Department of Neuroscience projects

Intercalated BSc Medical Sciences Research available projects

A postgraduate medical student looking at results on a screen

Projects: 

Relationship of Pathological Changes in the Posterior Cingulate Cortex in the Ageing Brain to Hippocampal Alzheimer’s Neuropathological Change

Main Supervisor:

Professor Stephen Wharton

s.wharton@sheffield.ac.uk

Second Supervisor:

Dr Julie Simpson

julie.simpson@sheffield.ac.uk

Other Supervisor(s):

Dr Rachel Waller

Type of Project:

Lab/Bench Project - primarily working in a lab environment

Aims and Objectives:

Neuropathological studies have shown that the earliest pathological changes in Alzheimer’s disease occur in the entorhinal cortex for neurofibrillary tangle (tau) pathology and in neocortex for Aβ plaques (Braak and Braak 1991, Thal, Rub et al. 2002). Aβ pathology involves the hippocampus at a later stage. However, imaging studies using positron emission tomography suggest that earliest stages of Aβ-pathology, which may be found in individuals with mild cognitive impairment, are in the posterior cingulate cortex and precuneus. This deposition is associated with metabolic abnormalities that can also be detected by PET scanning (Mattson, Palmqvist et al. 2019, Ottoy, Verhaeghe et al. 2019). The pathological changes in this brain region that may correlate with these changes and how these relate to the hippocampal tau changes are yet to be determined. The cingulate gyrus is part of the limbic system projecting into the entorhinal cortex and thus influencing the hippocampus. Pathological change in the posterior cingulate might therefore affect the hippocampus.

The aims of this project are to define the pathology in the posterior cingulate cortex to determine those changes that occur early and to determine how these relate to hippocampal tau pathology. The hypothesis is that Aβ pathology and neuroinflammatory (but not tau pathology) have a high prevalence at this site, occurring at the earliest stages of Alzheimer’s neuropathological change and at the earliest stages of hippocampal tau pathology. The study will use tissue donated to the Cognitive Function and Ageing Study. This is a longitudinal study of cognitive impairment and frailty in the ageing population. The neuropathology donor cohort, being population derived, contains a full spectrum of ageing pathology and allows assessment of pathological relationships in an unbiased way, without preselection into clinical groups (Wharton, Brayne et al. 2011).

Objectives

Define AD type pathology and neuroinflammatory changes in posterior cingulate cortex Determine relationship to stages of Alzheimer’s neuropathological change and to hippocampal pathology

Braak, H. and E. Braak (1991). "Neuropathological stageing of Alzheimer-related changes." Acta Neuropathol 82: 239-259.

Mattson, N., et al. (2019). "Staging b-amyloid pathology with amyloid positron emission tomography. ." JAMA Neurol doi: 10.1001/jamaneurol.2019.2214.

Ottoy, J., et al. (2019). "18F-FDG PET, the early phases and the delivery rate of 18F-AV45 PET as proxies of cerebral blood flow in Alzheimer's disease: validation against 15O-H2O PET. ." Alzheimer Dement 15: 1172-1182.

Thal, D., et al. (2002). "Phases of Ab-deposition in the human brain and its relevance for the development of AD." Neurology 58: 1791-1800.

Wharton, S., et al. (2011). "Epidemiological neuropathology: the MRC Cognitive Function and Ageing Study experience." J Alzheimer Dis 25: 359-372.

Research Methodology:

Aβ, tau, microglial and astrocytic pathology will be determined in posterior cingulate cortex using immunohistochemistry in human brain tissue samples. Ethical permission is already in place. Assessment of staining will be made by; i. semi-quantitative assessment of microscopical slides, ii. computer-aided image analysis. Statistical comparisons will be made with existing measures on other brain areas; i. hippocampus – tau stage and assessment of Aβ; ii AD pathology and neuroinflammatory measures on lateral temporal cortex to determine if prevalence of pathology is higher in posterior cingulate.

Expected Outcome:       

The population variation in pathology in the posterior cingulate cortex will be determined and the hypotheses tested that; i. this is an early involved area for Aβ as suggested by PET studies; ii. pathology here correlated with hippocampal tau stage suggesting neuroanatomical linkage of pathologies in these regions.

Additional Training:

Attendance at weekly lab group meeting and departmental seminar programme. Student will learn to use spreadsheets and statistical programmes (Excel, SPSS) as part of their work.

Ethical Approval:

Original research involving human tissues/human participants and/or patient details and information - UREC or NHS REC ethics approval obtained already

What are the views of people with genetic disease on reproductive medicine options?

Main Supervisor:

Dr alisdair mcneill

a.mcneill@sheffield.ac.uk

Second Supervisor:

Dr Megan Freeth

m.freeth@sheffield.ac.uk

Type of Project:

Qualitative Project/non-lab based - primarily using qualitative methods

Aims and Objectives:

There are several reproductive medicine options which can be used to make sure that someone with a genetic disease has a healthy child. Amniocentesis can be used to test a pregnancy, with termination of affected pregnancies. In preimplatantation genetic diagnosis the embryo is tested for the genetic disease and only unaffected embryos implanted. Despite the tremendous technical advances in this field relatively little is known about patients' views on the acceptability of these techniques and how they wish to receive information on them. In this project we will study the views of people with a given genetic disease (to be chosen after discussion with the student) on reproductive medicine options.

Research Methodology:

The student will undertake qualitative interviews on people affected by a defined genetic disease (n=10). This will involve a 30-45 minute interview based upon a written interview guide. The interviews are audio recorded and transcribed. The transcripts will be analysed using software called NVivo12. The transcripts are read to identify codes within the text (e.g. negative views on genetic testing, worry about having an affected child), these codes are then grouped under over arching "themes". This method enables us to ascertain the participants' views without the bias found when asking closed questions. The genetic disease could be selected to interest the student, but we would plan to focus on genetic eye disease or neurofibromatosis type 1.

Expected Outcome:       

An understanding of the views of people with a given genetic disease on the acceptability of techniques such as preimplantation genetic diagnosis. A peer reviewed research paper with the student as an author. The student will receive training in qualitative interviewing and an understanding of reproductive medicine options for genetic disease

Additional Training:

Introduction to qualitative research methods and full training and support in the performance of interviews and the thematic analysis.

Ethical Approval:

Original research involving human tissues/human participants and/or patient details and information - UREC or NHS REC ethics approval obtained already

Role of Remote Ischaemic Preconditioning (RIPC) on Activity, Fatigue and Gait in people with Multiple Sclerosis

Main Supervisor:

Dr Krishnan Padmakumari Sivaraman Nair

siva.nair@nhs.net

Second Supervisor:

Professor Claudia Mazza

c.mazza'sheffield.ac.uk

Type of Project:

Clinical project - based in the clinical environment with patients/including service evaluation

Aims and Objectives:

Primary Aims

  1. To assess whether RIPC can increase activity in people with MS
  2. To assess whether RIPC can reduce fatigue in people with MS
  3. To assess whether RIPC can improve gait in people with MS

Secondary Aims

  1. To assess whether RIPC can reduce the impact of MS on people’s life.
  2. To assess whether RIPC can improve the quality of life in people with MS.

Research Methodology:

Participants will be randomised to receive either RIPC or a sham intervention (sham). They will not be told which group they are in.

Participants and their carer will be taught how to perform the relevant intervention and be asked to do so at home every day for six weeks.

Physical activity, gait and fatigue will be compared before and after the intervention period. Participants will be asked to wear an activity monitor at home for 1 week before and after the intervention to measure levels of activity. To assess gait, participants will complete the 6 minute walk test wearing inertial sensors which measure gait and distance walked. The modified fatigue impact scale will be completed before and after the intervention and levels of exertion recorded after each 6 minute walk test.

Expected Outcome:       

Primary analysis will focus on the comparison of the outcome measures at baseline and after the 6 week home intervention period. As a secondary analysis, the outcome measures will be compared before and after the intervention within the visit.

Additional Training:

Progress in new technologies has given rise to devices and techniques which allow more objective evaluation of activity, gait and fatigue. This reduces the error margin caused by subjective techniques [4] and potentially shortens the time needed to detect changes resulting from an intervention. Among these technologies, the currently most adopted are wearable sensors and pressure insoles, dynamometry (DYN), and surface electromyography (sEMG). The INSIGNEO biomechanics laboratory, recently established as part of the NIHR Sheffield Biomedical Research Centre (BRC), is now equipped with all the state of the art sensors needed to perform the above type of assessments.

Wearable sensor systems (e.g. pressure and bend sensors, accelerometers and gyroscopes, heart rate monitors) allow for recording and characterisation of walking “out of the laboratory”, for example, in patient’s homes, at clinic visits, and during the course of their everyday lives. Their most common application is in the analysis of a patient’s motor performance, as recorded while the patient is performing traditionally established tests such as the six-minute walk, 10-minute walk, or timed up and go (the participant is asked to rise from a chair, walk seven metres, turn around, walk back to the chair, and sit down). In addition, wearable sensors can be used to monitor a patient’s gait and physical activity patterns for prolonged periods of time, such as while at home or at work. Wearable sensors allow the recording of several parameters, such as step and stride duration and frequency, gait speed, balance, symmetry and joint angles.

We aim to utilise the above technologies to assess whether RIPC can improve activity, gait and fatigue in people with Multiple Sclerosis. Using validated patient reported outcome measures we will also assess whether RIPC can reduce the impact of MS on people’s life and improve the quality of life in people with MS.

Ethical Approval:

Original research involving human tissues/human participants and/or patient details and information - UREC or NHS REC ethics approval obtained already

Cognitive assessment and correlation with brain imaging in a cohort of genetic ataxia

Main Supervisor:

Dr John Cooper-Knock

j.cooper-knock@sheffield.ac.uk

Second Supervisor:

Dr Channa Hewamadduma

chewamadduma1@sheffield.ac.uk

Other Supervisor(s):

Professor Marios Hadjivassiliou

Type of Project:

Clinical project - based in the clinical environment with patients/including service evaluation

Aims and Objectives:

We hypothesis that cognitive impairment is more frequent (novel clinical finding) in patients with SPG7 mutations compared to other HSP and ataxia causing genes

Objectives

  1. To assess cognitive function in SPG7, other HSP related mutations and cerebellar ataxias using the Schmahmann score (Hoche et al 2018) and MOCA
  2. To assess the cognitive function in age and gender matched normal controls
  3. Obtain data from NART assessment to correct for premorbid intellectual status
  4. Compare cognitive assessments with disease severity scales and MRI data already collected as standard of care
  5. Publish the findings

Research Methodology:

Patients with HSP and ataxia undergo detailed clinical assessments when attending clinics and also have had neuro imaging.

Schmahmann score has been developed to assess the cognitive function of patients with cerebellar dysfunction. Patients will be given information and those volunteering will be approached for informed consent to take part in the study. Schmahmann score, Montreal cognitive assessment scale and NART assessments will be carried out. The data will be collected in an anonymized database with the clinical details collected as part of standard of care.

Statistical analysis will be carried out in liaison with the department of statistics to compare categorical data sets.

Student will be trained how to conduct the clinical scores, assistance will be provided in statistical analysis. MSc student will also attend HSP and Ataxia clinics.

We aim to recruit at least SPG7 = 10 cases, SPG4 = 10, SCA = 10, normal control n=15

Expected Outcome:       

  1. Learning research methodology and systematic literature review
  2. Thorough knowledge in neurological examination skills
  3. Will learn skills in administering clinical scales to objectively assess severity
  4. Learn methods of cognitive assessment and gait assessment
  5. Analyse and correlate clinical data with MRI brain imaging data to bio markers that will predict cognitive decline and disease progression
  6. Present data at national and international conferences
  7. Publish outcome
  8. Obtain a well structured BMedSci with useful outcomes which will influence patient care

Additional Training:

The student will be attending the neurology specialist clinics with the consultant neurologist (Dr Channa Hewamadduma). Student will be trained in neurological examination and congitive assessment.

Student will receive guidance and direction in critical analysis of scientific literature

Student will also be trained in interpretation and analysis of MRI data

Statistical analysis will be done in collaboration with department of statistics and student will receive guidance and help

Ethical Approval:

Original research involving human tissues/human participants and/or patient details and information - UREC or NHS REC ethics approval needed

Novel electrical impedance spectroscopy for neurological disorders

Main Supervisor:

Dr James Alix

j.alix@sheffield.ac.uk

Second Supervisor:

Dr Jamie Healey

jamie.healey@nhs.net

Other Supervisor(s):

Dr Ali Ali, Consultant Stroke Physician

Type of Project:

Clinical project - based in the clinical environment with patients/including service evaluation

Aims and Objectives:

Electrical impedance spectroscopy uses imperceptible electrical currents to assess the structure of tissue. Here we will be applying the technique to muscle in the context of several neurological diseases - motor neurone disease, other neuromuscular diseases (e.g. peripheral neuropathy), stroke and age-related muscle loss.

The project will assess the utility of a novel method for assessing the presence and severity of the disease states.

The project will also assess the reliability of the technique and how it changes over time in these diseases.

Research Methodology:

The student will be fully hands on in the project and will participate in patient recruitment, data collection and analysis. They will learn to undertake the impedance spectroscopy recordings on the patients and develop the skills to lead the study visits. The study visits will take place in and around clinics in neurology, neurophysiology and stroke. They will gain experience how clinical research is performed and exposure to both the clinical and governance of such studies. The student will analyse the data they collect and present their work at team meetings. If the student has a particular interest in one of the conditions being studied there is flexibility to focus more on that disease area.

Expected Outcome:       

The project will generate data on the differences between healthy volunteers and patients will a several neurological diseases (motor neurone disease, stroke, age-related muscle loss). The project will also generate information on how reliable the device is and how acceptable it is to patients. These data are expected to be publishable and hence paper authorship is anticipated.

It is also expected that the student will present their work at a conference (at least one national conference). Previous students working on similar projects have won a several national/international prizes.

Additional Training:

The student will be taught to undertake the impedance spectroscopy recordings, as well as how to use quantitative measures of muscle strength and perform anthropometric measurements (measures of body shape and composition). Guidance on statistical tests will be provided and SPSS used; previous students have found that the statistics course compliments their research.

Ethical Approval:

Original research involving human tissues/human participants and/or patient details and information - UREC or NHS REC ethics approval obtained already.

Exploring the heterogeneity of a new mouse model of motor neurone disease

Main Supervisor:

Dr Richard Mead

r.j.mead@sheffield.ac.uk

Second Supervisor:

Dr James Alix

j.alix@sheffield.ac.uk

Type of Project:

Lab/Bench Project - primarily working in a lab environment

Aims and Objectives:

Motor neurone disease (MND) remains a fatal neurodegenerative condition. It is well known for its heterogeneity, some people develop rapdily progressive symptoms, while others progress more slowly.

Mouse models of MND have been a cornerstone of translational research for >20 years. Until recently, there have been significant omissions in the disease the models developed. These included: i). the lack of characteristc features on MND on histology (TDP inclusions) and ii). a lack of heterogeneity in the disease that the models develop.

The most common genetic variant of MND is the GGGGCC-repeat expansion of C9orf72 (~10% overall and ~50% of those with positive family history). Recently, a new mouse model, (C9orf72 BAC mice) expressing the mutated gene has been generated. This demonstrates both TDP pathology and heterogeneity in the disease phenotype (i.e. some mice get severe symptoms, some do not). These features make this model the most relevant for translational research.

The aim of this project is to further evaluate the heterogeneity in the disease phenotype using a variety of sophisticated behavioural and electrophysiological methods. The student will contribute to a high profile study being funded by the Motor Neurone Disease Association with the overall aim of better understanding the model and improving preclinical research.

Research Methodology:

The student will play a hands on role in collecting and analysing the results.

The student will undertake a home office licence course so that they can undertake in vivo studies. These will include assessments of behaviour, muscle function and electrophysiology.

The student will also undertake histological studies, analysing the health of different cell types across the nervous system.

Full training in all aspects of the study will be provided.

Expected Outcome:       

The work will contribute to our understanding of the onset and progression of disease in these mice. This will help the planning and implementation of future studies and improve the translational relevance of the model.

It is anticipated that the student will contribute results to a publication.

Additional Training:

The student will receive training in animal handling and multiple in vivo tests. These include assessments of how well the mice walk, how they interact socially with other mice, how well they can balance on a narrow beam (to assess coordination) and the function of the neuromuscular junction (electrophysiology).

Full training in standard lab histology techniques will also be provided.

The standard statistics taught as part of the intercalated year will provide the skills for data anlaysis.

Ethical Approval:

Non-human tissue - no ethics approval required.

Investigation of genomic and clinical real world data in high-recruiting rare disease indications of the 100,000 Genomes Project

Main Supervisor:

Dr Dennis Wang

dennis.wang@sheffield.ac.uk

Second Supervisor:

Janine Kirby

Other Supervisor(s):

Matthew Parker

Type of Project:

Quantitative Project/non-lab based - primarily using quantitative methods

Aims and Objectives:

The 100,000 Genome Project’s aim is to create a new genomic medicine service for the NHS – transforming the way people are cared for. Patients may be offered a diagnosis where there wasn’t one before. In time, there is the potential of new and more effective treatments. Combining genomic sequence data with medical records is a ground-breaking resource. Researchers will study how best to use genomics in healthcare and how best to interpret the data to help patients. The purpose of this project is 1) to identify the strongest areas of the baseline/EHR clinical data coverage in conditions, where participant numbers are high enough to facilitate meaningful follow-up analyses, and 2) to analyse genomics data across the whole available dataset to understand frequency and types of copy number variations (CNVs) in the overall sample and to investigate associated clinical phenotypes of two rare disorders (eg. Angelman Syndrome and Prader Willi Syndrome).

Research Methodology:

  1. Register and join the 100,000 Genomes Project GeCIP consortium
  2. Gain an overview of the distribution of recruitment across the spectrum of well defined Rare Diseases.
  3. Based on this distribution, set a suitable threshold for diseases considered to be 'high recruiting'.
  4. Mine the digital clinical data to identify phenotypes associated with well-defined indications rather than very broad definitions (e.g. “Intellectual disability”).
  5. Extract whole genome sequences of individuals defined by those indications.
  6. Measure the frequency of copy number variations in the genomes.

Expected Outcome:       

By the end of the project, the student will provide:

  • Important information about the feasibility of identifying rare diseases from the electronic health records of patients in the 100,000 Genomes Project.
  • Specific recommendations to the NHS on improving its genomic diagnostic services.
  • New genetic mutations associated with ultra-rare diseases that can be incorporated into diagnostic gene panels.

Additional Training:

The student will be able to attend modules on the MSc in Genomic Medicine, including Genomic Techniques, Genomics of Rare Diseases and Intro to Bioinformatics. Further one-one practical training in analysing genomics data will be provided by members of the Sheffield Bioinformatics Core and Genomics England. The student will also learn from a network of 100,000 Genomes Project researchers and attend national meetings. By the end of the project, the student will be able to interpret genetic data and electronic health records, apply data science methods, and understand the ethical implications of genetic diagnostics.

Ethical Approval:

Secondary data or tissue samples - UREC or NHS REC ethics approval already received for the intended research project

Investigating the link between infection and cognitive decline in patients with dementia

Main Supervisor:

Dr Julie Simpson

julie.simpson@sheffield.ac.uk

Second Supervisor:

Professor Steve Wharton

Other Supervisor(s):

Dr Vikki Ridger

Type of Project:

Lab/Bench Project - primarily working in a lab environment

Aims and Objectives:

Background. Many carers of people with dementia often notice that symptoms get worse following an infection. This suggests that systemic inflammation has direct effects on brain function and accelerates dementia. Systemic inflammation is associated with a large increase in the number of circulating neutrophils, which are the most abundant white blood cell. Neutrophils produce large numbers of small pouch-like vesicles which impact the function of blood vessels in the body. Endothelial cells lining blood vessels in the brain are normally very tightly linked together but in Alzheimer’s disease they become leaky, allowing the movement of damaging substances into the brain. Our research has shown that the vesicles produced by neutrophils enter human brain endothelial cells, affecting their leakiness, and that they contain small molecules called miRNAs which are able to control gene expression. We hypothesise that the miRNA content of neutrophil vesicles from dementia patients makes blood vessels in the brain more leaky, contributing to cognitive decline during an infection. This study aims to identify a potential mechanism linking infection and accelerated cognitive decline in dementia patients.

Specifically, we aim to

  1. compare the miRNA profile these vesicles from dementia patients to age and gender matched healthy controls.
  2. investigate if the candidate miRNAs are present in the vessels of dementia patient post-mortem human brain samples

Research Methodology:

We have developed a robust protocol to sequence the miRNA contents of vesicles isolated from dementia patients and healthy controls. To address Aim (i) we will perform a detailed analysis of this data and determine which miRNAs are contained within the vesicles and if the content differs in dementia patients.

To address Aim (ii) we will use RNAscope to detect and visualise miRNA in post-mortem human brain samples from patients with dementia, enabling us to determine if our candidate miRNAs are associated with leaky blood vessels in the brain of patients with Alzheimer’s disease.

Expected Outcome:       

The proposed research will advance our understanding of neutrophil derived microvesicles in AD, potentially providing a mechanistic explanation for the relationship between systemic inflammation, neuroinflammation and cognitive decline. Understanding how systemic inflammation contributes to dementia is essential to identify new therapeutic treatments.

Additional Training:

The student will be trained in a range of specific lab techniques, including bioinformatic analysis, immunohistochemistry, RNAscope, microscopy and image analysis. During their project the student will attend the weekly neuropathology meetings and have the opportunity to develop their communication skills by presenting their research at one of the weekly SITraN seminars, the Department of Neuroscience research day and/or the annual Medical School research meeting.

Ethical Approval:

Original research involving human tissues/human participants and/or patient details and information - UREC or NHS REC ethics approval needed.

Investigation of the role of ER-mitochondria interactions Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal dementia

Main Supervisor:

Dr Kurt De Vos

k.de_vos@sheffield.ac.uk

Second Supervisor:

Andrew Grierson

Type of Project:

Lab/Bench Project - primarily working in a lab environment

Aims and Objectives:

The aims of this project are to characterise a novel pathway that regulates ER–mitochondria interaction and to determine its involvement in ALS and PD.

Research Methodology:

Neurodegenerative disorders such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are devastating diseases with huge unmet medical need. The socio-economic burden associated with neurodegenerative disorders is enormous and is set to increase as the population ages. Our overall goal is to identify and develop new targets that can be the basis for the development of novel classes of neuroprotective drug candidates and treatments for neurodegeneration and will motivate subsequent clinical studies.

Perturbations to the communication between the endoplasmic reticulum (ER) and mitochondria at close contact sites between the organelles have been widely implicated in the aetiology of many adult-onset neurodegenerative diseases including ALS/FTD and PD. The precise causes of ER–mitochondria contact site disruption in disease and its contribution to neurodegeneration are poorly understood. However, human mutations in genes that regulate ER–mitochondria contact sites have been shown to cause genetic forms of neurodegeneration, demonstrating the importance of ER–mitochondria crosstalk for neuronal function and survival and suggesting that targeting the underlying causes of disruption may be of therapeutic benefit.

We have uncovered a novel kinase pathway that regulates ER–mitochondria contacts, and have data that suggest that upregulation of this pathway may be the underlying cause of ER–mitochondria contact disruption in SOD1-related ALS and α-synuclein-related PD.

The aim of this project is to investigate this novel pathway and its involvement in ALS and PD.

We will use a number of cell biological and biochemical techniques in our investigations. These will include among others cell culture and transfection, immunofluorescence microscopy, immunoblotting, PCR, and cloning.

Expected Outcome:       

We will discover the mechanism by which the kinase pathway regulates ER-Mitochondria communication. Specifically we will learn how the kinase pathway affects the tethers that link ER to mitochondria.

We will learn if the kinase pathway is involved in ALS and PD. Specifically we will learn if the pathway is unregulated in cellular models of SOD1, TDP-43, FUS and C9orf72-related ALS and in LRRK2, and synuclein-related PD.

Additional Training:

You will be taught all neccessary techniques and analysis methods.

Ethical Approval:

Non-human tissue - no ethics approval required.

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