Brain imaging

Brain imaging is a central research theme in Sheffield. There are strong collaborations within the Sheffield NIHR BRC focused on imaging in patients with ataxia, MND, Parkinson’s disease, dementia and epilepsy.

Brain DTI
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Overview

With the support of the BRC, 31P MR spectroscopy has been used to investigate brain energetics in MND and Parkinson’s disease and spectral editing techniques to investigate anti-oxidant status in neurodegenerative disease. 31P spectroscopy is being used in clinical trials to look for evidence of target engagement by novel therapies to give mechanistic insights and, as a novel biomarker, offers the hope of shortening trials for patients with severe neurological diseases.

The Imaging research group in Sheffield was founded in the late 1990s by Paul Griffiths - a world leader in the clinical translation of fetal in utero MR, leading the multicentre NIHR MERIDIAN trial. More recently we published a world first successful demonstration of hyperpolarised xenon perfusion imaging in a person following a stroke. The neuroimaging group have had long and productive collaborations with diabetes researchers, successively showing changes first in the spinal cord, then thalamus and finally the cerebral cortex in patients with diabetic neuropathy, and we are now engaged in mechanistic trials of novel treatments.

Sheffield has an important role in training and helping foster neuroimaging research with alumni working in Leeds, Manchester and the US. We are committed to developing young researchers who will continue to lead improvement of imaging and care for patients with neurological disease into the future. 

Sheffield were amongst the first research groups in the UK to adopt 3T MR imaging with Phillips and also have collaborated with GE on the evaluation of a ward-based 3T neonatal scanner. The University have invested heavily in neuroimaging with the building of a facility housing a research dedicated GE 3T Signa PET MR in the Royal Hallamshire Hospital, giving easy access for patients from neuroscience and oncology wards directly to the scanner. With the functional imaging possibilities of multinuclear MR imaging and new PET tracers emerging, these are exciting times for neuroscience imaging in Sheffield.

Ataxia

Ataxia is a condition characterised by loss of coordination, badly affecting mobility, self-caring and speech, because of either a problem with the cerebellum itself or problems with the information it is receiving from the peripheral nerves either from a peripheral neuropathy or spinal cord degeneration. There are many diverse causes, with over 175 genetic ataxias screened for, but numerically there are many more patients with acquired ataxia. Sheffield has the largest published cohort of adult patients with ataxia in the world, founded and led by Prof Marios Hadjivassiliou. Ataxia UK have named Sheffield as one two centres of excellence for ataxia in the country. The Sheffield ataxia clinic now has 2500 patients with adult onset ataxias.

We have developed and implemented into routine clinical practice proton MR spectroscopy of the cerebellum for use in the monitoring of patients with ataxia. We have shown the effects of keeping to a strict gluten free diet have on cerebellar MR spectroscopy, and we have demonstrated how it can be used to monitor response to immunosuppression in aggressive immune ataxia. Sheffield led on the development of international guidelines for the management of immune ataxias.

We have shown how MR spectroscopy helps in the early identification of patients with the cerebellar form of multiple system atrophy (MSA-C) and we are currently in the process of looking for new biomarkers in this devastating, fatal, condition with currently no accepted treatment.

A rapidly growing area of activity is on spastic paraplegias who often have clinical overlap with ataxia, especially in one the commonest forms, SPG7 mutation. Sheffield research led to the description of the novel finding of dentate nucleus T2 hyperintensity, which relates to the absence of normal, physiological iron accumulation in these structures as patients age. We are currently investigating these dentate nucleus findings in a large cohort of patients in Sheffield, looking for potential biomarkers for future therapies.

In other work, we are interested in Friederichs’ ataxia, and we are collaborating with Sheffield Children’s Hospital which is now the National centre for childhood ataxia.

Gluten related disease imaging

1 in 10 people in the UK population have an immunological response to the gluten that they eat as part of their normal diet. Gluten is found in wheat and barley based products, such as bread and pasta, and a wide array of foods. Sheffield has been at the centre of gluten related disease research since the 1990s, with seminal publications demonstrating the association with cerebellar disease and peripheral neuropathy. As well as focussing on gluten related ataxia, we are interested in the accelerated rate of white matter disease they accumulate. Gluten related white matter disease offers the possibility to look at theories of endothelial dysfunction. 

In the longer term, we wish to answer the question: what is the contribution (if any) of gluten sensitivity to the population risk of cognitive impairment in older age? We have found accelerated rates of white matter disease accumulation, but also more recently in cerebral atrophy for example in the thalamus, not just the cerebellum as is now more widely appreciated following the work done here in Sheffield.

Epilepsy

Epilepsy affects 0.5 – 1 % of the UK population and around 30% of patients with epilepsy do not have control of their seizures with medication. This drastically affects everyday life and can be life threatening. For these patients, surgery offers the potential for a seizure free outcome, and magnetic resonance imaging (MRI) is key to identifying potential surgical targets. Unfortunately, a significant proportion of these patients have brain abnormalities that are not detected by MRI. Without an identifiable abnormality on MRI, the chances of a successful surgical outcome are significantly diminished.

Our research aims to investigate new MRI methods that have the potential to identify brain abnormalities associated with epilepsy that are not currently identified by conventional imaging approaches. These include Arterial Spin Labelling, which is a non-invasive method for measuring local blood flow in the brain. Evidence suggests that blood supply is reduced in the region of the seizure focus during the interictal period and is increased during active seizures. Another promising technique is diffusion imaging, which measures the mobility of water molecules in brain tissues. This provides detailed insights into brain microstructure and shows promise of being able to identify some abnormalities more clearly than conventional imaging. Recent advances in multi-shell diffusion imaging, such as NODDI, appear to show even greater sensitivity to the microstructural changes associated with epilepsy.

However, despite these advances in imaging methodology, it is clear that there is no single technique that best identifies all abnormalities. Therefore, we are developing approaches that utilise the latest artificial intelligence techniques to combine information from all of the different imaging techniques, so that we can learn the imaging signatures associated with epilepsy and create a computational model that will automatically highlight regions that are suspected of corresponding to a seizure focus.  A successful outcome from these projects will ensure that more patients are able to benefit from surgery and have the potential for a seizure free future.

Fetal

Sheffield has been a centre for maternal and fetal MR imaging since the 1990s. Our research has focused on fetal neuroimaging using fast MR imaging techniques to avoid the need for fetal sedation. Prof Griffiths was PI on the MERIDIAN trial, which demonstrated the superiority of MR imaging for in utero imaging of cerebral abnormalities over US.

Neurodegenerative conditions

Parkinson’s disease (PD) is a common neurodegenerative disorder, typically affecting the over 60s, but younger patients can also be affected. PD mainly affects the dopaminergic neurons of Substantia Nigra Pars Compacta (SNPC) causing their death, which impacts the basal ganglia and leads to the typical motor symptoms of PD such as tremors and rigidity. Mitochondrial dysfunction plays a critical role in the development of both idiopathic and familial PD. 31P-MR Spectroscopy is a non-invasive technique, utilised here in Sheffield, that allows in vivo measurement of phosphorus compounds linked to brain energy metabolism such as free phosphate (Pi), phosphomonoester (PME), phosphodiester (PDE), and the high-energy phosphates (HEPs), i.e. ATP Phosphocreatine (PCr). These compounds are markers of oxidative phosphorylation and mitochondrial function. Changes in these measurements have been utilised to test if novel treatments for PD are improving mitochondrial function in studies funded by the Michael J Fox Foundation.

The Jenkins group have used 31P-MR Spectroscopy to look at mitochondrial function in another neurodegenerative condition; motor neuron disease. We published the first 31P-MRS study providing evidence of mitochondrial dysfunction in both brain and muscle in patients with ALS.

Diabetes

There has been a programme of research into diabetic neuropathy led by Prof Solomon Tesfaye, Prof Iain Wilkinson and Dr Dinesh Selvarajah for over 2 decades. The group have demonstrated the association of cord atrophy with peripheral neuropathy, and more recently thalamic and cortical changes in patients with diabetic neuropathy. Current work being led by Dr Selvarajah includes studies of cerebral physiological responses to novel interventions for this distressing and common condition, using the new University of Sheffield PET MR facility.

People, Projects & Publications

People
Current Projects / Grants
  • 2020 – 2023. Gluten as a risk factor for dementia.
  • 2020 – 2021. Advanced diffusion imaging: a new method to improve detection of seizure focus in patients with epilepsy.
  • 2020 – 2024. Resolution enhancement of diffusion tensor imaging using probabilistic models.
  • 2020 – 2024. Use of multimodal imaging for seizure focus detection in patients with epilepsy.
  • 2018 – 2021. Development of deep learning methods for fetal brain analysis.
Past Projects / Grants
  • 2015 – 2018. Multi-modal magnetic resonance imaging in type-2 diabetes mellitus.
  • 2011 – 2014. Perfusion in paediatric tumours.
Recent publications
REF 2021 illustration

Research Excellence Framework 2021 results

The results demonstrate our research and impact excellence across a broad range of disciplines and confirm that our research is having a significant positive impact on lives across the globe.