Publications by authors named "Nigel Hoggard"

91 Publications

Gluten and Autism Spectrum Disorder.

Nutrients 2021 Feb 9;13(2). Epub 2021 Feb 9.

Academic Departments of Neurosciences and Neuroradiology, Sheffield Teaching Hospitals NHS Trust, Sheffield S10 2JF, UK.

An expanding body of literature is examining connections between Autism Spectrum Disorder (ASD) and dietary interventions. While a number of specialist diets have been suggested as beneficial in ASD, gluten has received particularly close attention as a potentially exacerbating factor. Reports exist suggesting a beneficial effect of the gluten-free diet (GFD) in ameliorating behavioural and intellectual problems associated with ASD, while epidemiological research has also shown a comorbidity between ASD and coeliac disease. However, both caregivers and clinicians have expressed an uncertainty of the value of people with ASD going gluten-free, and as the GFD otherwise receives considerable public attention a discussion which focuses specifically on the interaction between ASD and gluten is warranted. In this review we discuss the historical context of ASD and gluten-related studies, and expand this to include an overview of epidemiological links, hypotheses of shared pathological mechanisms, and ultimately the evidence around the use and adoption of the GFD in people with ASD.
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http://dx.doi.org/10.3390/nu13020572DOI Listing
February 2021

Cerebrotendinous Xanthomatosis: diversity of presentation and refining treatment with chenodeoxycholic acid.

Cerebellum Ataxias 2021 Jan 28;8(1). Epub 2021 Jan 28.

Academic department of Neurosciences, Sheffield Teaching Hospitals NHS Trust and University of Sheffield, Royal hallamshire Hospital, Glossop Road, Sheffield, UK.

Background: Cerebrotendinous xanthomatosis (CTX) is a rare but treatable neurometabolic disorder of lipid storage and bile acid synthesis. Whilst CTX is said to present with the classic triad of juvenile onset cataracts, tendon xanthomata and progressive ataxia, the diversity of presentation can be such that the diagnosis may be substantially delayed resulting in permanent neurological disability.

Methods: A retrospective review of the clinical characteristics and imaging findings of 4 patients with CTX presenting to the Sheffield Ataxia Centre over a period of 25 years.

Results: Although CTX-related symptoms were present from childhood, the median age at diagnosis was 39 years. Only 1 of the 4 cases had tendon xanthomata, only 2 cases had juvenile onset cataracts and 3 had progressive ataxia with one patient presenting with spastic paraparesis. Serum cholestanol was elevated in all 4 patients, proving to be a reliable diagnostic tool. In addition, cholestanol was raised in the CSF of 2 patients who underwent lumbar puncture. Despite treatment with chenodeoxycholic acid (CDCA) and normalization of serum cholestanol, CSF cholestanol remained high in one patient, necessitating increase in the dose of CDCA. Further adjustments to the dose of CDCA in the patient with raised CSF cholestanol resulted in slowing of progression. Two of the patients who have had the disease for the longest continued to progress, one subsequently dying from pneumonia.

Conclusion: A high index of suspicion for CTX, even in the absence of the classical triad is essential in reaching such diagnosis. The earlier the diagnosis and treatment, the better the outcome.
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http://dx.doi.org/10.1186/s40673-021-00128-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844909PMC
January 2021

Magnetic resonance spectroscopy reveals mitochondrial dysfunction in amyotrophic lateral sclerosis.

Brain 2020 12;143(12):3603-3618

Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.

Mitochondrial dysfunction is postulated to be central to amyotrophic lateral sclerosis (ALS) pathophysiology. Evidence comes primarily from disease models and conclusive data to support bioenergetic dysfunction in vivo in patients is currently lacking. This study is the first to assess mitochondrial dysfunction in brain and muscle in individuals living with ALS using 31P-magnetic resonance spectroscopy (MRS), the modality of choice to assess energy metabolism in vivo. We recruited 20 patients and 10 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. 31P-MRS was acquired from cerebral motor regions and from tibialis anterior during rest and exercise. Bioenergetic parameter estimates were derived including: ATP, phosphocreatine, inorganic phosphate, adenosine diphosphate, Gibbs free energy of ATP hydrolysis (ΔGATP), phosphomonoesters, phosphodiesters, pH, free magnesium concentration, and muscle dynamic recovery constants. Linear regression was used to test for associations between brain data and clinical parameters (revised amyotrophic functional rating scale, slow vital capacity, and upper motor neuron score) and between muscle data and clinico-neurophysiological measures (motor unit number and size indices, force of contraction, and speed of walking). Evidence for primary dysfunction of mitochondrial oxidative phosphorylation was detected in the brainstem where ΔGATP and phosphocreatine were reduced. Alterations were also detected in skeletal muscle in patients where resting inorganic phosphate, pH, and phosphomonoesters were increased, whereas resting ΔGATP, magnesium, and dynamic phosphocreatine to inorganic phosphate recovery were decreased. Phosphocreatine in brainstem correlated with respiratory dysfunction and disability; in muscle, energy metabolites correlated with motor unit number index, muscle power, and speed of walking. This study provides in vivo evidence for bioenergetic dysfunction in ALS in brain and skeletal muscle, which appears clinically and electrophysiologically relevant. 31P-MRS represents a promising technique to assess the pathophysiology of mitochondrial function in vivo in ALS and a potential tool for future clinical trials targeting bioenergetic dysfunction.
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http://dx.doi.org/10.1093/brain/awaa340DOI Listing
December 2020

Treatment Response of Deferiprone in Infratentorial Superficial Siderosis: a Systematic Review.

Cerebellum 2021 Jan 6. Epub 2021 Jan 6.

Academic Department of Neurosciences, Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK.

Superficial siderosis describes haemosiderin deposition on the surface of the brain. When present on infratentorial structures, it can cause ataxia, sensorineural hearing loss and pyramidal signs. There is no proven treatment and patients experience slow progression of symptoms. Iron-chelating agents have been suggested as a therapeutic option and deferiprone is suited as it crosses the blood-brain barrier. However, deferiprone is reported to have a 1-2% risk of agranulocytosis. We performed a systematic review on treatment of infratentorial superficial siderosis with deferiprone based on PRISMA guidelines. Studies were included if in English or an English language translation was available, were about human subjects and referred to patients with ataxia. Studies were excluded if they did not possess an English translation, included animal studies or did not have ataxia. Studies were excluded if they discussed cerebral amyloid angiopathy or siderosis of other regions. Eleven papers were included. We identified 69 patients. Seventeen patients (25%) discontinued the drug. The most encountered adverse effect was anaemia (21.7%). Neutropaenia was observed in 8.7% and agranulocytosis in 5.8% of patients. Clinically, response varied, and stability or improvement was seen across neurological domains in 6 studies while 5 showed a mixed response. On imaging, 13 (28.9%) patients improved, 24 (53.3%) stabilised and 8 (17.8%) deteriorated. A prospective international centralised register of patients should be developed to inform the design and conduct of a multicentre, placebo-controlled, randomised clinical trial to evaluate the efficacy of deferiprone. The evidence from this systematic review is that deferiprone is a promising intervention.
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http://dx.doi.org/10.1007/s12311-020-01222-7DOI Listing
January 2021

Brain fog and non-coeliac gluten sensitivity: Proof of concept brain MRI pilot study.

PLoS One 2020 28;15(8):e0238283. Epub 2020 Aug 28.

Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, United Kingdom.

Aims: Non-Coeliac Gluten Sensitivity (NCGS) is poorly understood, particularly in terms of its neurological outcomes. We initially conducted a prospective postal survey to investigate its neurological presentation and symptom course. Results from this then motivated a follow-up pilot study utilising brain MRI to characterise potential diagnostic biomarkers for future research.

Methods: Patients with NCGS were recruited from a specialist centre and completed a prospective postal questionnaire (N = 125). This summarised symptoms experienced, their severity and their course. Onset time was compared by Chi-squared analysis to data from the same centre concerning coeliac disease patients (N = 224). Five respondents on a strict gluten-free diet who self-reported brain fog then attended a pilot study, completing MR brain imaging/questionnaires before/after a gluten challenge. "Baseline" data were assessed for abnormalities, while symptom severity and cerebral blood flow (CBF) were compared before/after challenge.

Results: Survey participants were aged 47 (85% female). Prevalence of neurological symptoms were: headaches (51%), brain fog (48%), balance issues (31%), tingling (19%). Median symptom resolution time was 48 hours, while onset was 90 minutes; onset pattern was not significantly different compared to CD patients (p = 0.322). Extra-intestinal symptoms worsened by 37%(±28) during a typical reaction. Predominantly non-statistical observations from the brain imaging study are discussed.

Conclusions: Neurological symptoms in NCGS are common, and onset time is comparable to that in CD. Brain imaging may be a useful future means of investigating physiological injury and responses to gluten in further study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238283PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454984PMC
October 2020

Cognitive Impairment in Coeliac Disease with Respect to Disease Duration and Gluten-Free Diet Adherence: A Pilot Study.

Nutrients 2020 Jul 8;12(7). Epub 2020 Jul 8.

Department of Neurology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals National Health Service Foundation Trust, Sheffield S10 2JF, UK.

Cognitive deficit has been reported in coeliac disease (CD), but previous reports often study heterogenous samples of patients at multiple stages of the disease, or lack control data. Healthy controls ( = 21), newly diagnosed CD patients (NCD; = 19) and established CD patients (ECD; = 35) were recruited from a specialist UK centre. Participants underwent a cognitive test battery that established seven overall domain scores. The SF-36 was administered as a quality of life (QoL) measure. Controlling for age, data were compared in between-group ANCOVAs with Tukey's post-hoc test. Any significant outcome was compared in the ECD group only, between patients who were gluten-free diet adherent vs. non-adherent (defined via Biagi score and serology results). NCD and ECD groups underperformed relative to controls, by comparable degrees, in visual (overall model: < 0.001) and verbal ( = 0.046) memory. The ECD group only underperformed in visuoconstructive abilities ( = 0.050). Regarding QoL, the NCD group reported lower vitality ( = 0.030), while the ECD group reported more bodily pain ( = 0.009). Comparisons based on dietary adherence were non-significant. These findings confirm cognitive deficit in CD. Dysfunction appears established at the point of diagnosis, after which it (predominantly) stabilises. While a beneficial effect of dietary treatment is therefore implied, future research is needed to establish to what extent any further decline is due to gluten exposure.
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http://dx.doi.org/10.3390/nu12072028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400804PMC
July 2020

Analysis of polyphenolic metabolites from in vitro gastrointestinal digested soft fruit extracts identify malvidin-3-glucoside as an inhibitor of PTP1B.

Biochem Pharmacol 2020 08 20;178:114109. Epub 2020 Jun 20.

The Rowett Institute, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.

Protein-tyrosine phosphatase 1B (PTP1B, EC 3.1.3.48) is an important regulator of insulin signalling. Herein, we employed experimental and computational biology techniques to investigate the inhibitory properties of phenolics, identified from four in vitro gastrointestinal digested (IVGD) soft fruits, on PTP1B. Analysis by LC-MS/MS identified specific phenolics that inhibited PTP1B in vitro. Enzyme kinetics identified the mode of inhibition, while dynamics, stability and binding mechanisms of PTP1B-ligand complex were investigated through molecular modelling, docking, molecular dynamics (MD) simulations, and MM/PBSA binding free energy estimation. IVGD extracts and specific phenolics identified from the four soft fruits inhibited PTP1B (P < 0.0001) activity. Among the phenolics tested, the greatest inhibition was shown by malvidin-3-glucoside (P < 0.0001) and gallic acid (P < 0.0001). Malvidin-3-glucoside (Ki = 3.8 µg/mL) was a competitive inhibitor and gallic acid (Ki = 33.3 µg/mL) a non-competitive inhibitor of PTP1B. Malvidin-3-glucoside exhibited better binding energy than gallic acid and the synthetic inhibitor Dephostatin (-7.38 > -6.37 > -5.62 kcal/mol) respectively. Principal component analysis demonstrated malvidin-3-glucoside PTP1B-complex occupies more conformational space where critical WPD-loop displayed a higher degree of motion. MM/PBSA binding free energy for malvidin-3-glucoside to PTP1B was found to be higher than other complexes mediated by Van der Waals energy rather than electrostatic interaction for the other two inhibitors (-80.32 ± 1.25 > -40.64 ± 1.43 > -21.63 ± 1.73 kcal/mol) respectively. Altogether, we have established novel insights into the specific binding of dietary phenolics and have identified malvidin-3-glucoside as an PTP1B inhibitor, which may be further industrially developed for the treatment of type-2 diabetes.
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http://dx.doi.org/10.1016/j.bcp.2020.114109DOI Listing
August 2020

Diagnostic Criteria for Primary Autoimmune Cerebellar Ataxia-Guidelines from an International Task Force on Immune-Mediated Cerebellar Ataxias.

Cerebellum 2020 Aug;19(4):605-610

Tokyo Medical University, Tokyo, Japan.

Aside from well-characterized immune-mediated ataxias with a clear trigger and/or association with specific neuronal antibodies, a large number of idiopathic ataxias are suspected to be immune mediated but remain undiagnosed due to lack of diagnostic biomarkers. Primary autoimmune cerebellar ataxia (PACA) is the term used to describe this later group. An International Task Force comprising experts in the field of immune ataxias was commissioned by the Society for Research on the Cerebellum and Ataxias (SRCA) in order to devise diagnostic criteria aiming to improve the diagnosis of PACA. The proposed diagnostic criteria for PACA are based on clinical (mode of onset, pattern of cerebellar involvement, presence of other autoimmune diseases), imaging findings (MRI and if available MR spectroscopy showing preferential, but not exclusive involvement of vermis) and laboratory investigations (CSF pleocytosis and/or CSF-restricted IgG oligoclonal bands) parameters. The aim is to enable clinicians to consider PACA when encountering a patient with progressive ataxia and no other diagnosis given that such consideration might have important therapeutic implications.
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http://dx.doi.org/10.1007/s12311-020-01132-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351847PMC
August 2020

Cognitive Deficit and White Matter Changes in Persons With Celiac Disease: A Population-Based Study.

Gastroenterology 2020 06 20;158(8):2112-2122. Epub 2020 Feb 20.

University of Sheffield, Academic Unit of Radiology, Royal Hallamshire Hospital, Sheffield, United Kingdom; University of Sheffield, Institute for in silico Medicine (INSIGNEO), Sheffield, United Kingdom.

Background & Aims: There is debate over the presence and prevalence of brain injury in patients with celiac disease. To validate previous reports, we investigated the prevalence of neuropsychological dysfunction in persons with celiac disease included in the National UK Biobank, which contains experimental medical data from 500,000 adults in the United Kingdom.

Methods: Biobank participants with celiac disease (n = 104; mean age, 63 years; 65% female) were matched with healthy individuals (controls, n = 198; mean age, 63 years; 67% female) for age, sex, level of education, body mass index, and diagnosis of hypertension. All participants were otherwise healthy. We compared scores from 5 cognitive tests and multiple choice responses to 6 questions about mental health between groups using the t test and chi-squared analyses. Groupwise analyses of magnetic resonance imaging brain data included a study of diffusion tensor imaging metrics (mean diffusivity, fractional anisotropy, radial diffusivity, axial diffusivity), voxel-based morphometry, and Mann-Whitney U comparisons of Fazekas grades.

Results: Compared with control individuals, participants with celiac disease had significant deficits in reaction time (P = .004), and significantly higher proportions had indications of anxiety (P = .025), depression (P = .015), thoughts of self-harm (P = .025), and health-related unhappiness (P = .010). Tract-based spatial statistics analysis showed significantly increased axial diffusivity in widespread locations, demonstrating white matter changes in the brains of participants with celiac disease. Voxel-based morphometry and Fazekas grade analyses did not differ significantly between groups.

Conclusions: In an analysis of data from the UK Biobank, we found participants with celiac disease to have cognitive deficit, indications of worsened mental health, and white matter changes, based on analyses of brain images. These findings support the concept that celiac disease is associated with neurologic and psychological features.
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http://dx.doi.org/10.1053/j.gastro.2020.02.028DOI Listing
June 2020

Comparison of Multivendor Single-Voxel MR Spectroscopy Data Acquired in Healthy Brain at 26 Sites.

Radiology 2020 04 11;295(1):171-180. Epub 2020 Feb 11.

From the Division of Neuroradiology, Park 367B, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 600 N Wolfe St, Baltimore, MD 21287 (M.P., M.M., A.B., K.L.C., G.O., N.A.J.P., M.G.S., R.A.E.E., P.B.B.); F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD (M.P., M.M., A.B., K.L.C., G.O., N.A.J.P., M.G.S., R.A.E.E., P.B.B.); Imaging Institute, Cleveland Clinic Foundation, Cleveland, OH (P.K.B.); Department of Radiology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH (P.K.B.); Department of Radiology, Haukeland University Hospital, Bergen, Norway (M.K.B.); Spinoza Centre for Neuroimaging, Amsterdam, the Netherlands (P.F.B., D.S.); Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (K.M.C.); Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD (K.L.C.); Department of Radiology, Taipei Medical University Shuang Ho Hospital, New Taipei City, Taiwan (D.Y.T.C.); Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (D.Y.T.C.); Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway (A.R.C., L.E.); NOreMENT-Norwegian Center for Mental Disorders Research, University of Bergen, Bergen, Norway (A.R.C., L.E.); Movement Control & Neuroplasticity Research Group, Department of Movement Sciences, Group of Biomedical Sciences, KU Leuven, Leuven, Belgium (K.C., C.M., S.P.S.); REVAL Rehabilitation Research Center, Hasselt University, Diepenbeek, Belgium (K.C.); Department of Radiology, Medical Physics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany (M.D., T.L.); Brain and Consciousness Research Centre, Taipei Medical University, Taipei, Taiwan (N.W.D.); School of Health Sciences, Purdue University, West Lafayette, IN (U.D., D.A.E., R.M.); Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN (U.D., D.A.E.); Department of Neuroimaging, Central Institute of Mental Health, Mannheim, Germany (G.E., M.S.); Department of Clinical Engineering, Haukeland University Hospital, Bergen, Norway (A.R.C., L.E.); Department of Clinical and Health Psychology, University of Florida, Gainesville, FL (M.A.F., E.C.P., A.J.W.); Center for Cognitive Aging and Memory, McKnight Brain Institute, University of Florida, Gainesville, FL (M.A.F., E.C.P., A.J.W.); Shandong Medical Imaging Research Institute, Shandong University, Jinan, China (F.G., G.W.); Department of Human Physiology, University of Oregon, Eugene, OR (I.G.); Department of Radiology, University of Calgary, Calgary, Canada (A.D.H.); Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (N. He, Y.L., H.X., F.Y.); Department of Neurology, BG University Hospital Bergmannsheil, Bochum, Germany (S.H., M.T.); Academic Unit of Radiology, University of Sheffield, Sheffield, England (N. Hoggard, I.D.W.); Department of Radiology, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei, Taiwan (T.W.H., J.K.L., J.F.L.); Department of Radiology, Maastricht University Medical Center, Maastricht, the Netherlands (J.F.A.J.); Department of Psychiatry, Columbia University, New York, NY (A.K.. M.M.O.); New York State Psychiatric Institute, New York, NY (A.K., F.L.); GE Healthcare, Calgary, Canada (R.M.L.); GE Healthcare, Taipei, Taiwan (C.Y.E.L.); Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL (J.R.L.); National High Magnetic Field Laboratory, Gainesville, FL (J.R.L.); Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN (R.M.); Department of Psychology, University of Washington, Seattle, WA (S.O.M., M.P.S.); Center for Mind and Brain, University of California, Davis, Davis, CA (S.N.); GE Healthcare, Berlin, Germany (R.N.); Department of Electrical and Computer Engineering, McMaster University, Hamilton, Canada (M.D.N.); Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC (J.J.P.); Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA (T.P.L.R.); Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Canada (N. Sailasuta, P.T.); Department of Psychiatry, University of Toronto, Toronto, Canada (N. Sailasuta); Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN (M.P.S.); School of Biomedical Engineering, McMaster University, Hamilton, Canada (N. Simard); Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium (S.P.S.); Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany (H.J.W., H.J.Z.); Department of Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.Z.); Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (A.Y.); and Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany (H.J.Z.).

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. values were derived through parametric bootstrapping of the linear mixed-effects models (denoted ). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of -acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol ( > .90), -acetylaspartate and -acetylaspartylglutamate ( = .13), or glutamate and glutamine ( = .11). Among the smaller resonances, no vendor effects were found for ascorbate ( = .08), aspartate ( > .90), glutathione ( > .90), or lactate ( = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020
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http://dx.doi.org/10.1148/radiol.2020191037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104702PMC
April 2020

The anthocyanins in black currants regulate postprandial hyperglycaemia primarily by inhibiting α-glucosidase while other phenolics modulate salivary α-amylase, glucose uptake and sugar transporters.

J Nutr Biochem 2020 04 26;78:108325. Epub 2019 Dec 26.

University of Aberdeen, Rowett Institute, School of Medicine, Medical Sciences and Nutrition, Aberdeen, AB25 2ZD, United Kingdom. Electronic address:

The hypoglycaemic effects of two Ribes sp. i.e., anthocyanin-rich black currants (BC) were compared to green currants (GC), which are low in anthocyanins to establish which compounds are involved in the regulation of postprandial glycaemia. We determined the effect of the currants on inhibiting carbohydrate digestive enzymes (α-amylase, α-glucosidase), intestinal sugar absorption and transport across CaCo-2 cells. The digestion of these currants was modelled using in vitro gastrointestinal digestion (IVGD) to identify the metabolites present in the digested extracts by LC-MS/MS. Freeze-dried BC and IVDG extracts inhibited yeast α-glucosidase activity (P<.0001) at lower concentrations than acarbose, whereas GC and IVDG GC at the same concentrations showed no inhibition. BC and GC both showed significant inhibitory effects on salivary α-amylase (P<.0001), glucose uptake (P<.0001) and the mRNA expression of sugar transporters (P<.0001). Taken together this suggests that the anthocyanins which are high in BC have their greatest effect on postprandial hyperglycaemia by inhibiting α-glucosidase activity. Phytochemical analysis identified the phenolics in the currants and confirmed that freeze-dried BC contained higher concentrations of anthocyanins compared to GC (39.80 vs. 9.85 g/kg dry weight). Specific phenolics were also shown to inhibit salivary α-amylase, α-glucosidase, and glucose uptake. However, specific anthocyanins identified in BC which were low in GC were shown to inhibit α-glucosidase. In conclusion the anthocyanins in BC appear to regulate postprandial hyperglycaemia primarily but not solely by inhibiting α-glucosidase while other phenolics modulate salivary α-amylase, glucose uptake and sugar transporters which together could lower the associated risk of developing type-2 diabetes.
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http://dx.doi.org/10.1016/j.jnutbio.2019.108325DOI Listing
April 2020

Correction to: Longitudinal multi-modal muscle-based biomarker assessment in motor neuron disease.

J Neurol 2020 01;267(1):257-258

Sheffield Institute for Translational Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.

The original version of this article unfortunately contained a mistake. The numbers in the Table 5 appear to have been reproduced wrongly as dates, rather than percentages.
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http://dx.doi.org/10.1007/s00415-019-09648-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954882PMC
January 2020

Longitudinal multi-modal muscle-based biomarker assessment in motor neuron disease.

J Neurol 2020 Jan 17;267(1):244-256. Epub 2019 Oct 17.

Sheffield Institute for Translational Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.

Background: Clinical phenotypic heterogeneity represents a major barrier to trials in motor neuron disease (MND) and objective surrogate outcome measures are required, especially for slowly progressive patients. We assessed responsiveness of clinical, electrophysiological and radiological muscle-based assessments to detect MND-related progression.

Materials And Methods: A prospective, longitudinal cohort study of 29 MND patients and 22 healthy controls was performed. Clinical measures, electrophysiological motor unit number index/size (MUNIX/MUSIX) and relative T2- and diffusion-weighted whole-body muscle magnetic resonance (MR) were assessed three times over 12 months. Multi-variable regression models assessed between-group differences, clinico-electrophysiological associations, and longitudinal changes. Standardized response means (SRMs) assessed sensitivity to change over 12 months.

Results: MND patients exhibited 18% higher whole-body mean muscle relative T2-signal than controls (95% CI 7-29%, p < 0.01), maximal in leg muscles (left tibialis anterior 71% (95% CI 33-122%, p < 0.01). Clinical and electrophysiological associations were evident. By 12 months, 16 patients had died or could not continue. In the remainder, relative T2-signal increased over 12 months by 14-29% in right tibialis anterior, right quadriceps, bilateral hamstrings and gastrocnemius/soleus (p < 0.01), independent of onset-site, and paralleled progressive weakness and electrophysiological loss of motor units. Highest clinical, electrophysiological and radiological SRMs were found for revised ALS-functional rating scale scores (1.22), tibialis anterior MUNIX (1.59), and relative T2-weighted leg muscle MR (right hamstrings: 0.98), respectively. Diffusion MR detected minimal changes.

Conclusion: MUNIX and relative T2-weighted MR represent objective surrogate markers of progressive denervation in MND. Radiological changes were maximal in leg muscles, irrespective of clinical onset-site.
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http://dx.doi.org/10.1007/s00415-019-09580-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954906PMC
January 2020

Is H-MR spectroscopy useful as a diagnostic aid in MSA-C?

Cerebellum Ataxias 2019 5;6. Epub 2019 Jul 5.

Academic Unit of Radiology, C Floor, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF UK.

Background: Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative disease with a cerebellar subtype where ataxic symptoms predominate (MSA-C) associated with autonomic dysfunction and a grave prognosis. The purpose of this analysis was to identify if cerebellar volumetry and MR spectroscopy obtained as part of routine clinical work up of patients with sporadic ataxia differentiates patients with multiple system atrophy- cerebellar type (MSA-C) from those with sporadic adult-onset ataxia of unknown etiology (SAOA) who's condition follows a more benign course.

Methods: Retrospective comparison was undertaken of 20 clinically probable or possible MSA-C patients, 20 age and sex matched patients with SAOA and 20 healthy control subjects. Single voxel H-MR spectroscopy of the cerebellar hemisphere and vermis and volumetric analysis of the cerebellum and brainstem were undertaken on baseline scans, comparing all groups.

Results: There was significant reduction in NAA/Cr levels in patients with MSA-C when compared to those with ISA ( = 0.005) and healthy controls ( < 0.001) in both the hemisphere and vermis. Brainstem volume was significantly reduced in MSA-C patients compared to SAOA patients ( < 0.001) and healthy controls ( < 0.001). There was no difference in cerebellar volume between MSA-C patients and SAOA patients.

Conclusion: This paper demonstrates that at presentation, MSA-C patients have a significant reduction of NAA/Cr in the cerebellum and significant decrease in brainstem volume when compared to SAOA and healthy controls. This is the first study to sucessfully show clinical utility of MR spectroscopy of the cerebellum for differentiating MSA-C from patients with SAOA.
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http://dx.doi.org/10.1186/s40673-019-0099-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612153PMC
July 2019

A Population Survey of Dietary Attitudes towards Gluten.

Nutrients 2019 Jun 5;11(6). Epub 2019 Jun 5.

Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK.

It is unclear how the prevalence of people who believe the gluten-free diet (GFD) to be generally healthy ("Lifestylers") is impacting the overall rates of self-reported gluten sensitivity (GS). We repeated a population survey from 2012 in order to examine how attitudes towards GS have changed over time. Our survey ( = 1004) was administered in Sheffield (UK) in 2015, replicating the 2012 experiment. The questionnaire included a food frequency survey and assessed self-reported GS as well as associated variables (prevalence, current diet, pre-existing conditions, etc.). The overall rates of key variables and chi-squared analysis in comparison to the previous survey were as follows: self-reported GS was 32.8% (previously 12.9%, < 0.001), pre-existing coeliac disease (CD) was 1.2% (previously 0.8%, = 0.370), following a GFD was 3.7% (previously 3.7%, = 0.997). Self-reported GS was positively associated with some pre-existing conditions, including anxiety, depression, chronic fatigue, headaches, and other food allergies/intolerances (including irritable bowel syndrome (IBS); chi-squared analyses, all < 0.001). Over a 3-year period, the fraction of people who self-reported GS increased by over 250%. Despite this, arguably more meaningful indications of underlying physiological GS remained comparable. This research suggests that the public perception of gluten is causing a marked increase in the number of people who erroneously believe they are sensitive to it.
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http://dx.doi.org/10.3390/nu11061276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628309PMC
June 2019

Tremor after long term lithium treatment; is it cortical myoclonus?

Cerebellum Ataxias 2019 22;6. Epub 2019 May 22.

2Department of Neurology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

Introduction: Tremor is a common side effect of treatment with lithium. Its characteristics can vary and when less rhythmical, distinction from myoclonus can be difficult.

Methods: We identified 8 patients on long-term treatment with lithium that developed upper limb tremor. All patients were assessed clinically and electrophysiologically, with jerk-locked averaging (JLA) and cross-correlation (CC) analysis, and five of them underwent brain MRI examination including spectroscopy (MRS) of the cerebellum.

Results: Seven patients (6 female) had action and postural myoclonus and one a regular postural and kinetic tremor that persisted at rest. Mean age at presentation was 58 years (range 42-77) after lengthy exposure to lithium (range 7-40 years). During routine monitoring all patients had lithium levels within the recommended therapeutic range (0.4-1 mmol/l). There was clinical and/or radiological evidence (on cerebellar MRS) of cerebellar dysfunction in 6 patients. JLA and/or CC suggested a cortical generator of the myoclonus in seven patients. All seven were on antidepressants and three additionally on neuroleptics, four of them had gluten sensitivity and two reported alcohol abuse.

Conclusions: A synergistic effect of different factors appears to be contributing to the development of cortical myoclonus after chronic exposure to lithium. We hypothesise that the cerebellum is involved in the generation of cortical myoclonus in these cases and factors aetiologically linked to cerebellar pathology like gluten sensitivity and alcohol abuse may play a role in the development of myoclonus. Despite the very limited evidence in the literature, lithium induced cortical myoclonus may not be so rare.
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http://dx.doi.org/10.1186/s40673-019-0100-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532190PMC
May 2019

Gluten Does Not Induce Gastrointestinal Symptoms in Healthy Volunteers: A Double-Blind Randomized Placebo Trial.

Gastroenterology 2019 09 23;157(3):881-883. Epub 2019 May 23.

Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2019.05.015DOI Listing
September 2019

Neurologic Deficits in Patients With Newly Diagnosed Celiac Disease Are Frequent and Linked With Autoimmunity to Transglutaminase 6.

Clin Gastroenterol Hepatol 2019 12 16;17(13):2678-2686.e2. Epub 2019 Mar 16.

Department of Neuroradiology, Sheffield Teaching Hospitals National Health Service Trust, Sheffield, United Kingdom.

Background & Aims: Celiac disease is an autoimmune disorder induced by ingestion of gluten that affects 1% of the population and is characterized by gastrointestinal symptoms, weight loss, and anemia. We evaluated the presence of neurologic deficits and investigated whether the presence of antibodies to Transglutaminase 6 (TG6) increases the risk of neurologic defects in patients with a new diagnosis of celiac disease.

Methods: We performed a prospective cohort study at a secondary-care gastroenterology center of 100 consecutive patients who received a new diagnosis of celiac disease based on gastroscopy and duodenal biopsy. We collected data on neurologic history, and patients were evaluated in a clinical examination along with magnetic resonance imaging of the brain, magnetic resonance (MR) spectroscopy of the cerebellum, and measurements of antibodies against TG6 in serum samples. The first 52 patients recruited underwent repeat MR spectroscopy at 1 year after a gluten-free diet (GFD). The primary aim was to establish if detection of antibodies against TG6 can be used to identify patients with celiac disease and neurologic dysfunction.

Results: Gait instability was reported in 24% of the patients, persisting sensory symptoms in 12%, and frequent headaches in 42%. Gait ataxia was found in 29% of patients, nystagmus in 11%, and distal sensory loss in 10%. Sixty percent of patients had abnormal results from magnetic resonance imaging, 47% had abnormal results from MR spectroscopy of the cerebellum, and 25% had brain white matter lesions beyond that expected for their age group. Antibodies against TG6 were detected in serum samples from 40% of patients-these patients had significant atrophy of subcortical brain regions compared with patients without TG6 autoantibodies. In patients with abnormal results from MR spectroscopy of the cerebellum, those on the GFD had improvements detected in the repeat MR spectroscopy 1 year later.

Conclusions: In a prospective cohort study of patients with a new diagnosis of celiac disease at a gastroenterology clinic, neurologic deficits were common and 40% had circulating antibodies against TG6. We observed a significant reduction in volume of specific brain regions in patients with TG6 autoantibodies, providing evidence for a link between autoimmunity to TG6 and brain atrophy in patients with celiac disease. There is a need for early diagnosis, increased awareness of the neurologic manifestations among clinicians, and reinforcement of adherence to a strict GFD by patients to avoid permanent neurologic disability.
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http://dx.doi.org/10.1016/j.cgh.2019.03.014DOI Listing
December 2019

Big GABA II: Water-referenced edited MR spectroscopy at 25 research sites.

Neuroimage 2019 05 3;191:537-548. Epub 2019 Mar 3.

Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA.

Accurate and reliable quantification of brain metabolites measured in vivo using H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T-weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels.
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http://dx.doi.org/10.1016/j.neuroimage.2019.02.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818968PMC
May 2019

Assessment of brain perfusion using hyperpolarized Xe MRI in a subject with established stroke.

J Magn Reson Imaging 2019 09 18;50(3):1002-1004. Epub 2019 Feb 18.

POLARIS, Academic Unit of Radiology, University of Sheffield, Sheffield, UK.

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http://dx.doi.org/10.1002/jmri.26686DOI Listing
September 2019

Novel genotype-phenotype and MRI correlations in a large cohort of patients with mutations.

Neurol Genet 2018 Dec 24;4(6):e279. Epub 2018 Oct 24.

Academic Directorate of Neurosciences (C.A.A.H., R.O'.M., M.K.R., S.P., Z.P., S.B., C.J.M., P.J.S., M.H.), Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital; Sheffield Institute for Translational Neuroscience (SITraN) (C.A.A.H., R.S., T.R., C.J.M., P.J.S., M.H.), University of Sheffield; Sheffield Diagnostic Genetics Service (N.J.B., J.M.), Sheffield Children's NHS Foundation Trust; Department of Clinical Neurophysiology (G.R., P.S.), Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital; Academic Unit of Radiology (N.H.), University of Sheffield, Royal Hallamshire Hospital; and Sheffield NIHR Biomedical Research Centre for Translational Neuroscience (C.A.A.H., N.H., R.S., P.S., S.B., C.J.M., P.J.S., M.H.), United Kingdom.

Objective: To clinically, genetically, and radiologically characterize a large cohort of patients.

Methods: We used data from next-generation sequencing panels for ataxias and hereditary spastic paraplegia to identify a characteristic phenotype that helped direct genetic testing for variations in . We analyzed MRI. We reviewed all published mutations for correlations.

Results: We identified 42 cases with biallelic mutations, including 7 novel mutations, including a large multi-exon deletion, representing one of the largest cohorts so far described. We identified a characteristic phenotype comprising cerebellar ataxia with prominent cerebellar dysarthria, mild lower limb spasticity, and a waddling gait, predominantly from a cohort of idiopathic ataxia. We report a rare brain MRI finding of dentate nucleus hyperintensity on T2 sequences with mutations. We confirm that the c.1529C>T allele is frequently present in patients with long-standing British ancestry. Based on the findings of the present study and existing literature, we confirm that patients with homozygous mutations involving the M41 peptidase domain of have a younger age at onset compared to individuals with mutations elsewhere in the gene (14 years difference, < 0.034), whereas c.1529C>T compound heterozygous mutations are associated with a younger age at onset compared to homozygous cases (5.4 years difference, < 0.022).

Conclusions: Mutant is common in sporadic ataxia. In patients with British ancestry, c.1529C>T allele represents the most frequent mutation. mutations can be clinically predicted by the characteristic hybrid spastic-ataxic phenotype described above, along with T2 hyperintensity of the dentate nucleus on MRI.
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http://dx.doi.org/10.1212/NXG.0000000000000279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244025PMC
December 2018

is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice.

Genes Nutr 2018 29;13:28. Epub 2018 Nov 29.

1Rowett Institute, University of Aberdeen, Aberdeen, AB25 2ZD UK.

Background: Energy homeostasis is regulated by the hypothalamus but fails when animals are fed a high-fat diet (HFD), and leptin insensitivity and obesity develops. To elucidate the possible mechanisms underlying these effects, a microarray-based transcriptomics approach was used to identify novel genes regulated by HFD and leptin in the mouse hypothalamus.

Results: Mouse global array data identified as a novel gene highly upregulated by both a HFD and leptin challenge. In situ hybridisation showed expression upregulation by HFD and leptin in all major hypothalamic nuclei in agreement with transcriptomic gene expression data. Immunohistochemistry and studies in the hypothalamic clonal neuronal cell line, mHypoE-N42 (N42), confirmed that alpha 1-antichymotrypsin (αAC), the protein encoded by , is localised to neurons and revealed that it is secreted into the media. expression in N42 neurons is upregulated by palmitic acid and by leptin, together with and , and all three genes are downregulated by the anti-inflammatory monounsaturated fat, oleic acid. Additionally, palmitate upregulation of in N42 neurons is blocked by the NFκB inhibitor, BAY11, and the upregulation of expression in the hypothalamus by HFD is blunted in IL-1 receptor 1 knockout ( ) mice.

Conclusions: These data demonstrate that expression is implicated in nutritionally mediated hypothalamic inflammation.
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http://dx.doi.org/10.1186/s12263-018-0619-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263559PMC
November 2018

The Significance of Low Titre Antigliadin Antibodies in the Diagnosis of Gluten Ataxia.

Nutrients 2018 Oct 5;10(10). Epub 2018 Oct 5.

Departments of Gastroenterology, Sheffield Teaching Hospitals NHS Trust, Sheffield S10 2JF, UK.

Background: Patients with gluten ataxia (GA) without enteropathy have lower levels of antigliadin antibodies (AGA) compared to patients with coeliac disease (CD). Magnetic Resonance Spectroscopy (NAA/Cr area ratio) of the cerebellum improves in patients with GA following a strict gluten-free diet (GFD). This is associated with clinical improvement. We present our experience of the effect of a GFD in patients with ataxia and low levels of AGA antibodies measured by a commercial assay.

Methods: Consecutive patients with ataxia and serum AGA levels below the positive cut-off for CD but above a re-defined cut-off in the context of GA underwent MR spectroscopy at baseline and after a GFD.

Results: Twenty-one consecutive patients with GA were included. Ten were on a strict GFD with elimination of AGA, 5 were on a GFD but continued to have AGA, and 6 patients did not go on a GFD. The NAA/Cr area ratio from the cerebellar vermis increased in all patients on a strict GFD, increased in only 1 out of 5 (20%) patients on a GFD with persisting circulating AGA, and decreased in all patients not on a GFD.

Conclusion: Patients with ataxia and low titres of AGA benefit from a strict GFD. The results suggest an urgent need to redefine the serological cut-off for circulating AGA in diagnosing GA.
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http://dx.doi.org/10.3390/nu10101444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213789PMC
October 2018

Cortical thickness and gyrification patterns in patients with psychogenic non-epileptic seizures.

Neurosci Lett 2018 06 12;678:124-130. Epub 2018 May 12.

Department of Psychology, University of Sheffield, Cathedral Court, 1 Vicar Lane, Sheffield, S1 2LT, United Kingdom.

Psychogenic non-epileptic seizures (PNES) are often viewed as manifestations of altered motor and sensory function resulting from psychological responses to adverse experiences. Yet many patients and non-expert healthcare professionals find it difficult to understand how severe disturbances in normal neurological functioning can solely result from underlying psychological mechanisms to the exclusion of other physical causes. Perhaps importantly, recent advances using neuroimaging techniques point to possible structural and functional correlates in PNES. In an attempt to further our understanding of the neurobiological correlates of this condition, we compared the brain scans of 20 patients with PNES (14 females, mean age 41.05, range 19-62) and 20 age- and gender-matched healthy controls (14 females, mean age 40.65, range 21-61) to investigate group differences for cortical thickness and gyrification patterns using FreeSurfer. Compared to controls, patients with PNES showed cortical thickness increases in motor, sensory and occipital areas as well as cortical thickness decreases in temporal and frontal brain regions. In addition, we observed age-related changes in cortical thickness in the right lateral occipital area in PNES. However, contrary to our prediction that atypical gyrification may be present, we did not find any evidence of abnormalities on a measure thought to reflect prenatal and early childhood cortical development and organization. Nor did we find significant correlations between cortical thickness results and clinical features. These findings partly corroborate, but also differ from previous morphometric studies in PNES. These inconsistencies likely reflect the aetiology and phenomenological heterogeneity of PNES.
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http://dx.doi.org/10.1016/j.neulet.2018.04.056DOI Listing
June 2018

Exaggerated startle in post-infectious opsoclonus myoclonus syndrome.

Clin Neurophysiol 2018 07 13;129(7):1372-1373. Epub 2018 Apr 13.

Department of Clinical Neurophysiology, Sheffield Teaching Hospitals NHS Foundation Trust, UK.

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http://dx.doi.org/10.1016/j.clinph.2018.03.026DOI Listing
July 2018

A randomised, double-blind, cross-over trial to evaluate bread, in which gluten has been pre-digested by prolyl endoprotease treatment, in subjects self-reporting benefits of adopting a gluten-free or low-gluten diet.

Br J Nutr 2018 03;119(5):496-506

1Rowett Institute,University of Aberdeen,Foresterhill AB25 2ZD,UK.

The aim of the present study was to determine if the enzyme Aspergillus niger prolyl endoprotease (ANPEP), which degrades the immunogenic proline-rich residues in gluten peptides, can be used in the development of new wheat products, suitable for gluten-sensitive (GS) individuals. We have carried out a double-blind, randomised, cross-over trial with two groups of adults; subjects, self-reporting benefits of adopting a gluten-free or low-gluten diet (GS, n 16) and a control non-GS group (n 12). For the trial, volunteers consumed four wheat breads: normal bread, bread treated with 0·8 or 1 % ANPEP and low-protein bread made from biscuit flour. Compared with controls, GS subjects had a favourable cardiovascular lipid profile - lower LDL (4·0 (sem 0·3) v. 2·8 (sem 0·2) mmol/l; P=0·008) and LDL:HDL ratio (3·2 (sem 0·4) v. 1·8 (sem 0·2); P=0·005) and modified haematological profile. The majority of the GS subjects followed a low-gluten lifestyle, which helps to reduce the gastrointestinal (GI) symptoms severity. The low-gluten lifestyle does not have any effect on the quality of life, fatigue or mental state of this population. Consumption of normal wheat bread increased GI symptoms in GS subjects compared with their habitual diet. ANPEP lowered the immunogenic gluten in the treated bread by approximately 40 %. However, when compared with the control bread for inducing GI symptoms, no treatment effects were apparent. ANPEP can be applied in the production of bread with taste, texture and appearance comparable with standard bread.
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http://dx.doi.org/10.1017/S0007114517003749DOI Listing
March 2018

Phenytoin-related ataxia in patients with epilepsy: clinical and radiological characteristics.

Seizure 2018 Mar 2;56:26-30. Epub 2018 Feb 2.

Academic Department of Neurosciences, Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK. Electronic address:

Purpose: Phenytoin is an effective anticonvulsant for focal epilepsy. Its use can be associated with long-term adverse effects including cerebellar ataxia. Whilst phenytoin is toxic to Purkinje cells in vitro; the clinical and radiological phenotype and mechanism of cerebellar degeneration in vivo remain unclear. We describe the prevalence, clinical and radiological characteristics of phenytoin-related ataxia.

Methods: Patients with epilepsy receiving treatment with phenytoin were recruited from the Epilepsy clinics at Royal Hallamshire Hospital, Sheffield, UK. Neurological examination was performed on all patients after recruitment. Patients were categorised into those with and without ataxia. We determined the severity of ataxia clinically (SARA score) and the pattern of cerebellar involvement by neuroimaging (MRI volumetry and MR spectroscopy).

Results: Forty-seven patients were recruited. Median duration of epilepsy was 24 years, median duration of phenytoin treatment was 15 years and current median phenytoin daily dose was 325 mg. Fifty-five percent of patients complained of poor balance. Clinical evidence of ataxia was seen in 40% patients. Gait, stance and heel-shin slide were the predominant features of cerebellar dysfunction. MRI demonstrated structural, volumetric and functional deficits of the cerebellum. Only one patient with ataxia had phenytoin levels above the normal range.

Conclusions: Cerebellar ataxia is present in 40% of patients with epilepsy and chronic exposure to phenytoin. Patients on long-term phenytoin have reduced cerebellar volume even if they have no clinical evidence of ataxia. Evidence of structural deficits on imaging suggests a predilection for vermian involvement.
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http://dx.doi.org/10.1016/j.seizure.2018.01.019DOI Listing
March 2018

Cerebellar ataxia with sensory ganglionopathy; does autoimmunity have a role to play?

Cerebellum Ataxias 2017 22;4:20. Epub 2017 Dec 22.

Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

Background And Purpose: Cerebellar ataxia with sensory ganglionopathy (SG) is a disabling combination of neurological dysfunction usually seen as part of some hereditary ataxias. However, patients may present with this combination without a genetic cause.

Methods: We reviewed records of all patients that have been referred to the Sheffield Ataxia Centre who had neurophysiological and imaging data suggestive of SG and cerebellar ataxia respectively. We excluded patients with Friedreich's ataxia, a common cause of this combination. All patients were screened for genetic causes and underwent extensive investigations.

Results: We identified 40 patients (45% males, mean age at symptom onset 53.7 ± 14.7 years) with combined cerebellar ataxia and SG. The majority of patients (40%) were initially diagnosed with cerebellar dysfunction and 30% were initially diagnosed with SG. For 30% the two diagnoses were made at the same time. The mean latency between the two diagnoses was 6.5 ± 8.9 years (range 0-44). The commonest initial manifestation was unsteadiness (77.5%) followed by patchy sensory loss (17.5%) and peripheral neuropathic pain (5%).Nineteen patients (47.5%) had gluten sensitivity, of whom 3 patients (7.5%) had biopsy proven coeliac disease. Other abnormal immunological tests were present in another 15 patients. Six patients had malignancy, which was diagnosed within 5 years of the neurological symptoms. Only 3 patients (7.5%) were classified as having a truly idiopathic combination of cerebellar ataxia with SG.

Conclusion: Our case series highlights that amongst patients with the unusual combination of cerebellar ataxia and SG, immune pathogenesis plays a significant role.
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http://dx.doi.org/10.1186/s40673-017-0079-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741885PMC
December 2017

Imaging in low-grade glioma: a guide for neurologists.

Pract Neurol 2018 Feb 5;18(1):27-34. Epub 2017 Dec 5.

Department of Neurology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

The management of low-grade glioma (LGG) is shifting as evidence has emergedthat refutes the previously commonplace imaging-based 'watch and wait' approach, in favour of early aggressive surgical resection. This coupled with the recent 2016 update to the World Health Organisation Classification of Tumours of the Central Nervous System is changing LGG imaging and management. Recently in the contemporary management of low-grade glioma and the changes to this grading system were discussed in detail. In this complementary article, we discuss the role of imaging in the diagnosis, surgical planning and post-treatment follow-up of LGG. We describe the principles of imaging these tumours and use several cases to highlight some difficult scenarios.
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http://dx.doi.org/10.1136/practneurol-2017-001686DOI Listing
February 2018

Anti-MAG associated cerebellar ataxia and response to rituximab.

J Neurol 2018 Jan 20;265(1):115-118. Epub 2017 Nov 20.

Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, England.

Background: Myelin-associated glycoprotein (MAG) is a glycoprotein specific to Schwann cells. Schwann cells produce myelin for nerve cells in the peripheral nervous system. MAG also plays a role in the central nervous system (CNS) by maintaining myelin integrity and inhibiting axonal regeneration from cerebellar neurons. There is a well-established link between distal demyelinating neuropathy and anti-MAG antibodies in patients with monoclonal gammopathy of unknown significance. We describe a series of five patients with anti-MAG antibodies with evidence of cerebellar rather than just sensory ataxia and our experience of treatment with rituximab.

Methods: Cerebellar ataxia was clinically suspected and confirmed using magnetic resonance spectroscopy (MRS) of the cerebellum. All patients underwent detailed nerve conduction studies.

Results: Four patients were males. The ages ranged from 64 to 82 years. All patients were anti-MAG positive and also had IgM monoclonal gammopathy. Four patients had neuropathy, whilst one had no evidence of neuropathy. All patients were treated with rituximab and showed improvement in the MRS parameters of the cerebellum.

Conclusion: Anti-MAG antibodies might be involved in the pathogenesis of idiopathic sporadic ataxias, even in the absence of peripheral neuropathy. Rituximab seems to be a promising therapeutic intervention for those cases.
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http://dx.doi.org/10.1007/s00415-017-8675-9DOI Listing
January 2018