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Motor Neurone Disease

Multiple Sclerosis

Parkinson’s disease

Psychogenic non-epileptic seizures


Subarachnoid (brain) haemorrhage

Funded Projects

Neuroscience research has become increasingly difficult to fund within the NHS over recent years.  Rising costs of clinical governance and increasing scrutiny of the expense of all hospital services mean that without external financial support many excellent research projects do not see the light of day.  Most sources of charitable research funding are targeted preferentially at academic units within universities.  Since many of the important advances in medicine come from clinical observations from NHS clinicians working closely with patients, we believe that it is crucially important to provide independent financial support to advance Neuroscience Research.

The Trustees of the Ryder Briggs Fund invite and consider applications for funding of research projects within Sheffield Teaching Hospitals NHS Foundation Trust Directorate of Neuroservices.  This may include medical or nursing research, fundamental science or clinical work, but the Trustees are biased towards projects which involve applied clinical research, that is research that may show more immediate benefits to patients.  The fund is locally managed and supported by donations from the people of South Yorkshire. 

Applications are scrutinized by the Trustees and funded according to their quality.  Almost all donations are used directly to fund research. Other costs, including accounting fees and expenses, amount to less than 0.5% of the fund each year.

Current projects

Stroke - Dr Kirsty Harkness

A combined clinical and laboratory investigation into the role of ADAMTS-13 in Stroke and Transient Ischaemic Attack (TIA): a pilot study.

NICE poster Research Fellow Alkistis Frentzou (left) and Dr Alison Coss, European Stroke Conference 2008, Nice

Stroke is a leading cause of death worldwide and further understanding of the pathological mechanisms of stroke and transient ischaemic attack (TIA) may enable the development of novel therapeutic targets. Various proteins and molecules are involved in modulating arterial thrombosis. Von Willebrand Factor (VWF) is a glycoprotein synthesized in endothelial cells and megakaryocytes and plays a critical role in platelet adhesion and aggregation. It is central to the process of thrombosis and embolism and is known to be increased following a stroke. The VWF cleaving protease, ADAMTS13, modulates the thrombotic cascade by cleaving high molecular weight multimers of VWF. However, so far the possible role of ADAMTS13 has not yet been systematically examined.

The hypothesis of our current study is that ADAMTS13 will be lower in the plasma of stroke and TIA patients. We have measured ADAMTS-13 antigen and activity and also vWF antigen levels in plasma of stroke/TIA patients (n=39) and control subjects (n=33). The stroke patients were classified into categories according to the Oxford Community Stroke Project classification (OCSP). ADAMTS13 activity levels were found to be significantly decreased in patients with partial arterial circulation infarct (PACI) stroke (p=0.010) as compared to the control group. ADAMTS-13 and vWF antigen levels showed no differences in any groups. Follow-up measurements showed a significant increase in ADAMTS-13 activity change in patients with PACI stroke (p=0.014). Our findings suggest that the decrease in ADAMTS-13 activity in patients that had PACI stroke might increase the risk of unexpected clotting in the brain and a recurrence of stroke. A manuscript of these results is currently in preparation.

Furthermore, we have also investigated the expression of ADAMTS-13 in cells of the central nervous system (CNS) and whether pro-inflammatory cytokines, which are known to be elevated in stroke and TIA, modulate its expression. ADAMTS-13 expression was examined in four different CNS derived cell lines, SHSY-5Y (human neuroblastoma), U373 (human astroglioma), CHME-3 (human foetal microglia) and hCMEC/D3 (adult human brain endothelial cells). All cell lines expressed ADAMTS-13 mRNA constitutively at different levels with neuroblastoma cells showing the highest. Furthermore, IL-1β was shown to down-regulate ADAMTS-13 mRNA expression in U373 cells and CHME-3 cells. TNF increased mRNA expression in SHSY-5Y cells at low concentrations. Alterations in ADAMTS-13 protein in all the cell lines tested was not detectable. We believe that the ability of the inflammatory cytokine IL-1β to significantly reduce ADAMTS-13 mRNA expression in human microglia and astroglioma cells suggests an important role in the haemostasis of the local microenvironment under inflammatory conditions. This in vitro cell work has already been presented at two international conferences, including the 17th European Stroke Conference, Nice 2008 and the 20th International Congress on Thrombosis, Greece 2008 and also used as preliminary data in a Welcome Trust grant for the continuation of the work. Furthermore, a manuscript entitled "Differential expression of ADAMTS-13 in cells of the central nervous system following cytokine treatment" has been submitted for publication in Neuroscience Research.


The role of transglutimases in immune mediated neurological diseases - Dr Marios Hadjivassiliou

The role of transglutaminases in immune mediated neurological diseases (with emphasis on gluten sensitivity related neurological dysfunction)

Determination and comparison of serum reactivity to TG2, TG3 and TG6Dr Hadjivassiliou

It appears that whilst IgA antibodies against TG2 (the autoantigen in celiac disease) are consistently present in all patients with enteropathy, antibodies against TG6 are present in patients with gluten ataxia, even in those who do not have an enteropathy. These antibodies are not found in patients with genetic ataxias or in healthy controls. Antibodies to TG6 can therefore serve as an additional marker for gluten sensitivity that is of particular value in patients with neurological dysfunction. We have also found a strong association between stiff person syndrome and gluten sensitivity, a condition that shows many similarities with gluten ataxia. Such patients also have circulating antibodies to TG6. Our data further show that there is clear linkage of gluten sensitivity with the HLA DQ2/DQ8 genotype also in neurology patients. However, the presence or not of an enteropathy is not a prerequisite for a diagnosis  of gluten sensitivity. Neither TG2 nor TG6-specific antibodies are strictly dependent on Ca2+-mediated activation of the enzyme but most patients have a population of antibodies that are directed to the “open” active conformation of the respective isozymes. Using an activated form of TG6 can therefore enhance sensitivity of antibody detection.

Determination of the specificity of circulating disease-related antibodies

TG2 IgA is rarely present in patients with gluten sensitivity but without clear evidence of enteropathy. In those patients with ataxia and enteropathy, inhibition studies have shown that separate antibody populations react with the two different transglutaminase isoforms (TG6 vs TG2). These data together with the finding that a proportion of patients with gluten ataxia tested positive exclusively for antibodies to TG6 provides evidence that ataxia patients develop populations of antibodies which are specific for or have greater avidity for TG6 than other enzyme isoforms. This indicates that in such patients TG6 catalyzes the reactions leading to antibody production. In collaboration with Prof Sollid in Oslo, we have demonstrated that TG6 can deamidate pathogenic gliadin sequences and also form covalent complexes with gliadin through autocatalytic crosslinking. However, it remains unclear in which locale such reactions occur (gut, CNS?) and why these would only or preferentially occur in a subset of patients. We have observed a shift from predominantly IgA to IgG class antibodies in neurology patients which may indicate that indeed extraintestinal production of antibodies may be significant. Post mortem analysis of brain tissue from a single patient with gluten ataxia revealed cerebellar IgA deposits that contained TG6. TG6 is not present at these sites in normal brain suggesting that perivascular TG6 accumulation is linked to the inflammatory response. This is reminiscent of the perivascular IgA deposits in the dermis in dermatitis herpetiformis and suggests that antigen presenting cells may hold the key to understanding extraintestinal manifestation of gluten sensitivity.

We would like to thank the Ryder Briggs Trust for funding this work which clearly would not have been possible without its support.


International Conference on Transglutaminases and Protein Crosslinking Reactions, Marrakesh, Morocco, 2007
D. Aeschlimann, P. Aeschlimann, A. Strigun, N. Woodroofe, and M. Hadjivassiliou. TG6-specific Antibodies in Sera from Patients with Celiac Disease: Implications for Extraintestinal Disease Manifestation.

International Congress on Autoimmunity, Porto, Portugal, 2008
D. Aeschlimann, P. Aeschlimann, A. Strigun, N. Woodroofe, and M. Hadjivassiliou. Autoantibodies in Gluten Ataxia recognize a Novel Neuronal Transglutaminase

International celiac disease conference, Amsterdam, The Netherlands, 2009
Jorunn Stamnaes, Siri Dørum, Burkhard Fleckenstein, Daniel Aeschlimann, Ludvig M. Sollid Gliadin T-cell epitope targeting by TG3 and TG6; implications for gluten ataxia and dermatitis herpetiformis.
Hadjivassiliou, M, Woodroofe, N., Aeschlimann, P, and Aeschlimann, D. Antibodies against TG6 as the only serological marker of gluten ataxia.

Association of British Neurologist meeting, Liverpool, June 2009
Hadjivassiliou, M., Aeschlimann, P, Sanders, D., Woodroofe, N., Aeschlimann, D, Maki M, Kaukinen K, Korporay-Szabo IM. TG6 ataxia


Hadjivassiliou, M., Aeschlimann, P., Strigun, A., Sanders, D., Woodroofe, N., and Aeschlimann, D. (2008). Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann. Neurol. 64, 332-343.

Boscolo, S., Lorenzon, A., Sblattero, D., Florian, F., Stebel, M., Marzari, R., Not, T., Aeschlimann, D., Ventura, A., Hadjivassiliou, M. and Tongiorgi, E. (2009). Anti-transglutaminase antibodies cause ataxia in mice. Submitted for publication

Hadjivassiliou, M., Aeschlimann, D., Grünewald, R.A., Sanders, D.S., Sharrack, B., and Woodroofe, N. (2009) Anti-GAD associated neurological diseases and gluten sensitivity. Submitted for publication

Hadjivassiliou, M, Sanders, D.S., Grünewald, R.A., Woodroofe, N. Boscolo, S., and Aeschlimann, D (2009). The neurology or gluten sensitivity. Lancet Neurol, in print


Psychogenic Non-Epileptic Seizures - Dr Markus Reuber

Psycho-education for patients with nonepileptic seizures – development of a trial platform and pilot study

Progress report from Dr Markus Reuber to Dr John Jarratt (Ryder Briggs Fund Trustee)

Dr Reuber

Research Project

We have made a very significant progress our plans of developing a trial platform for a prospective, randomized multicentre study of an early psychoeducational intervention for patients newly diagnosed with non-epileptic seizures (NES).

The treatment manual for the therapists and the patient workbooks have been completed. Research ethics and research governance approval for the planned pilot study have been secured. Based on the experience of a preliminary multicentre study (which was already underway when we applied for our grant to the Ryder Briggs Trust), we decided that we would be more likely to recruit patients for the intended pilot study of our psychoeducational intervention in Sheffield, Cardiff and at St Georges’s Hospital in London (rather than in Sheffield and Leeds, as originally planned). Recruitment for the pilot study is going to start in September 2009.  Before this date, therapists from the three participating centres will be invited for a one day training course which is currently being prepared and organised by Rebecca Mayer. We anticipate that we will have completed our pilot study by March 2010.

Other Progress

The funding received by the Ryder Briggs Trust has also allowed us to make progress with our wider research strategy. This should make it more likely that we will be successful with our application for a grant for the eventual randomised multicentre study from one of the major funding bodies such as the NIHR or the MRC. Gemma Lawton was an important member of the team which successfully applied for a research for patient benefit (RfPB) grant which we were able to secure earlier this year.  This grant will allow us to combine our pilot study of a psychotherapeutic intervention with a detailed qualitative analysis of the therapy experience of therapist and patients.  The results of this qualitative analysis should our therapy materials further. 

The RfPB funding has also allowed us to form a Research User Group, which will advise us on the design of and the materials used for the future multicentre study.

The RfPB grant has also enabled us to carry out an additional preliminary study in which we will follow up 50 patients with NES prospectively for 5 months after the diagnosis has been discussed with them. Patients enrolled in this study will not receive and additional treatment during the follow-up period. In this study, we will use the same outcome measures as in the planned randomised multicentre study. The results of this study will enable us to learn more about the “natural history” of NES after the communication of the diagnosis and more accurately to calculate the sample sizes of the eventual multicentre study. We have obtained research ethics and governance approval for this study and are currently recruiting in Sheffield, London, Cardiff, Manchester and Nottingham. Recruitment should be complete by the end of August 2009.

We have also published a first paper based on the work our research collaboration. Given that both Gemma and Rebecca have helped in the completion of the report and that their salaries were supported by the Ryder Briggs Trust, we have acknowledged your support in the paper a proof of which I have enclosed. It is due to be published in Epilepsia shortly.

We hope that the progress we have made satisfies your expectations. I remain very grateful for your support for a much neglected cause.

Link to Interscience abstract "Acceptability and effectiveness of a strategy for the communication of the diagnosis of psychogenic nonepileptic seizures"

Future projects

Evaluation of a Novel Treatment for Non-Dopa Responsive Parkinsonism - Mr Jeremy Rowe

Evaluation of a Novel Treatment for Non-Dopa Responsive Parkinsonism

Lead Applicant
Mr Jeremy Rowe
Consultant Neurosurgeon
Dept of Neurosurgery
Royal Hallamshire Hospital
S10 2JF

1. Summary
This is a pilot study to investigate prospectively the clinical response and efficacy of stimulating the pedunculo-pontine nucleus (PPN) in non-Dopa responsive Parkinsonism. The aim is to study eight patients with a diagnosis of progressive supranuclear palsy (PSP) or multi-system atrophy (MSA) who will undergoing deep brain stimulation (DBS) surgery for their movement disorder. Baseline assessments will examine motor function, cognitive function, mood and quality of life (QoL) before surgery and at  6, 12 and 24 months post surgery. Assessment at 6 months will be undertaken with the DBS device turned on and off in a blinded fashion. We will also examine the impact of surgery on the quality of life and mood of patients’ carers.

2. Clinical Relevance
MSA and PSP are degenerative conditions of non-dopa responsive parkinsonism for which no medical treatment currently exists. The possibility of an effective treatment is, therefore, of very significant importance.

In PSP and MSA the main dopamine pathway facilitating movement (the nigrostriatal path) is damaged rendering patients parkinsonian but unresponsive to dopamine. The nigrostriatal path normally activates the pedunculopontine nucleus (PPN) and so this activation is lost in these conditions. Experimentally, and in selected patients stimulating the PPN improves Parkinsonian symptoms and so is a promising approach for treating non-dopa responsive parkinsonism. There is therefore a theoretical basis and preliminary evidence that stimulation of the PPN may be an effective treatment.

We plan to carry out the project over three years. This would allow one year to recruit and implant patients and a minimum of two years follow-up. If successful the study may be extended beyond this and expanded from a pilot phase into a full clinical study. Whilst MSA and PSP present with problems with movement, impaired balance and falls, in the later stages of the disease there may be cognitive decline and dementia. The duration of the study and the neuropsychological assessments are essential to examine not only what happens to motor function, but whether there is any evidence that the disease process is changed by surgery and how.

3. Background
Both MSA and PSP are clinical diagnoses of Parkinsonism that do not respond to L-Dopa medication. They present with a lack of movement and postural instability that result in falls and severe disability. As the diseases progress cognitive difficulties also feature. Evidence suggests that both PSP and MSA are associated with destruction of dopamine receptors in the striatum (nigrostriatal degeneration), thereby rendering them unresponsive to dopamine medication. There is currently no specific therapy for either MSA or PSP, management being simply supportive care. Neither are there animal models of PSP or MSA on which to base research.

Recently there has been increasing interest in the PPN as a surgical target for DBS to treat movement disorders. Stimulating the PPN improves hypokinesia and axial stability in the Parkinsonian primate model, and does so by a non-dopaminergic path,] This has been translated to preliminary work implanting both the PPN and the subthalamic nucleus in patients with Parkinson’s disease, with the suggestion that stimulating the PPN alleviates symptoms that are unresponsive to dopamine. Based on this physiology we recently implanted the PPN in a patient with bilateral destruction of the striatum and a severe Parkinsonian/dystonic condition. This damage destroyed the nigrostriatal path thereby rendering him unresponsive to dopamine. A trial of dopamine therapy confirmed this. Normally the striatum activates the PPN, so we predicted that the PPN was underactive in this patient, and that by stimulating it Parkinsonian features might be improved. In practice, stimulating the PPN has improved his lack of movement, axial stability and his ability to talk.