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BACKGROUND AND OBJECTIVE: We explored dynamic changes in the choroid plexus (CP) in patients with relapsing-remitting multiple sclerosis (RRMS) and assessed its relationship with chronic lesion expansion and atrophy in various brain compartments. METHODS: Fifty-seven RRMS patients were annually assessed for a minimum of 48 months with 3D FLAIR, pre- and post-contrast 3D T1 and diffusion-weighted magnetic resonance imaging (MRI). The CP was manually segmented at baseline and last follow-up. RESULTS: The volume of CP significantly increased by 1.4% annually. However, the extent of CP enlargement varied considerably among individuals (ranging from -3.6 to 150.8 mm3 or -0.2% to 6.3%). The magnitude of CP enlargement significantly correlated with central (r = 0.70, p < 0.001) and total brain atrophy (r = -0.57, p < 0.001), white (r = -0.61, p < 0.001) and deep grey matter atrophy (r = -0.60, p < 0.001). Progressive CP enlargement was significantly associated with the volume and extent of chronic lesion expansion (r = 0.60, p < 0.001), but not with the number or volume of new lesions. CONCLUSION: This study provides evidence of progressive CP enlargement in patients with RRMS. Our findings also demonstrate that enlargement of the CP volume is linked to the expansion of chronic lesions and neurodegeneration of periventricular white and grey matter in RRMS patients.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/patologia , Plexo Corióideo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Atrofia/patologia , Esclerose Múltipla/patologiaRESUMO
BACKGROUND AND OBJECTIVES: Expansion of chronic lesions in multiple sclerosis (MS) patients and recently described cerebrospinal fluid (CSF)-related gradient of tissue damage are linked to microglial activation. The aim of this study was to investigate whether lesion expansion is associated with proximity to ventricular CSF spaces. METHODS: Pre- and post-gadolinium three-dimensional (3D)-T1, 3D FLAIR and diffusion tensor images were acquired from 36 relapsing-remitting MS (RRMS) patients. Lesional activity was analysed between baseline and 48 months at different distances from the CSF using successive 1 mm thick concentric bands radiating from the ventricles. RESULTS: Voxel-based analysis of the rate of lesion expansion demonstrated a clear periventricular gradient decreasing away from the ventricles. This was particularly apparent when lesions of equal diameter were analysed. Periventricular lesional tissue showed higher degree of tissue destruction at baseline that significantly increased during follow-up in bands close to CSF. This longitudinal change was proportional to degree of lesion expansion. Lesion-wise analysis revealed a gradual, centrifugal decrease in the proportion of expanding lesions from the immediate periventricular zone. DISCUSSION: Our data suggest that chronic white matter lesions in close proximity to the ventricles are more destructive, show a higher degree of expansion at the lesion border and accelerated tissue loss in the lesion core.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Ventrículos Cerebrais/diagnóstico por imagem , Ventrículos Cerebrais/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/patologia , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/patologiaRESUMO
INTRODUCTION/AIMS: We hypothesized that early, pretreatment axonal loss would predict long-term disability, supported by a pilot study of selected patients with chronic inflammatory demyelinating polyneuropathy (CIDP). To further test this hypothesis, we examined a larger consecutive group of CIDP patients. METHODS: Needle electromyography and motor and sensory nerve conduction studies were carried out in 30 CIDP patients at pretreatment and follow-up 5 to 28 years later. Changes in amplitudes were expressed as axonal Z scores and changes in conduction as demyelination Z scores and correlated with findings of the Inflammatory Rasch-built Overall Disability Scale (I-RODS), the Neuropathy Impairment Score (NIS), and isokinetic dynamometry (IKS). RESULTS: At follow-up, the median I-RODS score was 73, the NIS was 23, and the IKS was 56%. The median axonal Z score was unchanged at follow-up. Conversely, the corresponding demyelination Z scores improved. The initial axonal loss was correlated with the clinical outcome and was an independent predictor of outcome by multivariate regression analysis. Axonal loss at follow-up was also correlated with the clinical outcome. Only the follow-up demyelination Z score was correlated with the clinical outcomes. Furthermore, the latency until treatment initiation was predictive of all three clinical outcome scores at follow-up, and of axonal loss and demyelination at follow-up. DISCUSSION: The present study findings indicate that pretreatment axonal loss at diagnosis in CIDP is predictive of long-term disability, neurological impairment, and strength. A delay in treatment is associated with more pronounced axonal loss and a worse clinical outcome.
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Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Humanos , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Condução Nervosa/fisiologia , Projetos Piloto , Eletromiografia , BiomarcadoresRESUMO
The etiology of multiple sclerosis (MS), a demyelinating disease affecting the central nervous system (CNS), remains obscure. Although apoptosis of oligodendrocytes and neurons has been observed in MS lesions, the contribution of this cell death process to disease pathogenesis remains controversial. It is usually considered that MS-associated demyelination and axonal degeneration result from neuroinflammation and an autoimmune process targeting myelin proteins. However, experimental data indicate that oligodendrocyte and/or neuronal cell death may indeed precede the development of inflammation and autoimmunity. These findings raise the question as to whether neural cell apoptosis is the key event initiating and/or driving the pathological cascade, leading to clinical functional deficits in MS. Similarly, regarding axonal damage, a key pathological feature of MS lesions, the roles of inflammation-independent and cell autonomous neuronal processes need to be further explored. While oligodendrocyte and neuronal loss in MS may not necessarily be mutually exclusive, particular attention should be given to the role of neuronal apoptosis in the development of axonal loss. If proven, MS could be viewed primarily as a neurodegenerative disease accompanied by a secondary neuroinflammatory and autoimmune process.
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Doenças Desmielinizantes , Esclerose Múltipla , Doenças Neurodegenerativas , Apoptose , Doenças Desmielinizantes/patologia , Humanos , Inflamação , Esclerose Múltipla/patologiaRESUMO
Age is a critical risk factor for many neurologic conditions, including progressive multiple sclerosis. Yet the mechanisms underlying the relationship are unknown. Using lysolecithin-induced demyelinating injury to the mouse spinal cord, we characterized the acute lesion and investigated the mechanisms of increased myelin and axon damage with age. We report exacerbated myelin and axon loss in middle-aged (8-10 months of age) compared with young (6 weeks of age) female C57BL/6 mice by 1-3 d of lesion evolution in the white matter. Transcriptomic analysis linked elevated injury to increased expression of Cybb, the gene encoding the catalytic subunit of NADPH oxidase gp91phox. Immunohistochemistry in male and female Cx3cr1CreER/+:Rosa26tdTom/+ mice for gp91phox revealed that the upregulation in middle-aged animals occurred primarily in microglia and not infiltrated monocyte-derived macrophages. Activated NADPH oxidase generates reactive oxygen species and elevated oxidative damage was corroborated by higher malondialdehyde immunoreactivity in lesions from middle-aged compared with young mice. From a previously conducted screen for generic drugs with antioxidant properties, we selected the antihypertensive CNS-penetrant medication indapamide for investigation. We report that indapamide reduced superoxide derived from microglia cultures and that treatment of middle-aged mice with indapamide was associated with a decrease in age-exacerbated lipid peroxidation, demyelination and axon loss. In summary, age-exacerbated acute injury following lysolecithin administration is mediated in part by microglia NADPH oxidase activation, and this is alleviated by the CNS-penetrant antioxidant, indapamide.SIGNIFICANCE STATEMENT Age is associated with an increased risk for the development of several neurologic conditions including progressive multiple sclerosis, which is represented by substantial microglia activation. We demonstrate that in the lysolecithin demyelination model in young and middle-aged mice, the latter group developed greater acute axonal and myelin loss attributed to elevated oxidative stress through NADPH oxidase in lineage-traced microglia. We thus used a CNS-penetrant generic medication used in hypertension, indapamide, as we found it to have antioxidant properties in a previous drug screen. Following lysolecithin demyelination in middle-aged mice, indapamide treatment was associated with decreased oxidative stress and axon/myelin loss. We propose indapamide as a potential adjunctive therapy in aging-associated neurodegenerative conditions such as Alzheimer's disease and progressive multiple sclerosis.
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Envelhecimento/fisiologia , Anti-Hipertensivos/farmacologia , Axônios/patologia , Indapamida/farmacologia , Microglia/metabolismo , Bainha de Mielina/patologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Medicamentos Genéricos , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos/fisiologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 2/biossíntese , NADPH Oxidase 2/genética , NADPH Oxidases/metabolismo , TranscriptomaRESUMO
BACKGROUND: Axonal loss denervates muscle, leading to an increase of fat accumulation in the muscle. Therefore, fat fraction (FF) in whole limb muscle using MRI has emerged as a monitoring biomarker for axonal loss in patients with peripheral neuropathies. In this study, we are testing whether deep learning-based model can automate quantification of the FF in individual muscles. While individual muscle is smaller with irregular shape, manually segmented muscle MRI images have been accumulated in this lab; and make the deep learning feasible. PURPOSE: To automate segmentation on muscle MRI images through deep learning for quantifying individual muscle FF in patients with peripheral neuropathies. STUDY TYPE: Retrospective. SUBJECTS: 24 patients and 19 healthy controls. FIELD STRENGTH/SEQUENCES: 3T; Interleaved 3D GRE. ASSESSMENT: A 3D U-Net model was implemented in segmenting muscle MRI images. This was enabled by leveraging a large set of manually segmented muscle MRI images. B1+ and B1- maps were used to correct image inhomogeneity. Accuracy of the automation was evaluated using Pixel Accuracy (PA), Dice Coefficient (DC) in binary masks; and Bland-Altman and Pearson correlation by comparing FF values between manual and automated methods. STATISTICAL TESTS: PA and DC were reported with their median value and standard deviation. Two methods were compared using the ± 95% confidence intervals (CI) of Bland-Altman analysis and the Pearson's coefficient (r2 ). RESULTS: DC values were from 0.83 ± 0.17 to 0.98 ± 0.02 in thigh and from 0.63 ± 0.18 to 0.96 ± 0.02 in calf muscles. For FF values, the overall ± 95% CI and r2 were [0.49, -0.56] and 0.989 in thigh and [0.84, -0.71] and 0.971 in the calf. DATA CONCLUSION: Automated results well agreed with the manual results in quantifying FF for individual muscles. This method mitigates the formidable time consumption and intense labor in manual segmentations; and enables the use of individual muscle FF as outcome measures in upcoming longitudinal studies. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 1.
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Aprendizado Profundo , Doenças do Sistema Nervoso Periférico , Automação , Humanos , Imageamento por Ressonância Magnética , Doenças do Sistema Nervoso Periférico/diagnóstico por imagem , Estudos RetrospectivosRESUMO
BACKGROUND: Slow-burning inflammation is putatively associated with lesion expansion and leads to progressive loss of axons and disability worsening. OBJECTIVE: To investigate the incidence and extent of chronic white matter lesion expansion in relapsing-remitting multiple sclerosis (RRMS) patients and to evaluate its relationship with biomarkers of disease progression. METHODS: Pre- and post-gadolinium T1, fluid-attenuated inversion recovery (FLAIR) and diffusion tensor images were acquired from 33 patients. Lesional activity were analysed between baseline and 48 months using custom-designed software. RESULTS: A total of 569 lesions were identified as chronic at baseline, of which 261 were expanding, 236 were stable and 72 were shrinking. In addition, 139 new lesions (both confluent and free-standing) were observed. Chronic lesion expansion was associated with patient's age and accounted for the bulk (67.3%) of total brain lesion volume increase, while only 32.7% was attributable to new lesion formation. Change in chronic lesion volume correlated with the rate of brain atrophy (r = -0.57, p = 0.001), change of Expanded Disability Status Scale (EDSS; r = 0.38, p = 0.03) and an increase of isotropic diffusivity inside the lesions (r = 0.75, p < 0.001). CONCLUSION: Expansion of chronic lesions in RRMS patients is the primary determinant of increased T2 total lesion load. It significantly contributes to disease progression and partially driving axonal loss inside the lesions and brain damage outside of lesional tissue.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Encéfalo/diagnóstico por imagem , Progressão da Doença , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagemRESUMO
BACKGROUND: Neuroaxonal degeneration is one of the hallmarks of clinical deterioration in progressive multiple sclerosis (PMS). OBJECTIVE: To elucidate the association between neuroaxonal degeneration and both local cortical and connected white matter (WM) tract pathology in PMS. METHODS: Post-mortem in situ 3T magnetic resonance imaging (MRI) and cortical tissue blocks were collected from 16 PMS donors and 10 controls. Cortical neuroaxonal, myelin, and microglia densities were quantified histopathologically. From diffusion tensor MRI, fractional anisotropy, axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were quantified in normal-appearing white matter (NAWM) and white matter lesions (WML) of WM tracts connected to dissected cortical regions. Between-group differences and within-group associations were investigated through linear mixed models. RESULTS: The PMS donors displayed significant axonal loss in both demyelinated and normal-appearing (NA) cortices (p < 0.001 and p = 0.02) compared with controls. In PMS, cortical axonal density was associated with WML MD and AD (p = 0.003; p = 0.02, respectively), and NAWM MD and AD (p = 0.04; p = 0.049, respectively). NAWM AD and WML AD explained 12.6% and 22.6%, respectively, of axonal density variance in NA cortex. Additional axonal loss in demyelinated cortex was associated with cortical demyelination severity (p = 0.002), explaining 34.4% of axonal loss variance. CONCLUSION: Reduced integrity of connected WM tracts and cortical demyelination both contribute to cortical axonal loss in PMS.
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Esclerose Múltipla , Substância Branca , Imagem de Tensor de Difusão , Substância Cinzenta , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Substância Branca/diagnóstico por imagemRESUMO
OBJECTIVE: To evaluate: (a) the specific effect that the demyelination and axonal loss have on the DW signal, and (b) the impact of the sequence parameters on the sensitivity to damage of two clinically feasible DWI techniques, i.e. DKI and NODDI. METHODS: We performed a Monte Carlo simulation of water diffusion inside a novel synthetic model of white matter in the presence of axonal loss and demyelination, with three compartments with permeable boundaries between them. We compared DKI and NODDI in their ability to detect and assess the damage, using several acquisition protocols. We used the F test statistic as an index of the sensitivity for each DWI parameter to axonal loss and demyelination, respectively. RESULTS: DKI parameters significantly changed with increasing axonal loss, but, in most cases, not with demyelination; all the NODDI parameters showed sensitivity to both the damage processes (at p < 0.01). However, the acquisition protocol strongly affected the sensitivity to damage of both the DKI and NODDI parameters and, especially for NODDI, the parameter absolute values also. DISCUSSION: This work is expected to impact future choices for investigating white matter microstructure in focusing on specific stages of the disease, and for selecting the appropriate experimental framework to obtain optimal data quality given the purpose of the experiment.
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Doenças Desmielinizantes , Substância Branca , Simulação por Computador , Doenças Desmielinizantes/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão , Humanos , Substância Branca/diagnóstico por imagemRESUMO
PURPOSE: To use optic coherence tomography (OCT) to evaluate idiopathic intracranial hypertension (IIH) patients with subclinical segmental optic atrophy despite being under apparently effective treatment. METHODS: IIH patients underwent an OCT examination including the peripapillary retina never fiber layer (RNFL) thickness, ganglion cell complex (GCC) thickness, focal loss volume (FLV) and global loss volume (GLV) of the GCC, and total macular thickness measurements at presentation and at 3, 6, 9, and 12 months after the diagnosis. The obtained data were compared with healthy subjects. Subjects with and without subclinical segmental atrophy at the 12th month were compared according to the demographics, clinical findings, and the OCT parameters recorded at the beginning of the disease. RESULTS: Both eyes of 56 patients with papilledema due to IIH and 50 age- and sex-matched control subjects were included in this prospective case-control study. Regression of papilledema with regional axon loss on the peripapillary RNFL thickness map was found in 37 (33%) eyes in the IIH group. IIH patients with segmental atrophy had the following characteristics when compared to those without segmental atrophy at the beginning of the disease: higher CSF opening pressure, higher grade of papilledema, thicker mean peripapillary RNFL thickness, thinner GCC layer, greater FLV and GLV loss, and severe visual field loss. CONCLUSIONS: Axonal loss occurred in the patients despite apparent treatment. It would be appropriate to follow-up with aggressive medical treatment those patients who present with the following characteristics: higher CSF opening pressure, higher grade of papilledema, thicker mean peripapillary RNFL thickness, and thinner GCC.
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Papiledema , Pseudotumor Cerebral , Axônios , Estudos de Casos e Controles , Humanos , Papiledema/diagnóstico , Estudos Prospectivos , Pseudotumor Cerebral/complicações , Pseudotumor Cerebral/diagnóstico , Células Ganglionares da Retina , Tomografia de Coerência ÓpticaRESUMO
BACKGROUND: Multiple sclerosis (MS) affects both brain and spinal cord. However, studies of the neuraxis with advanced magnetic resonance imaging (MRI) are rare because of long acquisition times. We investigated neurodegeneration in MS brain and cervical spinal cord using neurite orientation dispersion and density imaging (NODDI). OBJECTIVE: The aim of this study was to investigate possible alterations, and their clinical relevance, in neurite morphology along the brain and cervical spinal cord of relapsing-remitting MS (RRMS) patients. METHODS: In total, 28 RRMS patients and 20 healthy controls (HCs) underwent brain and spinal cord NODDI at 3T. Physical and cognitive disability was assessed. Individual maps of orientation dispersion index (ODI) and neurite density index (NDI) in brain and spinal cord were obtained. We examined differences in NODDI measures between groups and the relationships between NODDI metrics and clinical scores using linear regression models adjusted for age, sex and brain tissue volumes or cord cross-sectional area (CSA). RESULTS: Patients showed lower NDI in the brain normal-appearing white matter (WM) and spinal cord WM than HCs. In patients, a lower NDI in the spinal cord WM was associated with higher disability. CONCLUSION: Reduced neurite density occurs in the neuraxis but, especially when affecting the spinal cord, it may represent a mechanism of disability in MS.
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Medula Cervical , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Encéfalo/diagnóstico por imagem , Medula Cervical/diagnóstico por imagem , Humanos , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Neuritos , Medula EspinalRESUMO
BACKGROUND: Gray matter (GM) atrophy in brain is one of the best predictors of long-term disability in multiple sclerosis (MS), and recent findings have revealed that localized GM atrophy is associated with clinical disabilities. GM atrophy associated with each disability mapped to a distinct brain region, revealing a disability-specific atlas (DSA) of GM loss. OBJECTIVE: To uncover the mechanisms underlying the development of localized GM atrophy. METHODS: We used voxel-based morphometry (VBM) to evaluate localized GM atrophy and Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-hYdrogel (CLARITY) to evaluate specific pathologies in mice with experimental autoimmune encephalomyelitis (EAE). RESULTS: We observed extensive GM atrophy throughout the cerebral cortex, with additional foci in the thalamus and caudoputamen, in mice with EAE compared to normal controls. Next, we generated pathology-specific atlases (PSAs), voxelwise mappings of the correlation between specific pathologies and localized GM atrophy. Interestingly, axonal damage (end-bulbs and ovoids) in the spinal cord strongly correlated with GM atrophy in the sensorimotor cortex of the brain. CONCLUSION: The combination of VBM with CLARITY in EAE can localize GM atrophy in brain that is associated with a specific pathology in spinal cord, revealing a PSA of GM loss.
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Encefalomielite Autoimune Experimental/patologia , Substância Cinzenta/patologia , Esclerose Múltipla/patologia , Córtex Sensório-Motor/patologia , Medula Espinal/patologia , Animais , Atrofia/patologia , Encefalomielite Autoimune Experimental/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Hidrogéis , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/diagnóstico por imagem , Córtex Sensório-Motor/diagnóstico por imagem , Medula Espinal/diagnóstico por imagemRESUMO
BACKGROUND: Recent basic and clinical evidence suggests amiloride may be neuroprotective in multiple sclerosis (MS) through the blockade of the acid sensing ion channel (ASIC). OBJECTIVE: To examine the neuroprotective efficacy of amiloride in acute optic neuritis (ON). METHODS: A total of 48 patients were recruited to a phase 2, double blind, single site, randomised controlled trial. Scanning laser polarimetry (GDx) at 6 months was the primary outcome measure and optical coherence tomography (OCT) and visual and electrophysiological measures were secondary outcome measures. Participants aged 18-55 years, ≤28 days of onset of first episode unilateral ON, were randomised to amiloride (10 mg daily for 5 months) or placebo ( clinicaltrials.gov , NCT 01802489). RESULTS: Intention-to-treat (ITT) cohort consisted of 43 patients; 23 placebo and 20 amiloride. No significant drug-related adverse events occurred. No significant differences were found in GDx ( p = 0.840). Visual evoked potentials (VEP) were significantly prolonged in the amiloride group compared to placebo ( p = 0.004). All other secondary outcome measures showed no significant difference. Baseline analysis of OCT data demonstrated a significant pre-randomisation thinning of ganglion cell layer. CONCLUSION: Amiloride has not demonstrated any neuroprotective benefit within this trial paradigm, but future neuroprotective trials in ON should target the window of opportunity to maximise potential neuroprotective benefit.
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Amilorida/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Neurite Óptica/tratamento farmacológico , Retina/efeitos dos fármacos , Adulto , Método Duplo-Cego , Potenciais Evocados Visuais/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurite Óptica/patologia , Retina/patologiaRESUMO
BACKGROUND: The importance of neurodegeneration in multiple sclerosis (MS) is increasingly well recognized. OBJECTIVES: To evaluate retinal pathology using optical coherence tomography (OCT) and to investigate possible associations between retinal layers' thickness and specific patterns of gray matter volume in patients with a new diagnosis of MS. METHODS: A total of 31 patients underwent OCT scans and brain magnetic resonance imaging. In total, 30 controls underwent the same OCT procedure. The association between focal cortical volume and OCT measurements was investigated with voxel-based morphometry (VBM). RESULTS: Compared to controls, patients' macular retinal nerve fiber layer (mRNFL), macular ganglion cell layer (mGCL), macular inner plexiform layer (mIPL), and macular ganglion cell-inner plexiform layer (mGCIPL) thickness were significantly reduced ( p = 0.0009, p = 0.0003, p = 0.0049, and p = 0.0007, respectively). Peripapillary RNFL (pRNFL) and temporal sector pRNFL (T-pRNFL) did not show any significant changes, although there was a trend toward T-pRNFL thinning ( p = 0.0254). VBM analysis showed that mGCIPL and pRNFL were significantly correlated with the volume reduction of occipital-parietal cortex ( p < 0.005). CONCLUSION: mRNFL, mGCL, and mIPL are significantly reduced in MS patients without concomitant pRNFL thinning. These retinal changes show a significant association with cortical regions that are known to be important for visuospatial performance.
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Progressão da Doença , Lobo Occipital/patologia , Lobo Parietal/patologia , Células Ganglionares da Retina/patologia , Adulto , Atrofia/diagnóstico por imagem , Atrofia/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Lobo Occipital/diagnóstico por imagem , Lobo Parietal/diagnóstico por imagem , Tomografia de Coerência ÓpticaRESUMO
BACKGROUND: To identify thickness variations in the retinal nerve fiber layer around the optic disc and macula in patients with cerebral vein thrombosis (CVT) without papilledema. METHODS: This study included 28 patients with CVT diagnosis and appropriate treatment. Detailed ophthalmologic examination found bilateral vision 10/10, vision field test normal and fundus examination found no papilledema images. The patients had macular and optic retinal nerve fiber layer thickness (RNFL) measured with spectral domain-optical coherence tomography (SD-OCT) (Optovue, Fremont, CA). Patients had retinal nerve fiber thickness compared with a control group. RESULTS: When the effect on the macula and RNFL near the optic nerve disk is investigated, there was significant thinning identified in the macula inferior inner, temporal inner, superior inner and temporal outer quadrants (p = 0.009, 0.001, 0.026, 0.014, respectively) and in the inferior temporal quadrant of the optic nerve disk (p = 0.020) in CVT patients compared to normal individuals. CONCLUSIONS: Even after appropriate treatment of CVT patients, axonal loss was identified with OCT. As a result, it may be important to use OCT measurements to monitor CVT treatment.
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Trombose Intracraniana/patologia , Fibras Nervosas/patologia , Doenças do Nervo Óptico/patologia , Retina/patologia , Células Ganglionares da Retina/patologia , Trombose Venosa/patologia , Adulto , Idoso , Axônios/patologia , Estudos de Casos e Controles , Feminino , Humanos , Macula Lutea/patologia , Masculino , Pessoa de Meia-Idade , Disco Óptico/patologia , Estudos Prospectivos , Tomografia de Coerência Óptica/métodosRESUMO
BACKGROUND: Spinal cord (SC) lesions in Theiler's murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) resemble important features of brain lesions in progressive multiple sclerosis (MS) including inflammation, demyelination, and axonal damage. The aim of the present study was a comparison of SC lesions in MS and TMEV-IDD focusing on spatial and temporal distribution of demyelination, inflammation, SC atrophy (SCA), and axonal degeneration/loss in major descending motor pathways. METHODS: TMEV and mock-infected mice were investigated clinically once a week. SC tissue was collected at 42, 98, 147, and 196 days post infection, and investigated using hematoxylin and eosin (HE) staining, immunohistochemistry targeting myelin basic protein (demyelination), Mac3 (microglia/macrophages), phosphorylated neurofilaments (axonal damage) and transmission electron microscopy. RESULTS: Demyelination prevailed in SC white matter in TMEV-IDD, contrasting a predominant gray matter involvement in MS. TMEV-infected mice revealed a significant loss of axons similar to MS. Ultrastructural analysis in TMEV-IDD revealed denuded axons, degenerative myelin changes, axonal degeneration, as well as remyelination. SCA is a consistent finding in the SC of MS patients and was also detected at a late time point in TMEV-IDD. CONCLUSION: This comparative study further indicates the suitability of TMEV-IDD as animal model also for the investigation of progressive SC lesions in MS.
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Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/virologia , Modelos Animais de Doenças , Esclerose Múltipla/patologia , Doenças da Medula Espinal/patologia , Medula Espinal/patologia , Theilovirus , Animais , Axônios/patologia , Feminino , Imuno-Histoquímica/métodos , CamundongosRESUMO
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Several biomarkers including proteins and lipids have been reported in MS cerebrospinal fluid (CSF), reflecting different aspects of the pathophysiology particularly of relapsing-remitting MS (RRMS). Sulfatide, abundant in the myelin sheath and a proposed target for autoimmune attack in MS, has been reported altered in MS CSF. Here, we investigated the potential of CSF sulfatide and its isoforms as biomarkers in MS. A highly sensitive and quantitative mass spectrometry method was employed to determine levels of sulfatide isoforms in CSF from RRMS and progressive MS (PMS) patients, and healthy donors (HD). We demonstrate that levels of total CSF sulfatide and C24:1, C26:1, and C26:1-OH isoforms were significantly increased in PMS compared with RRMS patients and HD, while C23:0-OH was significantly decreased in CSF from PMS patients compared to the other two groups. Multivariate discriminant analysis showed that CSF sulfatide isoform pattern in PMS patients was distinct and non-overlapping with that of RRMS patients and HD. Sulfatide levels did not correlate with tested biomarkers or clinical parameters. The results suggest that CSF sulfatide isoform levels may be used to discriminate the phenotype of MS and might play a role in the progression of the disease.
Assuntos
Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico , Sulfoglicoesfingolipídeos/líquido cefalorraquidiano , Adulto , Estudos de Casos e Controles , Citocinas/líquido cefalorraquidiano , Progressão da Doença , Feminino , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Análise de Componente Principal , Isoformas de Proteínas/líquido cefalorraquidiano , Curva ROC , Sulfoglicoesfingolipídeos/química , Linfócitos T/metabolismo , Adulto JovemRESUMO
BACKGROUND: Immunoablation and autologous hematopoietic stem cell transplantation (IA/aHSCT) halts relapses, white matter (WM) lesion formation, and pathological whole-brain (WB) atrophy in multiple sclerosis (MS) patients. Whether the latter was due to effects on gray matter (GM) or WM warranted further exploration. OBJECTIVE: To model GM and WM volume changes after IA/aHSCT to further understand the effects seen on WB atrophy. METHODS: GM and WM volume changes were calculated from serial baseline and follow-up magnetic resonance imaging (MRI) ranging from 1.5 to 10.5 years in 19 MS patients treated with IA/aHSCT. A mixed-effects model with two predictors (total busulfan dose and baseline T1-weighted WM lesion volume "T1LV") characterized the time-courses after IA/aHSCT. RESULTS: Accelerated short-term atrophy of 2.1% and 3.2% occurred in GM and WM, respectively, on average. Both busulfan dose and T1LV were significant predictors of WM atrophy, whereas only busulfan was a significant predictor of GM atrophy. Compared to baseline, a significant reduction in GM atrophy, not WM atrophy, was found. The average rates of long-term GM and WM atrophy were -0.18%/year (standard error (SE): 0.083) and -0.07%/year (SE: 0.14), respectively. CONCLUSION: Chemotherapy-related toxicity affected both GM and WM. WM was further affected by focal T1-weighted lesion-related pathologies. Long-term rates of GM and WM atrophy were comparable to those of normal-aging.
Assuntos
Encéfalo/patologia , Substância Cinzenta/patologia , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia , Substância Branca/patologia , Adulto , Atrofia/patologia , Encéfalo/efeitos dos fármacos , Feminino , Substância Cinzenta/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/efeitos adversos , Substância Branca/efeitos dos fármacos , Adulto JovemRESUMO
During the past decades, better understanding of relapsing-remitting multiple sclerosis disease mechanisms have led to the development of several disease-modifying therapies, reducing relapse rates and severity, through immune system modulation or suppression. In contrast, current therapeutic options for progressive multiple sclerosis remain comparatively disappointing and challenging. One possible explanation is a lack of understanding of pathogenic mechanisms driving progressive multiple sclerosis. Furthermore, diagnosis is usually retrospective, based on history of gradual neurological worsening with or without occasional relapses, minor remissions or plateaus. In addition, imaging methods as well as biomarkers are not well established. Magnetic resonance imaging studies in progressive multiple sclerosis show decreased blood-brain barrier permeability, probably reflecting compartmentalization of inflammation behind a relatively intact blood-brain barrier. Interestingly, a spectrum of inflammatory cell types infiltrates the leptomeninges during subpial cortical demyelination. Indeed, recent magnetic resonance imaging studies show leptomeningeal contrast enhancement in subjects with progressive multiple sclerosis, possibly representing an in vivo marker of inflammation associated to subpial demyelination. Treatments for progressive disease depend on underlying mechanisms causing central nervous system damage. Immunity sheltered behind an intact blood-brain barrier, energy failure, and membrane channel dysfunction may be key processes in progressive disease. Interfering with these mechanisms may provide neuroprotection and prevent disability progression, while potentially restoring activity and conduction along damaged axons by repairing myelin. Although most previous clinical trials in progressive multiple sclerosis have yielded disappointing results, important lessons have been learnt, improving the design of novel ones. This review discusses mechanisms involved in progressive multiple sclerosis, correlations between histopathology and magnetic resonance imaging studies, along with possible new therapeutic approaches.
Assuntos
Progressão da Doença , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagemRESUMO
BACKGROUND: Magnetic resonance imaging markers have been widely used to detect and quantify white matter pathologies in multiple sclerosis. We have recently developed a diffusion basis spectrum imaging (DBSI) to distinguish and quantify co-existing axonal injury, demyelination, and inflammation in multiple sclerosis patients and animal models. It could serve as a longitudinal marker for axonal loss, a primary cause of permanent neurological impairments and disease progression. METHODS: Eight 10-week-old female C57BL/6 mice underwent optic nerve DBSI, followed by a week-long recuperation prior to active immunization for experimental autoimmune encephalomyelitis (EAE). Visual acuity of all mice was assessed daily. Longitudinal DBSI was performed in mouse optic nerves at baseline (naïve, before immunization), before, during, and after the onset of optic neuritis. Tissues were perfusion fixed after final in vivo scans. The correlation between DBSI detected pathologies and corresponding immunohistochemistry markers was quantitatively assessed. RESULTS: In this cohort of EAE mice, monocular vision impairment occurred in all animals. In vivo DBSI detected, differentiated, and quantified optic nerve inflammation, demyelination, and axonal injury/loss, correlating nerve pathologies with visual acuity at different time points of acute optic neuritis. DBSI quantified, in the presence of optic nerve swelling, ~15% axonal loss at the onset of optic neuritis in EAE mice. CONCLUSIONS: Our findings support the notion that axonal loss could occur early in EAE mice. DBSI detected pathologies in the posterior visual pathway unreachable by optical coherence tomography and without confounding inflammation induced optic nerve swelling. DBSI could thus decipher the interrelationship among various pathological components and the role each plays in disease progression. Quantification of the rate of axonal loss could potentially serve as the biomarker to predict treatment outcome and to determine when progressive disease starts.