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1.
Eur J Neurol ; 29(8): 2299-2308, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35474598

RESUMO

BACKGROUND AND PURPOSE: Hypoperfusion, vascular pathology, and cardiovascular risk factors are associated with disease severity in multiple sclerosis (MS). We aimed to assess relationships between cerebral arterial blood flow (CABF) and serum neurofilament light chain (sNfL) as neuronal damage biomarkers. METHODS AND MATERIALS: Total CABF was measured in 137 patients (86 with clinically isolated syndrome/relapsing-remitting (RR) MS and 51 with progressive MS [PMS]) and 48 healthy controls using Doppler ultrasonography. sNfL was quantitated using a single-molecule assay (Simoa). Examination using 3.0-T magnetic resonance imaging (MRI) allowed quantification of T2 lesions and whole-brain volume (WBV). Multiple linear regression models determined the sNfL association with CABF after correction for demographic and MRI-derived variables. RESULTS: After adjustment for age, sex and body mass index (BMI), total CABF remained statistically significant and model comparisons showed that CABF explained an additional 2.6% of the sNfL variance (ß = -0.167, p = 0.044). CABF also remained significant in a stepwise regression model (ß = 0.18, p = 0.034) upon the inclusion of T2 lesion burden and WBV effects. Patients in the lowest CABF quartile (CABF ≤ 761 ml/min) had significantly higher sNfL levels (34.6 vs. 23.9 pg/ml, age and BMI-adjusted-p = 0.042) when compared to the highest quartile (CABF ≥ 1130 ml/min). CONCLUSION: Lower CABF is associated with increased sNfL in MS patients, highlighting the relationship between cerebral hypoperfusion and axonal pathology.


Assuntos
Esclerose Múltipla , Biomarcadores , Encéfalo/patologia , Circulação Cerebrovascular , Humanos , Filamentos Intermediários , Imageamento por Ressonância Magnética , Esclerose Múltipla/patologia , Proteínas de Neurofilamentos
2.
Neuroimage Clin ; 32: 102802, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34469848

RESUMO

BACKGROUND: Methodological challenges limit the use of brain atrophy and lesion burden measures in the follow-up of multiple sclerosis (MS) patients on clinical routine datasets. OBJECTIVE: To determine the feasibility of T2-FLAIR-only measures of lateral ventricular volume (LVV) and salient central lesion volume (SCLV), as markers of disability progression (DP) in MS. METHODS: A total of 3,228 MS patients from 9 MSBase centers in 5 countries were enrolled. Of those, 2,875 (218 with clinically isolated syndrome, 2,231 with relapsing-remitting and 426 with progressive disease subtype) fulfilled inclusion and exclusion criteria. Patients were scanned on either 1.5 T or 3 T MRI scanners, and 5,750 brain scans were collected at index and on average after 42.3 months at post-index. Demographic and clinical data were collected from the MSBase registry. LVV and SCLV were measured on clinical routine T2-FLAIR images. RESULTS: Longitudinal LVV and SCLV analyses were successful in 96% of the scans. 57% of patients had scanner-related changes over the follow-up. After correcting for age, sex, disease duration, disability, disease-modifying therapy and LVV at index, and follow-up time, MS patients with DP (n = 671) had significantly greater absolute LVV change compared to stable (n = 1,501) or disability improved (DI, n = 248) MS patients (2.0 mL vs. 1.4 mL vs. 1.1 mL, respectively, ANCOVA p < 0.001, post-hoc pair-wise DP vs. Stable p = 0.003; and DP vs. DI, p = 0.002). Similar ANCOVA model was also significant for SCLV (p = 0.03). CONCLUSIONS: LVV-based atrophy and SCLV-based lesion outcomes are feasible on clinically acquired T2-FLAIR scans in a multicenter fashion and are associated with DP over mid-term.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Atrofia/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Progressão da Doença , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Esclerose Múltipla Recidivante-Remitente/patologia
3.
Exp Neurol ; 335: 113488, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32991933

RESUMO

BACKGROUND: The human myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (huMOG-EAE) model, generates B-cell driven demyelination in mice, making it a suitable multiple sclerosis model to study B cell depletion. OBJECTIVES: We investigated the effect of subcutaneous anti-CD20 antibody treatment on huMOG-EAE gray matter (GM) pathology. METHODS: C57Bl/6, 8-week old mice were immunized with 200 huMOG1-125 and treated with 50 µg/mouse of anti-CD20 antibody (n = 16) or isotype control (n = 16). Serial brain volumetric 9.4 T MRI scans was performed at baseline, 1 and 5 wkPI. Disease severity was measured by clinical disability score (CDS) and performance on rotarod test. RESULTS: Anti-CD20 antibody significantly reduced brain volume loss compared with the isotype control across all timepoints longitudinally in the basal ganglia (p = 0.01), isocortex (p = 0.025) and thalamus (p = 0.023). The CDS was reduced significantly with anti-CD20 antibody vs. the isotype control at 3 (p = 0.003) and 4 (p = 0.03) wkPI, while a trend was observed at 5 (p = 0.057) and 6 (p = 0.086) wkPI. Performance on rotarod was also improved significantly at 3 (p = 0.007) and 5 (p = 0.01) wkPI compared with the isotype control. At cellular level, anti-CD20 therapy suppressed the percentage of proliferative nuclear antigen positive microglia in huMOG-EAE isocortex (p = 0.016). Flow cytometry confirmed that anti-CD20 antibody strongly depleted the CD19-expressing B cell fraction in peripheral blood mononuclear cells, reducing it from 39.7% measured in isotype control to 1.59% in anti-CD20 treated mice (p < 0.001). CONCLUSIONS: Anti-CD20 antibody treatment delayed brain tissue neurodegeneration in GM, and showed clinical benefit on measures of disease severity in huMOG-EAE mice.


Assuntos
Anticorpos/uso terapêutico , Antígenos CD20/imunologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/tratamento farmacológico , Substância Cinzenta/patologia , Glicoproteína Mielina-Oligodendrócito , Animais , Atrofia , Linfócitos B/imunologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Encefalomielite Autoimune Experimental/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Macrófagos/imunologia , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/imunologia , Equilíbrio Postural/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos
4.
J Neurol ; 266(4): 866-875, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30758665

RESUMO

BACKGROUND: Evidence regarding the role, if any, of dietary and lifestyle factors in the pathogenesis of multiple sclerosis (MS) is poorly understood. OBJECTIVE: To assess the effect of lifestyle-based risk factors linked to cardiovascular disease (CVD) on clinical and MRI-derived MS outcomes. METHODS: The study enrolled 175 MS or clinically isolated syndrome (CIS) patients and 42 age- and sex-matched healthy controls (HCs) who were longitudinally followed for 5.5 years. The 20-year CVD risk was calculated by Healthy Heart Score (HHS) prediction model which includes age, smoking, body mass index, dietary intake, exercise, and alcohol consumption. Baseline and follow-up MRI scans were obtained and cross-sectional and longitudinal changes of T2-lesion volume (LV), whole brain volume (WBV), white matter volume (WMV), gray matter volume (GMV), and lateral ventricular volume (LVV) were calculated. RESULTS: After correcting for disease duration, the baseline HHS values of the MS group were associated with baseline GMV (rs = - 0.20, p = 0.01), and longitudinal LVV change (rs = 0.19, p = 0.01). The association with LVV remained significant after adjusting for baseline LVV volumes (rs = 0.2, p = 0.008) in MS patients. The diet component of the HHS was associated with the 5-year T2-LV accrual (rs = - 0.191, p = 0.04) in MS. In the HC group, the HHS was associated with LVV (rs = 0.58, p < 0.001), GMV (rs = - 0.57, p < 0.001), WBV (rs = - 0.55, p = 0.001), T2-LV (rs = 0.41, p = 0.027), and WMV (rs = - 0.38, p = 0.042). Additionally, the HC HHS was associated with the 5-year change in LVV (rs = 0.54, p = 0.001) and in WBV (rs = - 0.45, p = 0.011). CONCLUSION: Lifestyle risk factors contribute to accelerated central brain atrophy in MS patients, whereas unhealthier diet is associated with MS lesion accrual. Despite the lower overall effect when compared to HCs, lifestyle-based modifications may still provide a beneficial effect on reducing brain atrophy in MS patients.


Assuntos
Encéfalo/diagnóstico por imagem , Doenças Desmielinizantes/diagnóstico por imagem , Doenças Desmielinizantes/epidemiologia , Dieta , Estilo de Vida , Atrofia , Encéfalo/patologia , Doenças Cardiovasculares/epidemiologia , Estudos de Casos e Controles , Estudos Transversais , Doenças Desmielinizantes/terapia , Progressão da Doença , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Fatores de Risco
5.
J Neurol Neurosurg Psychiatry ; 87(2): 181-7, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25722366

RESUMO

BACKGROUND: Cardiovascular (CV) risk factors have been associated with changes in clinical outcomes in patients with multiple sclerosis (MS). OBJECTIVES: To investigate the frequency of CV risks in patients with MS and their association with MRI outcomes. METHODS: In a prospective study, 326 patients with relapsing-remitting MS and 163 patients with progressive MS, 61 patients with clinically isolated syndrome (CIS) and 175 healthy controls (HCs) were screened for CV risks and scanned on a 3T MRI scanner. Examined CV risks included hypertension, heart disease, smoking, overweight/obesity and type 1 diabetes. MRI measures assessed lesion volumes (LVs) and brain atrophy. Association between individual or multiple CV risks and MRI outcomes was examined adjusting for age, sex, race, disease duration and treatment status. RESULTS: Patients with MS showed increased frequency of smoking (51.7% vs 36.5%, p = 0.001) and hypertension (33.9% vs 24.7%, p=0.035) compared with HCs. In total, 49.9% of patients with MS and 36% of HCs showed ≥ 2 CV risks (p = 0.003), while the frequency of ≥ 3 CV risks was 18.8% in the MS group and 8.6% in the HCs group (p = 0.002). In patients with MS, hypertension and heart disease were associated with decreased grey matter (GM) and cortical volumes (p < 0.05), while overweight/obesity was associated with increased T1-LV (p < 0.39) and smoking with decreased whole brain volume (p = 0.049). Increased lateral ventricle volume was associated with heart disease (p = 0.029) in CIS. CONCLUSIONS: Patients with MS with one or more CV risks showed increased lesion burden and more advanced brain atrophy.


Assuntos
Encéfalo/patologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla Recidivante-Remitente/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Atrofia , Efeitos Psicossociais da Doença , Etnicidade , Feminino , Substância Cinzenta/patologia , Humanos , Hipertensão/epidemiologia , Hipertensão/etiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/epidemiologia , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Fumar/efeitos adversos , Resultado do Tratamento , Adulto Jovem
6.
J Neuroimaging ; 25(5): 754-60, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25753576

RESUMO

OBJECTIVES: The clinical implications of white matter hyperintensities (WMH) in non-demented Parkinson's disease (PD) have not been thoroughly examined. To address this, we investigated the spatial distribution of WMH and their regional predilection in non-demented patients with mild PD. METHODS: Cognitive assessments classified the sample into patients with mild cognitive impairment (PD-MCI, n = 25) and patients with no cognitive impairment (PD-NCI, n = 65) based on the recent formal Movement Disorder Task Force diagnostic criteria. The mean age was 65.1 ± 7.7 years, disease duration was 5.3 ± 3.9 years, and Hoehn and Yahr stage was 1.9 ± .4. WMHs were outlined on T2-weighted imaging using a semi-automated technique. The spatial distribution of WMHs were compared between PD-MCI and PD-NCI using voxel-wise lesion probability maps (LPM). General linear models examined the associations between spatially specific WMHs and cognitive domains. RESULTS: LPM analyses showed significant differences in the spatial distribution of WMH in PD-MCI compared to PD-NCI in widespread regions of the brain (P < .05). PD-MCI demonstrated significantly greater total and periventricular WMHs compared to PD-NCI (P ≤ .02). Spatial distribution of WMHs was also significantly associated with global cognition, performance on the Frontal Assessment Battery and Fruit Fluency (P < .05). CONCLUSIONS: Voxel-wise LPM analysis revealed differences in the spatial distribution of WMH between PD-MCI and PD-NCI patients, particularly in the periventricular regions. A more widespread extent of WMH might be indicative of cognitive deterioration. Our findings warrant further longitudinal investigation into the importance of WMH spatial distribution as a predictor for conversion from PD to PD with dementia.


Assuntos
Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Imagem de Tensor de Difusão/métodos , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Substância Branca/patologia , Idoso , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
7.
J Neuroimmunol ; 263(1-2): 121-7, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23916695

RESUMO

OBJECTIVES: To investigate whether anti-herpesvirus antibodies are associated with serum cholesterol profiles in clinically isolated syndromes (CIS). METHODS: Pre-treatment serum samples from 118 high-risk CIS patients were analyzed for IgG antibodies against cytomegalovirus (anti-CMV), Epstein Barr virus (EBV) viral capsid antigen (VCA) and EBV nuclear antigen-1 (EBNA-1). A lipid profile consisting of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) was obtained. Clinical and MRI assessments were obtained at baseline, 6, 12, and 24 months after start of interferon-beta treatment. RESULTS: The study included 118 CIS patients (77 females, 41 males, 65.3% female; mean age: 28.1±SD 8.1 years). Anti-EBV EBNA-1 antibody levels were associated with LDL-C (p=0.009) and TC (p=0.008) levels. Anti-CMV positivity status was associated with reduced time to relapse (p=0.006) and the greater number of relapses (p=0.009) in patients with high HDL-C. Anti-EBV VCA antibody levels were associated with greater number of new T2 lesions (p=0.002) and with increased brain atrophy (p<0.001) in patients with high LDL-C. CONCLUSIONS: Our results indicate that higher levels of anti-EBV EBNA-1 antibodies are associated with higher LDL-C and TC levels. Anti-CMV positive individuals have greater disease progression in the presence of higher HDL-C levels. Individuals with higher levels of anti-EBV VCA antibodies have greater progression on MRI measures in the presence of higher LDL-C.


Assuntos
Autoanticorpos/sangue , Colesterol/sangue , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico , Progressão da Doença , Infecções por Vírus Epstein-Barr/imunologia , Herpesviridae/isolamento & purificação , Herpesvirus Humano 4/imunologia , Adulto , Citomegalovirus/isolamento & purificação , Doenças Desmielinizantes/virologia , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/sangue , Feminino , Herpesvirus Humano 4/isolamento & purificação , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Adulto Jovem
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