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1.
Mult Scler ; : 1352458519865739, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31339446

RESUMO

BACKGROUND: Structural cortical networks (SCNs) represent patterns of coordinated morphological modifications in cortical areas, and they present the advantage of being extracted from previously acquired clinical magnetic resonance imaging (MRI) scans. SCNs have shown pathophysiological changes in many brain disorders, including multiple sclerosis. OBJECTIVE: To investigate alterations of SCNs at the individual level in patients with clinically isolated syndrome (CIS), thereby assessing their clinical relevance. METHODS: We analyzed baseline data collected in a prospective multicenter (MAGNIMS) study. CIS patients (n = 60) and healthy controls (n = 38) underwent high-resolution 3T MRI. Measures of disability and cognitive processing were obtained for patients. Single-subject SCNs were extracted from brain 3D-T1 weighted sequences; global and local network parameters were computed. RESULTS: Compared to healthy controls, CIS patients showed altered small-world topology, an efficient network organization combining dense local clustering with relatively few long-distance connections. These disruptions were worse for patients with higher lesion load and worse cognitive processing speed. Alterations of centrality measures and clustering of connections were observed in specific cortical areas in CIS patients when compared with healthy controls. CONCLUSION: Our study indicates that SCNs can be used to demonstrate clinically relevant alterations of connectivity in CIS.

2.
Mult Scler ; : 1352458519845105, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31074686

RESUMO

BACKGROUND: The potential of multi-shell diffusion imaging to produce accurate brain connectivity metrics able to unravel key pathophysiological processes in multiple sclerosis (MS) has scarcely been investigated. OBJECTIVE: To test, in patients with a clinically isolated syndrome (CIS), whether multi-shell imaging-derived connectivity metrics can differentiate patients from controls, correlate with clinical measures, and perform better than metrics obtained with conventional single-shell protocols. METHODS: Nineteen patients within 3 months from the CIS and 12 healthy controls underwent anatomical and 53-direction multi-shell diffusion-weighted 3T images. Patients were cognitively assessed. Voxel-wise fibre orientation distribution functions were estimated and used to obtain network metrics. These were also calculated using a conventional single-shell diffusion protocol. Through linear regression, we obtained effect sizes and standardised regression coefficients. RESULTS: Patients had lower mean nodal strength ( p = 0.003) and greater network modularity than controls ( p = 0.045). Greater modularity was associated with worse cognitive performance in patients, even after accounting for lesion load ( p = 0.002). Multi-shell-derived metrics outperformed single-shell-derived ones. CONCLUSION: Connectivity-based nodal strength and network modularity are abnormal in the CIS. Furthermore, the increased network modularity observed in patients, indicating microstructural damage, is clinically relevant. Connectivity analyses based on multi-shell imaging can detect potentially relevant network changes in early MS.

3.
Ann Neurol ; 83(2): 210-222, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29331092

RESUMO

OBJECTIVE: Gray matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS. METHODS: We analyzed 3,604 brain high-resolution T1-weighted magnetic resonance imaging scans from 1,417 participants: 1,214 MS patients (253 clinically isolated syndrome [CIS], 708 relapsing-remitting [RRMS], 128 secondary-progressive [SPMS], and 125 primary-progressive [PPMS]), over an average follow-up of 2.41 years (standard deviation [SD] = 1.97), and 203 healthy controls (HCs; average follow-up = 1.83 year; SD = 1.77), attending seven European centers. Disability was assessed with the Expanded Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem, and cerebral white matter. Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-EDSS progression. RESULTS: SPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time-to-EDSS progression (hazard ratio = 0.73; 95% confidence interval, 0.65, 0.82; p < 0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (-1.45%), PPMS (-1.66%), and RRMS (-1.34%) than CIS (-0.88%) and HCs (-0.94%; p < 0.01). The rate of temporal GM atrophy in SPMS (-1.21%) was significantly faster than RRMS (-0.76%), CIS (-0.75%), and HCs (-0.51%). Similarly, the rate of parietal GM atrophy in SPMS (-1.24-%) was faster than CIS (-0.63%) and HCs (-0.23%; all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta = 0.04; p < 0.001). INTERPRETATION: This large, multicenter and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions. Ann Neurol 2018;83:210-222.

4.
Brain Pathol ; 28(3): 334-348, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28401686

RESUMO

Preventing chronic disease deterioration is an unmet need in people with multiple sclerosis, where axonal loss is considered a key substrate of disability. Clinically, chronic multiple sclerosis often presents as progressive myelopathy. Spinal cord cross-sectional area (CSA) assessed using MRI predicts increasing disability and has, by inference, been proposed as an indirect index of axonal degeneration. However, the association between CSA and axonal loss, and their correlation with demyelination, have never been systematically investigated using human post mortem tissue. We extensively sampled spinal cords of seven women and six men with multiple sclerosis (mean disease duration= 29 years) and five healthy controls to quantify axonal density and its association with demyelination and CSA. 396 tissue blocks were embedded in paraffin and immuno-stained for myelin basic protein and phosphorylated neurofilaments. Measurements included total CSA, areas of (i) lateral cortico-spinal tracts, (ii) gray matter, (iii) white matter, (iv) demyelination, and the number of axons within the lateral cortico-spinal tracts. Linear mixed models were used to analyze relationships. In multiple sclerosis CSA reduction at cervical, thoracic and lumbar levels ranged between 19 and 24% with white (19-24%) and gray (17-21%) matter atrophy contributing equally across levels. Axonal density in multiple sclerosis was lower by 57-62% across all levels and affected all fibers regardless of diameter. Demyelination affected 24-48% of the gray matter, most extensively at the thoracic level, and 11-13% of the white matter, with no significant differences across levels. Disease duration was associated with reduced axonal density, however not with any area index. Significant association was detected between focal demyelination and decreased axonal density. In conclusion, over nearly 30 years multiple sclerosis reduces axonal density by 60% throughout the spinal cord. Spinal cord cross sectional area, reduced by about 20%, appears to be a poor predictor of axonal density.

5.
Mult Scler ; 23(7): 1031-1034, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27600111

RESUMO

In patients who present with a clinically isolated syndrome (CIS), whose features are suggestive of multiple sclerosis (MS), fulfilling McDonald 2010 magnetic resonance imaging (MRI) criteria for dissemination in space (DIS) and dissemination in time (DIT) enables a diagnosis of MS. While ⩾1 periventricular lesion is included in the 2010 DIS criteria, earlier McDonald criteria required ⩾3 periventricular lesions to confirm DIS and recent Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS)-recommended DIS criteria also require ⩾3 lesions. We investigated the effect of varying the required number of periventricular lesions and found that the best combination of specificity and sensitivity for clinically definite MS was seen for ⩾1 periventricular lesion using both the McDonald 2010 and MAGNIMS 2016 criteria.


Assuntos
Ventrículos Cerebrais/diagnóstico por imagem , Técnicas de Apoio para a Decisão , Doenças Desmielinizantes/diagnóstico por imagem , Imagem por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Adolescente , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
6.
PLoS One ; 11(10): e0164890, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27741303

RESUMO

Diffusion tensor imaging (DTI) has recently started to be adopted into clinical investigations of spinal cord (SC) diseases. However, DTI applications to the lower SC are limited due to a number of technical challenges, related mainly to the even smaller size of the SC structure at this level, its position relative to the receiver coil elements and the effects of motion during data acquisition. Developing methods to overcome these problems would offer new means to gain further insights into microstructural changes of neurological conditions involving the lower SC, and in turn could help explain symptoms such as bladder and sexual dysfunction. In this work, the feasibility of obtaining grey and white matter (GM/WM) DTI indices such as axial/radial/mean diffusivity (AD/RD/MD) and fractional anisotropy (FA) within the lumbosacral enlargement (LSE) was investigated using a reduced field-of-view (rFOV) single-shot echo-planar imaging (ss-EPI) acquisition in 14 healthy participants using a clinical 3T MR system. The scan-rescan reproducibility of the measurements was assessed by calculating the percentage coefficient of variation (%COV). Mean FA was higher in WM compared to GM (0.58 and 0.4 in WM and GM respectively), AD and MD were higher in WM compared to GM (1.66 µm2ms-1 and 0.94 µm2ms-1 in WM and 1.2 µm2ms-1 and 0.82 µm2ms-1 in GM for AD and MD respectively) and RD was lower in WM compared to GM (0.58 µm2ms-1 and 0.63 µm2ms-1 respectively). The scan-rescan %COV was lower than 10% in all cases with the highest values observed for FA and the lowest for MD. This pilot study demonstrates that it is possible to obtain reliable tissue-specific estimation of DTI indices within the LSE using a rFOV ss-EPI acquisition. The DTI acquisition and analysis protocol presented here is clinically feasible and may be used in future investigations of neurological conditions implicating the lower SC.


Assuntos
Imagem por Ressonância Magnética , Medula Espinal/diagnóstico por imagem , Adulto , Feminino , Substância Cinzenta/diagnóstico por imagem , Voluntários Saudáveis , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Reprodutibilidade dos Testes , Razão Sinal-Ruído , Substância Branca/diagnóstico por imagem , Adulto Jovem
8.
Brain ; 139(Pt 3): 816-28, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26912640

RESUMO

In multiple sclerosis, microstructural damage of normal-appearing brain tissue is an important feature of its pathology. Understanding these mechanisms is vital to help develop neuroprotective strategies. The visual pathway is a key model to study mechanisms of damage and recovery in demyelination. Anterograde trans-synaptic degeneration across the lateral geniculate nuclei has been suggested as a mechanism of tissue damage to explain optic radiation abnormalities seen in association with demyelinating disease and optic neuritis, although evidence for this has relied solely on cross-sectional studies. We therefore aimed to assess: (i) longitudinal changes in the diffusion properties of optic radiations after optic neuritis suggesting trans-synaptic degeneration; (ii) the predictive value of early optic nerve magnetic resonance imaging measures for late optic radiations changes; and (iii) the impact on visual outcome of both optic nerve and brain post-optic neuritis changes. Twenty-eight consecutive patients with acute optic neuritis and eight healthy controls were assessed visually (logMAR, colour vision, and Sloan 1.25%, 5%, 25%) and by magnetic resonance imaging, at baseline, 3, 6, and 12 months. Magnetic resonance imaging sequences performed (and metrics obtained) were: (i) optic nerve fluid-attenuated inversion-recovery (optic nerve cross-sectional area); (ii) optic nerve proton density fast spin-echo (optic nerve proton density-lesion length); (iii) optic nerve post-gadolinium T1-weighted (Gd-enhanced lesion length); and (iv) brain diffusion-weighted imaging (to derive optic radiation fractional anisotropy, radial diffusivity, and axial diffusivity). Mixed-effects and multivariate regression models were performed, adjusting for age, gender, and optic radiation lesion load. These identified changes over time and associations between early optic nerve measures and 1-year global optic radiation/clinical measures. The fractional anisotropy in patients' optic radiations decreased (P = 0.018) and radial diffusivity increased (P = 0.002) over 1 year following optic neuritis, whereas optic radiation measures were unchanged in controls. Also, smaller cross-sectional areas of affected optic nerves at 3 months post-optic neuritis predicted lower fractional anisotropy and higher radial diffusivity at 1 year (P = 0.007) in the optic radiations, whereas none of the inflammatory measures of the optic nerve predicted changes in optic radiations. Finally, greater Gd-enhanced lesion length at baseline and greater optic nerve proton density-lesion length at 1 year were associated with worse visual function at 1 year (P = 0.034 for both). Neither the cross-sectional area of the affected optic nerve after optic neuritis nor the damage in optic radiations was associated with 1-year visual outcome. Our longitudinal study shows that, after optic neuritis, there is progressive damage to the optic radiations, greater in patients with early residual optic nerve atrophy, even after adjusting for optic radiation lesions. These findings provide evidence for trans-synaptic degeneration.


Assuntos
Neurite Óptica/complicações , Neurite Óptica/diagnóstico , Degeneração Retrógrada/diagnóstico , Degeneração Retrógrada/etiologia , Sinapses/patologia , Adulto , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Vias Visuais/patologia
9.
Lancet Neurol ; 15(3): 259-69, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26822749

RESUMO

BACKGROUND: Acute demyelinating optic neuritis, a common feature of multiple sclerosis, can damage vision through neurodegeneration in the optic nerve and in its fibres in the retina. Inhibition of voltage-gated sodium channels is neuroprotective in preclinical models. In this study we aimed to establish whether sodium-channel inhibition with phenytoin is neuroprotective in patient with acute optic neuritis. METHODS: We did a randomised, placebo-controlled, double-blind phase 2 trial at two UK academic hospitals in London and Sheffield. Patients with acute optic neuritis aged 18-60 years, presenting within 2 weeks of onset, with visual acuity of 6/9 or worse, were randomly assigned (1:1) by minimisation via a web-based service to oral phenytoin (maintenance dose 4 mg/kg per day if randomised before or on July 16, 2013, and 6 mg/kg per day if randomised on or after July 17, 2013) or placebo for 3 months, stratified by time from onset, centre, previous multiple sclerosis diagnosis, use of disease-modifying treatment, and use of corticosteroids for acute optic neuritis. Participants and treating and assessing physicians were masked to group assignment. The primary outcome was retinal nerve fibre layer (RNFL) thickness in the affected eye at 6 months, adjusted for fellow-eye RNFL thickness at baseline, analysed in a modified intention-to-treat population of all randomised participants who were followed up at 6 months. Safety was analysed in the entire population, including those who were lost to follow-up. The trial is registered with ClinicalTrials.gov, number NCT 01451593. FINDINGS: We recruited 86 participants between Feb 3, 2012, and May 22, 2014 (42 assigned to phenytoin and 44 to placebo). 29 were assigned to phenytoin 4 mg/kg and 13 to phenytoin 6 mg/kg. Five participants were lost to follow-up, so the primary analysis included 81 participants (39 assigned to phenytoin and 42 to placebo). Mean 6-month RNFL thickness in the affected eye at 6 months was 81.46 µm (SD 16.27) in the phenytoin group (a mean decrease of 16.69 µm [SD 13.73] from baseline) versus 74.29 µm (15.14) in the placebo group (a mean decrease of 23.79 µm [13.97] since baseline; adjusted 6-month difference of 7.15 µm [95% CI 1.08-13.22]; p=0.021), corresponding to a 30% reduction in the extent of RNFL loss with phenytoin compared with placebo. Treatment was well tolerated, with five (12%) of 42 patients having a serious adverse event in the phenytoin group (only one, severe rash, was attributable to phenytoin) compared with two (5%) of 44 in the placebo group. INTERPRETATION: These findings support the concept of neuroprotection with phenytoin in patients with acute optic neuritis at concentrations at which it blocks voltage-gated sodium channels selectively. Further investigation in larger clinical trials in optic neuritis and in relapsing multiple sclerosis is warranted. FUNDING: US National Multiple Sclerosis Society, Multiple Sclerosis Society of Great Britain and Northern Ireland, Novartis, UK National Institute for Health Research (NIHR), and NIHR UCLH/UCL Biomedical Research Centre.


Assuntos
Fármacos Neuroprotetores/farmacologia , Neurite Óptica/tratamento farmacológico , Avaliação de Resultados (Cuidados de Saúde) , Fenitoína/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/administração & dosagem , Fenitoína/administração & dosagem , Fenitoína/efeitos adversos , Bloqueadores do Canal de Sódio Disparado por Voltagem/administração & dosagem , Bloqueadores do Canal de Sódio Disparado por Voltagem/efeitos adversos
10.
Neuroimage Clin ; 10: 71-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26793433

RESUMO

Spinal cord (SC) atrophy, i.e. a reduction in the SC cross-sectional area (CSA) over time, can be measured by means of image segmentation using magnetic resonance imaging (MRI). However, segmentation methods have been limited by factors relating to reproducibility or sensitivity to change. The purpose of this study was to evaluate a fully automated SC segmentation method (PropSeg), and compare this to a semi-automated active surface (AS) method, in healthy controls (HC) and people with multiple sclerosis (MS). MRI data from 120 people were retrospectively analysed; 26 HC, 21 with clinically isolated syndrome, 26 relapsing remitting MS, 26 primary and 21 secondary progressive MS. MRI data from 40 people returning after one year were also analysed. CSA measurements were obtained within the cervical SC. Reproducibility of the measurements was assessed using the intraclass correlation coefficient (ICC). A comparison between mean CSA changes obtained with the two methods over time was performed using multivariate structural equation regression models. Associations between CSA measures and clinical scores were investigated using linear regression models. Compared to the AS method, the reproducibility of CSA measurements obtained with PropSeg was high, both in patients and in HC, with ICC > 0.98 in all cases. There was no significant difference between PropSeg and AS in terms of detecting change over time. Furthermore, PropSeg provided measures that correlated with physical disability, similar to the AS method. PropSeg is a time-efficient and reliable segmentation method, which requires no manual intervention, and may facilitate large multi-centre neuroprotective trials in progressive MS.


Assuntos
Medula Cervical/patologia , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Esclerose Múltipla/patologia , Adulto , Atrofia , Processamento Eletrônico de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos
11.
Neurology ; 86(2): 170-6, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26674332

RESUMO

OBJECTIVE: The temporal relationship between white matter (WM) and gray matter (GM) damage in vivo in early primary progressive multiple sclerosis (PPMS) was investigated testing 2 hypotheses: (1) WM tract abnormalities predict subsequent changes in the connected cortex ("primary WM damage model"); and (2) cortical abnormalities predict later changes in connected WM tracts ("primary GM damage model"). METHODS: Forty-seven patients with early PPMS and 18 healthy controls had conventional and magnetization transfer imaging at baseline; a subgroup of 35 patients repeated the protocol after 2 years. Masks of the corticospinal tracts, genu of the corpus callosum and optic radiations, and of connected cortical regions, were used for extracting the mean magnetization transfer ratio (MTR). Multiple regressions within each of 5 tract-cortex pairs were performed, adjusting for the dependent variable's baseline MTR; tract lesion load and MTR, spinal cord area, age, and sex were examined for potential confounding. RESULTS: The baseline MTR of most regions was lower in patients than in healthy controls. The tract-cortex pair relationships in the primary WM damage model were significant for the bilateral motor pair and right visual pair, while those in the primary GM damage model were only significant for the right motor pair. Lower lesion MTR at baseline was associated with lower MTR in the same tract normal-appearing WM at 2 years in 3 tracts. CONCLUSION: These results are consistent with the hypothesis that in early PPMS, cortical damage is for the most part a sequela of normal-appearing WM pathology, which, in turn, is predicted by abnormalities within WM lesions.


Assuntos
Mapeamento Encefálico , Substância Cinzenta/patologia , Imagem por Ressonância Magnética , Esclerose Múltipla/patologia , Fibras Nervosas Mielinizadas/patologia , Substância Branca/patologia , Adulto , Mapeamento Encefálico/métodos , Corpo Caloso/patologia , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tratos Piramidais/patologia
12.
Mult Scler ; 22(7): 910-20, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26432854

RESUMO

BACKGROUND: The in vivo relationship of spinal cord lesion features with clinical course and function in multiple sclerosis (MS) is poorly defined. OBJECTIVE: The objective of this paper is to investigate the associations of spinal cord lesion features on MRI with MS subgroup and disability. METHODS: We recruited 120 people: 25 clinically isolated syndrome, 35 relapsing-remitting (RR), 30 secondary progressive (SP), and 30 primary progressive (PP) MS. Disability was measured using the Expanded Disability Status Scale. We performed 3T axial cervical cord MRI, using 3D-fast-field-echo and phase-sensitive-inversion-recovery sequences. Both focal lesions and diffuse abnormalities were recorded. Focal lesions were classified according to the number of white matter (WM) columns involved and whether they extended to grey matter (GM). RESULTS: The proportion of patients with focal lesions involving at least two WM columns and extending to GM was higher in SPMS than in RRMS (p = 0.03) and PPMS (p = 0.015). Diffuse abnormalities were more common in both PPMS and SPMS, compared with RRMS (OR 6.1 (p = 0.002) and 5.7 (p = 0.003), respectively). The number of lesions per patient involving both the lateral column and extending to GM was independently associated with disability (p < 0.001). CONCLUSIONS: More extensive focal cord lesions, extension of lesions to GM, and diffuse abnormalities are associated with progressive MS and disability.


Assuntos
Doenças Desmielinizantes/diagnóstico por imagem , Imagem por Ressonância Magnética , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Medula Espinal/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adulto , Vértebras Cervicais , Estudos Transversais , Doenças Desmielinizantes/fisiopatologia , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Medula Espinal/fisiopatologia , Substância Branca/fisiopatologia , Adulto Jovem
13.
Neurol Neuroimmunol Neuroinflamm ; 2(6): e158, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26468472

RESUMO

OBJECTIVE: To compare the cancer risk of cladribine and other disease-modifying drugs (DMDs) in trials of people with relapsing multiple sclerosis (pwRMS). METHODS: Meta-analysis of phase III trials of licensed DMDs for pwRMS and a phase III trial of cladribine (CLARITY). Cancer rates were compared using Fisher exact test. RESULTS: Eleven trials were included. Investigated treatments included cladribine, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, alemtuzumab, and glatiramer acetate. The cancer rate in the CLARITY treatment group (0.34%) was not increased compared to all other treatment groups, whether including placebo-controlled trials only (0.6%, p = 0.4631) or all trials, i.e., including those with an active comparator arm (0.67%, p = 0.3669). No cancer was reported in the CLARITY placebo group, whereas the combined cancer rate of all other placebo groups was 1.19% (p = 0.0159). The cancer rate of zero in the CLARITY placebo group was also lower than that in the phase III trial of cladribine in people with clinically isolated syndrome (ORACLE MS, 2.91%, p = 0.0012). In fact, no difference was detected between cancer rates in the treatment groups of CLARITY (0.34%) and ORACLE MS (0.49%) (p = 0.6546). CONCLUSIONS: Our study does not support an increased cancer risk from cladribine in the doses used in CLARITY and ORACLE MS, which previously contributed to refusal of market authorization of cladribine in Europe. Longer-term follow-up is required to assess the safety profile of cladribine, as well as currently licensed DMDs, to definitively assess cancer risk.

14.
Neurology ; 85(13): 1115-22, 2015 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-26320199

RESUMO

OBJECTIVE: To develop a composite MRI-based measure of motor network integrity, and determine if it explains disability better than conventional MRI measures in patients with multiple sclerosis (MS). METHODS: Tract density imaging and constrained spherical deconvolution tractography were used to identify motor network connections in 22 controls. Fractional anisotropy (FA), magnetization transfer ratio (MTR), and normalized volume were computed in each tract in 71 people with relapse onset MS. Principal component analysis was used to distill the FA, MTR, and tract volume data into a single metric for each tract, which in turn was used to compute a composite measure of motor network efficiency (composite NE) using graph theory. Associations were investigated between the Expanded Disability Status Scale (EDSS) and the following MRI measures: composite motor NE, NE calculated using FA alone, FA averaged in the combined motor network tracts, brain T2 lesion volume, brain parenchymal fraction, normal-appearing white matter MTR, and cervical cord cross-sectional area. RESULTS: In univariable analysis, composite motor NE explained 58% of the variation in EDSS in the whole MS group, more than twice that of the other MRI measures investigated. In a multivariable regression model, only composite NE and disease duration were independently associated with EDSS. CONCLUSIONS: A composite MRI measure of motor NE was able to predict disability substantially better than conventional non-network-based MRI measures.


Assuntos
Encéfalo/patologia , Imagem por Ressonância Magnética/métodos , Atividade Motora/fisiologia , Esclerose Múltipla Recidivante-Remitente/patologia , Rede Nervosa/patologia , Índice de Gravidade de Doença , Adulto , Encéfalo/fisiopatologia , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Rede Nervosa/fisiopatologia
16.
Neurology ; 84(4): 367-73, 2015 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-25540312

RESUMO

OBJECTIVE: To investigate whether spinal cord (SC) lesion load, when quantified on axial images with high in-plane resolution, is associated with disability in multiple sclerosis (MS). METHODS: Twenty-eight healthy controls and 92 people with MS had cervical SC 3T MRI with axial phase sensitive inversion recovery, T2, and magnetization transfer (MT) sequences. We outlined all visible focal lesions from C2 to C4 to obtain lesion load and also measured upper cervical cord area. We measured MT ratio in normal-appearing cord tissue and in lesions. Disability was recorded using the Expanded Disability Status Scale (EDSS) and MS Functional Composite. We used linear regression models to determine associations with disability. RESULTS: SC lesion load was significantly higher in both secondary progressive MS (SPMS) (p = 0.008) and primary progressive MS (PPMS) (p = 0.02) compared to relapsing-remitting MS (RRMS); in each comparison, adjustment was made for age, sex, and brain volume. These differences were not evident when EDSS was added as a covariate. SC area was significantly lower in both SPMS (p < 0.001) and PPMS (p = 0.009) compared to RRMS. In a multiple regression model, cord lesion load (p < 0.001), cord area (p = 0.003), age (p < 0.001), and sex (p = 0.001) were independently associated with EDSS (R(2) = 0.58). Cord lesion load (p = 0.003), cord area (p = 0.034), and brain parenchymal fraction (p = 0.007) were independently associated with the 9-hole peg test (R(2) = 0.42). CONCLUSIONS: When quantified on axial MRI with high in-plane resolution, upper cervical cord lesion load is significantly and independently correlated with physical disability and is higher in progressive forms of MS than RRMS.


Assuntos
Medula Cervical/patologia , Imagem por Ressonância Magnética/métodos , Esclerose Múltipla Crônica Progressiva/patologia , Esclerose Múltipla Recidivante-Remitente/patologia , Doenças da Medula Espinal/patologia , Adulto , Atrofia/patologia , Avaliação da Deficiência , Feminino , Humanos , Imagem por Ressonância Magnética/instrumentação , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia
17.
Neurology ; 83(19): 1712-8, 2014 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-25298310

RESUMO

OBJECTIVES: To investigate whether (1) there were differences between HLA-DRB1*15-positive and -negative patients at baseline, and (2) HLA-DRB1*15-positive patients showed a greater development of brain and spinal cord damage, as assessed by MRI, and greater progression of disability, during a 5-year follow-up, compared with HLA-DRB1*15-negative patients. METHODS: HLA-DRB1*15 typing was performed in 41 patients with primary progressive multiple sclerosis (PPMS) who were recruited within 5 years of symptom onset. All patients and 18 healthy controls were studied clinically and with MRI at baseline, and every 6 months for 3 years, and then at 5 years. Magnetization transfer ratio parameters and volumes for brain gray matter and normal-appearing white matter, brain T2 lesion load, and spinal cord cross-sectional area were obtained. Patient disability was assessed at each visit using the Expanded Disability Status Scale and Multiple Sclerosis Functional Composite subscores. RESULTS: There were no significant differences between HLA-DRB1*15-positive and -negative patients at baseline. HLA-DRB1*15-positive patients showed a greater decline in brain magnetization transfer ratio for gray matter and normal-appearing white matter (both p = 0.005) than HLA-DRB1*15-negative patients over 5 years, while the same parameters did not change over time in healthy controls. HLA-DRB1*15-positive patients also showed a trend toward a faster increase in brain T2 lesion load than HLA-DRB1*15-negative patients (0.29 [95% confidence interval 0.20-0.38] vs 0.21 [0.13-0.30] mL/mo, p = 0.085) and higher T2 lesion volumes at all time points (average difference [95% confidence interval]: 10.58 mL [7.09-14.07], p < 0.001) during the follow-up, after adjusting for disease duration. CONCLUSIONS: These findings suggest that HLA-DRB1*15 influences the progression of brain pathology in PPMS.


Assuntos
Encéfalo/patologia , Cadeias HLA-DRB1/genética , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Crônica Progressiva/patologia , Medula Espinal/patologia , Adulto , Progressão da Doença , Feminino , Substância Cinzenta/patologia , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Substância Branca/patologia
18.
PLoS One ; 9(10): e105774, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25310093

RESUMO

Magnetic resonance spectroscopy (MRS) studies have previously described metabolite changes associated with aging of the healthy brain and provided insights into normal brain aging that can assist us in differentiating age-related changes from those associated with neurological disease. The present study investigates whether age-related changes in metabolite concentrations occur in the healthy cervical spinal cord. 25 healthy volunteers, aged 23-65 years, underwent conventional imaging and single-voxel MRS of the upper cervical cord using an optimised point resolved spectroscopy sequence on a 3T Achieva system. Metabolite concentrations normalised to unsuppressed water were quantified using LCModel and associations between age and spinal cord metabolite concentrations were examined using multiple regressions. A linear decline in total N-Acetyl-aspartate concentration (0.049 mmol/L lower per additional year of age, p = 0.010) and Glutamate-Glutamine concentration (0.054 mmol/L lower per additional year of age, p = 0.002) was seen within our sample age range, starting in the early twenties. The findings suggest that neuroaxonal loss and/or metabolic neuronal dysfunction, and decline in glutamate-glutamine neurotransmitter pool progress with aging.


Assuntos
Envelhecimento/metabolismo , Ácido Aspártico/metabolismo , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Medula Espinal/metabolismo , Adulto , Fatores Etários , Idoso , Colina/metabolismo , Creatina/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Valores de Referência , Adulto Jovem
19.
Hum Brain Mapp ; 35(3): 993-1003, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23281189

RESUMO

We characterized metabolic changes along the cortico-spinal tract (CST) in multiple sclerosis (MS) patients using a novel application of chemical shift imaging (CSI) and considering the spatial variation of metabolite levels. Thirteen relapsing-remitting (RR) and 13 primary-progressive (PP) MS patients and 16 controls underwent (1)H-MR CSI, which was applied to coronal-oblique scans to sample the entire CST. The concentrations of the main metabolites, i.e., N-acetyl-aspartate, myo-Inositol (Ins), choline containing compounds (Cho) and creatine and phosphocreatine (Cr), were calculated within voxels placed in regions where the CST is located, from cerebral peduncle to corona radiata. Differences in metabolite concentrations between groups and associations between metabolite concentrations and disability were investigated, allowing for the spatial variability of metabolite concentrations in the statistical model. RRMS patients showed higher CST Cho concentration than controls, and higher CST Ins concentration than PPMS, suggesting greater inflammation and glial proliferation in the RR than in the PP course. In RRMS, a significant, albeit modest, association between greater Ins concentration and greater disability suggested that gliosis may be relevant to disability. In PPMS, lower CST Cho and Cr concentrations correlated with greater disability, suggesting that in the progressive stage of the disease, inflammation declines and energy metabolism reduces. Attention to the spatial variation of metabolite concentrations made it possible to detect in patients a greater increase in Cr concentration towards the superior voxels as compared to controls and a stronger association between Cho and disability, suggesting that this step improves our ability to identify clinically relevant metabolic changes.


Assuntos
Imagem por Ressonância Magnética/métodos , Esclerose Múltipla Crônica Progressiva/metabolismo , Esclerose Múltipla Recidivante-Remitente/metabolismo , Tratos Piramidais/metabolismo , Adulto , Idoso , Colina/metabolismo , Avaliação da Deficiência , Humanos , Hidrogênio , Inositol/metabolismo , Imagem por Ressonância Magnética/instrumentação , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
20.
J Cereb Blood Flow Metab ; 34(1): 34-42, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24045400

RESUMO

Alterations in the overall cerebral hemodynamics have been reported in multiple sclerosis (MS); however, their cause and significance is unknown. While potential venous causes have been examined, arterial causes have not. In this study, a multiple delay time arterial spin labeling magnetic resonance imaging sequence at 3T was used to quantify the arterial hemodynamic parameter bolus arrival time (BAT) and cerebral blood flow (CBF) in normal-appearing white matter (NAWM) and deep gray matter in 33 controls and 35 patients with relapsing-remitting MS. Bolus arrival time was prolonged in MS in NAWM (1.0±0.2 versus 0.9±0.2 seconds, P=0.031) and deep gray matter (0.90±0.18 versus 0.80±0.14 seconds, P=0.001) and CBF was increased in NAWM (14±4 versus 10±2 mL/100 g/min, P=0.001). Prolonged BAT in NAWM (P=0.042) and deep gray matter (P=0.01) were associated with higher expanded disability status score. This study demonstrates alteration in cerebral arterial hemodynamics in MS. One possible cause may be widespread inflammation. Bolus arrival time was longer in patients with greater disability independent of atrophy and T2 lesion load, suggesting alterations in cerebral arterial hemodynamics may be a marker of clinically relevant pathology.


Assuntos
Velocidade do Fluxo Sanguíneo/fisiologia , Artérias Cerebrais/fisiopatologia , Circulação Cerebrovascular/fisiologia , Pessoas com Deficiência , Esclerose Múltipla/fisiopatologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Avaliação da Deficiência , Feminino , Humanos , Modelos Lineares , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Marcadores de Spin , Fatores de Tempo , Adulto Jovem
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