Publications
385 results found
Calabrese M, Preziosa P, Scalfari A, et al., 2024, Determinants and Biomarkers of Progression Independent of Relapses in Multiple Sclerosis., Ann Neurol
Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving "chronic" worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion-independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024.
Nicholas R, Magliozzi R, Marastoni D, et al., 2024, High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study., Ann Neurol, Vol: 95, Pages: 706-719
OBJECTIVE: Analysis of postmortem multiple sclerosis (MS) tissues combined with in vivo disease milestones suggests that whereas perivascular white matter infiltrates are associated with demyelinating activity in the initial stages, leptomeningeal immune cell infiltration, enriched in B cells, and associated cortical lesions contribute to disease progression. We systematically examine the association of inflammatory features and white matter demyelination at postmortem with clinical milestones. METHODS: In 269 MS brains, 20 sites were examined using immunohistochemistry for active lesions (ALs) and perivenular inflammation (PVI). In a subset of 22, a detailed count of CD20+ B cells and CD3+ T cells in PVIs was performed. RESULTS: ALs were detected in 22%, whereas high levels of PVI were detected in 52% of cases. ALs were present in 35% of cases with high levels of PVI. Shorter time from onset of progression to death was associated with increased prevalence and higher levels of PVI (both p < 0.0001). Shorter time from onset of progression to wheelchair use was associated with higher prevalence of ALs (odds ratio [OR] = 0.921, 95% confidence interval [CI] = 0.858-0.989, p = 0.0230) and higher level of PVI (OR = 0.932, 95% CI = 0.886-0.981, p = 0.0071). High levels of PVI were associated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocytes within the PVI. INTERPRETATION: ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. These features link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supporting the hypothesis that chronic inflammation drives progression in MS. ANN NEUROL 2024;95:706-719.
Knowles S, Middleton R, Cooze B, et al., 2024, Comparing the pathology, clinical, and demographic characteristics of younger and older-onset multiple sclerosis, Annals of Neurology, Vol: 95, Pages: 471-486, ISSN: 0364-5134
OBJECTIVE: Older people with multiple sclerosis (MS) have a less active radiological and clinical presentation, but many still attain significant levels of disability; but what drives worsening disability in this group? METHODS: We used data from the UK MS Register to characterize demographics and clinical features of late-onset multiple sclerosis (LOMS; symptom onset at ≥50 years), compared with adult-onset MS (AOMS; onset 18-49 years). We performed a pathology study of a separate MS cohort with a later onset (n = 18, mean age of onset 54 years) versus AOMS (n = 23, mean age of onset 29 years). RESULTS: In the Register cohort, there were 1,608 (9.4%) with LOMS. When compared with AOMS, there was a lower proportion of women, a higher proportion of primary progressive MS, a higher level of disability at diagnosis (median MS impact scale 36.7 vs. 28.3, p < 0.001), and a higher proportion of gait-related initial symptoms. People with LOMS were less likely to receive a high efficacy disease-modifying treatment and attained substantial disability sooner. Controlling for age of death and sex, neuron density in the thalamus and pons decreased with onset-age, whereas actively demyelinating lesions and compartmentalized inflammation was greatest in AOMS. Only neuron density, and not demyelination or the extent of compartmentalized inflammation, correlated with disability outcomes in older-onset MS patients. INTERPRETATION: The more progressive nature of older-onset MS is associated with significant neurodegeneration, but infrequent inflammatory demyelination. These findings have implications for the assessment and treatment of MS in older people. ANN NEUROL 2023.
Herranz E, Treaba CA, Barletta VT, et al., 2024, Characterization of cortico-meningeal translocator protein expression in multiple sclerosis., Brain
Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. Positron emission tomography targeting the 18 kDa mitochondrial Translocator Protein (TSPO) is a molecular-specific approach to quantify immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. The aim of this study was to characterize cortical and meningeal TSPO expression in a heterogeneous cohort of multiple sclerosis cases using in vivo simultaneous MR-PET with 11C-PBR28, a second-generation TSPO radioligand, and ex vivo immunohistochemistry. Forty-nine multiple sclerosis patients (21 with secondary progressive and 28 with relapsing-remitting multiple sclerosis) with mixed or high affinity binding for 11C-PBR28 underwent 90-min 11C-PBR28 simultaneous MR-PET. Tracer binding was measured using 60-90 min normalized standardized uptake value ratio values sampled at mid-cortical depth and ∼3 mm above the pial surface. Data in multiple sclerosis patients were compared to 21 age-matched healthy controls. To characterize the nature of 11C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was further described in post-mortem brain tissue from 20 cases with secondary progressive multiple sclerosis and five age-matched healthy donors. Relative to healthy controls, patients with multiple sclerosis exhibited abnormally increased TSPO signal in the cortex and meningeal tissue, diffusively in progressive disease and more localized in relapsing-remitting multiple sclerosis. In multiple sclerosis, increased meningeal TSPO levels were associated with increased Expanded Disability Status Scale scores (p = 0.007, by linear regression). Immunohistochemistry, validated using in-situ sequencing analysis, revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post-mortem secondary progressive multiple sclerosis cases relati
Nicholas R, Rodgers J, Witts J, et al., 2023, The impact of healthcare systems on the clinical diagnosis and disease-modifying treatment usage in relapse-onset multiple sclerosis: a real-world perspective in five registries across Europe, 38th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis, Publisher: SAGE PUBLICATIONS LTD, Pages: 131-132, ISSN: 1756-2856
Williams T, John N, Calvi A, et al., 2023, Cardiovascular risk factors in secondary progressive multiple sclerosis: A cross-sectional analysis from the MS-STAT2 randomized controlled trial., Eur J Neurol, Vol: 30, Pages: 2769-2780
BACKGROUND AND PURPOSE: There is increasing evidence that cardiovascular risk (CVR) contributes to disability progression in multiple sclerosis (MS). CVR is particularly prevalent in secondary progressive MS (SPMS) and can be quantified through validated composite CVR scores. The aim was to examine the cross-sectional relationships between excess modifiable CVR, whole and regional brain atrophy on magnetic resonance imaging, and disability in patients with SPMS. METHODS: Participants had SPMS, and data were collected at enrolment into the MS-STAT2 trial. Composite CVR scores were calculated using the QRISK3 software. Prematurely achieved CVR due to modifiable risk factors was expressed as QRISK3 premature CVR, derived through reference to the normative QRISK3 dataset and expressed in years. Associations were determined with multiple linear regressions. RESULTS: For the 218 participants, mean age was 54 years and median Expanded Disability Status Scale was 6.0. Each additional year of prematurely achieved CVR was associated with a 2.7 mL (beta coefficient; 95% confidence interval 0.8-4.7; p = 0.006) smaller normalized whole brain volume. The strongest relationship was seen for the cortical grey matter (beta coefficient 1.6 mL per year; 95% confidence interval 0.5-2.7; p = 0.003), and associations were also found with poorer verbal working memory performance. Body mass index demonstrated the strongest relationships with normalized brain volumes, whilst serum lipid ratios demonstrated strong relationships with verbal and visuospatial working memory performance. CONCLUSIONS: Prematurely achieved CVR is associated with lower normalized brain volumes in SPMS. Future longitudinal analyses of this clinical trial dataset will be important to determine whether CVR predicts future disease worsening.
Lerede A, Rodgers J, Middleton RM, et al., 2023, Patient-reported outcomes in multiple sclerosis: a prospective registry cohort study, Brain Communications, Vol: 5, Pages: 1-13, ISSN: 2632-1297
Registries have the potential to tackle some of the current limitations in determining the longterm impact of multiple sclerosis (MS). Online assessments using patient-reported outcomes(PROs) can streamline follow-up enabling large-scale, long-term, cost-effective, home-based,and patient-focused data collection. However, registry data are sparsely sampled and thesensitivity of PROs relative to clinician-reported scales is unknown, making it hard to fullyleverage their unique scope and scale to derive insights.This retrospective and prospective cohort study over 11 years involved 15,976 patients withmultiple sclerosis from the United Kingdom Multiples Sclerosis Register. Primary outcomeswere changes in two PROs: Multiple Sclerosis Impact Scale (MSIS-29) motor component, andMultiple Sclerosis Walking Scale (MSWS-12). First, we investigated their validity inmeasuring the impact of physical disability in multiple sclerosis, by looking at their sensitivityto disease subtype and duration. We grouped the available records (91,351 for MSIS-29 and68,092 for MSWS-12) by these two factors, and statistically compared the resulting groupsusing a novel approach based on Monte Carlo permutation analysis that was designed to copewith the intrinsic sparsity of registry data. Next, we used the PROs to draw novel insights intothe developmental time course of subtypes; in particular, the period preceding the transitionfrom relapsing to progressive forms.We report a robust main effect of disease subtype on the PROs and interactions of diseasesubtype with duration (all p<0.0001). Specifically, PROs worsen with disease duration for allsubtypes (all p<0.0001) apart from Benign MS (MSIS-29 motor: p=0.796; MSWS-12:p=0.983). Furthermore, the PROs of each subtype are statistically different from those of theother subtypes at all time bins (MSIS-29 motor: all p<0.05; MSWS-12: all p<0.01) exceptwhen comparing Relapsing Remitting MS with Benign MS and Primary Progressive MS withSecond
Titball RW, Lewis N, Nicholas R, 2023, Is <i>Clostridium perfringens</i> epsilon toxin associated with multiple sclerosis?, MULTIPLE SCLEROSIS JOURNAL, Vol: 29, Pages: 1057-1063, ISSN: 1352-4585
Crockett S, Hanna L, Singh A, et al., 2023, Carbon dioxide flushing versus saline flushing of thoracic aortic stents (INTERCEPTevar): protocol for a multicentre pilot randomised controlled trial, BMJ OPEN, Vol: 13, ISSN: 2044-6055
Barritt AW, Das E, Morley N, et al., 2023, Management approach including pembrolizumab for fingolimod-associated progressive multifocal leukoencephalopathy in a patient with relapsing-remitting multiple sclerosis, MULTIPLE SCLEROSIS JOURNAL, Vol: 29, Pages: 301-306, ISSN: 1352-4585
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- Citations: 2
Cortese R, Carrasco FP, Tur C, et al., 2023, Differentiating Multiple Sclerosis From AQP4-Neuromyelitis Optica Spectrum Disorder and MOG-Antibody Disease With Imaging, NEUROLOGY, Vol: 100, Pages: E308-E323, ISSN: 0028-3878
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- Citations: 10
Forsberg L, Spelman T, Klyve P, et al., 2023, Proportion and characteristics of secondary progressive multiple sclerosis in five European registries using objective classifiers, MULTIPLE SCLEROSIS JOURNAL-EXPERIMENTAL TRANSLATIONAL AND CLINICAL, Vol: 9
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- Citations: 1
Montgomery SM, Green L, Karoui H, et al., 2023, To wait, or too late? Modeling the effects of delayed ofatumumab treatment in relapsing-remitting multiple sclerosis., J Med Econ, Vol: 26, Pages: 139-148
BACKGROUND: Several disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis (RRMS) reduce relapse rates and slow disease progression. RRMS DMTs have varying efficacy and administration routes; DMTs prescribed first may not be the most effective on relapses or disease progression. Here, we aimed to quantify the benefit of initiating ofatumumab, a high-efficacy DMT, earlier in the treatment pathway. METHODS: Aggregate data from a real-world cohort of patients with RRMS, who were eligible for dimethyl fumarate (DMF) or ofatumumab treatment within the UK National Health Service (N = 615), were used to produce a simulated patient cohort. The cohort was tracked through a discrete event simulation (DES) model, based on the Expanded Disability Status Scale (EDSS), with a lifetime time horizon. Outcomes assessed were: mean number of relapses, time to wheelchair (EDSS ≥7), and time to death. Two modeling approaches were used. The first compared outcomes between two treatment sequences (base case: ofatumumab to natalizumab versus DMF to ofatumumab). The second incorporated a time-specific delay of 1-5 years for switching from DMF to ofatumumab; the difference in outcomes as a function of increasing delay to ofatumumab are reported. RESULTS: Compared with delayed ofatumumab, fewer relapses and increased time to wheelchair were predicted for earlier ofatumumab in the treatment-sequence approach (mean relapses over the lifetime time horizon: 8.63 versus 9.00; time to wheelchair: 17.55 versus 16.60 years). Time to death was similar for both sequences. At Year 10, a numerically greater proportion of patients receiving earlier ofatumumab had mild disease (EDSS 0-3: 44.12% versus 40.06%). Greater differences, reflecting poorer outcomes, were predicted for relapses and time to wheelchair with increasing delays to ofatumumab treatment. CONCLUSIONS: The DES model provided a means by which the magnitude of benefit associated with earl
Young CA, Mills RJ, Langdon D, et al., 2022, Measuring coping in multiple sclerosis: The Coping Index-MS, MULTIPLE SCLEROSIS JOURNAL, Vol: 28, Pages: 2274-2284, ISSN: 1352-4585
Simpson-Yap S, Pirmani A, Kalincik T, et al., 2022, Updated Results of the COVID-19 in MS Global Data Sharing Initiative Anti-CD20 and Other Risk Factors Associated With COVID-19 Severity, NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION, Vol: 9, ISSN: 2332-7812
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- Citations: 13
Simpson-Yap S, Pirmani A, De Brouwer E, et al., 2022, Severity of COVID19 infection among patients with multiple sclerosis treated with interferon-β, MULTIPLE SCLEROSIS AND RELATED DISORDERS, Vol: 66, ISSN: 2211-0348
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- Citations: 3
Lacinova K, Thokala P, Nicholas R, et al., 2022, ENTIMOS: A Discrete Event Simulation Model for Maximising Efficiency of Infusion Suites in Centres Treating Multiple Sclerosis Patients, APPLIED HEALTH ECONOMICS AND HEALTH POLICY, Vol: 20, Pages: 731-742, ISSN: 1175-5652
Rodgers J, Middleton R, Witts J, et al., 2022, DOWN BUT NOT OUT REPURPOSING DEPRESSION TREATMENTS FOR MULTIPLE SCLEROSIS WITH THE UK MS REGISTER, Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050
Evans M, Hanbury G, Lim E, et al., 2022, ACUTE DISSEMINATED ENCEPHALOMYELITIS ASSOCIATED WITH SARS-COV-2 VACCINE IN MULTIPLE SCLEROSIS: A CASE REPORT, Association-of-British-Neurologists (ABN) Annual Meeting, Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050
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- Citations: 1
Owen D, 2022, Human pharmacokinetics of XBD173 and etifoxine distinguish their potential for pharmacodynamic effects mediated by TSPO, British Journal of Clinical Pharmacology, Vol: 88, Pages: 4230-4236, ISSN: 0306-5251
XBD173 and etifoxine are translocator protein (TSPO) ligands that modulate inflammatory responses in preclinical models. Limited human pharmacokinetic data is available for either molecule, and the binding affinity of etifoxine for human TSPO is unknown. To allow for design of human challenge experiments, we derived pharmacokinetic data for orally administered etifoxine (50 mg 3 times daily) and XBD173 (90 mg once daily) and determined the binding affinity of etifoxine for TSPO. For XBD173, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 1.0 nM, which is similar to XBD173 binding affinity. For etifoxine, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 0.31 nM, substantially lower than the Ki for etifoxine in human brain derived here (7.8 μM, 95% CI 4.5–14.6 μM). We conclude that oral XBD173 dosing at 90 mg once daily will achieve pharmacologically relevant TSPO occupancy. However, the occupancy is too low for TSPO mediated effects after oral dosing of etifoxine at 50 mg 3 times daily.
Magliozzi R, Fadda G, Brown RA, et al., 2022, "Ependymal-in" gradient of thalamic damage in progressive multiple sclerosis, Annals of Neurology, Vol: 92, Pages: 670-685, ISSN: 0364-5134
Leptomeningeal and perivenular infiltrates are important contributors to cortical grey matter damage and disease progression in multiple sclerosis (MS). Whereas perivenular inflammation induces vasculocentric lesions, leptomeningeal involvement follows a subpial “surface-in” gradient. To determine whether similar gradient of damage occurs in deep grey matter nuclei, we examined the dorsomedial thalamic nuclei and cerebrospinal fluid (CSF) samples from 41 postmortem secondary progressive MS cases compared with 5 non-neurological controls and 12 controls with other neurological diseases. CSF/ependyma-oriented gradient of reduction in NeuN+ neuron density was present in MS thalamic lesions compared to controls, greatest (26%) in subventricular locations at the ependyma/CSF boundary and least with increasing distance (12% at 10 mm). Concomitant graded reduction in SMI31+ axon density was observed, greatest (38%) at 2 mm from the ependyma/CSF boundary and least at 10 mm (13%). Conversely, gradient of major histocompatibility complex (MHC)-II+ microglia density increased by over 50% at 2 mm at the ependyma/CSF boundary and only by 15% at 10 mm and this gradient inversely correlated with the neuronal (R = −0.91, p < 0.0001) and axonal (R = −0.79, p < 0.0001) thalamic changes. Observed gradients were also detected in normal-appearing thalamus and were associated with rapid/severe disease progression; presence of leptomeningeal tertiary lymphoid-like structures; large subependymal infiltrates, enriched in CD20+ B cells and occasionally containing CXCL13+ CD35+ follicular dendritic cells; and high CSF protein expression of a complex pattern of soluble inflammatory/neurodegeneration factors, including chitinase-3-like-1, TNFR1, parvalbumin, neurofilament-light-chains and TNF. Substantial “ependymal-in” gradient of pathological cell alterations, accompanied by presence of in
Dobson R, Craner M, Ed Waddingham E, et al., 2022, Evaluating the feasibility of a real world pharmacovigilance study (OPTIMISE:MS), MULTIPLE SCLEROSIS AND RELATED DISORDERS, Vol: 63, ISSN: 2211-0348
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- Citations: 1
Garjani A, Hunter R, Law GR, et al., 2022, Mental health of people with multiple sclerosis during the COVID-19 outbreak: A prospective cohort and cross-sectional case-control study of the UK MS Register, MULTIPLE SCLEROSIS JOURNAL, Vol: 28, Pages: 1060-1071, ISSN: 1352-4585
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- Citations: 13
Papadopoulos D, Gklinos P, Psarros G, et al., 2022, Disease-modifying treatments for multiple sclerosis have not affected the incidence of neoplasms in clinical trials over 3 decades: a meta-analysis with meta-regression, JOURNAL OF NEUROLOGY, Vol: 269, Pages: 3226-3237, ISSN: 0340-5354
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- Citations: 1
Koffman J, Penfold CJ, Cottrell L, et al., 2022, "I wanna live and not think about the future" what place for advance care planning for people living with severe multiple sclerosis and their families? A qualitative study, PLOS ONE, Vol: 17, ISSN: 1932-6203
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- Citations: 5
Young CA, Mills R, Langdon D, et al., 2022, The four self-efficacy trajectories among people with multiple sclerosis: Clinical associations and implications, JOURNAL OF THE NEUROLOGICAL SCIENCES, Vol: 436, ISSN: 0022-510X
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- Citations: 3
Zito A, Polidoro F, Neo C, et al., 2022, Clinical and radiological outcomes among MS patients treated with Alemtuzumab and Ocrelizumab: a Real World Experience, Publisher: SAGE PUBLICATIONS LTD, Pages: 171-172, ISSN: 1352-4585
Polidoro F, Zito A, Neo C, et al., 2022, PIRA among MS Patients Treated with Ocrelizumab and Alemtuzumab; A Real World Study, Publisher: SAGE PUBLICATIONS LTD, Pages: 174-175, ISSN: 1352-4585
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- Citations: 1
Rodgers J, Friede T, Vonberg FW, et al., 2022, The impact of smoking cessation on multiple sclerosis disease progression, BRAIN, Vol: 145, Pages: 1368-1378, ISSN: 0006-8950
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- Citations: 9
Pitteri M, Magliozzi R, Nicholas R, et al., 2022, Cerebrospinal fluid inflammatory profile of cognitive impairment in newly diagnosed multiple sclerosis patients, MULTIPLE SCLEROSIS JOURNAL, Vol: 28, Pages: 768-777, ISSN: 1352-4585
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- Citations: 10
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