Publications
385 results found
Cruz PMR, Matthews L, Boggild M, et al., 2016, Time- and Region-Specific Season of Birth Effects in Multiple Sclerosis in the United Kingdom, JAMA NEUROLOGY, Vol: 73, Pages: 954-960, ISSN: 2168-6149
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- Citations: 16
Martin J, Raffel JB, Nicholas R, 2016, Progressive Dwindling in Multiple Sclerosis: An Opportunity to Improve Care, PLOS One, Vol: 11, ISSN: 1932-6203
IntroductionIn the general ageing population, 40% of deaths occur following a prolonged trajectory of “progressive dwindling,” characterised by chronic accumulation of disability and frailty, and associated with increased dependency and reduced reserves. Those who progressively dwindle are poorly catered for by current healthcare systems and would benefit from a coordinated approach to their medical and social care, known as formative care. People with multiple sclerosis (pwMS) may be more likely to progressively dwindle, and may be appropriate targets for formative care pathways.ObjectivesTo determine the proportion of pwMS who follow a progressive dwindling trajectory prior to death. To relate trajectory to place of death, and examine what factors predict the progressively dwindling trajectory.MethodsA retrospective observational study of 582 deceased pwMS enrolled in the UK MS Tissue Bank, including death certificates and extensive clinical summaries.Results73.7% of pwMS had a “progressively dwindling” trajectory of dying. This was predicted by those who reach MS disease milestones earlier. 72.5% of pwMS died an MS-related death, which was predicted by an aggressive disease course from onset. Those who progressively dwindled were equally likely to die in hospital as those with other trajectories to death.ConclusionsThe progressively dwindling trajectory of dying is very common in pwMS, and can be predicted by earlier disease milestones. Pathways could target pwMS in these years prior to death, to improve care.
Colasanti A, Guo Q, Giannetti P, et al., 2016, Neuroinflammation and genesis of affective symptoms in multiple sclerosis: integrating evidence from TSPO PET and resting state FMRI, Bipolar Disorders, Vol: 18, Pages: 84-84, ISSN: 1398-5647
Feeney C, Scott G, Raffel J, et al., 2016, Kinetic analysis of the translocator protein positron emission tomography ligand [18F]GE-180 in the human brain, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 43, Pages: 2201-2210, ISSN: 1619-7089
PURPOSE: PET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO radioligand [(11)C]PK-11195 limits accurate quantification. [(18)F]GE-180, a novel TSPO ligand, displays superior binding to [(11)C]PK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of [(18)F]GE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures. METHODS: Ten volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of [(18)F]GE-180. Kinetic modelling of time-activity curves with one-tissue and two-tissue compartment models and Logan graphical analysis was applied to the data. The primary outcome measure was the total volume of distribution (V T) across various regions of interest (ROIs). Secondary outcome measures were the standardized uptake values (SUV), the distribution volume and SUV ratios estimated using a pseudoreference region. RESULTS: The two-tissue compartment model was the best model. The average regional delivery rate constant (K 1) was 0.01 mL cm(-3) min(-1) indicating low extraction across the blood-brain barrier (1 %). The estimated median V T across all ROIs was also low, ranging from 0.16 mL cm(-3) in the striatum to 0.38 mL cm(-3) in the thalamus. There were no significant differences in V T between HABs and MABs across all ROIs. CONCLUSION: A reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low V T estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of [(18)F]GE-180 in populations with neuroinflammatory disease is nee
Macdonell R, Nagels G, Laplaud D-A, et al., 2016, Improved patient-reported health impact of multiple sclerosis: The ENABLE study of PR-fampridine, MULTIPLE SCLEROSIS JOURNAL, Vol: 22, Pages: 944-954, ISSN: 1352-4585
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- Citations: 18
Nicotra A, Newman C, Johnson M, et al., 2016, Peripheral nerve dysfunction in middle-aged subjects born with thalidomide embryopathy, PLOS One, Vol: 11, ISSN: 1932-6203
BackgroundPhocomelia is an extremely rare congenital malformation that emerged as one extreme of arange of defects resulting from in utero exposure to thalidomide. Individuals with thalidomideembryopathy (TE) have reported developing symptoms suggestive of peripheral nervoussystem dysfunction in the mal-developed limbs in later life.MethodsCase control study comparing TE subjects with upper limb anomalies and neuropathicsymptoms with healthy controls using standard neurophysiological testing. Other causes ofa peripheral neuropathy were excluded prior to assessment.ResultsClinical examination of 17 subjects with TE (aged 50.4±1.3 [mean±standard deviation]years, 10 females) and 17 controls (37.9±9.0 years; 8 females) demonstrated features ofupper limb compressive neuropathy in three-quarters of subjects. Additionally there wereexamination findings suggestive of mild sensory neuropathy in the lower limbs (n = 1), L5radiculopathic sensory impairment (n = 1) and cervical myelopathy (n = 1). In TE there wereelectrophysiological changes consistent with a median large fibre neuropathic abnormality(mean compound muscle action potential difference -6.3 mV ([-9.3, -3.3], p = 0.0002) ([95%CI], p-value)) and reduced sympathetic skin response amplitudes (-0.8 mV ([-1.5, -0.2], p =0.0089)) in the affected upper limbs. In the lower limbs there was evidence of sural nervedysfunction (sensory nerve action potential -5.8 μV ([-10.7, -0.8], p = 0.0232)) and impairedwarm perception thresholds (+3.0°C ([0.6, 5.4], p = 0.0169)).ConclusionsWe found a range of clinical features relevant to individuals with TE beyond upper limb compressiveneuropathies supporting the need for a detailed neurological examination toexclude other treatable pathologies. The electrophysiological evidence of large and smallfibre axonal nerve dysfunction in symptomatic and asymptomatic limbs may be a result ofthe original insult and merits further investigation.
de Paula Alves Sousa A, Johnson KR, Nicholas R, et al., 2016, Intrathecal T-cell clonal expansions in patients with multiple sclerosis, Annals of Clinical and Translational Neurology, Vol: 3, Pages: 422-433, ISSN: 2328-9503
ObjectiveAnalysis of the T-cell receptor (TCR) repertoire in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) can reveal antigen-specific immune responses potentially implicated in the disease process. We applied a new unbiased deep-sequencing method for TCR repertoire analysis to accurately measure and compare receptor diversity and clonal expansions within the peripheral and CSF-trafficking T-cell populations of patients with MS and control individuals with idiopathic intracranial hypertension (IIH).MethodsPaired blood and CSF TCR β-chain libraries from five MS patients and five IIH controls were sequenced, yielding a total of 80 million reads.ResultsAlthough TCR repertoire diversity was greater in the blood and CSF compartments of MS patients when compared with IIH controls, it is notable that the frequency of clonal expansions was also significantly higher in both compartments of MS patients. Highly expanded T-cell clones were enriched in the CSF compartment of MS patients compared to peripheral blood, very few of them were detected in both compartments.InterpretationCollectively, our data provide a proof of principle that private compartmentalized T-cell expansion exists in the intrathecal space of MS patients.
Supratak A, Datta G, Wu C, et al., 2016, Remote Actigraphy for Quantitative Assessment of Walking Speed in People with MS, 68th Annual Meeting of the American-Academy-of-Neurology (AAN), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
Datta G, Battaglini M, Scott G, et al., 2016, Cortical [11C]PBR28 PET Measures of Microglial Inflammation Explain Differences in Cognitive Performance of People with MS, 68th Annual Meeting of the American-Academy-of-Neurology (AAN), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
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- Citations: 1
Datta G, Battaglini M, Scott G, et al., 2016, Cortical [11C]PBR28 PET Measures of Microglial Inflammation Explain Differences in Cognitive Performance of People with MS, 68th Annual Meeting of the American-Academy-of-Neurology (AAN), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
Datta G, Battaglini M, Scott G, et al., 2016, Cortical [11C]PBR28 PET Measures of Microglial Inflammation Explain Differences in Cognitive Performance of People with MS, 68th Annual Meeting of the American-Academy-of-Neurology (AAN), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
Datta G, Battaglini M, Scott G, et al., 2016, Cortical [11C]PBR28 PET Measures of Microglial Inflammation Explain Differences in Cognitive Performance of People with MS, 68th Annual Meeting of the American-Academy-of-Neurology (AAN), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
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- Citations: 1
Datta G, Battaglini M, Scott G, et al., 2016, Cortical [11C]PBR28 PET Measures of Microglial Inflammation Explain Differences in Cognitive Performance of People with MS, 68th Annual Meeting of the American-Academy-of-Neurology (AAN), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
Datta G, Battaglini M, Scott G, et al., 2016, Cortical [11C]PBR28 PET Measures of Microglial Inflammation Explain Differences in Cognitive Performance of People with MS, 68th Annual Meeting of the American-Academy-of-Neurology (AAN), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
Porter J, Arie G, Nicholas R, et al., 2016, Transcriptome Profiles from Relapsing-Remitting Multiple Sclerosis Patients Show Aberrant Immunological Phenotypes Compared with Healthy Controls, 68th Annual Meeting of the American-Academy-of-Neurology (AAN), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
Porter J, Arie G, Nicholas R, et al., 2016, Transcriptome Profiles from Relapsing-Remitting Multiple Sclerosis Patients Show Aberrant Immunological Phenotypes Compared with Healthy Controls, 68th Annual Meeting of the American-Academy-of-Neurology (AAN), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
Arie G, Porter J, Wang Y-F, et al., 2016, Tecfidera Modulates Transcriptional Expression of Genes Involved in Regulation of the Immune Response and Antigen Processing, 68th Annual Meeting of the American-Academy-of-Neurology (AAN), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
Collins F, Nicholas R, Malik O, et al., 2016, The role of Autologous Haematopoietic Stem Cell Transplant in MS - Updated results from the Pan-London MS group, 42nd Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation, Publisher: NATURE PUBLISHING GROUP, Pages: S494-S495, ISSN: 0268-3369
Scalfari A, Lederer C, Daumer M, et al., 2016, The relationship of age with the clinical phenotype in multiple sclerosis, MULTIPLE SCLEROSIS JOURNAL, Vol: 22, Pages: 1750-1758, ISSN: 1352-4585
Nicholas R, Magliozzi R, Campbell G, et al., 2016, Temporal lobe cortical pathology and inhibitory GABA interneuron cell loss are associated with seizures in multiple sclerosis, Multiple Sclerosis Journal, Vol: 22, Pages: 25-35, ISSN: 1477-0970
Background: Seizures are recognised in multiple sclerosis (MS), but their true incidence and the mechanismby which they are associated with MS is unclear.Objective: The objective of this paper is to determine the lifetime frequency of seizures in the UnitedKingdom MS Tissue Bank (UKMSTB) population and any pathological features associated with seizures.Methods: We evaluated 255 individuals from the UKMSTB. A subset underwent analysis of corticalthickness, grey matter lesion (GML) (type and number) and cortical neuronal numbers (total and GABAergic).Results: A total of 37/255 patients had seizures (14.5% lifetime incidence); in 47% they were associatedwith concurrent infection. In those with seizures, death and wheelchair use occurred earlier and in 59%seizures developed after 15 years of disease. Seizures were associated with Type 1 GMLs and reducedcortical thickness in the middle temporal gyrus. Localised selective GABAergic interneuron loss in layersIV and VI was related to GMLs but was not explained by the presence of inflammation or by mitochondrial dysfunction within Type I GMLs. Conclusion: We confirm that seizure frequency rises in MS. Type I GMLs in the temporal lobe underlie a loss of inhibitory interneurons in cortical layers IV and VI and these changes could together with concurrent infection enhance susceptibility to seizures.
Colasanti A, Guo, Giannetti P, et al., 2015, Hippocampal neuroinflammation, functional connectivity and depressive symptoms in multiple sclerosis, Biological Psychiatry, Vol: 80, Pages: 62-72, ISSN: 1873-2402
BackgroundDepression, a condition commonly comorbid with multiple sclerosis (MS), is associated more generally with elevated inflammatory markers and hippocampal pathology. We hypothesized that neuroinflammation in the hippocampus is responsible for depression associated with MS. We characterized the relationship between depressive symptoms and hippocampal microglial activation in patients with MS using the 18-kDa translocator protein radioligand [18F]PBR111. To evaluate pathophysiologic mechanisms, we explored the relationships between hippocampal neuroinflammation, depressive symptoms, and hippocampal functional connectivities defined by resting-state functional magnetic resonance imaging.MethodsThe Beck Depression Inventory (BDI) was administered to 11 patients with MS and 22 healthy control subjects before scanning with positron emission tomography and functional magnetic resonance imaging. We tested for higher [18F]PBR111 uptake in the hippocampus of patients with MS relative to healthy control subjects and examined the correlations between [18F]PBR111 uptake, BDI scores, and hippocampal functional connectivities in the patients with MS.ResultsPatients with MS had an increased hippocampal [18F]PBR111 distribution volume ratio relative to healthy control subjects (p = .024), and the hippocampal distribution volume ratio was strongly correlated with the BDI score in patients with MS (r = .86, p = .006). Hippocampal functional connectivities to the subgenual cingulate and prefrontal and parietal regions correlated with BDI scores and [18F]PBR111 distribution volume ratio.ConclusionsOur results provide evidence that hippocampal microglial activation in MS impairs the brain functional connectivities in regions contributing to maintenance of a normal affective state. Our results suggest a rationale for the responsiveness of depression in some patients with MS to effective control of brain neuroinflammation. Our findings also lend support to further investigation of t
Raffel J, Gafson A, Dahdaleh S, et al., 2015, EARLY PREDICTION OF LONG-TERM RESPONSE TO NATALIZUMAB IN MULTIPLE SCLEROSIS, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050
McGuigan C, Craner M, Guadagno J, et al., 2015, Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group, Journal of Neurology Neurosurgery and Psychiatry, Vol: 87, Pages: 117-125, ISSN: 1468-330X
The use of natalizumab for highly active relapsing-remitting multiple sclerosis (MS) is influenced by the occurrence of progressive multifocal leukoencephalopathy (PML). Through measurement of the anti-JCV antibody index, and in combination with the presence or absence of other known risk factors, it may be possible to stratify patients with MS according to their risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI including a diffusion-weighted imaging sequence. This paper describes a practical consensus guideline for treating neurologists, based on current evidence, for the introduction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naïve patients with MS, either currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status. Recommendations for the frequency and type of MRI screening in patients with varying index-associated PML risks are also discussed. This consensus paper presents a simple and pragmatic algorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into standard PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue natalizumab treatment to be managed with a more individualised analysis of their PML risk.
Raffel J, Gafson AR, Malik O, et al., 2015, Anti-JC virus antibody titres increase over time with natalizumab treatment., Multiple Sclerosis Journal, Vol: 21, Pages: 1833-1838, ISSN: 1477-0970
BACKGROUND: Anti-JC virus antibody status is a risk factor for progressive multifocal leukoencephalopathy after natalizumab treatment in multiple sclerosis. Previous studies have used a cross-sectional approach to conclude that the presence and duration of natalizumab treatment does not influence anti-JCV Ab seropositivity. OBJECTIVES: Using a longitudinal approach, we measured change in anti-JCV Ab results after natalizumab treatment. METHODS: Anti-JCV Ab results (n = 1154) from the second-generation STRATIFY JCV™ DxSelect™ test were analysed from an observational cohort of MS patients on natalizumab (n = 485; n = 340 with repeat testing; n = 657 repeat tests on natalizumab). RESULTS: Across sequential paired tests, seroconversion rate was greater than seroreversion rate (40/364 (11.0%) versus 18/293 (6.1%); p < 0.05). Moreover, anti-JCV Ab index increased across longitudinal paired tests (mA-B 0.102; paired t(656) = 5.0; p < 0.0001). This magnitude of Ab level increase far exceeds that expected due to increasing age alone. CONCLUSION: Our data suggest that natalizumab therapy is associated with a significant and substantial increase in anti-JCV Ab index over time. Further work should focus on the underlying mechanisms of this phenomenon, and the clinical relevance to risk stratification.
Howell OW, Schulz-Trieglaff EK, Carassiti D, et al., 2015, Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space, NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, Vol: 41, Pages: 798-813, ISSN: 0305-1846
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- Citations: 68
Colasanti A, Guo Q, Giannetti P, et al., 2015, Hippocampal inflammation and depression in multiple sclerosis: integrating evidence from TSPO PET and resting state fMRI, 31st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE Publications (UK and US), Pages: 492-493, ISSN: 1477-0970
Datta G, Battaglini M, Scott G, et al., 2015, Positron emission tomography imaging in multiple sclerosis highlights a diffuse inflammatory response in brain that appears normal on conventional magnetic resonance imaging, 31st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE Publications (UK and US), Pages: 477-478, ISSN: 1477-0970
Roever C, Nicholas R, Straube S, et al., 2015, Changing EDSS Progression in Placebo Cohorts in Relapsing MS: A Systematic Review and Meta-Regression, PLOS One, Vol: 10, ISSN: 1932-6203
BackgroundRecent systematic reviews of randomised controlled trials (RCTs) in relapsing multiple sclerosis (RMS) revealed a decrease in placebo annualized relapse rates (ARR) over the past two decades. Furthermore, regression to the mean effects were observed in ARR and MRI lesion counts. It is unclear whether disease progression measured by the expanded disability status scale (EDSS) exhibits similar features.MethodsA systematic review of RCTs in RMS was conducted extracting data on EDSS and baseline characteristics. The logarithmic odds of disease progression were modelled to investigate time trends. Random-effects models were used to account for between-study variability; all investigated models included trial duration as a predictor to correct for unequal study durations. Meta-regressions were conducted to assess the prognostic value of a number of study-level baseline variables.ResultsThe systematic literature search identified 39 studies, including a total of 19,714 patients. The proportion of patients in placebo controls experiencing a disease progression decreased over the years (p<0.001). Meta-regression identified associated covariates including the size of the study and its duration that in part explained the time trend. Progression probabilities tended to be lower in the second year of a study compared to the first year with a reduction of 28% in progression odds from year 1 to year 2 (p = 0.017).ConclusionEDSS disease progression exhibits similar behaviour over time as the ARR and point to changes in trial characteristics over the years. This needs to be considered in comparisons between historical and recent trials.
Nicholas R, Raffel J, Malik O, 2015, Progressive multifocal leukoencephalopathy presenting with posterior fossa radiological features in the context of natalizumab therapy in relapsing-remitting multiple sclerosis, 31st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 585-585, ISSN: 1352-4585
Ali R, Nicholas R, Marley S, et al., 2015, Preliminary results of a phase 2 trial of autologous mesenchymal cell therapy in MS (STREAMS), 31st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 556-556, ISSN: 1352-4585
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