Publications by authors named "Richard Nicholas"

160 Publications

The impact of smoking cessation on multiple sclerosis disease progression.

Brain 2021 Oct 8. Epub 2021 Oct 8.

Population Data Science, Swansea University Medical School, Swansea, SA2 8PP, UK.

The negative impact of smoking in MS is well established, however, there is much less evidence as to whether smoking cessation is beneficial to progression in MS. Adults with MS registered on the United Kingdom MS Register (2011-2020) formed this retrospective and prospective cohort study. Primary outcomes were changes in 3 patient reported outcomes (PROs): normalised MS Physical Impact Scale (MSIS-29-Phys), normalised MS Walking Scale (MSWS-12) and the Hospital Anxiety and Depression Scale (HADS-Anxiety and HADS-Depression). Time to event outcomes were clinically significant increases in the PROs. 7983 participants were included, 4130 (51.7%) of these had ever smoked; of whom 1315 (16.5%) were current smokers and 2815/4130 (68.2%) were former smokers. For all PROs, current smokers at the time of completing their first questionnaire had higher PRO scores indicating higher disability compared to those who had never smoked (∼10 points difference in MSIS-29-Phys and MSWS-12; 1.5-1.8 point for HADS-anxiety and HADS-depression). There was no improvement in PRO scores with increasing time since quitting in former smokers. 923 participants formed the prospective parallel group, which demonstrated that MSIS-29-phy 5.03, [3.71, 6.34], MSWS-12 5.28, [3.62, 6.94] and HADS-depression 0.71, [0.47, 0.96] worsened over a period of 4 years, whereas HADS-anxiety remained stable. Smoking status was significant at year 4; current smokers had higher MSIS-29-Phys and HADS-Anxiety scores (3.05 [0.22, 5.88], 1.14 [0.52,1.76]) while former smokers had a lower MSIS-29 score of -2.91[-5.03, -0.79]. 4642 participants comprised the time to event analysis. Still smoking was associated with a shorter time to worsening event in all PROs (MSIS-29-Phys: n = 4436, p = 0.0013; MSWS-12: n = 3902, p = 0.0061; HADS-anxiety: n = 4511, p = 0.0017; HADS-depression: n = 4511, p < 0.0001). Worsening in motor disability (MSIS-29-Phys and MSWS-12) was independent of baseline HADS-anxiety and HADS-depression scores. There was no statistically significant difference in the rate of worsening between never and former smokers. When smokers quit, there is a slowing in the rate of motor disability deterioration so that it matches the rate of motor decline in those who have never smoked. This suggests that smoking cessation is beneficial for people with MS.
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http://dx.doi.org/10.1093/brain/awab385DOI Listing
October 2021

Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis.

Neurology 2021 Oct 5. Epub 2021 Oct 5.

Neurology Department, Hospital Universitario de CEMIC, Argentina.

Background: People with multiple sclerosis (MS) are a vulnerable group for severe COVID- 19, particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international sample of people with MS.

Methods: Data from 12 data-sources in 28 countries were aggregated (sources could include patients from 1-12 countries). Demographic (age, sex), clinical (MS-phenotype, disability), and DMT (untreated, alemtuzumab, cladribine, dimethyl-fumarate, glatiramer acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other DMTs) covariates were queried, alongside COVID-19 severity outcomes, hospitalisation, ICU admission, requiring artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression, adjusted for age, sex, MS-phenotype, and EDSS.

Results: 657(28.1%) with suspected and 1,683(61.9%) with confirmed COVID-19 were analysed. Among suspected+confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalised, 5.4% and 7.2% were admitted to ICU, 4.1% and 5.4% required artificial ventilation, and 3.2% and 3.9% died. Older age, progressive MS-phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl-fumarate, ocrelizumab and rituximab were associated with hospitalisation (aOR=1.56,95%CI=1.01- 2.41; aOR=2.43,95%CI=1.48-4.02) and ICU admission (aOR=2.30,95%CI=0.98-5.39;aOR=3.93,95%CI=1.56-9.89), though only rituximab was associated with higher risk of artificial ventilation (aOR=4.00,95%CI=1.54-10.39). Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalisation (aOR=1.75,95%CI=1.29- 2.38; aOR=2.76,95%CI=1.87-4.07) and ICU admission (aOR=2.55,95%CI=1.49-4.36;aOR=4.32,95%CI=2.27-8.23) but only rituximab with artificial ventilation (aOR=6.15,95%CI=3.09-12.27). Compared to natalizumab, ocrelizumab and rituximab wereassociated with hospitalisation (aOR=1.86,95%CI=1.13-3.07; aOR=2.88,95%CI=1.68-4.92) and ICU admission (aOR=2.13,95%CI=0.85-5.35; aOR=3.23,95%CI=1.17-8.91), but only rituximab with ventilation (aOR=5.52,95%CI=1.71-17.84). Importantly, associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS-phenotype, and EDSS found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity.

Conclusions: Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalisation, ICU admission, and requiring artificial ventilation, and ocrelizumab with hospitalisation and ICU admission. Despite the study's cross-sectional design, the internal and external consistency of these results with prior studies suggests rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.
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http://dx.doi.org/10.1212/WNL.0000000000012753DOI Listing
October 2021

Influence of individual, illness and environmental factors on place of death among people with neurodegenerative diseases: a retrospective, observational, comparative cohort study.

BMJ Support Palliat Care 2021 Sep 6. Epub 2021 Sep 6.

Department of Palliative Care, Policy and Rehabiltation, Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, London, UK

Background: In long-term neurological conditions, location of death is poorly understood but is seen as a marker of quality of dying.

Objective: To examine individual, illness and environmental factors on place of death among people with multiple sclerosis (MS) and Parkinson's disease (PD) in isolation or in combination and compare them with people without either condition.

Methods: Retrospective, observational, comparative cohort study of 582 people with MS, 579 people with PD and 95 controls from UK Multiple Sclerosis and Parkinson's Disease Tissue Bank. A subset of people with MS and PD were selected for analysis of individual clinical encounters 2 years before death and further subset of all groups for analysis of impact of advance care planning (ACP) and recognition of dying.

Results: People with MS died more often (50.8%) in hospital than those with PD (35.3%). Examining individual clinical encounters over 2 years (4931 encounters) identified increased contact with services 12 months before death ((1, 58)=69.71, p<0.0001) but was not associated with non-hospital deaths ((1, 58)=1.001, p=0.321). The presence of ACPs and recognition of dying were high among people with MS and PD and both associated with a non-hospital death. ACPs were more likely to prevent hospital deaths when initiated by general practitioners (GPs) compared with other professional groups (χ=68.77, p=0.0007).

Conclusions: For people with MS and PD, ACPs contribute to reducing dying in hospital. ACPs appear to be most effective when facilitated by GPs underlining the importance of primary care involvement in delivering holistic care at the end of life.
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http://dx.doi.org/10.1136/bmjspcare-2021-003105DOI Listing
September 2021

Willingness to receive a COVID-19 vaccine in people with multiple sclerosis - UK MS Register survey.

Mult Scler Relat Disord 2021 Jul 27;55:103175. Epub 2021 Jul 27.

UK MS Register, Swansea SA2 8PP, UK.

Background & Methods: We conducted an online COVID-19 survey as the vaccines became available, utilising the UK MS Register, to understand people with multiple sclerosis (pwMS) views on COVID-19 vaccination and the subsequent vaccine uptake rates.

Results & Conclusion: 94.4% of 3191 pwMS surveyed indicated they would get a COVID-19 vaccine, while 5.6% would not. PwMS who have previously had an influenza vaccine, increasing age and the perception of having sufficient information about the vaccine were associated with increased likelihood of getting a vaccine. 51.7% of 3191 pwMS completed a follow-up survey indicating they received at least 1 dose of a COVID-19 vaccine. The proportion having had the vaccination based on their prior opinions was 53.2% in 'Yes' group and 27.0% in 'No' group, the latter reflecting a change based on their initial views. More information on COVID-19 vaccine safety in pwMS would be helpful for people to make informed decisions.
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http://dx.doi.org/10.1016/j.msard.2021.103175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313796PMC
July 2021

Cerebrospinal fluid inflammatory profile of cognitive impairment in newly diagnosed multiple sclerosis patients.

Mult Scler 2021 Jul 30:13524585211032510. Epub 2021 Jul 30.

Neurology Section, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Background: The cerebrospinal fluid (CSF) molecular milieu is a marker of diffuse intrathecal inflammation in the meninges that, in turn, targets the grey matter (GM) in multiple sclerosis (MS). Cognitive impairment (CI) is associated with brain damage in MS and is often present early in people with MS (pwMS).

Objective: To investigate whether a specific CSF inflammatory profile is associated with different degrees of CI in newly diagnosed pwMS.

Methods: Sixty-nine pwMS and 43 healthy controls (HCs) underwent neuropsychological testing. The presence and levels of 57 inflammatory mediators in the CSF were assessed.

Results: Apparently cognitively normal (ACN) pwMS had impaired executive functioning compared to HCs but performed better than pwMS with mild and severe CI (mCI and sCI) in all tests. CSF mediators involving innate immunity and immune activation and recruitment, differentiate ACN from pwMS with mCI, while CSF mediators related to B- and T-cell immunity and chemotaxis differentiate both ACN and mCI from those with sCI. CXCL13 was the only molecule that differentiated sCI from mCI pwMS.

Conclusion: Specific CSF molecular patterns, reflecting the involvement of both innate and adaptive immune responses, are associated with the severity of CI in newly diagnosed pwMS.
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http://dx.doi.org/10.1177/13524585211032510DOI Listing
July 2021

Autologous Hematopoietic Stem Cell Transplantation in Active Multiple Sclerosis: A Real-world Case Series.

Neurology 2021 08 12;97(9):e890-e901. Epub 2021 Jul 12.

From the Department of Brain Sciences (R.S.N., A.M., A.S., P.M.), Faculty of Medicine, and Centre for Haematology (E.O., I.G.), Faculty of Medicine, Imperial College London; Imperial College Healthcare NHS Trust (R.S.N., O.M., V.S.-C., A.S., E.O., I.G., P.M.); Department of Neurology (E.E.R., E.S.), King's College Hospital, London, UK; Department of Neurosciences, Drug and Child Health (A.M.), University of Florence, Italy; Barts Health NHS Trust (B.T.); Department of Haematological Medicine (V.M., M.A.K.), King's College Hospital NHS Foundation Trust; Queen Square MS Centre (O.C.), Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, UK; Department of Health Sciences (DISSAL) (M.P.S.), University of Genova; and IRCCS Ospedale Policlinico San Martino (M.P.S.), Genova, Italy.

Objective: To examine outcomes in people with multiple sclerosis (PwMS) treated with autologous hematopoietic stem cell transplantation (AHSCT) in a real-world setting.

Methods: This was a retrospective cohort study of PwMS treated with AHSCT at 2 centers in London, UK, consecutively between 2012 and 2019 who had ≥6 months of follow-up or died at any time. Primary outcomes were survival free of multiple sclerosis (MS) relapses, MRI new lesions, and worsening of Expanded Disability Status Scale (EDSS) score. Adverse events rates were also examined.

Results: The cohort includes 120 PwMS; 52% had progressive MS (primary or secondary) and 48% had relapsing-remitting MS. At baseline, the median EDSS score was 6.0; 90% of the evaluable cases showed MRI activity in the 12 months preceding AHSCT. Median follow-up after AHSCT was 21 months (range 6-85 months). MS relapse-free survival was 93% at 2 years and 87% at 4 years after AHSCT. No new MRI lesions were detected in 90% of participants at 2 years and in 85% at 4 years. EDSS score progression-free survival (PFS) was 75% at 2 years and 65% at 4 years. Epstein-Barr virus reactivation and monoclonal paraproteinemia were associated with worse PFS. There were 3 transplantation-related deaths within 100 days (2.5%), all after fluid overload and cardiac or respiratory failure.

Conclusions: Efficacy outcomes of AHSCT in this real-world cohort are similar to those reported in more stringently selected clinical trial populations, although the risks may be higher.

Classification Of Evidence: This study is rated Class IV because of the uncontrolled, open-label design.
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http://dx.doi.org/10.1212/WNL.0000000000012449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408506PMC
August 2021

Challenges of developing, conducting, analysing and reporting a COVID-19 study as the COVID-19 pandemic unfolds: an online co-autoethnographic study.

BMJ Open 2021 06 16;11(6):e048788. Epub 2021 Jun 16.

Mental Health and Clinical Neurosciences Academic Unit, University of Nottingham School of Medicine, Nottingham, UK.

Objectives: To capture the complexities and unique experience of a newly formed multidisciplinary and multicentre research team developing and deploying a COVID-19 study and to identify lessons learnt.

Design: Co-autoethnographic study.

Setting: Staff at two UK academic institutions, a national charity and two major UK hospitals.

Participants: Researchers, clinicians, academics, statisticians and analysts, patient and public involvement representatives and national charity.

Methods: The sampling frame was any content discussed or shared between research team members (emails, meeting minutes, etc), standard observational dimensions and reflective interviews with team members. Data were thematically analysed.

Results: Data from 34 meetings and >50 emails between 17 March and 5 August 2020 were analysed. The analysis yielded seven themes with 'Managing our stress' as an overarching theme.

Conclusions: Mutual respect, flexibility and genuine belief that team members are doing the best they can under the circumstances are essential for completing a time-consuming study, requiring a rapid response during a pandemic. Acknowledging and managing stress and a shared purpose can moderate many barriers, such as the lack of face-to-face interactions, leading to effective team working.
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http://dx.doi.org/10.1136/bmjopen-2021-048788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210677PMC
June 2021

Investigation of the correlation between mildly deleterious mtDNA Variations and the clinical progression of multiple sclerosis.

Mult Scler Relat Disord 2021 Aug 29;53:103055. Epub 2021 May 29.

Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa. Electronic address:

Background: Evidence suggests that mitochondrial DNA (mtDNA) variation at a population level may influence susceptibility to, or the clinical progression of Multiple Sclerosis (MS).

Objective: To determine if mtDNA population variation is linked to the clinical progress of MS.

Methods: Using the complete mtDNA sequences of 217 MS patients, we applied the new 'variant load' model, designed as a framework by which to examine the role of mtDNA variation in the context of complex clinical disease.

Results: No significant association was detected between mtDNA 'variant load'and the clinical measures of progression.

Conclusion: Our results suggest that mtDNA population variation does not play a substantial role in the clinical progression of MS; however, modest effects and/or effects in a subgroup of patients cannot be entirely excluded. Results do not exclude the possibility of detecting an association between variation and more strictly quantified variables obtained from histopathologically-stained specimens. The results further illustrate the method's applicabilityto other disease phenotypes.
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http://dx.doi.org/10.1016/j.msard.2021.103055DOI Listing
August 2021

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.

Mult Scler 2021 Jun 3:13524585211020435. Epub 2021 Jun 3.

Mental Health and Clinical Neurosciences Academic Unit, University of Nottingham, Nottingham, UK/Institute of Mental Health, University of Nottingham, Nottinghamshire Healthcare NHS Foundation Trust, Nottingham, UK.

Background: People with MS (pwMS) have had higher rates of anxiety and depression than the general population before the COVID-19 pandemic, placing them at higher risk of experiencing poor psychological wellbeing during the pandemic.

Objective: To assess mental health and its social/lifestyle determinants in pwMS during the first wave of the outbreak in the United Kingdom.

Methods: This is a community-based, prospective longitudinal cohort and cross-sectional case-control online questionnaire study. It includes 2010 pwMS from the UK MS Register and 380 people without MS.

Results: The Hospital Anxiety and Depression Scale scores of pwMS for anxiety and depression during the outbreak did not change from the previous year. PwMS were more likely to have anxiety (using General Anxiety Disorder-7) and/or depression (using Patient Health Questionnaire-9) than controls during the outbreak (OR: 2.14, 95% CI: 1.58-2.91). PwMS felt lonelier (OR: 1.37, 95% CI: 1.04-1.80) reported worse social support (OR: 1.90, 95% CI: 1.18-3.07) and reported worsened exercise habits (OR: 1.65, 95% CI: 1.18-2.32) during the outbreak than controls.

Conclusion: Early in the pandemic, pwMS remained at higher risk of experiencing anxiety and depression than the general population. It is important that multidisciplinary teams improve their support for the wellbeing of pwMS, who are vulnerable to the negative effects of the pandemic on their lifestyle and social support.
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http://dx.doi.org/10.1177/13524585211020435DOI Listing
June 2021

COVID-19 is associated with new symptoms of multiple sclerosis that are prevented by disease modifying therapies.

Mult Scler Relat Disord 2021 Jul 5;52:102939. Epub 2021 May 5.

Mental Health and Clinical Neuroscience Academic Unit, School of Medicine, University of Nottingham, Nottingham, UK; Clinical Neurology, Nottingham University Hospitals NHS Trust, Nottingham, UK. Electronic address:

Background: Infections can trigger exacerbations of multiple sclerosis (MS). The effects of the coronavirus disease 2019 (COVID-19) on MS are not known. The aim of this study was to understand the impact of COVID-19 on new and pre-existing symptoms of MS.

Methods: The COVID-19 and MS study is an ongoing community-based, prospective cohort study conducted as part of the United Kingdom MS Register. People with MS and COVID-19 were invited by email to complete a questionnaire about their MS symptoms during the infection. An MS exacerbation was defined as developing new MS symptoms and/or worsening of pre-existing MS symptoms.

Results: Fifty-seven percent (230/404) of participants had an MS exacerbation during their infection; 82 developed new MS symptoms, 207 experienced worsened pre-existing MS symptoms, and 59 reported both. Disease modifying therapies (DMTs) reduced the likelihood of developing new MS symptoms during the infection (OR 0.556, 95%CI 0.316-0.978). Participants with a higher pre-COVID-19 webEDSS (web-based Expanded Disability Status Scale) score (OR 1.251, 95%CI 1.060-1.478) and longer MS duration (OR 1.042, 95%CI 1.009-1.076) were more likely to experience worsening of their pre-existing MS symptoms during the infection.

Conclusion: COVID-19 infection was associated with exacerbation of MS. DMTs reduced the chance of developing new MS symptoms during the infection.
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http://dx.doi.org/10.1016/j.msard.2021.102939DOI Listing
July 2021

CSF parvalbumin levels reflect interneuron loss linked with cortical pathology in multiple sclerosis.

Ann Clin Transl Neurol 2021 03 23;8(3):534-547. Epub 2021 Jan 23.

Neurology Section, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Introduction And Methods: In order to verify whether parvalbumin (PVALB), a protein specifically expressed by GABAergic interneurons, could be a MS-specific marker of grey matter neurodegeneration, we performed neuropathology/molecular analysis of PVALB expression in motor cortex of 40 post-mortem progressive MS cases, with/without meningeal inflammation, and 10 control cases, in combination with cerebrospinal fluid (CSF) assessment. Analysis of CSF PVALB and neurofilaments (Nf-L) levels combined with physical/cognitive/3TMRI assessment was performed in 110 naïve MS patients and in 32 controls at time of diagnosis.

Results: PVALB gene expression was downregulated in MS (fold change = 3.7 ± 1.2, P < 0.001 compared to controls) reflecting the significant reduction of PVALB+ cell density in cortical lesions, to a greater extent in MS patients with high meningeal inflammation (51.8, P < 0.001). Likewise, post-mortem CSF-PVALB levels were higher in MS compared to controls (fold change = 196 ± 36, P < 0.001) and correlated with decreased PVALB+ cell density (r = -0.64, P < 0.001) and increased MHC-II+ microglia density (r = 0.74, P < 0.01), as well as with early age of onset (r = -0.69, P < 0.05), shorter time to wheelchair (r = -0.49, P < 0.05) and early age of death (r = -0.65, P < 0.01). Increased CSF-PVALB levels were detected in MS patients at diagnosis compared to controls (P = 0.002). Significant correlation was found between CSF-PVALB levels and cortical lesion number on MRI (R = 0.28, P = 0.006) and global cortical thickness (R = -0.46, P < 0.001), better than Nf-L levels. CSF-PVALB levels increased in MS patients with severe cognitive impairment (mean ± SEM:25.2 ± 7.5 ng/mL) compared to both cognitively normal (10.9 ± 2.4, P = 0.049) and mild cognitive impaired (10.1 ± 2.9, P = 0.024) patients.

Conclusions: CSF-PVALB levels reflect loss of cortical interneurons in MS patients with more severe disease course and might represent an early, new MS-specific biomarker of cortical neurodegeneration, atrophy, and cognitive decline.
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http://dx.doi.org/10.1002/acn3.51298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951111PMC
March 2021

"I Will Respect the Autonomy of My Patient": A Scoping Review of Shared Decision Making in Multiple Sclerosis.

Int J MS Care 2020 Nov-Dec;22(6):285-293. Epub 2020 Dec 28.

Background: Patient autonomy is a bioethical principle that was strengthened in the revised Declaration of Geneva. Shared decision making (SDM) is particularly relevant in the management of multiple sclerosis (MS) because many preference-sensitive decisions have to be made during the disease course. We aimed to summarize the available evidence on SDM in the MS field and to inform future research and practice.

Methods: We performed a scoping review by searching MEDLINE (past 5 years). Studies were included if they reported primary/secondary research and focused on SDM related to people with MS. Data were grouped into topics, with results presented in narrative form.

Results: From 865 references, we included 55 studies conducted mostly in Europe. Half of the studies were observational, followed by qualitative (20%), mixed-methods (17%), randomized controlled trials (RCTs, 5%), quasi-experimental (5%), and reviews (4%). Most studies addressed people with relapsing-remitting MS (85%); the remaining addressed health care professionals, patients' significant others, or a combination. We identified five main topics: decisions on disease-modifying drugs, decisions on chronic cerebrospinal venous insufficiency treatment, information provision and patient education, health literacy, and risk knowledge.

Conclusions: The high proportion of included studies on SDM in MS in Europe suggests an earlier adoption of these concepts in this area. Decisions on disease-modifying drugs was the prevalent topic. Only 5% of studies were RCTs, indicating that more research is needed to study the effectiveness of SDM interventions. Studies addressing people with primary and secondary progressive MS are also needed.
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http://dx.doi.org/10.7224/1537-2073.2020-027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780705PMC
December 2020

Analyzing coagulation dynamics during treatment of vascular malformations with thromboelastography.

Pediatr Blood Cancer 2021 02 19;68(2):e28824. Epub 2020 Nov 19.

Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Background/objectives: Slow-flow vascular malformations are abnormal vessels that can lead to activation and consumption of coagulation factors and thrombosis, known as localized intravascular coagulopathy (LIC). Most clinical and research evidence of vascular malformation hemostasis relies on conventional coagulation studies, which may not provide a complete picture. Thromboelastograpy (TEG) is a tool that can provide real-time assessment of a patient's coagulation dynamics, and may allow for a more individualized treatment approach. We hypothesized that patients with slow-flow vascular malformations will have changes in TEG parameters peri-procedure that will help predict blood product or medication administration.

Design/methods: Institutional Review Board approved prospective study of patients with slow-flow vascular malformations undergoing a sedated, minor procedure. TEG and conventional coagulation studies were obtained preprocedure, 15 min, and when possible, at 30 min after the start of the procedure.

Results: Twenty-five patients were enrolled. Median age was 15 years (range 3-47 years). Procedures included laser and/or sclerotherapy. There were no changes in TEG parameters from baseline to 15 min or 30 min. The following decreased from baseline to 15 min: fibrinogen 313 to 287 mg/dL (P = .001), D-dimer 1.3 to 1.1 mg/L (P = .02), hemoglobin 12.8 to 11.8 g/dL (P = .001), and platelet count 272 000 to 256 000 (P = .006). No patient had a bleeding/thrombotic complication during or within 1 week postprocedure.

Conclusion: We saw no change in TEG parameters or bleeding or clotting complications despite significant numerical changes in conventional coagulation profiles, suggesting that conventional studies may not be as useful in determining risks of bleeding or thrombotic complications peri-procedure for minor procedures.
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http://dx.doi.org/10.1002/pbc.28824DOI Listing
February 2021

The impact of the face-to-face consultation on decisional conflict in complex decision-making in multiple sclerosis: A pilot study.

Mult Scler J Exp Transl Clin 2020 Oct-Dec;6(4):2055217320959802. Epub 2020 Oct 20.

Centre for Neuroscience, Faculty of Medicine, Imperial College London, London, UK.

Background: The role of face-to-face consultations in medicine is increasingly being challenged. Disease activity, national guidelines, life goals e.g. pregnancy, multiple therapies and side effects need to be considered on starting disease modifying treatments (DMTs) in people with multiple sclerosis (pwMS).

Objectives: We studied the impact of a face-to-face consultation on decision making, using decisional conflict (DC) as the primary outcome.

Methods: Prospective cohort study of 73 pwMS attending clinics who were making decisions about DMTs followed for one year. Prerequisites and consultation features were measured with the SURE scale for DC used as the primary outcome at baseline and at one year.

Results: The patient activation measure (PAM) was the only driver prior to the consultation associated with DC (p = 0.02) showing those less engaged were more likely to have DC. Overall, 51/73 (70%) of people made their treatment decision or reinforced a former decision during the consultation. We found making a treatment decision between the original consultation and the follow-up was associated with resolving DC (p = 0.008).

Conclusions: Patient engagement impacts DC but the HCP delivering the optimal Shared Decision Making (SDM) approach is additionally significant in reducing DC. In complex decisions there is a clear role for face-to-face consultations in current practice.
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http://dx.doi.org/10.1177/2055217320959802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594484PMC
October 2020

Intrathecal Inflammation in Progressive Multiple Sclerosis.

Int J Mol Sci 2020 Nov 3;21(21). Epub 2020 Nov 3.

Department of Neurosciences, Biomedicine and Movements Sciences, University of Verona, 37134 Verona, Italy.

Progressive forms of multiple sclerosis (MS) are associated with chronic demyelination, axonal loss, neurodegeneration, cortical and deep gray matter damage, and atrophy. These changes are strictly associated with compartmentalized sustained inflammation within the brain parenchyma, the leptomeninges, and the cerebrospinal fluid. In progressive MS, molecular mechanisms underlying active demyelination differ from processes that drive neurodegeneration at cortical and subcortical locations. The widespread pattern of neurodegeneration is consistent with mechanisms associated with the inflammatory molecular load of the cerebrospinal fluid. This is at variance with gray matter demyelination that typically occurs at focal subpial sites, in the proximity of ectopic meningeal lymphoid follicles. Accordingly, it is possible that variations in the extent and location of neurodegeneration may be accounted for by individual differences in CSF flow, and by the composition of soluble inflammatory factors and their clearance. In addition, "double hit" damage may occur at sites allowing a bidirectional exchange between interstitial fluid and CSF, such as the Virchow-Robin spaces and the periventricular ependymal barrier. An important aspect of CSF inflammation and deep gray matter damage in MS involves dysfunction of the blood-cerebrospinal fluid barrier and inflammation in the choroid plexus. Here, we provide a comprehensive review on the role of intrathecal inflammation compartmentalized to CNS and non-neural tissues in progressive MS.
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http://dx.doi.org/10.3390/ijms21218217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663229PMC
November 2020

A realist review of advance care planning for people with multiple sclerosis and their families.

PLoS One 2020 16;15(10):e0240815. Epub 2020 Oct 16.

Florence Nightingale Faculty of Nursing, Midwifery & Palliative Care, King's College London, Cicely Saunders Institute, London, United Kingdom.

Background: Advance care planning (ACP) is reported to improve the quality of outcomes of care among those with life-limiting conditions. However, uptake is low among people living with multiple sclerosis (MS) and little is known about why or how people with MS engage in this process of decision-making.

Aims: To develop and refine an initial theory on engagement in ACP for people with MS and to identify ways to improve its uptake for those who desire it.

Methods: Realist review following published protocol and reporting following Realist and Meta-narrative Evidence Synthesis: Evolving Standards (RAMESES) guidelines. A multi-disciplinary team searched MEDLINE, PsychInfo, CINAHL, Scopus, Web of Science, Embase, Google Scholar in addition to other sources from inception to August 2019. Quantitative or qualitative studies, case reports, and opinion or discussion articles related to ACP and/or end of life discussions in the context of MS were included, as well as one article on physical disability and one on motor neuron disease, that contributed important contextual information. Researchers independently screened abstracts and extracted data from full-text articles. Using abductive and retroductive analysis, each article was examined for evidence to support or refute 'context, mechanism, and outcome' (CMO) hypotheses, using the Integrated Behaviour Model to guide theory development. Quality was assessed according to methodological rigour and relevance of evidence. Those studies providing rich descriptions were synthesised using a realist matrix to identify commonalities across CMO configurations.

Results: Of the 4,034 articles identified, 33 articles were included in the synthesis that supported six CMO hypotheses that identified contexts and mechanisms underpinning engagement in ACP for people with MS and included: acceptance of their situation, prior experiences, confidence, empowerment, fear (of being a burden, of death and of dying) and the desire for autonomy. Acceptance of self as a person with a life-limiting illness was imperative as it enabled people with MS to see ACP as pertinent to them. We identified the context of MS-its long, uncertain disease trajectory with periods of stability punctuated by crisis-inhibited triggering of mechanisms. Similarly, the absence of skills and confidence in advanced communication skills among health professionals prevented possibilities for ACP discussions taking place.

Conclusion: Although mechanisms are inhibited by the context of MS, health professionals can facilitate greater uptake of ACP among those people with MS who want it by developing their skills in communication, building trusting relationships, sharing accurate prognostic information and sensitively discussing death and dying.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240815PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567361PMC
December 2020

Iminophosphorano-Substituted Bispyridinylidenes: Redox Potentials and Substituent Constants from Tolman Electronic Parameters.

Chemistry 2020 Dec 26;26(72):17371-17375. Epub 2020 Nov 26.

Department of Chemistry, University of New Brunswick, Fredericton, New Brunswick, E3B 5A3, Canada.

Bispyridinylidenes (BPYs) have emerged as an important class of neutral organic electron donors, with redox potentials that vary widely with choice of substituent. Methods to predict the effect of substitution on the redox potential are therefore highly desirable. Here we show that the redox potential of BPYs featuring iminophosphorano substituents (R P=N-), which represent the most reducing class of BPYs, can be predicted based on the well-known Tolman electronic parameter (TEP) for the respective phosphine fragment (R P). Moreover, building on earlier work relating redox potentials to Hammett-type substituent constants, it is now possible to quantitatively predict σ values for iminophosphorano substituents from TEP values. These results provide a path for precisely tailoring redox potentials of iminophosphorano-substituted BPYs, but also give quantitative descriptors for how these highly versatile iminophosphorano substituents can impact the properties of any molecular scaffold.
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http://dx.doi.org/10.1002/chem.202004153DOI Listing
December 2020

A Rapid Electronic Cognitive Assessment Measure for Multiple Sclerosis: Validation of Cognitive Reaction, an Electronic Version of the Symbol Digit Modalities Test.

J Med Internet Res 2020 09 23;22(9):e18234. Epub 2020 Sep 23.

Department of Neurology, Charing Cross Hospital, Imperial College London, London, United Kingdom.

Background: Incorporating cognitive testing into routine clinical practice is a challenge in multiple sclerosis (MS), given the wide spectrum of both cognitive and physical impairments people can have and the time that testing requires. Shortened paper and verbal assessments predominate but still are not used routinely. Computer-based tests are becoming more widespread; however, changes in how a paper test is implemented can impact what exactly is being assessed in an individual. The Symbol Digit Modalities Test (SDMT) is one validated test that forms part of the cognitive batteries used in MS and has some computer-based versions. We developed a tablet-based SDMT variant that has the potential to be ultimately deployed to patients' own devices.

Objective: This paper aims to develop, validate, and deploy a computer-based SDMT variant, the Cognition Reaction (CoRe) test, that can reliably replicate the characteristics of the paper-based SDMT.

Methods: We carried out analysis using Pearson and intraclass correlations, as well as a Bland-Altman comparison, to examine consistency between the SDMT and CoRe tests and for test-retest reliability. The SDMT and CoRe tests were evaluated for sensitivity to disability levels and age. A novel metric in CoRe was found: question answering velocity could be calculated. This was evaluated in relation to disability levels and age for people with MS and compared with a group of healthy control volunteers.

Results: SDMT and CoRe test scores were highly correlated and consistent with 1-month retest values. Lower scores were seen in patients with higher age and some effect was seen with increasing disability. There was no learning effect evident. Question answering velocity demonstrated a small increase in speed over the 90-second duration of the test in people with MS and healthy controls.

Conclusions: This study validates a computer-based alternative to the SDMT that can be used in clinics and beyond. It enables accurate recording of elements of cognition relevant in MS but offers additional metrics that may offer further value to clinicians and people with MS.
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http://dx.doi.org/10.2196/18234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542403PMC
September 2020

Defective CD19+CD24CD38 transitional B-cell function in patients with relapsing-remitting MS.

Mult Scler 2021 07 14;27(8):1187-1197. Epub 2020 Sep 14.

Wolfson Neuroscience Laboratory, Department of Brain Sciences, Imperial College London, London, UK.

Background: Multiple sclerosis (MS) is characterized by central nervous system (CNS) infiltration of T and B cells, excess inflammatory cytokine and chemokine production and failure of immune regulation. CD19+CD24CD38 transitional B cells producing interleukin (IL)-10 have been shown to suppress interferon-γ (IFNγ) and tumour necrosis factor-α (TNFα) production by CD4+ T cells and to be dysfunctional in autoimmune arthritis and systemic lupus erythematosus.

Objective: We hypothesized that transitional B-cell-dependent immune regulation could be defective in MS and examined their function in healthy subjects and patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: A total of 62 healthy donors and 21 RRMS subjects donated peripheral blood for the study. IL-10-producing B cells, IFNγ and TNFα-producing T cells and proliferating T cells were quantified by flow cytometry.

Results: In healthy individuals, CD19+CD24CD38 transitional B cells produce more IL-10 than CD19+CD24+CD38+ naive and CD19+CD24CD38- memory B cells and are able to suppress CD4+ T-cell proliferation and IFNγ and TNFα-production. In subjects with RRMS, CD19+CD24CD38 transitional B cells produce significantly less IL-10 and to fail to suppress effector T-cell function.

Conclusion: CD19+CD24CD38 transitional B cells physiologically represent the most potent regulatory B-cell subset and are functionally defective in patients with RRMS, an abnormality that may contribute to the immune pathological process.
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http://dx.doi.org/10.1177/1352458520951536DOI Listing
July 2021

Aging, Cellular Senescence, and Progressive Multiple Sclerosis.

Front Cell Neurosci 2020 30;14:178. Epub 2020 Jun 30.

Department of Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, London, United Kingdom.

Aging is one of the most important risk factors for the development of several neurodegenerative diseases including progressive multiple sclerosis (MS). Cellular senescence (CS) is a key biological process underlying aging. Several stressors associated with aging and MS pathology, such as oxidative stress, mitochondrial dysfunction, cytokines and replicative exhaustion are known triggers of cellular senescence. Senescent cells exhibit stereotypical metabolic and functional changes, which include cell-cycle arrest and acquiring a pro-inflammatory phenotype secreting cytokines, growth factors, metalloproteinases and reactive oxygen species. They accumulate with aging and can convert neighboring cells to senescence in a paracrine manner. In MS, accelerated cellular senescence may drive disease progression by promoting chronic non-remitting inflammation, loss or altered immune, glial and neuronal function, failure of remyelination, impaired blood-brain barrier integrity and ultimately neurodegeneration. Here we discuss the evidence linking cellular senescence to the pathogenesis of MS and the putative role of senolytic and senomorphic agents as neuroprotective therapies in tackling disease progression.
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http://dx.doi.org/10.3389/fncel.2020.00178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338849PMC
June 2020

Development of Autoimmune Thyroid Disease in Multiple Sclerosis Patients Post-Alemtuzumab Improves Treatment Response.

J Clin Endocrinol Metab 2020 09;105(9)

Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK.

Context: Alemtuzumab is an anti-CD52 monoclonal antibody used in the treatment of relapsing-remitting multiple sclerosis (MS). Between 20% and 40% of alemtuzumab-treated MS patients develop autoimmune thyroid disease (AITD) as a side effect.

Objective: The objective of this work is to determine whether MS disease progression following alemtuzumab treatment differs in patients who develop AITD compared to those who do not.

Design, Setting, And Patients: A retrospective analysis of 126 patients with relapsing-remitting MS receiving alemtuzumab from 2012 to 2017 was conducted at a tertiary referral center.

Main Outcome Measures: Thyroid status, new relapses, Expanded Disability Status Scale (EDSS) score change, and disability progression following alemtuzumab were evaluated.

Results: Twenty-six percent (33 out of 126, 25 female, 8 male) of alemtuzumab-treated patients developed AITD, 55% of which was Graves disease. EDSS score following alemtuzumab was reduced in patients who developed AITD compared to those who did not (median [interquartile range]; AITD: -0.25 [-1 to 0.5] vs non-AITD: 0 [1-0]. P = .007]. Multivariable regression analysis confirmed that the development of AITD was independently associated with EDSS score improvement (P = .011). Moreover, AITD patients had higher relapse-free survival following alemtuzumab (P = .023). There was no difference in the number of new focal T2 lesions and contrast-enhancing magnetic resonance imaging lesions developed following alemtuzumab between the 2 groups.

Conclusion: Graves disease was the most common form of AITD developed by MS patients following alemtuzumab. This study suggests that MS patients who develop AITD may have an improved response to alemtuzumab, as measured by reduced disability and lower relapse rate.
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http://dx.doi.org/10.1210/clinem/dgaa453DOI Listing
September 2020

COVID-19 in people with multiple sclerosis: A global data sharing initiative.

Mult Scler 2020 09 14;26(10):1157-1162. Epub 2020 Jul 14.

MSBase Registry, Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.

Background: We need high-quality data to assess the determinants for COVID-19 severity in people with MS (PwMS). Several studies have recently emerged but there is great benefit in aligning data collection efforts at a global scale.

Objectives: Our mission is to scale-up COVID-19 data collection efforts and provide the MS community with data-driven insights as soon as possible.

Methods: Numerous stakeholders were brought together. Small dedicated interdisciplinary task forces were created to speed-up the formulation of the study design and work plan. First step was to agree upon a COVID-19 MS core data set. Second, we worked on providing a user-friendly and rapid pipeline to share COVID-19 data at a global scale.

Results: The COVID-19 MS core data set was agreed within 48 hours. To date, 23 data collection partners are involved and the first data imports have been performed successfully. Data processing and analysis is an on-going process.

Conclusions: We reached a consensus on a core data set and established data sharing processes with multiple partners to address an urgent need for information to guide clinical practice. First results show that partners are motivated to share data to attain the ultimate joint goal: better understand the effect of COVID-19 in PwMS.
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http://dx.doi.org/10.1177/1352458520941485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361123PMC
September 2020

Using amyloid PET imaging to diagnose Alzheimer's disease in patients with multiple sclerosis.

J Neurol 2020 Nov 18;267(11):3268-3273. Epub 2020 Jun 18.

Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, W6 8RP, UK.

Background: Cognitive dysfunction affects 40-60% of individuals with multiple sclerosis (MS). The neuropsychological profile commonly consists of a subcortical pattern of deficits, although a proportion of patients have a severe progressive cortical dementia. However, patients with MS can be affected by other neurodegenerative diseases, such as Alzheimer's disease (AD). Little is known about the co-existence of these two conditions but distinguishing dementia due to MS alone from a coexisting neurodegenerative disease is challenging. Amyloid PET imaging has allowed improved AD diagnosis, especially in patients with atypical presentations or multiple possible causes of cognitive impairment. Amyloid PET demonstrates increased cortical signal in AD, whereas reductions in subcortical uptake are associated with demyelination. To the authors knowledge, there are no reports of clinical Amyloid PET use in MS patients with dementia.

Methods: Here, three MS patients presenting to the Cognitive Neurology Clinic with progressive cognitive impairment are described. Due to lack of diagnostic clarity from standard investigations, they underwent Amyloid PET Imaging with F-florbetapir according to established appropriate use criteria and after review by a multidisciplinary team.

Results: Two patients were diagnosed with AD based on positive Amyloid PET imaging and were subsequently started on cholinesterase inhibitor treatment. The other patient had a negative scan, leading to further investigations and identification of another potential cause of worsening cognitive impairment.

Conclusions: The experience from this case series suggests that Amyloid PET Imaging may be of diagnostic value in selected patients with MS and dementia. In these individuals, it may provide diagnostic clarity and assist with therapeutic decisions.
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http://dx.doi.org/10.1007/s00415-020-09969-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578168PMC
November 2020

COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.

Neurol Neuroimmunol Neuroinflamm 2020 09 26;7(5). Epub 2020 May 26.

From the Department of Imaging (L.D., A.G., D. Mallon, F.T., B.J.), Imperial College Healthcare NHS Trust; Department of Neurosciences (J.V., I.H.J., A.E.), Imperial College Healthcare NHS Trust; Northwest London Pathology (D. Muir); Department of Hematology (A.L.), Imperial College Healthcare NHS Trust; Centre for Neuroinflammation and Neurodegeneration (R.N.), Faculty of Medicine, Imperial College London; and Department of Visual Neuroscience (R.N.), UCL Institute of Ophthalmology, London, United Kingdom.

Objective: To describe a novel case of coronavirus disease 2019 (COVID-19)-associated acute necrotizing encephalopathy (ANE) in a patient with aplastic anemia where there was early brain stem-predominant involvement.

Methods: Evaluation of cause, clinical symptoms, and treatment response.

Results: A 59-year-old woman with a background of transfusion-dependent aplastic anemia presented with seizures and reduced level of consciousness 10 days after the onset of subjective fever, cough, and headache. Nasopharyngeal swab testing for severe acute respiratory syndrome coronavirus (SARS-CoV-2) was positive, and CT during admission demonstrated diffuse swelling of the brain stem. She required intubation and mechanical ventilation for airway protection, given her reduced level of consciousness. The patient's condition deteriorated, and MRI on day 6 demonstrated worsening brain stem swelling with symmetrical hemorrhagic lesions in the brain stem, amygdalae, putamina, and thalamic nuclei. Appearances were consistent with hemorrhagic ANE with early brain stem involvement. The patient showed no response to steroid therapy and died on the eighth day of admission.

Conclusions: COVID-19 may be associated with an acute severe encephalopathy and, in this case, was considered most likely to represent an immune-mediated phenomenon. As the pandemic continues, we anticipate that the spectrum of neurologic presentation will broaden. It will be important to delineate the full clinical range of emergent COVID-19-related neurologic disease.
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http://dx.doi.org/10.1212/NXI.0000000000000789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286661PMC
September 2020

18F-GE180, a radioligand for the TSPO protein: not ready for clinical trials in multiple sclerosis.

Eur J Nucl Med Mol Imaging 2020 09 8;47(10):2242-2243. Epub 2020 May 8.

Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.

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http://dx.doi.org/10.1007/s00259-020-04844-5DOI Listing
September 2020

Effect of allopurinol on phosphocreatine recovery and muscle function in older people with impaired physical function: a randomised controlled trial.

Age Ageing 2020 10;49(6):1003-1010

Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.

Background: Allopurinol has vascular antioxidant effects and participates in purinergic signalling within muscle. We tested whether allopurinol could improve skeletal muscle energetics and physical function in older people with impaired physical performance.

Methods: We conducted a randomised, double blind, parallel group, placebo-controlled trial, comparing 20 weeks of allopurinol 600 mg once daily versus placebo. We recruited community-dwelling participants aged 65 and over with baseline 6-min walk distance of <400 m and no contraindications to magnetic resonance imaging scanning. Outcomes were measured at baseline and 20 weeks. The primary outcome was post-exercise phosphocreatine (PCr) recovery rate measured using 31P magnetic resonance spectroscopy of the calf. Secondary outcomes included 6-min walk distance, short physical performance battery (SPPB), lean body mass measured by bioimpedance, endothelial function and quality of life.

Results: In total, 124 participants were randomised, mean age 80 (SD 6) years. A total of 59 (48%) were female, baseline 6-min walk distance was 293 m (SD 80 m) and baseline SPPB was 8.5 (SD 2.0). Allopurinol did not significantly improve PCr recovery rate (treatment effect 0.10 units [95% CI, -0.07 to 0.27], P = 0.25). No significant changes were seen in endothelial function, quality of life, lean body mass or SPPB. Allopurinol improved 6-min walk distance (treatment effect 25 m [95% 4-46, P = 0.02]). This was more pronounced in those with high baseline oxidative stress and urate.

Conclusion: Allopurinol improved 6-min walk distance but not PCr recovery rate in older people with impaired physical function. Antioxidant strategies to improve muscle function for older people may need to be targeted at subgroups with high baseline oxidative stress.
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http://dx.doi.org/10.1093/ageing/afaa061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583523PMC
October 2020

Longitudinal Assessment of Multiple Sclerosis with the Brain-Age Paradigm.

Ann Neurol 2020 07 6;88(1):93-105. Epub 2020 May 6.

Centre for Medical Image Computing, Department of Computer Science, University College London, London, UK.

Objective: During the natural course of multiple sclerosis (MS), the brain is exposed to aging as well as disease effects. Brain aging can be modeled statistically; the so-called "brain-age" paradigm. Here, we evaluated whether brain-predicted age difference (brain-PAD) was sensitive to the presence of MS, clinical progression, and future outcomes.

Methods: In a longitudinal, multicenter sample of 3,565 magnetic resonance imaging (MRI) scans, in 1,204 patients with MS and clinically isolated syndrome (CIS) and 150 healthy controls (mean follow-up time: patients 3.41 years, healthy controls 1.97 years), we measured "brain-predicted age" using T1-weighted MRI. We compared brain-PAD among patients with MS and patients with CIS and healthy controls, and between disease subtypes. Relationships between brain-PAD and Expanded Disability Status Scale (EDSS) were explored.

Results: Patients with MS had markedly higher brain-PAD than healthy controls (mean brain-PAD +10.3 years; 95% confidence interval [CI] = 8.5-12.1] versus 4.3 years; 95% CI = 2.1 to 6.4; p < 0.001). The highest brain-PADs were in secondary-progressive MS (+13.3 years; 95% CI = 11.3-15.3). Brain-PAD at study entry predicted time-to-disability progression (hazard ratio 1.02; 95% CI = 1.01-1.03; p < 0.001); although normalized brain volume was a stronger predictor. Greater annualized brain-PAD increases were associated with greater annualized EDSS score (r = 0.26; p < 0.001).

Interpretation: The brain-age paradigm is sensitive to MS-related atrophy and clinical progression. A higher brain-PAD at baseline was associated with more rapid disability progression and the rate of change in brain-PAD related to worsening disability. Potentially, "brain-age" could be used as a prognostic biomarker in early-stage MS, to track disease progression or stratify patients for clinical trial enrollment. ANN NEUROL 2020 ANN NEUROL 2020;88:93-105.
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http://dx.doi.org/10.1002/ana.25746DOI Listing
July 2020

B cell rich meningeal inflammation associates with increased spinal cord pathology in multiple sclerosis.

Brain Pathol 2020 07 26;30(4):779-793. Epub 2020 Apr 26.

Department of Brain Sciences, Faculty of Medicine, Imperial College, London, UK.

Increased inflammation in the cerebral meninges is associated with extensive subpial cortical grey matter pathology in the forebrain and a more severe disease course in a substantial proportion of secondary progressive multiple sclerosis (SPMS) cases. It is not known whether this relationship extends to spinal cord pathology. We assessed the contribution of meningeal and parenchymal immune infiltrates to spinal cord pathology in SPMS cases characterized in the presence (F+) or absence (F-) of lymphoid-like structures in the forebrain meninges. Transverse cryosections of cervical, thoracic and lumbar cord of 22 SPMS and five control cases were analyzed for CD20+ B cells, CD4+ and CD8+ T cells, microglia/macrophages (IBA-1+), demyelination (myelin oligodendrocyte glycoprotein+) and axon density (neurofilament-H+). Lymphoid-like structures containing follicular dendritic cell networks and dividing B cells were seen in the spinal meninges of 3 out of 11 F+ SPMS cases. CD4+ and CD20+ cell counts were increased in F+ SPMS compared to F- SPMS and controls, whilst axon loss was greatest in motor and sensory tracts of the F+ SPMS cases (P < 0.01). The density of CD20+ B cells of the spinal leptomeninges correlated with CD4+ T cells and total B and T cells of the meninges; with the density of white matter perivascular CD20+ and CD4+ lymphocytes (P < 0.05); with white matter lesion area (P < 0.05); and the extent of axon loss (P < 0.05) in F+ SPMS cases only. We show that the presence of lymphoid-like structures in the forebrain is associated with a profound spinal cord pathology and local B cell rich meningeal inflammation associates with the extent of cord pathology. Our work supports a principal role for B cells in sustaining inflammation and tissue injury throughout the CNS in the progressive disease stage.
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http://dx.doi.org/10.1111/bpa.12841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018043PMC
July 2020

Matching-adjusted indirect treatment comparison of siponimod and other disease modifying treatments in secondary progressive multiple sclerosis.

Curr Med Res Opin 2020 07 14;36(7):1157-1166. Epub 2020 Apr 14.

Novartis Pharma AG, Basel, Switzerland.

Siponimod, interferon beta-1a (IFNβ-1a), IFNβ-1b and natalizumab have been evaluated as treatments for secondary progressive multiple sclerosis (SPMS) in separate randomized controlled trials (RCTs), but not head-to-head. These trials included heterogeneous patient populations, which limits the use of standard network meta-analysis (NMA) for indirect treatment comparison (ITC) of relative efficacy. Matching-adjusted indirect comparison (MAIC) aims to correct these cross-trial differences. We compared siponimod to other disease modifying treatments (DMTs) in SPMS using MAIC. Individual patient data (IPD) were available for siponimod (EXPAND), while only published summary data were available for IFNβ-1a (Nordic Study, SPECTRIMS, IMPACT), IFNβ-1b (North American Study, European Study) and natalizumab (ASCEND). MAICs were conducted between siponimod and the other DMTs by re-weighting patients in EXPAND based on logistic regression. Siponimod was determined to be statistically significantly more effective for the outcome of time to 6 month confirmed disability progression (CDP) compared with 22 µg IFNβ-1a and 250 µg IFNβ-1b, and for the outcome of time to CDP-3 compared with 60 µg IFNβ-1a. Siponimod was numerically but not statistically superior for CDP in all other comparisons. For annualized relapse rate (ARR), with the exception of natalizumab, siponimod was numerically but not statistically superior to all comparators. EXPAND provides evidence of the efficacy of siponimod compared with placebo, and these MAICs complement this by demonstrating improved efficacy of siponimod relative to DMTs. Siponimod offers a significant therapeutic advance that may slow disease progression compared to other DMTs in an EXPAND-like population with secondary progressive disease.
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http://dx.doi.org/10.1080/03007995.2020.1747999DOI Listing
July 2020
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