severity.
The PhD will investigate this area further. It will utilise the unique resource available in the stroke research group at Cambridge which runs a National clinic for CADASIL and other rare monogenic forms of/ stroke, and collaborates widely within Europe on this topic. The student will collect data from patients with monogenic forms of stroke, take advantage of our large existing database, utilise resources such as UK biobank. They will use this data to investigate why there is such variety in disease severity and try to identify modifying factors which can be targeted therapeutically. The project can include a number of the following according to the interest of the student; genetic statistical analysis, epidemiology analysis, MRI analysis, assessing patients clinically and cognitively.
Further reading
Cho BPH, Jolly AA, Nannoni S, Tozer D, Bell S, Markus HS. Association of NOTCH3 Variant Position With Stroke Onset and Other Clinical Features Among Patients With CADASIL. Neurology. 2022 May 31:10.1212/WNL.0000000000200744. doi: 10.1212/WNL.0000000000200744. Epub ahead of print. PMID: 35641310.
Cho BPH, Nannoni S, Harshfield EL, Tozer D, Gräf S, Bell S, Markus HS. NOTCH3 variants are more common than expected in the general population and associated with stroke and vascular dementia: an analysis of 200 000 participants. J Neurol Neurosurg Psychiatry. 2021 Jul;92(7):694-701.
Dr Luca Peruzzotti Jametti (lp429@cam.ac.uk) – Neurology
Microglial Function in Postnatal Development and Maternal Immune Activation
Microglia, the brain’s resident immune cells, play a key role in brain development, learning and memory, as well as in the behavioural adaptation to various environmental challenges (like stress, inadequate nutrition, and viral infections), which have been linked to the development of depression, schizophrenia, and autism spectrum disorders (ASDs).
‘Dark microglia’ is a newly described microglia phenotype that is rarely present under steady state conditions. Rather, dark microglia become abundant in development, chronic stress, aging, and neurodegeneration, where they play a major role in the remodelling of neuronal circuits, especially at synapses.
This PhD project will investigate the role and function of microglia and dark microglia in normal development and following experimental maternal immune activation (MIA) in wild type and genetically modified laboratory animals with dysfunctional dark microglia.
Combining disease modelling, behavioural and histopathological analyses, with cellular phenotyping and spatial proteomics, this project aims at providing new molecular insights into the function of microglia in development, which will help generating new strategies to target innate immune function in neurodevelopmental disorders. Website
Dr Stefano Pluchino (spp24@cam.ac.uk) – Neurology
A Cell Interactome Approach to Model, Characterise and understand Novel Mechanisms of Disease in Progressive Multiple Sclerosis
(co-supervised with A Nicaise and I Mohorianou)
Recent work suggests that cellular ageing, known as senescence, of endogenous stem-like cells in the brain may contribute to the chronic inflammation and neurodegeneration seen in people with progressive multiple sclerosis (PMS). Using an inducible system, that directly reprograms human fibroblasts into induced neural stem cells (iNSCs), we have generated patient PMS iNSC lines, which display a pro-inflammatory senescent phenotype that is transferred horizontally to non-senescent cells. Towards studying how these cells can communicate with neighbouring cells within a complex environment, we have developed a hybrid brain organoid system where developmentally mature brain organoids are cut at the air liquid interface (ALICOs) and iNSCs are transplanted and integrate within the tissue.
This project aims at providing new insights into the function and impact of disease-associated iNSCs on cerebral organoids, potentially promoting/inducing (i) chronic inflammation and senescence, (ii) impairing the longevity of the ALICO, and (iii) mimicking the neurodegeneration and brain atrophy seen in PMS patients.
We have developed a novel RABID sequencing-based approach, where the interactome between exogenous and endogenous cells within the hybrid ALICO system is analysed via the use of rabies virus barcodes and downstream single cell sequencing. Techniques will consist of generation of viruses and viral transductions, cell culture, organoid culture, FACS, single cell sequencing, data analysis and interpretation. Combining human based disease modelling, organoids, and state of the art interactome analysis this project aims to uncover new mechanisms by which PMS stem cells contribute to ongoing inflammation and neurodegeneration.
Metabolic Determinants of Astrocyte – Microglial Interactions in Smoldering Brain Disease
(co-supervised with C Willis)
Progressive multiple sclerosis (PMS) is characterised by a persistent state of inflammation that is mediated, in part, by microglia. Activated microglia communicate with astrocytes in the local microenvironment to perpetuate this inflammation. Recent work suggests that end-products of cell metabolism (metabolites) can guide the activation of microglia and their communication with the microenvironment. Among tricarboxylic acid cycle metabolites, succinate plays a key signalling role in conditions of persistent neuroinflammation. Intracellular succinate guides pro-inflammatory microglia effector functions whereas extracellular succinate released by microglia signals to surrounding cells through its metabolic sensor succinate receptor 1 (SUCNR1). We hypothesise this establishes a feedback loop that regulates the dynamics of the acquisition of pro- and anti-inflammatory features by microglia and astrocytes, respectively.
This project will first investigate the role and function of SUCNR1 in directing the response of human microglia in pro-inflammatory conditions in vitro using a state-of-the-art gene editing technique to modify the expression of SUCNR1 on human microglia. From this, the succinate-SUCNR1 signalling axis between human microglia and astrocytes will be explored using a sophisticated co-culture system.
Combining human disease modelling in a dish with advanced molecular biology and imaging techniques, this project aims to provide new molecular insights into the function of SUCNR1 on human microglia in inflammatory conditions. This will uncover new signalling functions of immunometabolites in chronic neuroinflammation, unveil novel mechanisms of neuroimmune interactions, and be instrumental in discovering new and relevant therapeutic targets to help stop the accumulation of irreversible disabilities in PMS patients.
Disease Pacemaker Stem Cells in Neurodegenerative Disease
(co-supervised with A Quaegebeur)
The presence and role of neural stem cells (NSCs) in the adult human brain is a long-debated issue in neuroscience. Recent work has demonstrated that stem-like cells exist in the embryonic, foetal, and human adult brain where they persist well into adulthood and can even contribute to neurogenesis. However, their role in neurodegenerative disease is unknown. Ongoing work in the lab has led to the hypothesis that NSCs may become dysfunctional in neurodegenerative disease resulting in senescence chronic inflammation, and thereby acting as pacemaker cells driving neuronal demise. This ambitious project aims to identify disease-associated NSCs and their phenotype in the context of human neurodegeneration using spatial biology approaches, including imaging mass cytometry, RNA scope and single nuclear RNA sequencing. Relying on post-mortem brain tissue of different stages of Alzheimer’s disease, traumatic brain injury, vascular dementia and chronic stroke, this project will study NSCs in a range of human diseases characterised by neurodegeneration and neuronal injury. Ongoing work in the lab identifies NSC-specific markers based on transcriptomics and protein profiling experiments in brains with progressive multiple sclerosis, enabling to investigate the distribution of NSCs in a wide range of diseases. Spatial transcriptomics and proteomic approaches will allow to study their phenotype and dysfunction in relation to other cell types and local pathology. This project will shed light on the role of NSCs in neurodegeneration and has the potential to identify an entirely novel mechanism of neurodegeneration in human disease.
Mr Stephen Price (sjp58@cam.ac.uk) –Neurosurgery
(co-supervised with Dr Chao Li)
Artificial Intelligence for Neuro-Oncology
Multiparametric MRI encompasses complementary information and promises to characterise brain tumours that widely disrupt the brain. Brain network offers a model to understand brain function and structure. In particular, structural networks derived from diffusion MRI can indicate the white matter connectivity between separated brain regions, while functional networks derived from resting-state functional MRI can reflect the functional co-activation across the brain cortices.
Recent development in deep learning, including convolutional neural networks and graph neural networks, promises to effectively leverage the rich information from multiparametric MRI and graph data, providing unique opportunities to develop state-of-the-art deep learning models for clinical neuroscience. This project offers a unique opportunity to understand the brain using artificial intelligence within the clinical context, which may be translated to impact patient care.
Dr Annelies Quaegebeur (aq244@cam.ac.uk) – Neuropathology
Molecular Mechanisms of Microglia-Driven Neurodegeneration in Human Tauopathies
(PhD or MPhil)
Neuroinflammation is associated with many neurodegenerative disorders. In experimental animals of tauopathies, microglia were shown to play a role in tau propagation and synapse loss, however the molecular and cellular processes driving tau accumulation and neurodegeneration in the context of human disease remain poorly understood. We are investigating the role of microglial responses in human tauopathies with progressive supranuclear palsy (PSP) as the demonstrator condition. Using advanced spatial biology and high-resolution imaging techniques we will characterise the molecular signatures of microglia and their interactions with tau aggregates and other cell types. This project relies on the large collection of well-characterised PSP brains in the Cambridge Brain Bank, enabling to study microglia in a large range of disease severities. With this strategy we anticipate to better understand the role of microglia in PSP and tauopathies, and hence, to guide the design of novel neuroimmune therapies and new disease biomarkers.
Characterisation of Microglial Activation and Synapse loss in Progressive Supranuclear Palsy
Progressive supranuclear palsy is a devastating neurodegenerative disorder causing dementia-parkinsonism as a result of pathological accumulation of tau aggregates in the brain. Our overarching interest is to identify cellular and molecular processes that are driving disease with the ultimate aim to identify new therapeutic targets and disease biomarkers. Our focus is on microglial activation and synapse loss, which are processes that have been demonstrated by PET imaging studies to occur in PSP patients in life and to correlate with disease severity. This project is centred around the large Cambridge Brain Bank collection of PSP brains from patients characterised in life by longitudinal clinical and imaging studies at the Cambridge Centre for Parkinson-Plus, representing a unique resource for translational research in the field of tauopathies. The objective is to better understand the relationship between neuroinflammation and synapse loss by studying their distributions and comparing to PET-imaging data. The work will include immunohistochemistry, confocal microscopy, image analysis, protein and RNA expression profiling in post-mortem brain tissue. Key to this project is the close link to the ongoing research at the Cambridge Centre for Parkinson-Plus.
Dr Tim Rittman (tr332@medschl.cam.ac.uk)
Translating Artificial Intelligence Applied to Neuroimaging into Clinical Practice for Dementia
Despite a number of academic studies using Artificial Intelligence and neuroimaging to predict diagnosis and prognosis in dementia, there have been very few examples of these methods benefiting patients. This PhD will use data from open datasets of neuroimaging data (such as the Alzheimer’s Disease Neuroimaging Initiative) to develop AI methods for the diagnosis and prognosis in dementia, and make use of the locally coordinated UK-wide study Quantitative MRI in the NHS – Memory Clinics (QMIN-MC) as an example of real world data for validation. Alongside methodological development, the PhD will involve working with clinicians and patient groups to identify ethical issues and barriers to the introduction of AI into routine clinical use in memory clinics.
Professor Chris Rodgers (ctr28@cam.ac.uk) – WBIC
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 ctr28@cam.ac.uk and I will be happy to discuss the details with you.
Dr Emmanuel Stamatakis (eas46@cam.ac.uk) – Anesthesia
https://sites.google.com/site/ccigcambridge/
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.
Dr Peter Smielewski(ps10011@cam.ac.uk) – Neurosurgery
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.
Dr Jelle van den Ameele (jv361@cam.ac.uk) Neurology and Mitochondrial Biology Unit
(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.
Metabolism of Genome Regulation during Brain Development
DNA replication, histone modification and transcription all have specific metabolic requirements. 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 how metabolic enzymes contribute to regulation of gene expression. Taking advantage of genetically encoded metabolite sensors, we will study nucleus/cytoplasm metabolite ratios in vivo in the Drosophila brain in neural stem cells, neurons and glia. We next will identify metabolic enzymes that show dynamic nuclear localisation, study whether they associate directly with the DNA, and profile the cell-type specific genome-wide impact of metabolic changes on transcription and histone modifications in vivo. Finally, we will determine how these are affected by acute and chronic mitochondrial dysfunction.
The project will rely mostly on confocal imaging, CRISPR/Cas9-mediated genome editing and novel cell-type specific in vivo chromatin profiling technology based on DamID-seq.
Clinical Features of Mitochondrial Disease in SDH Mutation Carriers
One of the enzymes involved in mitochondrial energy production is Succinate Dehydrogenase (SDH), also known as Complex II of the electron transport chain. Mutations in SDHx genes increase the risk of developing tumours, which is not a typical sign of mitochondrial disease. However, in some patients, SDHx mutations can also cause decreased eyesight and blindness.
It is not known how common mitochondrial disease symptoms are in patients with SDHx mutations. We plan to perform detailed visual tests in patients with SDHx mutations, to detect signs of mitochondrial dysfunction. In addition, we will explore prevalence of SDHx variants and the clinical phenotypes associated with these in large genomic databases. Together, this will help us understand better the genetic causes of mitochondrial diseases, provide insight into the impact on patients’ daily lives, open potential treatment avenues and improve symptomatic screening and management for SDHx mutation carriers.
References
1. van den Ameele J, Krautz R, Cheetham SW, et al., Reduced chromatin accessibility correlates with resistance to Notch activation. Nat Commun. 2022;13(1):2210.
2. 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.
3.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.
4.van den Ameele J, Brand AH. Neural stem cell temporal patterning and brain tumour growth rely on oxidative phosphorylation. eLife. 2019;8:e47887.
5.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.
Dr Guy Williams (gbw1000@cam.ac.uk) WBIC
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.
Fast Imaging Methods
Conventional magnetic resonance imaging (and spectroscopy) acquisitions either fully or heavily sample k-space to produce usable datasets. Sparse imaging methods, reconstructing using prior knowledge, receiver coil geometry, or otherwise inferring unacquired data, have been highly successful in reducing imaging time. This project is to develop such methods, and assess their application to imaging research in the clinical populations studied in the WBIC. 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. Please also get in contact if you have other interests in MR methodology or physics and its application to neuroscience to discuss potential variants of the above projects.
Dr Caroline Williams-Gray (chm27@medschl.cam.ac.uk) – Neurology
Investigating the Immune Basis of Parkinson’s Disease (PhD only)
It is now well established that immune activation occurs in Parkinson’s disease, but whether it plays a critical role in disease onset and progression remains uncertain. This is a critical question to address given that the immune system is a tractable target for disease-modifying therapy. The Williams-Gray lab investigates the immune component of Parkinson’s disease through neuropathological studies on post-mortem human brain, PET brain imaging studies, analysis of blood and cerebrospinal fluid samples, and interventional clinical studies. The project will extend this work to include investigation of cases at high risk of developing Parkinson’s in order to determine whether immune activation precedes and predicts disease onset, and will involve characterising how the immune response changes with evolution from early to mid and late-stage disease. Studies will involve measuring immune activation and dysregulation in patient-derived biological samples, determining drivers of Parkinson’s related immune activation in-vitro, and investigating how immune responses are linked to longitudinal clinical measures and outcomes. The impact of ageing of the immune system (immunosenescence) and its relevance to Parkinson’s onset and progression will also be explored. Laboratory techniques will include immunophenotyping using flow cytometry, multiplex immunoassays, and in vitro assays of immune cell function. Brain imaging markers of neuroinflammation may also be incorporated. Ultimate aims of the project will be to identify the most critical immune pathways for therapeutic targeting in Parkinson’s, as well as to identify immune biomarkers which will allow patient selection for future clinical trials of immune-based therapies, and the longitudinal monitoring of such therapies.
Dr Patrick Yu-Wai-Man (py237@cam.ac.uk) – Neuro-Ophthalmology and Genetics (PhD only)
I am an academic neuro-ophthalmologist with a major research interest in mitochondrial genetics and inherited eye diseases. My research group is focused on dissecting the disease mechanisms leading to progressive retinal ganglion cell loss in inherited optic neuropathies by using a combination of patient tissues, induced pluripotent stem cells and animal models.
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 am the Director of the Cambridge Clinical Vision Laboratory that was set up as a cross-cutting facility to support advanced therapeutics on the Cambridge Biomedical Campus.
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.
Project Themes:
- Gene discovery in inherited optic neuropathies
- Dissecting disease mechanisms using iPSC-derived retinal ganglion cells
- Zebrafish models of Wolfram syndrome and therapeutics
- Biomarker discovery and novel gene therapies for inherited optic neuropathies
Publications:
https://pubmed.ncbi.nlm.nih.gov/?term=YU-WAI-MAN+P&sort=pubdate
Cambridge MRC DTP and iCASE
Projects available for the Cambridge MRC DTP and iCASE Programe,
Please select a supervisor from Clinical Neurosciences if you are interested.
