91Ö±²¥

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 91Ö±²¥ 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 . 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.

91Ö±²¥ 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. 

91Ö±²¥ 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 91Ö±²¥.

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. 91Ö±²¥ has the largest published cohort of adult patients with ataxia in the world, founded and led by Prof Marios Hadjivassiliou. Ataxia UK have named 91Ö±²¥ as one two centres of excellence for ataxia in the country. The 91Ö±²¥ 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. 91Ö±²¥ 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. 91Ö±²¥ 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 91Ö±²¥, looking for potential biomarkers for future therapies.

In other work, we are interested in Friederichs’ ataxia, and we are collaborating with 91Ö±²¥ 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. 91Ö±²¥ 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 91Ö±²¥.

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

91Ö±²¥ 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 91Ö±²¥, 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 .

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 91Ö±²¥ PET MR facility.

People, Projects & Publications

People

Professor Nigel Hoggard

Professor of Neuroradiology
Clinical Medicine, School of Medicine and Population Health

My research focuses on adult neuroadiology, mainly, the imaging of gluten related neurological disease and degenerative cerebellar diseases.

Email

n.hoggard@sheffield.ac.uk

Telephone

+44 114 215 9607

Open staff member portrait in a modal window

Professor Paul Griffiths

Professor of Radiology
Clinical Medicine, School of Medicine and Population Health

Paediatric neuroimaging. Neonatal neuroimaging. Fetal neuroimaging. Developmental brain abnormalities. Acquired brain pathology in the fetus and neonate. Neurological rare diseases

Email

p.griffiths@sheffield.ac.uk

Telephone

+44 114 215 9604

Open staff member portrait in a modal window

Dr Paul Armitage

Senior Technical Specialist (MRI)
Clinical Medicine, School of Medicine and Population Health

Quantitative MRI:
Diffusion, Perfusion, Permeability, Relaxometry.
Image Processing:
Registration, Segmentation.
Applications:
Epilepsy, Stroke, Dementia, Ataxia, Tumours, Fetal.

Email

p.armitage@sheffield.ac.uk

Telephone

+44 114 215 9149

Open staff member portrait in a modal window

Dr Iain Croall

Postdoctoral Research Fellow
Clinical Medicine, School of Medicine and Population Health

Email

I.Croall@sheffield.ac.uk

Telephone

+44 114 215 9151

Open staff member portrait in a modal window

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

• Anton A, Mead RJ, Shaw PJ, Edden RAE, Bigley J, Jenkins TM, Wild JM, Hoggard N, Wilkinson ID. . J Magn Reson Imaging. 2021 Jul 28. doi: 10.1002/jmri.27842. Online ahead of print.

• Newrick L, Hoggard N, Hadjivassiliou M. . Cerebellum Ataxias. 2021 Jun 13;8(1):16. doi: 10.1186/s40673-021-00139-z

• Kular S, Griffin K, Batty R, Hoggard N, Connolly D. . Clin Radiol. 2021 Sep;76(9):712.e9-712.e13. doi: 10.1016/j.crad.2021.05.009.

• Hadjivassiliou M, Croall ID, Grünewald RA, Trott N, Sanders DS, Hoggard N. . Nutrients. 2021 May 28;13(6):1846. doi: 10.3390/nu13061846. 

• Hadjivassiliou M, Zis P, Sanders DS, Hoggard N, Sarrigiannis PG. . Nutrients. 2021 Apr 20;13(4):1373. doi: 10.3390/nu13041373.

• Croall ID, Hoggard N, Hadjivassiliou M. . Nutrients. 2021 Feb 9;13(2):572. doi: 10.3390/nu13020572.

• Islam M, Hoggard N, Hadjivassiliou M. . Cerebellum Ataxias. 2021 Jan 28;8(1):5. doi: 10.1186/s40673-021-00128-2.

• Sassani M, Alix JJ, McDermott CJ, Baster K, Hoggard N, Wild JM, Mortiboys HJ, Shaw PJ, Wilkinson ID, Jenkins TM. . Brain. 2020 Dec 1;143(12):3603-3618. doi: 10.1093/brain/awaa340.

• Flores Martin A, Shanmugarajah P, Hoggard N, Hadjivassiliou M. . Cerebellum. 2021 Jun;20(3):454-461. doi: 10.1007/s12311-020-01222-7. 

• Hadjivassiliou M, Sarrigiannis PG, Shanmugarajah PD, Sanders DS, Grünewald RA, Zis P, Hoggard N. . Cerebellum. 2021 Apr;20(2):179-185. doi: 10.1007/s12311-020-01203-w. 

• Pattrick M, Sarrigiannis PG, Kruger S, Davies B, Hoggard N, Irani SR, Unwin Z, Zis P, Blackburn DJ, Hadjivassiliou M. . J Neurol. 2020 Oct;267(10):3096-3099. doi: 10.1007/s00415-020-10182-1.

• Croall ID, Hoggard N, Aziz I, Hadjivassiliou M, Sanders DS. . PLoS One. 2020 Aug 28;15(8):e0238283. doi: 10.1371/journal.pone.0238283.

• Payne T, Sassani M, Buckley E, Moll S, Anton A, Appleby M, Maru S, Taylor R, McNeill A, Hoggard N, Mazza C, Wilkinson ID, Jenkins T, Foltynie T, Bandmann O. , The 'UP' study. BMJ Open. 2020 Aug 5;10(8):e038911. doi: 10.1136/bmjopen-2020-038911.

• Croall ID, Tooth C, Venneri A, Poyser C, Sanders DS, Hoggard N, Hadjivassiliou M.  Nutrients. 2020 Jul 8;12(7):2028. doi: 10.3390/nu12072028.

• Hadjivassiliou M, Grunewald RA, Shanmugarajah PD, Sarrigiannis PG, Zis P, Skarlatou V, Hoggard N. . Cerebellum. 2020 Oct;19(5):680-684. doi: 10.1007/s12311-020-01152-4.

• Hadjivassiliou M, Graus F, Honnorat J, Jarius S, Titulaer M, Manto M, Hoggard N, Sarrigiannis P, Mitoma H. . Cerebellum. 2020 Aug;19(4):605-610. doi: 10.1007/s12311-020-01132-8.

• Arthurs OJ, Goh V; RCR Academic Committee. . Clin Radiol. 2020 May;75(5):348-350. doi: 10.1016/j.crad.2020.03.001. 

• Croall ID, Sanders DS, Hadjivassiliou M, Hoggard N. . Gastroenterology. 2020 Jun;158(8):2112-2122. doi: 10.1053/j.gastro.2020.02.028. 

• Považan M, Mikkelsen M, Berrington A, Bhattacharyya PK, Brix MK, Buur PF, Cecil KM, Chan KL, Chen DYT, Craven AR, Cuypers K, Dacko M, Duncan NW, Dydak U, Edmondson DA, Ende G, Ersland L, Forbes MA, Gao F, Greenhouse I, Harris AD, He N, Heba S, Hoggard N, Hsu TW, Jansen JFA, Kangarlu A, Lange T, Lebel RM, Li Y, Lin CE, Liou JK, Lirng JF, Liu F, Long JR, Ma R, Maes C, Moreno-Ortega M, Murray SO, Noah S, Noeske R, Noseworthy MD, Oeltzschner G, Porges EC, Prisciandaro JJ, Puts NAJ, Roberts TPL, Sack M, Sailasuta N, Saleh MG, Schallmo MP, Simard N, Stoffers D, Swinnen SP, Tegenthoff M, Truong P, Wang G, Wilkinson ID, Wittsack HJ, Woods AJ, Xu H, Yan F, Zhang C, Zipunnikov V, Zöllner HJ, Edden RAE, Barker PB. . Radiology. 2020 Apr;295(1):171-180. doi: 10.1148/radiol.2020191037. 

• Jenkins TM, Alix JJP, Fingret J, Esmail T, Hoggard N, Baster K, McDermott CJ, Wilkinson ID, Shaw PJ. . J Neurol. 2020 Jan;267(1):244-256. doi: 10.1007/s00415-019-09580-x. 

• Kadodwala VH, Hadjivassiliou M, Currie S, Skipper N, Hoggard N.  Cerebellum Ataxias. 2019 Jul 5;6:7. doi: 10.1186/s40673-019-0099-0. 

• Croall ID, Trott N, Rej A, Aziz I, O'Brien DJ, George HA, Hossain MY, Marks LJS, Richardson JI, Rigby R, Hadjivassiliou M, Hoggard N, Sanders DS. . Nutrients. 2019 Jun 5;11(6):1276. doi: 10.3390/nu11061276.

• Kugler EC, Frost J, Silva V, Plant K, Chhabria K, Chico TJA, Armitage PA. . Development. 2022 Jan 10:dev.199720. doi: 10.1242/dev.199720. Online ahead of print.

• Stringer MS, Heye AK, Armitage PA, Chappell F, Valdés Hernández MDC, Makin SDJ, Sakka E, Thrippleton MJ, Wardlaw JM. . Neuroimage Clin. 2021;32:102883. doi: 10.1016/j.nicl.2021.102883. 

• Rampun A, Jarvis D, Griffiths PD, Zwiggelaar R, Scotney BW, Armitage PA. . J Imaging. 2021 Oct 1;7(10):200. doi: 10.3390/jimaging7100200.

• Kugler E, Snodgrass R, Bowley G, Plant K, Serbanovic-Canic J, Hamilton N, Evans PC, Chico T, Armitage P. . Vasc Biol. 2021 Jul 29;3(1):1-16. doi: 10.1530/VB-21-0009. eCollection 2021.

• Valdés Hernández MDC, Grimsley-Moore T, Sakka E, Thrippleton MJ, Chappell FM, Armitage PA, Makin S, Wardlaw JM. . Front Neurol. 2021 Mar 5;12:640498. doi: 10.3389/fneur.2021.640498. 

• Best JG, Ambler G, Wilson D, Lee KJ, Lim JS, Shiozawa M, Koga M, Li L, Lovelock C, Chabriat H, Hennerici M, Wong YK, Mak HKF, Prats-Sanchez L, Martínez-Domeño A, Inamura S, Yoshifuji K, Arsava EM, Horstmann S, Purrucker J, Lam BYK, Wong A, Kim YD, Song TJ, Lemmens R, Eppinger S, Gattringer T, Uysal E, Tanriverdi Z, Bornstein NM, Ben Assayag E, Hallevi H, Molad J, Nishihara M, Tanaka J, Coutts SB, Polymeris A, Wagner B, Seiffge DJ, Lyrer P, Algra A, Kappelle LJ, Al-Shahi Salman R, Jäger HR, Lip GYH, Fischer U, El-Koussy M, Mas JL, Legrand L, Karayiannis C, Phan T, Gunkel S, Christ N, Abrigo J, Leung T, Chu W, Chappell F, Makin S, Hayden D, Williams DJ, Mess WH, Nederkoorn PJ, Barbato C, Browning S, Wiegertjes K, Tuladhar AM, Maaijwee N, Guevarra AC, Yatawara C, Mendyk AM, Delmaire C, Köhler S, van Oostenbrugge R, Zhou Y, Xu C, Hilal S, Gyanwali B, Chen C, Lou M, Staals J, Bordet R, Kandiah N, de Leeuw FE, Simister R, Hendrikse J, Kelly PJ, Wardlaw J, Soo Y, Fluri F, Srikanth V, Calvet D, Jung S, Kwa VIH, Engelter ST, Peters N, Smith EE, Hara H, Yakushiji Y, Orken DN, Fazekas F, Thijs V, Heo JH, Mok V, Veltkamp R, Ay H, Imaizumi T, Gomez-Anson B, Lau KK, Jouvent E, Rothwell PM, Toyoda K, Bae HJ, Marti-Fabregas J, Werring DJ; Microbleeds International Collaborative Network. . Lancet Neurol. 2021 Apr;20(4):294-303. doi: 10.1016/S1474-4422(21)00024-7. 

• Valdés Hernández MDC, Grimsley-Moore T, Chappell FM, Thrippleton MJ, Armitage PA, Sakka E, Makin S, Wardlaw JM. . Front Neurol. 2021 Mar 1;12:634460. doi: 10.3389/fneur.2021.634460. 

• Bernal J, Valdés-Hernández MDC, Escudero J, Heye AK, Sakka E, Armitage PA, Makin S, Touyz RM, Wardlaw JM, Thrippleton MJ. . Neuroimage. 2021 Apr 15;230:117786. doi: 10.1016/j.neuroimage.2021.117786. 

• Teh K, Armitage P, Tesfaye S, Selvarajah D, Wilkinson ID. . PLoS One. 2020 Dec 15;15(12):e0243907. doi: 10.1371/journal.pone.0243907. 

• Bernal J, Valdés-Hernández M, Escudero J, Sakka E, Armitage PA, Makin S, Touyz RM, Wardlaw JM. . J Imaging. 2020 Jun 5;6(6):43. doi: 10.3390/jimaging6060043.

• Royston R, Oliver C, Howlin P, Dosse A, Armitage P, Moss J, Waite J. . J Autism Dev Disord. 2020 Mar;50(3):893-903. doi: 10.1007/s10803-019-04317-1.

• Bernal J, Valdés-Hernández MDC, Escudero J, Viksne L, Heye AK, Armitage PA, Makin S, Touyz RM, Wardlaw JM. . Magn Reson Imaging. 2020 Feb;66:240-247. doi: 10.1016/j.mri.2019.11.001. 

• Gattringer T, Valdes Hernandez M, Heye A, Armitage PA, Makin S, Chappell F, Pinter D, Doubal F, Enzinger C, Fazekas F, Wardlaw JM. . Transl Stroke Res. 2020 Jun;11(3):402-411. doi: 10.1007/s12975-019-00741-8. 

• Ahmed H, Hallam R, Webster G, Rej A, Croall ID, Coleman SH, Key T, Buckle R, Shaw CC, Goodwin J, Aziz I, Sanders DS. . Nutr J. 2021 Sep 8;20(1):79. doi: 10.1186/s12937-021-00737-x.

• Markus HS, Egle M, Croall ID, Sari H, Khan U, Hassan A, Harkness K, MacKinnon A, O'Brien JT, Morris RG, Barrick TR, Blamire AM, Tozer DJ, Ford GA; PRESERVE Study Team. . Stroke. 2021 Aug;52(8):2484-2493. doi: 10.1161/STROKEAHA.120.032054.