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3.
Proc Natl Acad Sci U S A ; 116(22): 11020-11027, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31072935

RESUMO

Understanding the mode of action of drugs is a challenge with conventional methods in clinical trials. Here, we aimed to explore whether simvastatin effects on brain atrophy and disability in secondary progressive multiple sclerosis (SPMS) are mediated by reducing cholesterol or are independent of cholesterol. We applied structural equation models to the MS-STAT trial in which 140 patients with SPMS were randomized to receive placebo or simvastatin. At baseline, after 1 and 2 years, patients underwent brain magnetic resonance imaging; their cognitive and physical disability were assessed on the block design test and Expanded Disability Status Scale (EDSS), and serum total cholesterol levels were measured. We calculated the percentage brain volume change (brain atrophy). We compared two models to select the most likely one: a cholesterol-dependent model with a cholesterol-independent model. The cholesterol-independent model was the most likely option. When we deconstructed the total treatment effect into indirect effects, which were mediated by brain atrophy, and direct effects, simvastatin had a direct effect (independent of serum cholesterol) on both the EDSS, which explained 69% of the overall treatment effect on EDSS, and brain atrophy, which, in turn, was responsible for 31% of the total treatment effect on EDSS [ß = -0.037; 95% credible interval (CI) = -0.075, -0.010]. This suggests that simvastatin's beneficial effects in MS are independent of its effect on lowering peripheral cholesterol levels, implicating a role for upstream intermediate metabolites of the cholesterol synthesis pathway. Importantly, it demonstrates that computational models can elucidate the causal architecture underlying treatment effects in clinical trials of progressive MS.

4.
Clin Pharmacol Ther ; 105(5): 1082-1090, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30986336
5.
Mult Scler Relat Disord ; 28: 193-196, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30623857

RESUMO

BACKGROUND: Current treatments for relapsing remitting multiple sclerosis (RRMS) reduce inflammation, but have a partial or modest effect on disability. This effect may require a much longer follow-up than standard trial design, in particular in RRMS with relatively-preserved functional reserve. We aimed to assess the long-term clinical evolution of RRMS patients exposed to atorvastatin in two trials (ACTIVE and ARIANNA). METHODS: We retrospectively looked at 69 participants randomized with atorvastatin or placebo as add-on therapy to interferon-beta for 24 months at a single MS centre. We recorded relapses, 1-point EDSS progression and progression to EDSS 4.0. Cox regression was performed for these three questions. A Poisson regression model was used to evaluate the association between atorvastatin treatment and annualized relapse rate (ARR). RESULTS: After 8.4 ±â€¯2.3 (3.7-11.9) years from trial, the use of atorvastatin was associated with reduced risk of 1-point EDSS progression (HR = 0.440; 95%CI = 0.225-0.861; p = 0.017), and of EDSS 4.0 (HR = 0.310; 95%CI = 0.123-0.784; p = 0.013). We found no significant association between atorvastatin and relapses. DISCUSSION: These data suggest that a delayed treatment effect may be seen with atorvastatin added to interferon-beta, eight years after entering the clinical trials. Long-term follow-up of trial cohorts should be mandated.


Assuntos
Atorvastatina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/terapia , Adulto , Avaliação da Deficiência , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Fatores de Tempo
6.
Artigo em Inglês | MEDLINE | ID: mdl-30467211

RESUMO

Adult-onset leukodystrophies and genetic leukoencephalopathies comprise a diverse group of neurodegenerative disorders of white matter with a wide age of onset and phenotypic spectrum. Patients with white matter abnormalities detected on MRI often present a diagnostic challenge to both general and specialist neurologists. Patients typically present with a progressive syndrome including various combinations of cognitive impairment, movement disorders, ataxia and upper motor neuron signs. There are a number of important and treatable acquired causes for this imaging and clinical presentation. There are also a very large number of genetic causes which due to their relative rarity and sometimes variable and overlapping presentations can be difficult to diagnose. In this review, we provide a structured approach to the diagnosis of inherited disorders of white matter in adults. We describe clinical and radiological clues to aid diagnosis, and we present an overview of both common and rare genetic white matter disorders. We provide advice on testing for acquired causes, on excluding small vessel disease mimics, and detailed advice on metabolic and genetic testing available to the practising neurologist. Common genetic leukoencephalopathies discussed in detail include CSF1R, AARS2, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and mitochondrial and metabolic disorders.

7.
Mult Scler Relat Disord ; 27: 370-377, 2018 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-30476873

RESUMO

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system that mainly affects young adults. While there is no cure for MS, disease modifying treatments (DMTs) reduce the relapse rate and partial accrual of disability. More effective DMTs may have higher risks including life-threatening infections or secondary autoimmunity. The complexity and novelty of available treatments cause challenges for clinicians when prescribing treatments and for people with MS (PwMS) when deciding what trade-offs they are willing and ready to make. OBJECTIVE: To explore the experience of people with relapsing remitting MS (PwRRMS) and their perspectives in choosing treatments. METHODS: Critical interpretive synthesis was employed to review and synthesis the published literature. Eighty-three publications were selected in a multi-step systematic process. RESULTS: Findings are presented in four interrelated areas: the influence of the clinical evidence-base in decision making; the meaning of DMT efficacy for PwRRMS; the influence of models of decision-making and information acquisition practices in PwRRMS; and the importance of psychosocial dimensions in DMT decision making. Synthesis of the findings revealed that alongside medical and individual reasoning, contextual circumstances play an important role in making treatment decisions. CONCLUSION: This review identifies and explains the importance of diverse contextual circumstances (clinical, social, psychological) that are important for PwRRMS when making treatment decisions. The findings demonstrate the importance of eliciting, understanding and addressing such contextual factors.

8.
BMJ Open ; 8(8): e021944, 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30166303

RESUMO

INTRODUCTION: The major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin reuptake inhibitor) and riluzole (glutamate antagonist). METHODS AND ANALYSIS: Patients with progressing SPMS will be randomised 1:1:1:1 to amiloride, fluoxetine, riluzole or matched placebo and followed for 96 weeks. The primary outcome will be the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalisation, of Atrophy method. With a sample size of 90 per arm, this will give 90% power to detect a 40% reduction in PBVC in any active arm compared with placebo and 80% power to detect a 35% reduction (analysing by analysis of covariance and with adjustment for multiple comparisons of three 1.67% two-sided tests), giving a 5% overall two-sided significance level. MS-SMART is not powered to detect differences between the three active treatment arms. Allowing for a 20% dropout rate, 110 patients per arm will be randomised. The study will take place at Neuroscience centres in England and Scotland. ETHICS AND DISSEMINATION: MS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007). Results of the study will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: NCT01910259; 2012-005394-31; ISRCTN28440672.

9.
Mult Scler ; : 1352458518794063, 2018 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-30141723

RESUMO

BACKGROUND: Progression is the major driver of disability and cost in multiple sclerosis (MS). However, the search for treatments in progressive multiple sclerosis (PMS) has not mirrored the success in relapsing MS. OBJECTIVES: To assess changes in PMS trials over time. METHODS: PubMed, MEDLINE and Embase were searched to identify randomised, double-blind, placebo-controlled trials in PMS. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used, study quality was assessed and trends were examined by regression. RESULTS: Placebo groups of 43 studies published between 1988 and 2018 were included. The mean age at trial entry increased by 9.8 years per decade (95% confidence interval (CI): [2.7; 4.9]; p < 0.001). Mean baseline Expanded Disability Status Scale (EDSS) scores increased by 0.36 points (95% CI: [0.09; 0.62]; p = 0.009) and disease durations at baseline were prolonged by 1.8 years (95% CI: [0.7; 2.9]; p = 0.003) per decade. The trials became larger, specifically placebo groups increased by about 222 patients (95% CI: [36; 409]; p = 0.021) and 88 patients (95% CI: [12; 165]; p = 0.025) per decade for primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS), respectively. The proportion of patients on placebo experiencing disability progression within 24 months decreased by 7.6 percentage points (95% CI: [1.2; 14.1]; p = 0.022) per year. CONCLUSION: Over three decades, PMS trial populations changed and are now older, with a longer disease duration and more disability, with lower on-trial progression rates.

10.
Mult Scler ; : 1352458518791374, 2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-30073908

RESUMO

We provide clinical commentary on this edition's case report of immune-mediated encephalitis related to daclizumab therapy.

11.
CNS Drugs ; 32(6): 499-526, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29968175

RESUMO

Multiple sclerosis is an immune-mediated inflammatory disease of the central nervous system characterised by demyelination, neuroaxonal loss and a heterogeneous clinical course. Multiple sclerosis presents with different phenotypes, most commonly a relapsing-remitting course and, less frequently, a progressive accumulation of disability from disease onset (primary progressive multiple sclerosis). The majority of people with relapsing-remitting multiple sclerosis, after a variable time, switch to a stage characterised by gradual neurological worsening known as secondary progressive multiple sclerosis. We have a limited understanding of the mechanisms underlying multiple sclerosis, and it is believed that multiple genetic, environmental and endogenous factors are elements driving inflammation and ultimately neurodegeneration. Axonal loss and grey matter damage have been regarded as amongst the leading causes of irreversible neurological disability in the progressive stages. There are over a dozen disease-modifying therapies currently licenced for relapsing-remitting multiple sclerosis, but none of these has provided evidence of effectiveness in secondary progressive multiple sclerosis. Recently, there has been some early modest success with siponimod in secondary progressive multiple sclerosis and ocrelizumab in primary progressive multiple sclerosis. Finding treatments to delay or prevent the courses of secondary progressive multiple sclerosis is an unmet and essential goal of the research in multiple sclerosis. In this review, we discuss new findings regarding drugs with immunomodulatory, neuroprotective or regenerative properties and possible treatment strategies for secondary progressive multiple sclerosis. We examine the field broadly to include trials where participants have progressive or relapsing phenotypes. We summarise the most relevant results from newer investigations from phase II and III randomised controlled trials over the past decade, with particular attention to the last 5 years.

12.
J Neurol ; 265(8): 1795-1802, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29846780

RESUMO

Proton magnetic resonance spectroscopy yields metabolic information and has proved to be a useful addition to structural imaging in neurological diseases. We applied short-echo time Spectroscopic Imaging in a cohort of 42 patients with secondary progressive multiple sclerosis (SPMS). Linear modelling with respect to brain tissue type yielded metabolite levels that were significantly different in white matter lesions compared with normal-appearing white matter, suggestive of higher myelin turnover (higher choline), higher metabolic rate (higher creatine) and increased glial activity (higher myo-inositol) within the lesions. These findings suggest that the lesions have ongoing cellular activity that is not consistent with the usual assumption of 'chronic' lesions in SPMS, and may represent a target for repair therapies.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/metabolismo , Estudos de Coortes , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Espectroscopia de Prótons por Ressonância Magnética
13.
Lancet Neurol ; 17(6): 489-491, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29778353
14.
Lancet Neurol ; 17(2): 118, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29413308
15.
Neurology ; 90(11): e955-e962, 2018 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-29467307

RESUMO

OBJECTIVE: To assess safety, tolerability, and efficacy of the antigen-specific immunotherapy ATX-MS-1467 in participants with relapsing multiple sclerosis using different treatment protocols to induce tolerance. METHODS: Two open-label trials in adult participants with relapsing multiple sclerosis were conducted. Study 1 was a multicenter, phase 1b safety evaluation comparing intradermal (i.d.) (cohort 1) with subcutaneous (cohort 2) administration in 43 participants. Both cohorts received ATX-MS-1467 dosed at 25, 50, 100, 400, and 800 µg at 14-day intervals over 8 weeks, followed by 8 weeks with 4 additional 800-µg doses at 14-day intervals and 32 weeks off study medication. Study 2 was a phase 2a, multicenter, single-arm trial enrolling 37 participants. ATX-MS-1467 was titrated from 50 µg i.d. on day 1 to 200 µg on day 15 and 800 µg on day 29 followed by biweekly administration of 800 µg for 16 weeks and 16 weeks off study medication. Efficacy was evaluated on MRI parameters and clinical variables. Safety endpoints included treatment-emergent adverse events and injection-site reactions. RESULTS: In study 1, there was a significant decrease in new/persisting T1 gadolinium-enhanced (GdE) lesions in cohort 1 from baseline to week 16, returning to baseline values at week 48. In study 2, the number of T1 GdE lesions were significantly reduced on treatment and remained reduced at study completion. Safety results were unremarkable in both studies. CONCLUSION: Relatively slow ATX-MS-1467 titration and a longer full-dose i.d. treatment period is associated with reduction in GdE lesions and a sustained effect post treatment. Further trials of ATX-MS-1467 are warranted. CLASSIFICATION OF EVIDENCE: This work provides Class IV evidence that for patients with relapsing multiple sclerosis, slow ATX-MS-1467 titration and a longer full-dose i.d. treatment period is associated with reduction in GdE lesions.

16.
Nat Rev Neurol ; 14(2): 75-93, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29326424

RESUMO

Increasing numbers of drugs are being developed for the treatment of multiple sclerosis (MS). Measurement of relevant outcomes is key for assessing the efficacy of new drugs in clinical trials and for monitoring responses to disease-modifying drugs in individual patients. Most outcomes used in trial and clinical settings reflect either clinical or neuroimaging aspects of MS (such as relapse and accrual of disability or the presence of visible inflammation and brain tissue loss, respectively). However, most measures employed in clinical trials to assess treatment effects are not used in routine practice. In clinical trials, the appropriate choice of outcome measures is crucial because the results determine whether a drug is considered effective and therefore worthy of further development; in the clinic, outcome measures can guide treatment decisions, such as choosing a first-line disease-modifying drug or escalating to second-line treatment. This Review discusses clinical, neuroimaging and composite outcome measures for MS, including patient-reported outcome measures, used in both trials and the clinical setting. Its aim is to help clinicians and researchers navigate through the multiple options encountered when choosing an outcome measure. Barriers and limitations that need to be overcome to translate trial outcome measures into the clinical setting are also discussed.

17.
Patient ; 11(4): 391-402, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29313265

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a chronic disabling, inflammatory, and degenerative disease of the central nervous system that, in most cases, requires long-term disease-modifying treatment (DMT). The drugs used vary in efficacy and adverse effect profiles. Several studies have used attribute-based stated-preference methods, primarily to investigate patient preferences for initiating or escalating DMT. OBJECTIVES: To conduct a systematic review of attribute-based stated-preference studies in people with MS to identify common methods employed and to assess study quality, with reference to the specific challenges of this disease area. METHODS: We conducted a systematic search for studies related to attribute-based stated-preference and MS in multiple databases, including Cochrane and MEDLINE. Studies were included if they were published in a peer-reviewed journal, were on the topic of MS, and used a survey methodology that measured stated preferences for attributes of a whole. Analysis was conducted using narrative synthesis and summary statistics. Study quality was judged against the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) conjoint analysis checklist. RESULTS: We identified 16 relevant articles reporting 17 separate studies, all but one focusing on DMTs. Most studies were discrete-choice experiments. Study quality was generally high, but we recommend the following: (1) that consideration of sample sizes be improved, (2) that survey design choices be justified and documented, (3) that qualitative approaches for attribute and level selection be incorporated to better involve patients, and (4) that reporting of experimental practice be improved. The effects of DMTs on reproduction and the impact of how risk and uncertainty are presented were identified as neglected research topics. The ISPOR conjoint analysis checklist was found to be unsuitable for the assessment of study quality. CONCLUSION: Attribute-based stated preference is a useful method with which to examine the preferences of people with MS in their choice of DMT. However, further research embracing the methodological recommendations identified, particularly greater use of qualitative methods in attribute development, is needed.

18.
Clin Med (Lond) ; 17(6): 530-536, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29196354

RESUMO

This article reviews our current understanding and modern treatment of multiple sclerosis (MS). MS is a disabling condition resulting in devastating social and economic impacts. As MS can affect any part of the central nervous system, the presentation is often diverse; however, there are key features that can be useful in the clinic. We comment on the diagnostic criteria and review the main subtypes of MS, including clinically isolated syndrome, relapsing remitting MS, secondary progressive MS and primary progressive MS. Although the underlying aetiology of MS is still not known, we summarise those with most evidence of association. Finally, we aim to present treatment strategies for managing the acute relapse, disease-modifying therapies and MS symptoms. This review highlights that progressive MS is an area where there is currently a paucity of available disease-modifying treatments and this will be a major focus for future development.


Assuntos
Glucocorticoides/uso terapêutico , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Adjuvantes Imunológicos/uso terapêutico , Alemtuzumab/uso terapêutico , Crotonatos/uso terapêutico , Doenças Desmielinizantes/tratamento farmacológico , Fumarato de Dimetilo/uso terapêutico , Cloridrato de Fingolimode/uso terapêutico , Acetato de Glatiramer/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Interferon beta-1a/uso terapêutico , Interferon beta-1b/uso terapêutico , Mitoxantrona/uso terapêutico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/uso terapêutico , Toluidinas/uso terapêutico
19.
Mult Scler ; 23(12): 1573-1578, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29041871

RESUMO

The failure of a majority of clinical trials in progressive multiple sclerosis (MS) has highlighted the need to reconsider how these trials are designed and conducted, and many areas deserve focus. Basic scientists are reconceptualising the pathophysiology of progressive MS into three broad areas: systemic inflammation, compartmentalized inflammation and non-inflammatory neurodegeneration, with the latter two becoming predominant as the disease progresses. This framework will guide the choice of experimental therapies. Previous clinical trials have highlighted how participant selection can have a significant impact on study outcome. Phase 2 biomarkers which are biologically stable, dynamically changing over time, and easy to assess in multi-centre studies are greatly needed. Shortcomings inherent in the Expanded Disability Status Scale are prompting the development and validation of better clinical measures. The standard two-arm, fixed-duration trial paradigm has been challenged with new, innovative approaches that can test more therapies efficiently. International collaboratives such as the Progressive MS Alliance will support increased dialogue with regulators, industry and other funding agencies. Better engagement with people living with progressive MS will transform them from simply being the recipient of MS therapies to partners in the search for new treatments. Focused, targeted action will drive further development of effective therapies for progressive MS.


Assuntos
Ensaios Clínicos como Assunto , Esclerose Múltipla Crônica Progressiva/terapia , Projetos de Pesquisa , Humanos
20.
Lancet Neurol ; 16(8): 591-600, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28600189

RESUMO

BACKGROUND: In the 24-month MS-STAT phase 2 trial, we showed that high-dose simvastatin significantly reduced the annualised rate of whole brain atrophy in patients with secondary progressive multiple sclerosis (SPMS). We now describe the results of the MS-STAT cognitive substudy, in which we investigated the treatment effect on cognitive, neuropsychiatric, and health-related quality-of-life (HRQoL) outcome measures. METHODS: We did a secondary analysis of MS-STAT, a 24-month, double-blind, controlled trial of patients with SPMS done at three neuroscience centres in the UK between Jan 28, 2008, and Nov 4, 2011. Patients were randomly assigned (1:1) to either 80 mg simvastatin (n=70) or placebo (n=70). The cognitive assessments done were the National Adult Reading Test, Wechsler Abbreviated Scale of Intelligence, Graded Naming Test, Birt Memory and Information Processing Battery (BMIPB), Visual Object and Space Perception battery (cube analysis), Frontal Assessment Battery (FAB), and Paced Auditory Serial Addition Test. Neuropsychiatric status was assessed using the Hamilton Depression Rating Scale and the Neuropsychiatric Inventory Questionnaire. HRQoL was assessed using the self-reported 36-Item Short Form Survey (SF-36) version 2. Assessments were done at study entry, 12 months, and 24 months. Patients, treating physicians, and outcome assessors were masked to treatment allocation. Analyses were by intention to treat. MS-STAT is registered with ClinicalTrials.gov, number NCT00647348. FINDINGS: Baseline assessment revealed impairments in 60 (45%) of 133 patients on the test of frontal lobe function (FAB), and in between 13 (10%) and 43 (33%) of 130 patients in tests of non-verbal and verbal memory (BMIPB). Over the entire trial, we noted significant worsening on tests of verbal memory (T score decline of 5·7 points, 95% CI 3·6-7·8; p<0·0001) and non-verbal memory (decline of 6·8 points, 4·8-8·7; p<0·0001). At 24 months, the FAB score was 1·2 points higher in the simvastatin-treated group than in the placebo group (95% CI 0·2-2·3). The simvastatin group also had a 2·5 points better mean physical component score of the SF-36 (95% CI 0·3-4·8; p=0·028). A treatment effect was not noted for any other outcomes. INTERPRETATION: To our knowledge, this SPMS cohort is the largest studied to date with comprehensive longitudinal cognitive, neuropsychiatric, and HRQoL assessments. We found evidence of a positive effect of simvastatin on frontal lobe function and a physical quality-of-life measure. Although we found no effect of simvastatin on the other outcome measures, these potential effects warrant confirmation and underline the importance of fully assessing cognition and quality of life in progressive multiple sclerosis treatment trials. FUNDING: The Moulton Foundation, the Berkeley Foundation, the Multiple Sclerosis Trials Collaboration, the Rosetrees Trust, a personal contribution from A W Pidgley CBE, and the National Institute for Health Research University College London Hospitals Biomedical Research Centre and University College London.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Função Executiva/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Avaliação de Resultados (Cuidados de Saúde) , Qualidade de Vida , Sinvastatina/farmacologia , Adulto , Disfunção Cognitiva/etiologia , Método Duplo-Cego , Função Executiva/fisiologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Masculino , Transtornos da Memória/etiologia , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/complicações , Sinvastatina/administração & dosagem
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