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BACKGROUND: Thalamic volume (TV) is a sensitive biomarker of disease burden of injury in multiple sclerosis (MS) and appears to reflect overall lesion loads. Ibudilast showed significant treatment effect on brain atrophy and magnetization transfer ratio (MTR) of normal-appearing brain tissue but not in new/enlarging T2 lesion in the SPRINT-MS randomized clinical trial. OBJECTIVE: To evaluate the effect of ibudilast on thalamic tissue integrity and volume in the SPRINT-MS. METHODS: A total of 255 participants with progressive MS were randomized to oral ibudilast or placebo, and thalamic MTR and normalized TV over 96 weeks were quantified. Mixed-effect modeling assessed treatment effects on the thalamic MTR and TV, separately. Similarly, the measures were compared between the participants with confirmed disability progression (CDP). RESULTS: Ibudilast's treatment effect was observed compared to placebo for thalamic MTR (p = 0.03) but not for TV (p = 0.68) while TV correlated with T2 lesion volume (p < 0.001). CDP associated with thalamic MTR (p = 0.04) but not with TV (p = 0.7). CONCLUSION: Ibudilast showed an effect on thalamic MTR, which was associated with CDP, suggesting a clinically relevant effect on thalamic tissue integrity. However, the treatment effect was not observed in TV, suggesting that thalamic atrophy is more closely associated with global inflammatory activity than local tissue integrity. CLINICALTRIALS.GOV: NCT01982942.
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Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Humanos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Imageamento por Ressonância Magnética , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Piridinas/uso terapêutico , Atrofia/tratamento farmacológico , Atrofia/patologiaRESUMO
BACKGROUND: Detecting cortical demyelination using magnetic resonance imaging (MRI) in multiple sclerosis (MS) remains a challenge. Magnetization transfer ratio (MTR), T1-weighted/T2-weighted ratio (T1T2R), and T2-weighted (T2w) signal are sensitive to cortical demyelination, but their accuracy is unknown. OBJECTIVES: To quantify the sensitivity, specificity, and accuracy of postmortem T1T2R, MTR, and T2w in detecting cortical demyelination. METHODS: In situ postmortem MRIs from 9 patients were used to measure T1T2R, MTR, and T2w along the midline of cortical gray matter and classified as normal or abnormal. MRIs were co-registered and compared to hemispheric myelin staining. The sensitivity, specificity, and accuracy of T1T2R, MTR, and T2w in detecting cortical demyelination were measured. RESULTS: The mean age (standard deviation) at death was 64.7 (+/-13.7) years with a disease duration of 23.8 (+/-10.5) years. The sensitivity was 78% for MTR, 75% for T1T2R, and 63% for T2w. The specificity was 46% (T2w), 13% (T1T2R), and 29% (MTR). The accuracy was 71% (T2w), 39% (MTR), and 42% (T1T2R). There were no significant differences between different MRI measures in cortical demyelination or intracortical/subpial lesion detection. CONCLUSIONS: Although somewhat sensitive, the modest specificity of conventional MRI modalities for cortical demyelination indicates that they are influenced by cortical changes other than demyelination. Improved acquisition and post-processing are needed to reliably measure cortical lesion load.
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Imageamento por Ressonância Magnética , Esclerose Múltipla , Idoso , Autopsia , Encéfalo/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Bainha de Mielina/patologiaRESUMO
Although multiple sclerosis has traditionally been considered a white matter disease, extensive research documents the presence and importance of grey matter injury including cortical and deep regions. The deep grey matter exhibits a broad range of pathology and is uniquely suited to study the mechanisms and clinical relevance of tissue injury in multiple sclerosis using magnetic resonance techniques. Deep grey matter injury has been associated with clinical and cognitive disability. Recently, MRI characterization of deep grey matter properties, such as thalamic volume, have been tested as potential clinical trial end points associated with neurodegenerative aspects of multiple sclerosis. Given this emerging area of interest and its potential clinical trial relevance, the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative held a workshop and reached consensus on imaging topics related to deep grey matter. Herein, we review current knowledge regarding deep grey matter injury in multiple sclerosis from an imaging perspective, including insights from histopathology, image acquisition and post-processing for deep grey matter. We discuss the clinical relevance of deep grey matter injury and specific regions of interest within the deep grey matter. We highlight unanswered questions and propose future directions, with the aim of focusing research priorities towards better methods, analysis, and interpretation of results.
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Encéfalo/patologia , Substância Cinzenta/patologia , Esclerose Múltipla/patologia , HumanosRESUMO
OBJECTIVE: Thalamic atrophy is among the earliest brain changes detected in patients with multiple sclerosis (MS) and the degree of thalamic atrophy is a strong predictor of disability progression. The causes of thalamic atrophy are not fully understood. Here, we investigate the contributions of thalamic demyelinated lesions, thalamic neuronal loss, and cerebral white matter (WM) lesions to thalamic volume. METHODS: We used postmortem in situ magnetic resonance imaging (MRI) scans of 95 subjects with MS to correlate thalamic lesion volumes with global MRI metrics. We histologically characterized thalamic demyelination patterns and compared neuronal loss and neuritic pathology in the thalami with the extremes of volume. RESULTS: Grossly apparent thalamic discolorations in cm-thick brain slices were T2/fluid-attenuated inversion recovery (FLAIR) hyperintense, T1-hypointense, and appeared as perivascular demyelinated lesions with dystrophic neurons/axons. Subependymal demyelinated lesions with axonal loss and microglial/macrophage activation were also observed. The 12 subjects with the least thalamic volume had a 17.6% reduction of median neuronal density in the dorsomedial/ventrolateral and pulvinar nuclei compared with the 14 subjects with the greatest thalamic volume (p = 0.03). After correcting for age, disease duration, sex, and T2 lesion volume, the total (p = 0.20), ovoid (p = 0.31), or subependymal (p = 0.44) MRI thalamic lesion volumes correlated with thalamic volume. Thalamic volume correlated with cerebral T2 lesion volume (Spearman's rho = -0.65, p < 0.001; p < 0.0001 after correcting for age, disease duration, and sex). INTERPRETATION: Our findings suggest the degeneration of efferent/afferent thalamic projections and/or a neurodegenerative process as greater contributors to thalamic atrophy than thalamic demyelinating lesions. ANN NEUROL 2020 ANN NEUROL 2020;88:81-92.
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Esclerose Múltipla/patologia , Tálamo/patologia , Substância Branca/patologia , Idoso , Atrofia/diagnóstico por imagem , Atrofia/patologia , Progressão da Doença , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Neurônios/patologia , Pulvinar/diagnóstico por imagem , Pulvinar/patologia , Tálamo/diagnóstico por imagem , Substância Branca/diagnóstico por imagemRESUMO
OBJECTIVE: Describe magnetic resonance imaging (MRI) susceptibility changes in progressive multifocal leukoencephalopathy (PML) and identify neuropathological correlates. METHODS: PML cases and matched controls with primary central nervous system lymphoma (PCNSL) were retrospectively identified. MRI brain at 3 T and 7 T were reviewed. MRI-pathology correlations in fixed brain autopsy tissue were conducted in three subjects with confirmed PML. RESULTS: With PML (n = 26 total, n = 5 multiple sclerosis natalizumab-associated), juxtacortical changes on susceptibility-weighted imaging (SWI) or gradient echo (GRE) sequences were noted in 3/3 cases on 7 T MRI and 14/22 cases (63.6%) on 1.5 T or 8/22 (36.4%) 3 T MRI. Similar findings were only noted in 3/25 (12.0%) of PCNSL patients (odds ratio (OR) 12.83, 95% confidence interval (CI), 2.9-56.7, p < 0.001) on 1.5 or 3 T MRI. On susceptibility sequences available prior to diagnosis of PML, 7 (87.5%) had changes present on average 2.7 ± 1.8 months (mean ± SD) prior to diagnosis. Postmortem 7 T MRI showed SWI changes corresponded to areas of increased iron density along the gray-white matter (GM-WM) junction predominantly in macrophages. CONCLUSION: Susceptibility changes in PML along the GM-WM junction can precede noticeable fluid-attenuated inversion recovery (FLAIR) changes and correlates with iron accumulation in macrophages.
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Leucoencefalopatia Multifocal Progressiva , Substância Branca , Encéfalo/diagnóstico por imagem , Humanos , Ferro , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Macrófagos , Imageamento por Ressonância Magnética , Natalizumab , Estudos Retrospectivos , Substância Branca/diagnóstico por imagemRESUMO
BACKGROUND: People with multiple sclerosis (MS) may be at higher risk for complications from the 2019 coronavirus (COVID-19) pandemic due to use of immunomodulatory disease modifying therapies (DMTs) and greater need for medical services. OBJECTIVES: To evaluate risk factors for COVID-19 susceptibility and describe the pandemic's impact on healthcare delivery. METHODS: Surveys sent to MS patients at Cleveland Clinic, Johns Hopkins, and Vall d'Hebron-Centre d'Esclerosi Múltiple de Catalunya in April and May 2020 collected information about comorbidities, DMTs, exposures, COVID-19 testing/outcomes, health behaviors, and disruptions to MS care. RESULTS: There were 3028/10,816 responders. Suspected or confirmed COVID-19 cases were more likely to have a known COVID-19 contact (odds ratio (OR): 4.38; 95% confidence interval (CI): 1.04, 18.54). In multivariable-adjusted models, people who were younger, had to work on site, had a lower education level, and resided in socioeconomically disadvantaged areas were less likely to follow social distancing guidelines. 4.4% reported changes to therapy plans, primarily delays in infusions, and 15.5% a disruption to rehabilitative services. CONCLUSION: Younger people with lower socioeconomic status required to work on site may be at higher exposure risk and are potential targets for educational intervention and work restrictions to limit exposure. Providers should be mindful of potential infusion delays and MS care disruption.
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Infecções por Coronavirus/epidemiologia , Emprego , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/terapia , Terapia Ocupacional , Modalidades de Fisioterapia , Pneumonia Viral/epidemiologia , Classe Social , Adulto , Fatores Etários , Betacoronavirus , COVID-19 , Comorbidade , Infecções por Coronavirus/prevenção & controle , Atenção à Saúde , Gerenciamento Clínico , Suscetibilidade a Doenças , Escolaridade , Feminino , Comportamentos Relacionados com a Saúde , Acessibilidade aos Serviços de Saúde , Terapia por Infusões no Domicílio , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Obesidade/epidemiologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Fatores de Risco , SARS-CoV-2 , Espanha/epidemiologia , Estados Unidos/epidemiologiaRESUMO
This case report is of a septuagenarian man on chronic low-dose prednisone who presented with disseminated nocardiosis (Nocardia cyriacigeorgica) that was initially mistaken for metastatic brain cancer. Neurologists should be aware of the potential for opportunistic infections with steroid use and to consider a definite tissue diagnosis with culture and histopathology prior to treatment.
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Anti-Inflamatórios/efeitos adversos , Hospedeiro Imunocomprometido , Nocardiose/imunologia , Nocardiose/patologia , Prednisona/efeitos adversos , Idoso , Encéfalo/microbiologia , Encéfalo/patologia , Humanos , Masculino , Nocardiose/diagnóstico , Infecções Oportunistas/imunologia , Infecções Oportunistas/patologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tela Subcutânea/microbiologia , Tela Subcutânea/patologiaRESUMO
Multiple sclerosis (MS) is an autoimmune disease of the CNS. Studies in animal models of MS have shown that GM-CSF produced by T cells is necessary for the development of autoimmune CNS inflammation. This suggests that GM-CSF may have a pathogenic role in MS as well, and a clinical trial testing its blockade is ongoing. However, there have been few reports on GM-CSF production by T cells in MS. The objective of this study was to characterize GM-CSF production by T cells of MS patients and to determine the effect of IFN-ß therapy on its production. GM-CSF production by peripheral blood (PB) T cells and the effects of IFN-ß were characterized in samples of untreated and IFN-ß-treated MS patients versus healthy subjects. GM-CSF production by T cells in MS brain lesions was analyzed by immunofluorescence. Untreated MS patients had significantly greater numbers of GM-CSF(+)CD4(+) and CD8(+) T cells in PB compared with healthy controls and IFN-ß-treated MS patients. IFN-ß significantly suppressed GM-CSF production by T cells in vitro. A number of CD4(+) and CD8(+) T cells in MS brain lesions expressed GM-CSF. Elevated GM-CSF production by PB T cells in MS is indicative of aberrant hyperactivation of the immune system. Given its essential role in animal models, abundant GM-CSF production at the sites of CNS inflammation suggests that GM-CSF contributes to MS pathogenesis. Our findings also reveal a potential mechanism of IFN-ß therapy, namely suppression of GM-CSF production.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Interferon beta/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Adulto , Encéfalo/citologia , Encéfalo/imunologia , Encéfalo/patologia , Feminino , Humanos , Inflamação/imunologia , Interferon gama/biossíntese , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologiaAssuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Fibrinogênio/metabolismo , Inflamação/metabolismo , Esclerose Múltipla/metabolismo , Animais , Encéfalo/patologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Humanos , Esclerose Múltipla/patologiaRESUMO
Background: Cognitive dysfunction is a known symptom of multiple sclerosis (MS), with memory recognized as a frequently impacted domain. Here, we used high-resolution MRI at 7 tesla to build on cross-sectional work by evaluating the longitudinal relationship of diffusion tensor imaging (DTI) measures of the fornix to episodic memory performance. Methods: A sample of 80 people with multiple sclerosis (mean age 51.9 ± 8.1 years; 24% male) underwent baseline clinical evaluation, neuropsychological assessment, and MRI. Sixty-four participants had follow-up neuropsychological testing after 1-2 years. Linear regression was used to assess the relationship of baseline imaging measures to follow-up episodic memory performance, measured using the Selective Reminding Test and Brief Visuospatial Memory Test. A reduced prediction model included cognitive function at baseline, age, sex, and disease course. Results: Radial (ß = -0.222, p < 0.026; likelihood ratio test (LRT) p < 0.018), axial (ß = -0.270, p < 0.005; LRT p < 0.003), and mean (ß = -0.242, p < 0.0139; LRT p < 0.009) diffusivity of the fornix significantly added to the model, with follow-up analysis indicating that a longer prediction interval may increase accuracy. Conclusion: These results suggest that fornix DTI has predictive value specific to memory function in MS and warrants additional investigation in the drive to develop predictors of disease progression.
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Axonal loss in multiple sclerosis (MS) is a key component of disease progression and permanent neurologic disability. MS is a heterogeneous demyelinating and neurodegenerative disease of the central nervous system (CNS) with varying presentation, disease courses, and prognosis. Immunomodulatory therapies reduce the frequency and severity of inflammatory demyelinating events that are a hallmark of MS, but there is minimal therapy to treat progressive disease and there is no cure. Data from patients with MS, post-mortem histological analysis, and animal models of demyelinating disease have elucidated patterns of MS pathogenesis and underlying mechanisms of neurodegeneration. MRI and molecular biomarkers have been proposed to identify predictors of neurodegeneration and risk factors for disease progression. Early signs of axonal dysfunction have come to light including impaired mitochondrial trafficking, structural axonal changes, and synaptic alterations. With sustained inflammation as well as impaired remyelination, axons succumb to degeneration contributing to CNS atrophy and worsening of disease. These studies highlight the role of chronic demyelination in the CNS in perpetuating axonal loss, and the difficulty in promoting remyelination and repair amidst persistent inflammatory insult. Regenerative and neuroprotective strategies are essential to overcome this barrier, with early intervention being critical to rescue axonal integrity and function. The clinical and basic research studies discussed in this review have set the stage for identifying key propagators of neurodegeneration in MS, leading the way for neuroprotective therapeutic development. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.
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Esclerose Múltipla , Doenças Neurodegenerativas , Animais , Esclerose Múltipla/terapia , Doenças Neurodegenerativas/etiologia , Sistema Nervoso Central/patologia , Axônios/patologia , Progressão da DoençaRESUMO
INTRODUCTION: Although it is known that continuous noninvasive ventilation (CNIV) can prolong life in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), in this study we explore similar claims for diaphragm pacing (DP). METHODS: NIV and DP users' vital capacities (VCs) over time and duration of NIV and CNIV dependence were analyzed for 354 non-DP and 8 DP ALS/MND patients. RESULTS: Patients had a higher rate of monthly VC decline before NIV use (5.1 ± 7.6%) than during NIV use (2.5 ± 3.6%) (P < 0.01, 95% CI 0.84-4.5); the decline for 4 DP users was 3.7-20%. Fifty-five ALS/MND patients used part-time NIV for 19.9 ± 27.6 months until tracheostomy/death, whereas 113 others used it for 10.9 ± 10.5 months until CNIV dependence for another 12.8 ± 16.2 months. After placement, 7 DP users were CNIV dependent in 8.0 ± 7.0 months, whereas 6 underwent tracheostomy/died in 18.2 ± 13.7 months. CONCLUSIONS: CNIV prolonged the survival of 113 of the 354 non-DP and 6 DP ALS/MND patients by 12.8 and 10.2 months, respectively. DP provided no benefit on VC or mechanical ventilation-free survival.
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Esclerose Lateral Amiotrófica/complicações , Diafragma/fisiopatologia , Ventilação não Invasiva/métodos , Paralisia Respiratória/etiologia , Paralisia Respiratória/reabilitação , Idoso , Esclerose Lateral Amiotrófica/mortalidade , Esclerose Lateral Amiotrófica/terapia , Análise de Variância , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Capacidade Vital/fisiologiaRESUMO
Thalamic volume is associated with clinical disability in multiple sclerosis (MS) and is vulnerable to secondary neurodegeneration due to its extensive connectivity throughout the central nervous system (CNS). Using a model of autoimmune demyelination that exhibits CNS-infiltrating immune cells in both spinal cord white matter and optic nerve, we sought to evaluate neurodegenerative changes due to lesions affecting the spino- and retino-thalamic pathways. We found comparable axonal loss in spinal cord white matter and optic nerve during the acute phase of disease consistent with synaptic loss, but not neuronal cell body loss in the thalamic nuclei that receive input from these discrete pathways. Loss of spinal cord neurons or retinal ganglion cells retrograde to their respective axons was not observed until the chronic phase of disease, where optical coherence tomography (OCT) documented reduced inner retinal thickness. In patients with relapsing-remitting MS without a history of optic neuritis, OCT measures of inner retinal volume correlated with retino-thalamic (lateral geniculate nucleus) and spino-thalamic (ventral posterior nucleus) volume as well as neuroperformance measures. These data suggest retinal imaging may serve as an important noninvasive predictor of neurodegeneration in MS.
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Esclerose Múltipla , Neurite Óptica , Substância Branca , Humanos , Esclerose Múltipla/diagnóstico por imagem , Neurite Óptica/diagnóstico por imagem , Células Ganglionares da Retina , Tomografia de Coerência Óptica/métodosRESUMO
OBJECTIVE: To compare clinical and imaging features of multiple sclerosis (MS) severity between Black Americans (BAs) and White Americans (WAs) and to evaluate the role of socioeconomic status. METHODS: We compared BA and WA participants in the Multiple Sclerosis Partners Advancing Technology Health Solutions (MS PATHS) cohort with respect to MS characteristics, including self-reported disability, objective neurologic function assessments, and quantitative brain MRI measurements, after covariate adjustment (including education level, employment, or insurance as socioeconomic indicators). In a subgroup, we evaluated within-race, neighborhood-level indicators of socioeconomic status (SES) using 9-digit zip codes. RESULTS: Of 1,214 BAs and 7,530 WAs with MS, BAs were younger, had lower education level, and were more likely to have Medicaid insurance or to be disabled or unemployed than WAs. BAs had worse self-reported disability (1.47-fold greater odds of severe vs mild disability, 95% confidence interval [CI] 1.18, 1.86) and worse performances on tests of cognitive processing speed (-5.06 fewer correct, 95% CI -5.72, -4.41), walking (0.66 seconds slower, 95% CI 0.36, 0.96), and manual dexterity (2.11 seconds slower, 95% CI 1.69, 2.54). BAs had more brain MRI lesions and lower overall and gray matter brain volumes, including reduced thalamic (-0.77 mL, 95% CI -0.91, -0.64), cortical (-30.63 mL, 95% CI -35.93, -25.33), and deep (-1.58 mL, 95% CI -1.92, -1.23) gray matter volumes. While lower SES correlated with worse neuroperformance scores in WAs, this association was less clear in BAs. CONCLUSION: We observed a greater burden of disease in BAs with MS relative to WAs with MS, despite adjustment for SES indicators. Beyond SES, future longitudinal studies should also consider roles of other societal constructs (e.g., systemic racism). Such studies will be important for identifying prognostic factors; developing optimal treatment strategies among BAs with MS is warranted.
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Esclerose Múltipla/etnologia , Esclerose Múltipla/patologia , Classe Social , Adulto , Negro ou Afro-Americano , Encéfalo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Índice de Gravidade de Doença , População BrancaRESUMO
BACKGROUND: Comprehensive and efficient assessments are necessary for clinical care and research in chronic diseases. Our objective was to assess the implementation of a technology-enabled tool in MS practice. METHOD: We analyzed prospectively collected longitudinal data from routine multiple sclerosis (MS) visits between September 2015 and May 2018. The MS Performance Test, comprising patient-reported outcome measures (PROMs) and neuroperformance tests (NPTs) self-administered using a tablet, was integrated into routine care. Descriptive statistics, Spearman correlations, and linear mixed-effect models were used to examine the implementation process and relationship between patient characteristics and completion of assessments. RESULTS: A total of 8022 follow-up visits from 4199 patients (median age 49.9 [40.2-58.8] years, 32.1% progressive course, and median disease duration 13.6 [5.9-22.3] years) were analyzed. By the end of integration, the tablet version of the Timed 25-Foot Walk was obtained in 89.0% of patients and the 9-Hole Peg Test in 94.8% compared with 74.2% and 64.3%, respectively before implementation. The greatest increase in data capture occurred in processing speed and low-contrast acuity assessments (0% prior vs 78.4% and 36.7%, respectively, following implementation). Four PROMs were administered in 41%-98% of patients compared with a single depression questionnaire with a previous capture rate of 70.6%. Completion rates and time required to complete each NPT improved with subsequent visits. Younger age and lower disability scores were associated with shorter completion time and higher completion rates. CONCLUSIONS: Integration of technology-enabled data capture in routine clinical practice allows acquisition of comprehensive standardized data for use in patient care and clinical research.
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Previously we showed that insulin-like growth factor-I (IGF-I) promotes sustained phosphorylation of Akt in oligodendrocyte progenitor cells (OPCs) and that Akt phosphorylation is required for survival of these cells. The direct mechanisms, however, by which IGF-I promotes Akt phosphorylation are currently undefined. Recently, cholesterol-enriched membranes (CEMs) have been implicated in regulation of growth factor-mediated activation of the PI3K/Akt pathway and survival of mature oligodendrocytes; however, less is know about their role in OPC survival. In the present study, we investigate the role of CEMs in IGF-I-mediated Akt phosphorylation and OPC survival. We report that acute disruption of membrane cholesterol with methyl-beta-cyclodextrin results in altered OPC morphology and inhibition of IGF-I-mediated Akt phosphorylation. We also report that long-term inhibition of cholesterol biosynthesis with 25-hydroxycholesterol blocks IGF-I stimulated Akt phosphorylation and cell survival. Moreover, we show that the PI3K regulatory subunit, p85, Akt, and the IGF-IR are sequestered within cholesterol-enriched fractions in steady-state stimulation of the IGF-IR and that phosphorylated Akt and IGF-IR are present in cholesterol-enriched fractions with IGF-I stimulation. Together, the results of these studies support a role for CEMs or "lipid rafts" in IGF-I-mediated Akt phosphorylation and provide a better understanding of the mechanisms by which IGF-I promotes OPC survival.
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Colesterol/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Microdomínios da Membrana/metabolismo , Oligodendroglia/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células-Tronco/metabolismo , Animais , Animais Recém-Nascidos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Hidroxicolesteróis/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/ultraestrutura , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/ultraestrutura , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor IGF Tipo 1/efeitos dos fármacos , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/ultraestrutura , beta-Ciclodextrinas/farmacologiaRESUMO
We describe a rapid tissue donation program for individuals with multiple sclerosis (MS) that requires scientists and technicians to be on-call 24/7, 365 days a year. Participants consent to donate their brain and spinal cord. Most patients were followed by neurologists at the Cleveland Clinic Mellen Center for MS Treatment and Research. Their clinical courses and neurological disabilities are well-characterized. Soon after death, the body is transported to the MS Imaging Center, where the brain is scanned in situ by 3 T magnetic resonance imaging (MRI). The body is then transferred to the autopsy room, where the brain and spinal cord are removed. The brain is divided into two hemispheres. One hemisphere is immediately placed in a slicing box and alternate 1 cm-thick slices are either fixed in 4% paraformaldehyde for two days or rapidly frozen in dry ice and 2-methylbutane. The short-fixed brain slices are stored in a cryopreservation solution and used for histological analyses and immunocytochemical detection of sensitive antigens. Frozen slices are stored at -80 °C and used for molecular, immunocytochemical, and in situ hybridization/RNA scope studies. The other hemisphere is placed in 4% paraformaldehyde for several months, placed in the slicing box, re-scanned in the 3 T magnetic resonance (MR) scanner and sliced into centimeter-thick slices. Postmortem in situ MR images (MRIs) are co-registered with 1 cm-thick brain slices to facilitate MRI-pathology correlations. All brain slices are photographed and brain white-matter lesions are identified. The spinal cord is cut into 2 cm segments. Alternate segments are fixed in 4% paraformaldehyde or rapidly frozen. The rapid procurement of postmortem MS tissues allows pathological and molecular analyses of MS brains and spinal cords and pathological correlations of brain MRI abnormalities. The quality of these rapidly-processed postmortem tissues (usually within 6 h of death) is of great value to MS research and has resulted in many high-impact discoveries.
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Autopsia/métodos , Esclerose Múltipla/patologia , Encéfalo/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Medula Espinal/patologia , Substância Branca/patologiaRESUMO
Magnetic resonance imaging has been crucial in the development of anti-inflammatory disease-modifying treatments. The current landscape of multiple sclerosis clinical trials is currently expanding to include testing not only of anti-inflammatory agents, but also neuroprotective, remyelinating, neuromodulating, and restorative therapies. This is especially true of therapies targeting progressive forms of the disease where neurodegeneration is a prominent feature. Imaging techniques of the brain and spinal cord have rapidly evolved in the last decade to permit in vivo characterization of tissue microstructural changes, connectivity, metabolic changes, neuronal loss, glial activity, and demyelination. Advanced magnetic resonance imaging techniques hold significant promise for accelerating the development of different treatment modalities targeting a variety of pathways in MS.
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Mapeamento Encefálico/métodos , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico por imagem , Animais , Atrofia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/fisiopatologia , Ensaios Clínicos como Assunto , Progressão da Doença , Humanos , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia , Medula Espinal/fisiopatologiaRESUMO
Neoplasms and reactivation of latent viruses have been observed in individuals taking fingolimod. Merkel cell carcinoma (MCC), a rare neuroendocrine skin cancer, is associated with immunosuppression and can be triggered by the oncogenic Merkel cell polyoma virus (MCPyV). We report a case of a 61-year-old man with multiple sclerosis who developed MCPyV-positive MCC 4 years after starting fingolimod. This is the second report of MCC associated with MCPyV in an individual on fingolimod.