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BACKGROUND: Progression independent of relapse activity (PIRA) has been described since the early stage of relapsing multiple sclerosis (RMS). However, little is known about the relation between PIRA and inflammatory activity that is particularly important at this stage of the disease. METHOD: We included 110 patients in a prospective study within 18 months of RMS onset. MRI examinations and clinical visits were scheduled on the same day for months 0, 6, 12, 24, 36, 60, 84, 120, 180 and 240. RESULTS: The mean (SD) age of patients was 30 (6.7) years at inclusion and median (range) follow-up 15 (9-20) years. Analysis of 1118 between-visit intervals revealed 93 confirmed disability accumulation events in 68 (62%) patients: 50 (54%) events related to relapse activity worsening and 43 (46%) PIRA events, including 17 (18%) with MRI activity. The risk of PIRA between two visits (stable event as the reference category) was associated with Expanded Disability Status Scale (EDSS) score (HR: 1.41; 95% CI: 1.18 to 1.69; p<0.001), disease duration (HR: 0.75; 95% CI: 0.62 to 0.90; p<0.005) and new lesions between the visits (HR: 1.09 per lesion; 95% CI: 1.01 to 1.17; p<0.05). As compared with PIRA events with MRI activity, PIRA events without such activity occurred in patients with more disability (mean EDSS score 3, p<0.05), longer disease duration (mean 11 years, p<0.001) and greater number of T2-weighted lesions (p<0.05). CONCLUSION: This study evidenced that inflammatory activity increases the risk of PIRA in early RMS, arguing that a significant part of PIRA is accessible to treatment targeting inflammation in these patients.
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Whole brain ionic and metabolic imaging has potential as a powerful tool for the characterization of brain diseases. We combined sodium MRI (23 Na MRI) and 1 H-MR Spectroscopic Imaging (1 H-MRSI), assessing changes within epileptogenic networks in comparison with electrophysiologically normal networks as defined by stereotactic EEG (SEEG) recordings analysis. We applied a multi-echo density adapted 3D projection reconstruction pulse sequence at 7 T (23 Na-MRI) and a 3D echo-planar spectroscopic imaging sequence at 3 T (1 H-MRSI) in 19 patients suffering from drug-resistant focal epilepsy who underwent presurgical SEEG. We investigated 23 Na MRI parameters including total sodium concentration (TSC) and the sodium signal fraction associated with the short component of T2 * decay (f), alongside the level of metabolites N-acetyl aspartate (NAA), choline compounds (Cho), and total creatine (tCr). All measures were extracted from spherical regions of interest (ROIs) centered between two adjacent SEEG electrode contacts and z-scored against the same ROI in controls. Group comparison showed a significant increase in f only in the epileptogenic zone (EZ) compared to controls and compared to patients' propagation zone (PZ) and non-involved zone (NIZ). TSC was significantly increased in all patients' regions compared to controls. Conversely, NAA levels were significantly lower in patients compared to controls, and lower in the EZ compared to PZ and NIZ. Multiple regression analyzing the relationship between sodium and metabolites levels revealed significant relations in PZ and in NIZ but not in EZ. Our results are in agreement with the energetic failure hypothesis in epileptic regions associated with widespread tissue reorganization.
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Epilepsia , Prótons , Humanos , Imageamento por Ressonância Magnética/métodos , Eletroencefalografia/métodos , Epilepsia/diagnóstico por imagem , Epilepsia/cirurgia , Epilepsia/metabolismo , Sódio/metabolismoRESUMO
PURPOSE: To study the relative contributions of brain and upper cervical spinal cord compartmental atrophy to disease aggressiveness in amyotrophic lateral sclerosis (ALS). METHODS: Twenty-nine ALS patients and 24 age- and gender-matched healthy controls (HC) were recruited. Disease duration and the Revised-ALS Functional Rating Scale (ALSFRS-R) at baseline, 3- and 6-months follow-up were assessed. Patients were clinically differentiated into fast (n=13) and slow (n=16) progressors according to their ALSFRS-R progression rate. Brain grey (GM) and white matter, brainstem sub-structures volumes and spinal cord cross-sectional area (SC-CSA) at C1-C2 vertebral levels were measured from a 3D-T1-weighted MRI. RESULTS: Fast progressors showed significant GM, medulla oblongata and SC atrophy compared to HC (p<0.001, p=0.013 and p=0.008) and significant GM atrophy compared to slow progressors (p=0.008). GM volume correlated with the ALSFRS-R progression rate (Rho/p=-0.487/0.007), the ALSFRS-R at 3-months (Rho/p=0.622/0.002), and ALSFRS-R at 6-months (Rho/p=0.407/0.039). Medulla oblongata volume and SC-CSA correlated with the ALSFRS-R at 3-months (Rho/p=0.510/0.015 and Rho/p=0.479/0.024). MRI measures showed high performance to discriminate between fast and slow progressors. CONCLUSION: Our study suggests an association between compartmental atrophy and disease aggressiveness. This result is consistent with the combination of upper and lower motor neuron degeneration as the main driver of disease worsening and severity in ALS. Our study highlights the potential of brain and spinal cord atrophy measured by MRI as biomarker of disease aggressiveness signature.
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Esclerose Lateral Amiotrófica , Medula Cervical , Substância Branca , Humanos , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/patologia , Medula Cervical/diagnóstico por imagem , Imageamento por Ressonância Magnética , Atrofia/patologiaRESUMO
OBJECTIVE: Quantification of brain injury in patients with variable disability despite similar disease duration may be relevant to identify the mechanisms underlying disability in multiple sclerosis (MS). We aimed to compare grey-matter sodium abnormalities (GMSAs), a parameter reflecting neuronal and astrocyte dysfunction, in MS patients with benign multiple sclerosis (BMS) and non-benign multiple sclerosis (NBMS). METHODS: We identified never-treated BMS patients in our local MS database of 1352 patients. A group with NBMS was identified with same disease duration. All participants underwent 23Na magnetic resonance imaging (MRI). The existence of GMSA was detected by statistical analysis. RESULTS: In total, 102 individuals were included (21 BMS, 25 NBMS and 56 controls). GMSA was detected in 10 BMS and 19 NBMS (11/16 relapsing-remitting multiple sclerosis (RRMS) and 8/9 secondary progressive multiple sclerosis (SPMS) patients) (p = 0.05). On logistic regression including the presence or absence of GMSA, thalamic volume, cortical grey-matter volume and T2-weighted lesion load, thalamic volume was independently associated with BMS status (odds ratio (OR) = 0.64 for each unit). Nonetheless, the absence of GMSA was independently associated when excluding patients with significant cognitive alteration (n = 7) from the BMS group (OR = 4.6). CONCLUSION: Detection of GMSA in individuals and thalamic volume are promising to differentiate BMS from NBMS as compared with cortical or whole grey-matter atrophy and T2-weighted lesions.
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Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Biomarcadores , Encéfalo/patologia , Substância Cinzenta/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/patologia , Esclerose Múltipla Crônica Progressiva/diagnóstico , SódioRESUMO
A novel magnetic resonance imaging (MRI) acquisition and reconstruction method for obtaining a series of dynamic sodium 23Na-MRI acquisitions was designed to non-invasively assess the signal variations of brain sodium during a hand motor task in 14 healthy human volunteers on an ultra high field (7T) MR scanner. Regions undergoing activation and deactivation were identified with reference to conventional task-related BOLD functional MRI (fMRI). Activation observed in the left central regions, the supplementary motor areas and the left cerebellum induced an increase in the sodium signal observed at ultra short echo time and a decrease in the 23Na signal observed at long echo time. Based on a simple model of two distinct sodium pools (namely, restricted and mobile sodium), the ultra short echo time measures the totality of sodium whereas the long echo time is mainly sensitive to mobile sodium. This activation pattern is consistent with previously described processes related to an influx of Na+ into the intracellular compartments and a moderate increase in the cerebral blood volume (CBV). In contrast, deactivation observed in the right central regions ipsilateral to the movement, the precuneus and the left cerebellum induced a slight decrease in sodium signal at ultra short echo time and an increase of sodium signal at longer echo times. This inhibitory pattern is compatible with a slight decrease in CBV and an efflux of intracellular Na+ to the extracellular compartments that may reflect neural dendritic spine and astrocytic shrinkage, and an increase of sodium in the extracellular fraction. In conclusion, cerebral dynamic 23Na MRI experiments can provide access to the ionic transients following a functional task occurring within the neuro-glial-vascular ensemble. This has the potential to open up a novel non-invasive window on the mechanisms underlying brain function.
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Mapeamento Encefálico/métodos , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Imageamento por Ressonância Magnética/métodos , Neuroglia/metabolismo , Sódio/metabolismo , Adulto , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Desempenho Psicomotor , Isótopos de Sódio , Adulto JovemRESUMO
Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that mainly affects the upper and lower motor neurons. Recent sodium (23Na) MRI studies have shown that abnormal sodium concentration is related to neuronal suffering in neurodegenerative conditions. Purpose To use 23Na MRI to investigate abnormal sodium concentrations and map their distribution in the brains of study participants with ALS as compared with healthy control subjects. Materials and Methods Twenty-seven participants with ALS (mean age, 54 years ± 10 [standard deviation], eight women) and 30 healthy control subjects (mean age, 50 years ± 10; 16 women) were prospectively recruited between September 2015 and October 2017 and were examined by using conventional proton MRI and sodium MRI at 3 T. Voxel-based statistical mapping was used to compare quantitative whole-brain total sodium concentration (TSC) maps in participants with ALS with those in control subjects and to localize regions of abnormal elevated TSC. Potential overlap of abnormal elevated TSC with regions of atrophy as detected with 1H MRI also was investigated. Results Voxel-based statistical mapping analyses revealed higher sodium concentration in motor regions (bilateral precentral gyri, corticospinal tracts, and the corpus callosum) of participants with ALS (two-sample t test, P < .005; age and sex as covariates). In these regions, mean TSC was higher in participants with ALS (mean, 45.6 mmol/L wet tissue ± 3.2) than in control subjects (mean, 41.8 mmol/L wet tissue ± 2.7; P < .001; Cohen d = 1.28). Brain regions showing higher TSC represented a volume of 15.4 cm3 that did not overlap with gray matter atrophy occupying a volume of 16.9 cm3. Elevated TSC correlated moderately with corticospinal conduction failure assessed with transcranial magnetic stimulation in the right upper limb (Spearman ρ = -0.57; 95% confidence interval: -0.78, -0.16; P = .005; n = 23). Conclusion Quantitative 23Na MRI is sensitive to alterations of brain sodium homeostasis within disease-relevant regions in patients with amyotrophic lateral sclerosis (ALS). This supports further investigation of abnormal sodium concentration as a potential marker of neurodegenerative processes in patients with ALS that could be used as a secondary endpoint in clinical trials. © RSNA, 2019 Online supplemental material is available for this article.
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Esclerose Lateral Amiotrófica/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Imageamento por Ressonância Magnética/métodos , Tratos Piramidais/patologia , Isótopos de Sódio/farmacocinética , Adulto , Idoso , Esclerose Lateral Amiotrófica/metabolismo , Encéfalo/patologia , Estudos de Avaliação como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tratos Piramidais/metabolismoRESUMO
BACKGROUND: Increase of brain total sodium concentrations (TSC) is present in multiple sclerosis (MS), but its pathological involvement has not been assessed yet. OBJECTIVE: To determine in vivo the metabolic counterpart of brain sodium accumulation. MATERIALS/METHODS: Whole brain 23Na-MR imaging and 3D-1H-EPSI data were collected in 21 relapsing-remitting multiple sclerosis (RRMS) patients and 20 volunteers. Metabolites and sodium levels were extracted from several regions of grey matter (GM), normal-appearing white matter (NAWM) and white matter (WM) T2 lesions. Metabolic and ionic levels expressed as Z-scores have been averaged over the different compartments and used to explain sodium accumulations through stepwise regression models. RESULTS: MS patients showed significant 23Na accumulations with lower choline and glutamate-glutamine (Glx) levels in GM; 23Na accumulations with lower N-acetyl aspartate (NAA), Glx levels and higher Myo-Inositol (m-Ins) in NAWM; and higher 23Na, m-Ins levels with lower NAA in WM T2 lesions. Regression models showed associations of TSC increase with reduced NAA in GM, NAWM and T2 lesions, as well as higher total-creatine, and smaller decrease of m-Ins in T2 lesions. GM Glx levels were associated with clinical scores. CONCLUSION: Increase of TSC in RRMS is mainly related to neuronal mitochondrial dysfunction while dysfunction of neuro-glial interactions within GM is linked to clinical scores.
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Substância Cinzenta/metabolismo , Esclerose Múltipla Recidivante-Remitente/metabolismo , Sódio/metabolismo , Substância Branca/metabolismo , Adulto , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Espectroscopia de Prótons por Ressonância Magnética , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto JovemRESUMO
In light of technical advancements supporting exploration of MR signals other than 1H, sodium (23Na) has received attention as a marker of ionic homeostasis and cell viability. Here, we evaluate for the first time the possibility that 23Na-MRI is sensitive to pathological processes occurring in human epilepsy. A normative sample of 27 controls was used to normalize regions of interest (ROIs) from 1424 unique brain locales on quantitative 23Na-MRI and high-resolution 1H-MPRAGE images. ROIs were based on intracerebral electrodes in ten patients undergoing epileptic network mapping. The stereo-EEG gold standard was used to define regions as belonging to primarily epileptogenic, secondarily irritative and to non-involved regions. Estimates of total sodium concentration (TSC) on 23Na-MRI and cerebrospinal fluid (CSF) on 1H imaging were extracted for each patient ROI, and normalized against the same region in controls. ROIs with disproportionate CSF contributions (ZCSF≥1.96) were excluded. TSC levels were found to be elevated in patients relative to controls except in one patient, who suffered non-convulsive seizures during the scan, in whom we found reduced TSC levels. In the remaining patients, an ANOVA (F1100= 12.37, p<0.0001) revealed a highly significant effect of clinically-defined zones (F1100= 11.13, p<0.0001), with higher normalized TSC in the epileptogenic zone relative to both secondarily irritative (F1100= 11, p=0.0009) and non-involved regions (F1100= 17.8, p<0.0001). We provide the first non-invasive, in vivo evidence of a chronic TSC elevation alongside ZCSF levels within the normative range, associated with the epileptogenic region even during the interictal period in human epilepsy, and the possibility of reduced TSC levels due to seizure. In line with modified homeostatic mechanisms in epilepsy - including altered mechanisms underlying ionic gating, clearance and exchange - we provide the first indication of 23Na-MRI as an assay of altered sodium concentrations occurring in epilepsy associated with the organization of clinically relevant divisions of pathological cortex.
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Córtex Cerebral , Eletrocorticografia/métodos , Epilepsia/diagnóstico por imagem , Epilepsia/metabolismo , Homeostase/fisiologia , Imageamento por Ressonância Magnética/métodos , Sódio/metabolismo , Adulto , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Epilepsia/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prótons , Sódio/líquido cefalorraquidiano , Adulto JovemRESUMO
BACKGROUND: Intermittent theta burst stimulation (iTBS) of the primary motor cortex improves transiently lower limbs spasticity in multiple sclerosis (MS). However, the cerebral mechanisms underlying this effect have never been investigated. OBJECTIVE: To assess whether modulation of spasticity induced by iTBS is underlined by functional reorganization of the primary motor cortices. METHODS: A total of 17 patients with MS suffering from lower limbs spasticity were randomized to receive real iTBS or sham iTBS during the first half of a 5-week indoor rehabilitation programme. Spasticity was assessed using the Modified Ashworth Scale and the Visual Analogue Scale at baseline, after the stimulation session and at the end of the rehabilitation programme. Resting-state functional magnetic resonance imaging (fMRI) was performed at the three time points, and brain functional networks topology was analysed using graph-theoretical approach. RESULTS: At the end of stimulation, improvement of spasticity was greater in real iTBS group than in sham iTBS group ( p = 0.026). iTBS had a significant effect on the balance of the connectivity degree between the stimulated and the homologous primary motor cortex ( p = 0.005). Changes in inter-hemispheric balance were correlated with improvement of spasticity (rho = 0.56, p = 0.015). CONCLUSION: This longitudinal resting-state fMRI study evidences that functional reorganization of the primary motor cortices may underlie the effect of iTBS on spasticity in MS.
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Conectoma/métodos , Córtex Motor , Esclerose Múltipla/terapia , Espasticidade Muscular/terapia , Avaliação de Resultados em Cuidados de Saúde , Ritmo Teta/fisiologia , Estimulação Magnética Transcraniana/métodos , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Espasticidade Muscular/etiologiaRESUMO
BACKGROUND: While gray matter (GM) perfusion abnormalities have been evidenced in multiple sclerosis (MS) patients, the relationships with disability still remain unclear. Considering that atrophy is known to impact on perfusion, we aimed to assess perfusion abnormalities in GM of MS patients, outside atrophic regions and investigate relationships with disability. METHODS: Brain perfusion of 23 relapsing remitting MS patients and 16 matched healthy subjects were assessed at 3T using the pseudo-continuous arterial spin labeling magnetic resonance imaging technique. In order to locate potential GM perfusion abnormalities in regions spared by atrophy, we combined voxelwise comparisons of GM cerebral blood flow (CBF) maps (cortex and deep GM) (P<0.005, FWE-corrected) and voxel-based-morphometry analysis (P<0.005, FDR-corrected) to exclude atrophic regions. Disability was assessed using the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite score (MSFC). RESULTS: In patients, significant GM hypoperfusion outside atrophic regions was depicted only in bilateral thalami. No other cluster was found to be hypoperfused compared to controls. Perfusion of thalami was correlated to MSFC (P=0.011, rho=0.523). A trend of correlation was found between perfusion of thalami and EDSS (P=0.061, rho=-0.396). CONCLUSION: In relapsing remitting MS, perfusion abnormalities in thalamic regions contribute to disability. These findings suggest that functional impairments of thalami, representing a major brain hub, may disturb various cerebral functions even before structural damage.
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Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/patologia , Tálamo/irrigação sanguínea , Tálamo/diagnóstico por imagem , Tálamo/patologia , Adulto , Atrofia/diagnóstico por imagem , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Avaliação da Deficiência , Feminino , Substância Cinzenta , Humanos , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla Recidivante-Remitente/complicações , Índice de Gravidade de Doença , Marcadores de SpinRESUMO
PURPOSE: To detect local metabolic abnormalities over the complete human brain in multiple sclerosis (MS) patients, we used optimized fast volumic echo planar spectroscopic imaging (3D-EPSI). MATERIALS AND METHODS: Weighted mean combination of two 3D-EPSI covering the whole brain acquired at 3T in AC-PC and AC-PC+15° axial planes was performed to obtain high-quality metabolite maps for five metabolites: N-acetyl aspartate (NAA), glutamate+glutamine (Glx), choline (Cho), myo-inositol (m-Ins), and creatine+phosphocreatine (tCr). After spatial normalization, maps from 19 patients suffering from relapsing-remitting MS were compared to 19 matched controls using statistical mapping analyses to determine the topography of metabolic abnormalities. Probabilistic white matter (WM) T2 lesion maps and gray matter (GM) atrophy maps were also generated. RESULTS: Two-group analysis of variance (ANOVA) (SPM8, P < 0.005, false discovery rate [FDR]-corrected P < 0.05 at the cluster level with age and sex as confounding covariates) comparing patients and controls matched for age and sex showed clusters of abnormal metabolite levels with 1) decreased NAA (around -15%) and Glx (around 20%) predominantly in GM within prefrontal cortices, motor cortices, bilateral thalami, and mesial temporal cortices in line with neuronal/neuro-astrocytic dysfunction; 2) increased m-Ins (around + 20%) inside WM T2 lesions and in the normal-appearing WM of temporal-occipital lobes, suggesting glial activation. CONCLUSION: We demonstrate the ability to noninvasively map over the complete brain-from vertex to cerebellum-with a validated sequence, the metabolic abnormalities associated with MS, for characterizing the topography of pathological processes affecting widespread areas of WM and GM and its functional impact. J. Magn. Reson. Imaging 2016;44:411-419.
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Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/metabolismo , Adulto , Biomarcadores/metabolismo , Estudos de Viabilidade , Feminino , Humanos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Imagem Molecular/métodos , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Processamento de Sinais Assistido por Computador , Distribuição Tecidual , Adulto JovemRESUMO
BACKGROUND: Macrophages are important components of inflammatory processes in multiple sclerosis, closely linked to axonal loss, and can now be observed in vivo using ultra-small superparamagnetic iron oxide (USPIO). In the present 1-year longitudinal study, we aimed to determine the prevalence and the impact on tissue injury of macrophage infiltration in patients after the first clinical event of multiple sclerosis. METHODS: Thirty-five patients, 32 years mean age, were imaged in a mean of 66 days after their first event using conventional magnetic resonance imaging, gadolinium (Gd) to probe blood-brain barrier integrity, USPIO to study macrophage infiltration and magnetization transfer ratio (MTR) to assess tissue structure integrity. Statistics were performed using two-group repeated-measures ANOVA. Any patient received treatment at baseline. RESULTS: At baseline, patients showed 17 USPIO-positive lesions reflecting infiltration of macrophages present from the onset. This infiltration was associated with local higher loss of tissue structure as emphasized by significant lower MTRnorm values (p<0.03) in USPIO(+)/Gd(+) lesions (n=16; MTRnormUSPIO(+)/Gd(+)=0.78 at baseline, MTRnormUSPIO(+)/Gd(+)=0.81 at M12) relative to USPIO(-)/Gd(+) lesions (n=67; MTRnormUSPIO(-)/Gd(+)=0.82 at baseline, MTRnormUSPIO(-)/Gd(+)=0.85 at M12). No interaction in MTR values was observed during the 12 months follow-up (lesion type × time). CONCLUSION: Infiltration of activated macrophages evidenced by USPIO enhancement, is present at the onset of multiple sclerosis and is associated with higher and persistent local loss of tissue structure. Macrophage infiltration affects more tissue structure while tissue recovery during the following year has a similar pattern for USPIO and Gd-enhanced lesions, leading to relative higher persistent local loss of tissue structure in lesions showing USPIO enhancement at baseline.
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Encéfalo/diagnóstico por imagem , Meios de Contraste/administração & dosagem , Doenças Desmielinizantes/diagnóstico por imagem , Dextranos/administração & dosagem , Macrófagos/patologia , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita/administração & dosagem , Degeneração Neural , Adulto , Encéfalo/patologia , Doenças Desmielinizantes/patologia , Progressão da Doença , Feminino , França , Humanos , Estudos Longitudinais , Ativação de Macrófagos , Masculino , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: The compensatory effect of brain functional connectivity enhancement in relapsing-remitting multiple sclerosis (RRMS) remains controversial. OBJECTIVE: To characterize the relationships between brain functional connectivity changes and disability progression in RRMS. METHODS: Long-range connectivity, short-range connectivity, and density of connections were assessed using graph theoretical analysis of resting-state functional magnetic resonance imaging (fMRI) data acquired in 38 RRMS patients (disease duration: 120 ± 32 months) and 24 controls. All subjects were explored at baseline and all patients and six controls 2 years later. RESULTS: At baseline, levels of long-range and short-range brain functional connectivity were higher in patients compared to controls. During the follow-up, decrease in connections' density was inversely correlated with disability progression. Post-hoc analysis evidenced differential evolution of brain functional connectivity metrics in patients according to their level of disability at baseline: while patients with lowest disability at baseline experienced an increase in all connectivity metrics during the follow-up, patients with higher disability at baseline showed a decrease in the connectivity metrics. In these patients, decrease in the connectivity metrics was associated with disability progression. CONCLUSION: The study provides two main findings: (1) brain functional connectivity enhancement decreases during the disease course after reaching a maximal level, and (2) decrease in brain functional connectivity enhancement participates in disability progression.
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Encéfalo/fisiopatologia , Conectoma/métodos , Progressão da Doença , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Índice de Gravidade de Doença , Adulto , Encéfalo/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagemRESUMO
OBJECT: Sodium accumulation is involved in neuronal injury occurring in multiple sclerosis (MS). We aimed to assess sodium accumulation in progressive MS, known to suffer from severe neuronal injury. MATERIALS AND METHODS: 3D-(23)Na-MRI was obtained on a 3T-MR-scanner in 20 progressive MS patients [11 primary-progressive (PPMS) and nine secondary-progressive (SPMS)] and 15 controls. Total sodium concentrations (TSC) within grey matter (GM), normal-appearing white matter (WM) and lesions were extracted. Statistical mapping analyses of TSC abnormalities were also performed. RESULTS: Progressive MS patients presented higher GM-TSC values (48.8 ± 3.1 mmol/l wet tissue vol, p < 0.001) and T2lesions-TSC values (50.9 ± 2.2 mmol/l wet tissue vol, p = 0.01) compared to GM and WM of controls. Statistical mapping analysis showed TSC increases in PPMS patients confined to motor and somatosensory cortices, prefrontal cortices, pons and cerebellum. In SPMS, TSC increases were associated with areas involving: primary motor, premotor and somatosensory cortices; prefrontal, cingulate and visual cortices; the corpus callosum, thalami, brainstem and cerebellum. Anterior prefrontal and premotor cortices TSC were correlated with disability. CONCLUSION: Sodium accumulation is present in progressive MS patients, more restricted to the motor system in PPMS and more widespread in SPMS. Local brain sodium accumulation appears as a promising marker to monitor patients with progressive MS.
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Encéfalo/patologia , Esclerose Múltipla/patologia , Fibras Nervosas Mielinizadas/patologia , Neurônios/metabolismo , Sódio/química , Adulto , Idoso , Mapeamento Encefálico , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismoRESUMO
BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving rapid motor neuron degeneration leading to brain, primarily precentral, atrophy. Neurofilament light chains are a robust prognostic biomarker highly specific to ALS, yet associations between neurofilament light chains and MR imaging outcomes are not well-understood. We investigated the role of neurofilament light chains as mediators among neuroradiologic assessments, precentral neurodegeneration, and disability in ALS. MATERIALS AND METHODS: We retrospectively analyzed a prospective cohort of 29 patients with ALS (mean age, 56 [SD, 12] years; 18 men) and 36 controls (mean age, 49 [SD, 11] years; 18 men). Patients underwent 3T (n = 19) or 7T (n = 10) MR imaging, serum (n = 23) and CSF (n = 15) neurofilament light chains, and clinical (n = 29) and electrophysiologic (n = 27) assessments. The control group had equivalent 3T (n = 25) or 7T (n = 11) MR imaging. Two trained neuroradiologists performed blinded qualitative assessments of MR imaging anomalies (n = 29 patients, n = 36 controls). Associations between precentral cortical thickness and neurofilament light chains and clinical and electrophysiologic data were analyzed. RESULTS: We observed extensive cortical thinning in patients compared with controls. MR imaging analyses showed significant associations between precentral cortical thickness and bulbar or arm impairment following distributions corresponding to the motor homunculus. Finally, uncorrected results showed positive interactions among precentral cortical thickness, serum neurofilament light chains, and electrophysiologic outcomes. Qualitative MR imaging anomalies including global atrophy (P = .003) and FLAIR corticospinal tract hypersignal anomalies (P = .033), correlated positively with serum neurofilament light chains. CONCLUSIONS: Serum neurofilament light chains may be an important mediator between clinical symptoms and neuronal loss according to cortical thickness. Furthermore, MR imaging anomalies might have underestimated prognostic value because they seem to indicate higher serum neurofilament light chain levels.
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Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Masculino , Humanos , Pessoa de Meia-Idade , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Estudos Retrospectivos , Estudos Prospectivos , Filamentos Intermediários , Neurônios Motores/patologia , Imageamento por Ressonância Magnética/métodos , Atrofia/patologiaRESUMO
OBJECTIVES: Compelling evidence indicates a significant involvement of cortical lesions in the progressive phase of multiple sclerosis (MS), significantly contributing to late-stage disability. Despite the promise of ultra-high-field magnetic resonance imaging (MRI) in detecting cortical lesions, current evidence falls short in providing insights into the existence of such lesions during the early stages of MS or their underlying cause. This study delineated, at the early stage of MS, (1) the prevalence and spatial distribution of cortical lesions identified by 7 T MRI, (2) their relationship with white matter lesions, and (3) their clinical implications. MATERIALS AND METHODS: Twenty individuals with early-stage relapsing-remitting MS (disease duration <1 year) underwent a 7 T MRI session involving T1-weighted MP2RAGE, T2*-weighted multiGRE, and T2-weighted FLAIR sequences for cortical and white matter segmentation. Disability assessments included the Expanded Disability Status Scale, the Multiple Sclerosis Functional Composite, and an extensive evaluation of cognitive function. RESULTS: Cortical lesions were detected in 15 of 20 patients (75%). MP2RAGE revealed a total of 190 intracortical lesions (median, 4 lesions/case [range, 0-44]) and 216 leukocortical lesions (median, 2 lesions/case [range, 0-75]). Although the number of white matter lesions correlated with the total number of leukocortical lesions (r = 0.91, P < 0.001), no correlation was observed between the number of white matter or leukocortical lesions and the number of intracortical lesions. Furthermore, the number of leukocortical lesions but not intracortical or white-matter lesions was significantly correlated with cognitive impairment (r = 0.63, P = 0.04, corrected for multiple comparisons). CONCLUSIONS: This study highlights the notable prevalence of cortical lesions at the early stage of MS identified by 7 T MRI. There may be a potential divergence in the underlying pathophysiological mechanisms driving distinct lesion types, notably between intracortical lesions and white matter/leukocortical lesions. Moreover, during the early disease phase, leukocortical lesions more effectively accounted for cognitive deficits.
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INTRODUCTION: Identifying biomarkers reflecting cellular dysfunctions in early Parkinson's disease patients (ePD) is needed to develop targeted therapeutic strategies. We aimed to determine if cellular energetic dysfunction related to increased brain sodium concentration would be co-located to microstructural alterations and iron deposition in ePD. METHODS: We prospectively included 12 ePD (mean disease duration 20.0 ± 10.2 months) and 13 healthy controls (HC), scanned with a 7 T 1H and 23Na MRI. Complementary voxel-based and region-based assessments were performed, the latter utilizing a high-resolution multimodal template we created (combining quantitative T1 maps (qT1), transverse relaxation rate (R2*), quantitative magnetic susceptibility mapping (QSM) images) from 200 subjects. This template allowed a precise multiparametric assessment of sodium concentration, QSM, R2*, qT1, mean diffusivity, and fractional anisotropy values. A two-sided p-value<0.05 was considered statistically significant after the Bonferroni correction. RESULTS: Relative to HC, ePD showed significantly higher sodium concentration in left Substantia nigra (SN) pars reticulata (46.13 mM ± 3.52 vs 38.60 mM ± 6.10, p = 0.038), a subpart of the SN pars compacta (SNc) and ventral tegmental area, Putamen, Globus Pallidum external, accumbens nucleus and claustrum. Significantly increased QSM and R2* values, and decreased T1 values, were limited to the Nigrosomes 1 (Nig) and right SNc (all p < 0.05). QSM values in the Nig were significantly correlated to UPDRS-III scores (r = 0.91,p < 0.001). CONCLUSION: In ePD, brain sodium accumulation was broad and dissociated from iron accumulation. As with iron accumulation, a sodium-related pathophysiological approach could lead to identifying potential new therapeutic agents and deserves further investigation.
Assuntos
Sobrecarga de Ferro , Imageamento por Ressonância Magnética , Doença de Parkinson , Humanos , Doença de Parkinson/metabolismo , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/fisiopatologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Sobrecarga de Ferro/metabolismo , Sódio/metabolismo , Substância Negra/diagnóstico por imagem , Substância Negra/metabolismo , Metabolismo Energético/fisiologia , Estudos ProspectivosRESUMO
Sodium imaging (23Na-MRI) is of interest in neurological conditions given potential sensitivity to the physiological and metabolic status of tissues. Benchmarks have so far been restricted to parenchyma or grey/white matter (GM/WM). We investigate (1) the availability of evidence, (2) regional pooled estimates and (3) variability attributable to region/methodology. MEDLINE literature search for tissue sodium concentration (TSC) measured in specified 'healthy' brain regions returned 127 reports, plus 278 retrieved from bibliographies. 28 studies met inclusion criteria, including 400 individuals. Reporting variability led to nested data structure, so we used multilevel meta-analysis and a random effects model to pool effect sizes. The pooled mean from 141 TSC estimates was 40.51 mM (95% CI 37.59-43.44; p < 0.001, I2Total=99.4%). Tissue as a moderator was significant (F214 = 65.34, p-val < .01). Six sub-regional pooled means with requisite statistical power were derived. We were unable to consider most methodological and demographic factors sought because of non-reporting, but each factor included beyond tissue improved model fit. Significant residual heterogeneity remained. The current estimates provide an empirical point of departure for better understanding in 23Na-MRI. Improving on current estimates supports: (1) larger, more representative data collection/sharing, including (2) regional data, and (3) agreement on full reporting standards.
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Encéfalo , Imageamento por Ressonância Magnética , Humanos , Encéfalo/metabolismo , Imageamento por Ressonância Magnética/métodos , Sódio/metabolismo , Substância Cinzenta/metabolismo , Espectroscopia de Ressonância MagnéticaRESUMO
PURPOSE: To quantify brain sodium accumulations and characterize for the first time the spatial location of sodium abnormalities at different stages of relapsing-remitting (RR) multiple sclerosis (MS) by using sodium 23 ((23)Na) magnetic resonance (MR) imaging. MATERIALS AND METHODS: This study was approved by the local committee on ethics, and written informed consent was obtained from all participants. Three-dimensional (23)Na MR imaging data were obtained with a 3.0-T unit in two groups of patients with RR MS-14 with early RR MS (disease duration <5 years) and 12 with advanced RR MS (disease duration >5 years)-and 15 control subjects. Quantitative assessment of total sodium concentration (TSC) levels within compartments (MS lesions, white matter [WM], and gray matter [GM]) as well as statistical mapping analyses of TSC abnormalities were performed. RESULTS: TSC was increased inside demyelinating lesions in both groups of patients, whereas increased TSC was observed in normal-appearing WM and GM only in those with advanced RR MS. In patients, increased TSC inside GM was correlated with disability (as determined with the Expanded Disability Status Scale [EDSS] score; P = .046, corrected) and lesion load at T2-weighted imaging (P = .003, corrected) but not with disease duration (P = .089, corrected). Statistical mapping analysis showed confined TSC increases inside the brainstem, cerebellum, and temporal poles in early RR MS and widespread TSC increases that affected the entire brain in advanced RR MS. EDSS score correlated with TSC increases inside motor networks. CONCLUSION: TSC accumulation dramatically increases in the advanced stage of RR MS, especially in the normal-appearing brain tissues, concomitant with disability. Brain sodium MR imaging may help monitor the occurrence of tissue injury and disability.
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Encéfalo/metabolismo , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla Recidivante-Remitente/metabolismo , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Sódio/metabolismo , Adulto , Área Sob a Curva , Avaliação da Deficiência , Feminino , Humanos , Aumento da Imagem , Interpretação de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Estatísticas não ParamétricasRESUMO
BACKGROUND: Previous studies have demonstrated that intrathecal synthesis of IgM is observed in multiple sclerosis (MS) and correlates with a worse disease course. These results suggest that IgM participates in the formation of MS lesions. OBJECTIVE: The aim of the present study was to assess the potential association between the level of intrathecal synthesis of IgM measured after a clinically isolated syndrome (CIS) and the subsequent formation of brain lesions. METHODS: Fifty seven patients with a CIS and a high risk developing MS were enrolled in a longitudinal study. Examination of cerebrospinal fluid was performed after the CIS and included measures of intrathecal IgM and IgG synthesis. Patients were assessed with the same 1.5 Tesla magnetic resonance imaging (MRI) system at baseline and after a mean follow-up period of 49 months (range 36-60). Spearman Rank correlation was used to assess the potential correlations between levels of intrathecal immunoglobulin synthesis and MRI data. RESULTS: The level of intrathecal IgM synthesis was correlated with the number of gadolinium-enhancing lesions at baseline (p = 0.01) and with accrual of brain lesions during the follow-up period (p = 0.02). By taking into account brain sub-regions, we demonstrated that the level of intrathecal IgM synthesis was only correlated with the increased number of lesions in the periventricular regions (p = 0.004). The level of intrathecal IgG synthesis was not correlated with any MRI data. CONCLUSION: The present longitudinal study demonstrates that the level of intrathecal IgM synthesis measured after a CIS is associated with subsequent lesion accrual during the first years of MS. This result emphasizes the involvement of IgM in plaque formation.