Imperial College London

DrRichardNicholas

Faculty of MedicineDepartment of Brain Sciences

Professor of Practice (Neurology)
 
 
 
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12L12CLab BlockCharing Cross Campus

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Summary

 

Publications

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223 results found

Karamita M, Papadopoulos D, Mitsikostas DD, Gorgoulis V, Probert L, Nicholas Ret al., 2017, Axonal damage and motor impairment correlate with glial cell senescence in a model of multiple sclerosis, 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 790-791, ISSN: 1352-4585

Conference paper

Dorsey-Campbell R, Motlagh BE, Quinn T, Delacruz D, Felongco T, Walters P, Scalfari A, Singh-Curry V, Malik O, Nicholas Ret al., 2017, Discontinuation of dimethyl fumarate in relapsing multiple sclerosis in a single centre, 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 893-894, ISSN: 1352-4585

Conference paper

Magliozzi R, Roncaroli F, Muraro P, Howell O, Reynolds R, Friede T, Nicholas Ret al., 2017, The impact of high level of perivenular inflammation on active white matter lesions and disease progression in multiple sclerosis, 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 172-172, ISSN: 1352-4585

Conference paper

Gallagher PJ, McGuigan C, Nicholas R, Hobart J, Ford H, Petheram K, Sharrack B, Robertson N, Mazibrada G, Scolding N, Wilson M, Pearson O, Silber E, Rog D, Turner B, Harikrishnan S, Duddy M, Gray O, Jones J, Overell Jet al., 2017, Alemtuzumab after Natalizumab SWitch in Evolving Rapidly Severe Multiple Sclerosis (ANSWERS MS), 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 357-358, ISSN: 1352-4585

Conference paper

Alidina A, Raffel J, Nicholas R, 2017, Using lumbar puncture to exclude progressive multifocal leukoencephalopathy in people with multiple sclerosis on natalizumab: real life experience in a single centre, 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 918-918, ISSN: 1352-4585

Conference paper

Datta G, Colasanti A, Rabiner EA, Gunn RN, Malik O, Ciccarelli O, Nicholas R, Van Vlierberghe E, Van Hecke W, Searle G, Santos-Ribeiro A, Matthews PMet al., 2017, Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis, Brain, Vol: 140, Pages: 2927-2938, ISSN: 1460-2156

Brain magnetic resonance imaging is an important tool in the diagnosis and monitoring of multiple sclerosis patients. However, magnetic resonance imaging alone provides limited information for predicting an individual patient’s disability progression. In part, this is because magnetic resonance imaging lacks sensitivity and specificity for detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. The aim of this study was to test for an association between 18 kDa translocator protein brain positron emission tomography signal, which arises largely from microglial activation, and measures of subsequent disease progression in multiple sclerosis patients. Twenty-one patients with multiple sclerosis (seven with secondary progressive disease and 14 with a relapsing remitting disease course) underwent T1- and T2-weighted and magnetization transfer magnetic resonance imaging at baseline and after 1 year. Positron emission tomography scanning with the translocator protein radioligand 11C-PBR28 was performed at baseline. Brain tissue and lesion volumes were segmented from the T1- and T2-weighted magnetic resonance imaging and relative 11C-PBR28 uptake in the normal-appearing white matter was estimated as a distribution volume ratio with respect to a caudate pseudo-reference region. Normal-appearing white matter distribution volume ratio at baseline was correlated with enlarging T2-hyperintense lesion volumes over the subsequent year (ρ = 0.59, P = 0.01). A post hoc analysis showed that this association reflected behaviour in the subgroup of relapsing remitting patients (ρ = 0.74, P = 0.008). By contrast, in the subgroup of secondary progressive patients, microglial activation at baseline was correlated with later progression of brain atrophy (ρ = 0.86, P = 0.04). A regression model including the baseline normal-appearing white matter distribution volume ratio, T2 lesion volume and normal-appearing white matter magnet

Journal article

Cencioni MT, Magliozzi R, Nicholas R, Ali R, Malik O, Reynolds R, Borsellino G, Battistini L, Muraro PAet al., 2017, Programmed death 1 is highly expressed on CD8(+) CD57(+) T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein-Barr virus., Immunology, Vol: 152, Pages: 660-676, ISSN: 0019-2805

Growing evidence points to a deregulated response to Epstein-Barr virus (EBV) in the central nervous system of patients with multiple sclerosis (MS) as a possible cause of disease. We have investigated the response of a subpopulation of effector CD8(+) T cells to EBV in 36 healthy donors and in 35 patients with MS in active and inactive disease. We have measured the expression of markers of degranulation, the release of cytokines, cytotoxicity and the regulation of effector functions by inhibitory receptors, such as programmed death 1 (PD-1) and human inhibitor receptor immunoglobulin-like transcript 2 (ILT2). We demonstrate that polyfunctional cytotoxic CD8(+) CD57(+) T cells are able to kill EBV-infected cells in healthy donors. In contrast, an anergic exhaustion-like phenotype of CD8(+) CD57(+) T cells with high expression of PD-1 was observed in inactive patients with MS compared with active patients with MS or healthy donors. Detection of CD8(+) CD57(+) T cells in meningeal inflammatory infiltrates from post-mortem MS tissue confirmed the association of this cell phenotype with the disease pathological process. The overall results suggest that ineffective immune control of EBV in patietns with MS during remission may be one factor preceding and enabling the reactivation of the virus in the central nervous system and may cause exacerbation of the disease.

Journal article

Datta G, Colasanti A, Kalk N, Owen DR, Scott G, Rabiner EI, Gunn R, Lingford-Hughes A, Malik O, Ciccarelli O, Nicholas R, Nie L, Battaglini M, De Stefano N, Matthews Pet al., 2017, [(11)C]PBR28 or [(18)F]PBR111 detect white matter inflammatory heterogeneity in multiple sclerosis, Journal of Nuclear Medicine, Vol: 58, Pages: 1477-1482, ISSN: 1535-5667

Objective: To assess microglial activation in lesions and in normal appearing white matter of multiple sclerosis (MS) patients using positron emission tomography (PET). Methods: 34 MS patients (7 with secondary progressive MS (SPMS), 27 with relapsing remitting MS (RRMS)) and 30 healthy volunteers, genetically stratified for translocator protein (TSPO), binding status underwent PET scanning with TSPO radioligands ((11)C-PBR28 or (18)F-PBR111). Regional TSPO availability was measured as a distribution volume ratio (DVR) relative to the caudate (a pseudo-reference region). White matter lesions (WML) were classified as "active" (DVR highest in the lesion), "peripherally active" (peri-lesional DVR highest), "inactive" (DVR highest in surrounding normal appearing white matter, NAWM) or "undifferentiated" (similar DVR across lesion, peri-lesional and NAWM volumes). Results: The mean DVR in NAWM of patients was greater than that of the healthy volunteer white matter for both radioligands. Uptake for individual WML in patients was heterogeneous, but the median WML DVR and NAWM DVR for individual patients were strongly correlated (ρ = 0.94, P = 4x10-11). A higher proportion of lesions were inactive in patients with SPMS (35 %) than RRMS (23 %), but active lesions were found in all patients, including those on highly efficacious treatments. Conclusion: TSPO radioligand uptake was increased in brains of MS patients relative to healthy controls with two TSPO radiotracers. WML showed heterogeneous patterns of uptake. Active lesions were found in patients with both RRMS and SPMS. Their independent prognostic significance needs further investigation.

Journal article

Kamourieh S, Gananandan K, Raffel J, Nicholas Ret al., 2017, Natalizumab granule cell neuronopathy: FDG-PET in diagnosis and immune reconstitution with G-CSF, Neurology, Neuroimmunology and Neuroinflammation, Vol: 4, ISSN: 2332-7812

Granule cell neuronopathy (GCN) is a rare presentation of JC virus (JCV) infection targeting the cerebellum.1 To date, 2 cases have been described in patients prescribed natalizumab for MS.2,3 Recent case reports have acknowledged the importance of controlled reconstitution of host immunity in treating JCV-related neurologic disorders.4 In particular, granulocyte-colony stimulating factor (G-CSF) has emerged as a potential treatment.5Here, we report a case of natalizumab-associated GCN where diagnosis was aided by the novel use of FDG-PET, and immune reconstitution driven by G-CSF lead to disease stabilization and subsequent improvement.

Journal article

Montgomery SM, Kusel J, Nicholas R, Adlard Net al., 2017, Costs and effectiveness of fingolimod versus alemtuzumab in the treatment of highly active relapsing-remitting multiple sclerosis in the UK: re-treatment, discount, and disutility, Journal of Medical Economics (JME), Vol: 20, Pages: 962-973, ISSN: 1941-837X

Objective: Patients with relapsing-remitting multiple sclerosis (RRMS) treated with disease modifying therapies (DMTs) who continue to experience disease activity may be considered for escalation therapies such as fingolimod, or may be considered for alemtuzumab. Previous economic modeling used Markov models; applying one alternative technique, discrete event simulation (DES) modeling, allows re-treatment and long-term adverse events (AEs) to be included in the analysis.Methods: A DES was adapted to model relapse-triggered re-treatment with alemtuzumab and the effect of including ongoing quality-adjusted life year (QALY) decrements for AEs that extend beyond previous 1-year Markov cycles. As the price to the NHS of fingolimod in the UK is unknown, due to a confidential patient access scheme (PAS), a variety of possible discounts were tested. The interaction of re-treatment assumptions for alemtuzumab with the possible discounts for fingolimod was tested to determine which DMT resulted in lower lifetime costs. The lifetime QALY results were derived from modeled treatment effect and short- and long-term AEs.Results: Most permutations of fingolimod PAS discount and alemtuzumab re-treatment rate resulted in fingolimod being less costly than alemtuzumab. As the percentage of patients who are re-treated with alemtuzumab due to experiencing a relapse approaches 100% of those who relapse whilst on treatment, the discount required for fingolimod to be less costly drops below 5%. Consideration of treatment effect alone found alemtuzumab generated 0.2 more QALYs/patient; the inclusion of AEs up to a duration of 1 year reduced this advantage to only 0.14 QALYs/patient. Modeling AEs with a lifetime QALY decrement found that both DMTs generated very similar QALYs with the difference only 0.04 QALYs/patient.Conclusions: When the model captured alemtuzumab re-treatment and long-term AE decrements, it was found that fingolimod is cost-effective compared to alemtuzumab, assuming appl

Journal article

Raffel J, Wallace A, Gveric D, Reynolds R, Friede T, Nicholas Ret al., 2017, Patient-reported outcomes and survival in multiple sclerosis: a 10-year retrospective cohort study using the Multiple Sclerosis Impact Scale-29, PLOS Medicine, Vol: 14, ISSN: 1549-1277

BackgroundThere is increasing emphasis on using patient-reported outcomes (PROs) to complement traditional clinical outcomes in medical research, including in multiple sclerosis (MS). Research, particularly in oncology and heart failure, has shown that PROs can be prognostic of hard clinical endpoints such as survival time (time from study entry until death). However, unlike in oncology or cardiology, it is unknown whether PROs are associated with survival time in neurological diseases. The Multiple Sclerosis Impact Scale–29 (MSIS-29) is a PRO sensitive to short-term change in MS, with questions covering both physical and psychological quality of life. This study aimed to investigate whether MSIS-29 scores can be prognostic for survival time in MS, using a large observational cohort of people with MS.Methods and findingsFrom 15 July 2004 onwards, MSIS-29 questionnaires were completed by people with MS registered with the MS Society Tissue Bank (n = 2,126, repeated 1 year later with n = 872 of the original respondents). By 2014, 264 participants (12.4%) had died. Higher baseline MSIS-29 physical (MSIS-29-PHYS) score was associated with reduced survival time (subgroup with highest scores versus subgroup with lowest scores: hazard ratio [HR] 5.7, 95% CI 3.1–10.5, p < 0.001). Higher baseline MSIS-29 psychological score was also associated with reduced survival time (subgroup with highest scores versus subgroup with lowest scores: HR 2.8, 95% CI 1.8–4.4, p < 0.001). In those with high baseline MSIS-29 scores, mortality risk was even greater if the MSIS-29 score worsened over 1 year (HR 2.3, 95% CI 1.2–4.4, p = 0.02). MSIS-29-PHYS scores were associated with survival time independent of age, sex, and patient-reported Expanded Disability Status Scale score in a Cox regression analysis (per 1-SD increase in MSIS-29-PHYS score: HR 1.8, 95% CI 1.1–2.9, p = 0.03). A limitation of the study is that this cohort had high baseline age and disabi

Journal article

Rhone E, Silber E, Mccormick J, Nicholas R, Malik O, Muraro P, Pagliuca A, Kazmi Met al., 2017, Investigating frequency of EBV reactivation following autologous HSCT in patients with multiple sclerosis, 43rd Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: S495-S495, ISSN: 0268-3369

Conference paper

Rhone E, Silber E, Mccormick J, Nicholas R, Malik O, Muraro P, Pagliuca A, Kazmi Met al., 2017, Autologous haematopoietic stem cell transplant in multiple sclerosis: Updated results from the Pan-London MS group, 43rd Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: S482-S483, ISSN: 0268-3369

Conference paper

Monsalvo S, Gabriel I, Sevillano B, Palanicawandar R, Innes A, Milojkovic D, Macdonald D, Chaidos A, Jakob C, Pavlu J, Nicholas R, Malik O, Kazmi M, Silber E, Kanfer E, Muraro P, Apperley JF, Olavarria Eet al., 2017, Exacerbation of multiple sclerosis symptoms in patients undergoing autologous stem cell transplantation, 43rd Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: S419-S420, ISSN: 0268-3369

Conference paper

Muraro PA, Martin R, Mancardi GL, Nicholas R, Sormani MP, Saccardi Ret al., 2017, Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis, Nature Reviews Neurology, Vol: 13, Pages: 391-405, ISSN: 1759-4758

Autologous haematopoietic stem cell transplantation (AHSCT) is a multistep procedure that enables destruction of the immune system and its reconstitution from haematopoietic stem cells. Originally developed for the treatment of haematological malignancies, the procedure has been adapted for the treatment of severe immune-mediated disorders. Results from ~20 years of research make a compelling case for selective use of AHSCT in patients with highly active multiple sclerosis (MS), and for controlled trials. Immunological studies support the notion that AHSCT causes qualitative immune resetting, and have provided insight into the mechanisms that might underlie the powerful treatment effects that last well beyond recovery of immune cell numbers. Indeed, studies have demonstrated that AHSCT can entirely suppress MS disease activity for 4–5 years in 70–80% of patients, a rate that is higher than those achieved with any other therapies for MS. Treatment-related mortality, which was 3.6% in studies before 2005, has decreased to 0.3% in studies since 2005. Current evidence indicates that the patients who are most likely to benefit from and tolerate AHSCT are young, ambulatory and have inflammatory MS activity. Clinical trials are required to rigorously test the efficacy, safety and cost-effectiveness of AHSCT against highly active MS drugs.

Journal article

Chan D, Binks S, Nicholas JM, Frost C, Cardoso MJ, Ourselin S, Wilkie D, Nicholas R, Chataway Jet al., 2017, Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial, Lancet Neurology, Vol: 16, Pages: 591-600, ISSN: 1474-4422

BackgroundIn the 24-month MS-STAT phase 2 trial, we showed that high-dose simvastatin significantly reduced the annualised rate of whole brain atrophy in patients with secondary progressive multiple sclerosis (SPMS). We now describe the results of the MS-STAT cognitive substudy, in which we investigated the treatment effect on cognitive, neuropsychiatric, and health-related quality-of-life (HRQoL) outcome measures.MethodsWe did a secondary analysis of MS-STAT, a 24-month, double-blind, controlled trial of patients with SPMS done at three neuroscience centres in the UK between Jan 28, 2008, and Nov 4, 2011. Patients were randomly assigned (1:1) to either 80 mg simvastatin (n=70) or placebo (n=70). The cognitive assessments done were the National Adult Reading Test, Wechsler Abbreviated Scale of Intelligence, Graded Naming Test, Birt Memory and Information Processing Battery (BMIPB), Visual Object and Space Perception battery (cube analysis), Frontal Assessment Battery (FAB), and Paced Auditory Serial Addition Test. Neuropsychiatric status was assessed using the Hamilton Depression Rating Scale and the Neuropsychiatric Inventory Questionnaire. HRQoL was assessed using the self-reported 36-Item Short Form Survey (SF-36) version 2. Assessments were done at study entry, 12 months, and 24 months. Patients, treating physicians, and outcome assessors were masked to treatment allocation. Analyses were by intention to treat. MS-STAT is registered with ClinicalTrials.gov, number NCT00647348.FindingsBaseline assessment revealed impairments in 60 (45%) of 133 patients on the test of frontal lobe function (FAB), and in between 13 (10%) and 43 (33%) of 130 patients in tests of non-verbal and verbal memory (BMIPB). Over the entire trial, we noted significant worsening on tests of verbal memory (T score decline of 5·7 points, 95% CI 3·6–7·8; p<0·0001) and non-verbal memory (decline of 6·8 points, 4·8–8·7; p<0·

Journal article

Houston S, Nandoskar A, Nicholas R, Chataway J, Greenwood J, Dubis AMet al., 2017, Microvascular Abnormalities and Inner Retinal Thickness in Multiple Sclerosis, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404

Conference paper

Montgomery SM, Maruszczak MJ, Slater D, Kusel J, Nicholas R, Adlard Net al., 2017, A discrete event simulation to model the cost-utility of fingolimod and natalizumab in rapidly evolving severe relapsing-remitting multiple sclerosis in the UK, JOURNAL OF MEDICAL ECONOMICS, Vol: 20, Pages: 474-482, ISSN: 1369-6998

Journal article

Nandoskar A, Raffel J, Scalfari AS, Friede T, Nicholas RSet al., 2017, Pharmacological Approaches to the Management of Secondary Progressive Multiple Sclerosis, DRUGS, Vol: 77, Pages: 885-910, ISSN: 0012-6667

Journal article

Raffel J, Sridharan S, Nicholas R, 2017, [C-11]PBR-28 positron emission tomography in multiple sclerosis: Neuroinflammation or otherwise?, Annals of Neurology, Vol: 81, Pages: 323-324, ISSN: 0364-5134

Journal article

Raffel J, Gafson AR, Dahdaleh S, Malik O, Jones B, nicholas Ret al., 2017, Inflammatory Activity on Natalizumab Predicts Short-term but not Long-term Disability in Multiple Sclerosis, PLOS One, Vol: 12, ISSN: 1932-6203

BACKGROUND: In people with multiple sclerosis treated with interferon-beta or glatiramer acetate, new MRI lesions and relapses during the first year of treatment predict a poor prognosis. OBJECTIVE: To study this association in those receiving natalizumab. METHODS: Data were collected on relapses, new MRI activity, and Modified Rio Score after initiation of natalizumab in an observational cohort of 161 patients with high baseline disability. These were correlated with Expanded Disability Status Scale (EDSS) progression at years 1, 2, 3, and 3-7 after treatment initiation, versus pre-treatment baseline. RESULTS: 46/161 patients had a relapse in the first year and 44/161 had EDSS progression by year 2. Relapses and Modified Rio Score in the first year of treatment predicted EDSS progression at year 1 and 2 after treatment initiation. However, this effect disappeared with longer follow-up. Paradoxically, there was a trend towards inflammatory activity on treatment (first year Modified Rio Score, relapses, and MRI activity) predicting a lower risk of EDSS progression by years 3-7, although this did not reach statistical significance. Those with and without EDSS progression did not differ in baseline age, EDSS, or pre-treatment relapse rate. Relapses in year 0-1 predicted further relapses in years 1-3. CONCLUSIONS: Breakthrough inflammatory activity after natalizumab treatment is predictive of short-term outcome measures of relapses or EDSS progression, but does not predict longer term EDSS progression, in this cohort with high baseline disability.

Journal article

Datta G, Violante IR, Scott G, Zimmerman K, Santos-Ribeiro A, Rabiner EA, Gunn RN, Malik O, Ciccarelli O, Nicholas R, Matthews PMet al., 2016, Translocator positron-emission tomography and magnetic resonance spectroscopic imaging of brain glial cell activation in multiple sclerosis., Multiple Sclerosis, Vol: 23, Pages: 1469-1478, ISSN: 1352-4585

BACKGROUND: Multiple sclerosis (MS) is characterised by a diffuse inflammatory response mediated by microglia and astrocytes. Brain translocator protein (TSPO) positron-emission tomography (PET) and [myo-inositol] magnetic resonance spectroscopy (MRS) were used together to assess this. OBJECTIVE: To explore the in vivo relationships between MRS and PET [(11)C]PBR28 in MS over a range of brain inflammatory burden. METHODS: A total of 23 patients were studied. TSPO PET imaging with [(11)C]PBR28, single voxel MRS and conventional magnetic resonance imaging (MRI) sequences were undertaken. Disability was assessed by Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC). RESULTS: [(11)C]PBR28 uptake and [ myo-inositol] were not associated. When the whole cohort was stratified by higher [(11)C]PBR28 inflammatory burden, [ myo-inositol] was positively correlated to [(11)C]PBR28 uptake (Spearman's ρ = 0.685, p = 0.014). Moderate correlations were found between [(11)C]PBR28 uptake and both MRS creatine normalised N-acetyl aspartate (NAA) concentration and grey matter volume. MSFC was correlated with grey matter volume (ρ = 0.535, p = 0.009). There were no associations between other imaging or clinical measures. CONCLUSION: MRS [ myo-inositol] and PET [(11)C]PBR28 measure independent inflammatory processes which may be more commonly found together with more severe inflammatory disease. Microglial activation measured by [(11)C]PBR28 uptake was associated with loss of neuronal integrity and grey matter atrophy.

Journal article

Lewin A, Hamilton S, Witkover A, Langford P, Nicholas R, Chataway J, Bangham CRet al., 2016, Free serum haemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis [version 1; peer review: 1 approved, 2 approved with reservations], Wellcome Open Research, Vol: 1, ISSN: 2398-502X

Background A major cause of disability in secondary progressive multiple sclerosis (SPMS) is progressive brain atrophy, whose pathogenesis is not fully understood. The objective of this study was to identify protein biomarkers of brain atrophy in SPMS. Methods We used surface-enhanced laser desorption-ionization time-of-flight mass spectrometry to carry out an unbiased search for serum proteins whose concentration correlated with the rate of brain atrophy, measured by serial MRI scans over a 2-year period in a well-characterized cohort of 140 patients with SPMS. Protein species were identified by liquid chromatography-electrospray ionization tandem mass spectrometry. Results There was a significant (p<0.004) correlation between the rate of brain atrophy and a rise in the concentration of proteins at 15.1 kDa and 15.9 kDa in the serum. Tandem mass spectrometry identified these proteins as alpha-haemoglobin and beta-haemoglobin, respectively.  The abnormal concentration of free serum haemoglobin was confirmed by ELISA (p<0.001). The serum lactate dehydrogenase activity was also highly significantly raised (p<10(-12)) in patients with secondary progressive multiple sclerosis. Conclusions An underlying low-grade chronic intravascular haemolysis is a potential source of the iron whose deposition along blood vessels in multiple sclerosis plaques contributes to the neurodegeneration and consequent brain atrophy seen in progressive disease. Chelators of free serum iron will be ineffective in preventing this neurodegeneration, because the iron (Fe(2+)) is chelated by haemoglobin.

Journal article

Newbould R, Muraro P, Bishop C, Waldman Aet al., 2016, Analysis of ageing-associated grey matter volume in patients with multiple sclerosis shows excess atrophy in subcortical regions, NeuroImage-Clinical, Vol: 13, Pages: 9-15, ISSN: 2213-1582

Age of onset in multiple sclerosis (MS) exerts an influence on the course of disease. This study examined whether global and regional brain volumes differed between “younger” and “older” onset MS subjects who were matched for short disease duration, mean 1.9 years and burden as measured by the MS Severity Score and relapses.21 younger-onset MS subjects (age 30.4 ± 3.2 years) were compared with 17 older-onset (age 48.7 ± 3.3 years) as well as age-matched controls (n = 31, 31.9 ± 3.5 years and n = 21, 47.3 ± 4.0 years). All subjects underwent 3D volumetric T1 and T2-FLAIR imaging. White matter (WM) and grey matter (GM) lesions were outlined manually. Lesions were filled prior to tissue and structural segmentation to reduce classification errors.Volume loss versus control was predominantly in the subcortical GM, at > 13% loss. Younger and older-onset MS subjects had similar, strong excess loss in the putamen, thalamus, and nucleus accumbens. No excess loss was detected in the amygdala or pallidum. The hippocampus and caudate showed significant excess loss in the younger group (p < 0.001) and a strong trend in the older-onset group.These results provide a potential imaging correlate of published neuropsychological studies that reported the association of younger age at disease onset with impaired cognitive performance, including decreased working memory.

Journal article

Bermel R, Comi G, Eralinna J-P, Leist TP, Nicholas R, Oreja-Guevara C, Siva A, Van Wijmeersch B, Wiendl H, Bernasconi C, Buffels R, Csoboth C, Han J, Musch B, Vermersch Pet al., 2016, Design of two phase III open-label trials evaluating ocrelizumab in patients with relapsing-remitting multiple sclerosis and suboptimal response to disease-modifying treatment, 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 615-616, ISSN: 1352-4585

Conference paper

Gafson AR, Nicholas R, Giovannoni G, Matthews PMet al., 2016, Plasma cytokine concentration changes in multiple sclerosis patients after treatment with dimethyl fumarate, 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 670-671, ISSN: 1352-4585

Conference paper

Chan D, Binks S, Nicholas J, Frost C, Alsanousi A, Fox N, Wilkie D, Nicholas R, Chataway Jet al., 2016, Effect of high-dose simvastatin on cognition in secondary progressive multiple sclerosis (MS-STAT cognitive): a randomised, placebo-controlled, Phase 2 trial., 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 82-83, ISSN: 1352-4585

Conference paper

Datta G, Colasanti A, Kalk NJ, Owen DR, Scott G, Rabiner EA, Gunn RN, Lingford-Hughes AR, Malik O, Ciccarelli O, Nicholas R, Battaglini M, Stefano ND, Matthews PMet al., 2016, In vivo translocator protein positron emission tomography imaging detects a heterogeneity of lesion inflammatory activity in multiple sclerosis not evident by MRI., 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 36-37, ISSN: 1352-4585

Conference paper

Mitchell B, Raffel J, Nicholas R, 2016, Increasing area level deprivation in England impacts age of progression and wheelchair use in multiple sclerosis, 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 503-503, ISSN: 1352-4585

Conference paper

Connell L, Daws R, Hampshire A, Nicholas R, Raffel Jet al., 2016, Validating a participant-led computerised cognitive battery in people with multiple sclerosis, 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 140-141, ISSN: 1352-4585

Conference paper

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