RESUMO
Brain abnormalities in neuromyelitis optica spectrum disorder (NMOSD) are highly heterogeneous and often non-specific. Extensive white matter involvement has been described and frequently manifests with encephalopathy requiring prompt intervention. Rarely, this may represent the only manifestation at onset without concurrent suggestive features of the disease, thus making diagnosis challenging. NMOSD may potentially occur at any age, but it seems that this disorder has distinctive clinical features in the elderly. We describe a case of NMOSD presenting as rapidly progressive leukoencephalopathy with atypical clinical and magnetic resonance imaging (MRI) findings in a 69-year-old woman.
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Leucoencefalopatias/diagnóstico por imagem , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/imunologia , Idoso , Aquaporina 4/imunologia , Autoanticorpos/sangue , Autoanticorpos/líquido cefalorraquidiano , Diagnóstico Diferencial , Progressão da Doença , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Leucoencefalopatias/patologia , Imageamento por Ressonância Magnética , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/patologia , Troca Plasmática , Rituximab/uso terapêutico , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/patologia , Resultado do Tratamento , Substância Branca/diagnóstico por imagem , Substância Branca/patologiaRESUMO
BACKGROUND: Lysozyme is a widely distributed enzyme present in a variety of tissue and body fluids. Human and hen egg white lysozyme are used as validated model to study protein folding and stability and to understand protein misfolding and aggregation. We recently found that ceftriaxone, a ß-lactam antibiotic able to overcome the blood-brain barrier, successfully eliminated the cellular toxic effects of misfolded proteins as Glial Fibrillary Acidic Protein (GFAP) and α-synuclein. To further understand the anti-amyloidogenic properties of ceftriaxone, we studied its activity towards lysozyme aggregation with the aim to investigate a possible chaperone-like activity of this molecule. METHODS: Here we present the results obtained from fluorescence and synchrotron radiation circular dichroism spectroscopies and from molecular docking and molecular dynamics about the lysozyme-ceftriaxone interaction at neutral and acidic pH values. RESULTS: We found that ceftriaxone exhibits comparable affinity constants to lysozyme in both experimental pH conditions and that its addition enhanced lysozyme stability reducing its aggregation propensity in acidic conditions. Computational methods allowed the identification of the putative binding site of ceftriaxone, thus rationalizing the spectroscopic results. CONCLUSIONS: Spectroscopy data and molecular dynamics indicated a protective effect of ceftriaxone on pathological aggregation phenomena suggesting a chaperone-like effect of this molecule on protein folding. General significance These results, in addition to our previous studies on α-synuclein and GFAP, confirm the property of ceftriaxone to inhibit the pathological protein aggregation of lysozyme also by a chaperone-like mechanism, extending the potential therapeutic application of this molecule to some forms of human hereditary systemic amyloidosis.
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Ceftriaxona/química , Chaperonas Moleculares , Muramidase/química , Muramidase/metabolismo , Multimerização Proteica , Animais , Sítios de Ligação , Ceftriaxona/administração & dosagem , Biologia Computacional , Humanos , Concentração de Íons de Hidrogênio , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Dobramento de ProteínaRESUMO
BACKGROUND: GFAP is the major intermediate filament protein in mature astrocytes. Its increased expression and aggregation was firstly associated to Alexander's disease, and successively in different neurological diseases including scrapie, Alzheimer's and Creutzfeld-Jacob diseases. Recently, ceftriaxone a multi-potent ß-lactam antibiotic able to overcome the blood-brain barrier, successfully eliminated the cellular toxic effects of misfolded mutated GFAP, similarly to phenytoin sodium, in a cellular model of Alexander's disease and inhibited α-synuclein aggregation protecting PC12 cells from the exposure to 6-hydroxydopamine. METHODS: In this study, synchrotron radiation circular dichroism spectroscopy has been used to obtain structural information about the GFAP-ceftriaxone (phenytoin) interactions, while computational methods allowed the identification of the relevant putative binding site of either ceftriaxone or phenytoin on the dimer structure of GFAP, permitting to rationalize the spectroscopic experimental results. RESULTS: We found that GFAP exhibited enhanced stability upon the addition of two equivalents of each ligands with ceftriaxone imparting a more spontaneous interactions and a more ordered complex system than phenytoin. CONCLUSIONS: SRCD data and MD models indicate a stronger protective effect of ceftriaxone in neurological disorders characterized by an increased production and polymerization of GFAP. GENERAL SIGNIFICANCE: This result, in addition to our previous works in which we documented that ceftriaxone interacts with α-synuclein inhibiting its pathological aggregation and that a cyclical treatment with this molecule in a patient with adult-onset Alexander's disease halted, and partly reversed, the progression of neurodegeneration, suggests the possibility of a chaperone-like effect of ceftriaxone on protein involved in specific neurodegenerative diseases.
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Doença de Alexander/tratamento farmacológico , Ceftriaxona/química , Proteína Glial Fibrilar Ácida/metabolismo , Agregação Patológica de Proteínas/tratamento farmacológico , alfa-Sinucleína/metabolismo , Doença de Alexander/metabolismo , Doença de Alexander/patologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Sítios de Ligação/efeitos dos fármacos , Ceftriaxona/administração & dosagem , Proteína Glial Fibrilar Ácida/química , Proteína Glial Fibrilar Ácida/genética , Humanos , Proteínas de Filamentos Intermediários/química , Proteínas de Filamentos Intermediários/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Degeneração Neural/tratamento farmacológico , Degeneração Neural/patologia , Células PC12 , Fenitoína/administração & dosagem , Fenitoína/química , Agregação Patológica de Proteínas/metabolismo , Ratos , alfa-Sinucleína/biossíntese , alfa-Sinucleína/químicaRESUMO
Natalizumab is effective against multiple sclerosis (MS), but is associated with progressive multifocal leukoencephalopathy (PML), fatal disease caused by the JCV polyomavirus. The SF2/ASF (splicing factor2/alternative splicing factor) inhibits JCV in glial cells. We wondered about SF2/ASF modulation in the blood of natalizumab-treated patients and if this could influence JCV reactivation. Therefore, we performed a longitudinal study of MS patients under natalizumab, in comparison to patients under fingolimod and to healthy blood donors. Blood samples were collected at time intervals. The expression of SF2/ASF and the presence and expression of JCV in PBMC were analyzed. A bell-shaped regulation of SF2/ASF was observed in patients treated with natalizumab, increased in the first year of therapy, and reduced in the second one, while slightly changed, if any, in patients under fingolimod. Notably, SF2/ASF was up-regulated, during the first year, only in JCV DNA-positive patients, or with high anti-JCV antibody response; the expression of the JCV T-Ag protein in circulating B cells was inversely related to SF2/ASF protein expression. The SF2/ASF reduction, parallel to JCV activation, during the second year of therapy with natalizumab, but not with fingolimod, may help explain the increased risk of PML after the second year of treatment with natalizumab, but not with fingolimod. We propose that SF2/ASF has a protective role against JCV reactivation in MS patients. This study suggests new markers of disease behavior and, possibly, help in re-evaluations of therapy protocols.
Assuntos
Interações Hospedeiro-Patógeno , Fatores Imunológicos/uso terapêutico , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/uso terapêutico , Fatores de Processamento de Serina-Arginina/genética , Adulto , Anticorpos Antivirais/sangue , Relação Dose-Resposta a Droga , Feminino , Cloridrato de Fingolimode/uso terapêutico , Regulação da Expressão Gênica , Humanos , Vírus JC/efeitos dos fármacos , Vírus JC/genética , Vírus JC/crescimento & desenvolvimento , Leucoencefalopatia Multifocal Progressiva/imunologia , Leucoencefalopatia Multifocal Progressiva/virologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/virologia , Neuroglia/efeitos dos fármacos , Neuroglia/imunologia , Neuroglia/virologia , Fatores de Processamento de Serina-Arginina/imunologia , Transdução de Sinais , Ativação Viral/efeitos dos fármacosRESUMO
BACKGROUND: The etiologic determinants of stroke in young adults remain a diagnostic challenge in up to one-fourth of cases. Increasing evidences led to consider Fabry's disease (FD) as a possible cause to check up. We aimed at evaluating the prevalence of unrecognized FD in a cohort of patients with juvenile stroke in northern Sardinia. METHODS: For this study, we enrolled 178 patients consecutively admitted to our Neurological Ward for ischemic stroke, transient ischemic attack, intracerebral haemorrhage, neuroradiological evidence of silent infarcts, or white matter lesions possibly related to cerebral vasculopathy at brain MRI, and cerebral venous thrombosis. The qualifying events have to occur between 18 and 55 years of age. RESULTS: We identified two patients with an α-galactosidase A gene variant, with a prevalence of 0.9 %. According to recent diagnostic criteria, one patient, included for the occurrence of multiple white matter lesions at brain MRI, had a diagnosis of definite FD, the other, included for ischemic stroke, had a diagnosis of uncertain FD. CONCLUSIONS: Our study places in a middle position among studies that found a prevalence of FD up to 4 % and others that did not find any FD patients. Our findings confirm that FD should be considered in the differential diagnosis of patients with juvenile stroke, particularly those with a personal or familial history positive for cerebrovascular events, or evidence of combined cardiologic and/or renal impairment. All types of cerebrovascular disorders should be screened for FD, including patients with white matter lesions possibly related to cerebral vasculopathy at brain MRI.
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Transtornos Cerebrovasculares/complicações , Doença de Fabry/diagnóstico , Adolescente , Adulto , Estudos de Coortes , Doença de Fabry/genética , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Mutação , Adulto Jovem , alfa-Galactosidase/genéticaAssuntos
Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico , Glicoproteína Mielina-Oligodendrócito/imunologia , Proteínas de Neurofilamentos/sangue , Adolescente , Adulto , Fatores Etários , Idoso , Anticorpos/sangue , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Criança , Doenças Desmielinizantes/líquido cefalorraquidiano , Doenças Desmielinizantes/imunologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/imunologia , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Neuroimagem , Adulto JovemRESUMO
Heterozygous mutations of the GFAP gene are responsible for Alexander disease, a neurodegenerative disorder characterized by intracytoplasmic Rosenthal fibers (RFs) in dystrophic astrocytes. In vivo and in vitro models have shown co-localization of mutant GFAP proteins with the small heat shock proteins (sHSPs) HSP27 and alphaB-crystallin, ubiquitin and proteasome components. Results reported by several recent studies agree on ascribing an altered cytoskeletal pattern to mutant GFAP proteins, an effect which induces mutant proteins accumulation, leading to impaired proteasome function and autophagy induction. On the basis of the protective role shown by both these small heat shock proteins (sHSPs), and on the already well established neuroprotective effects of curcumin in several diseases, we have investigated the effects of this compound in an in vitro model of Alexander disease, consisting in U251-MG astrocytoma cells transiently transfected with a construct encoding for GFAP carrying the p.R239C mutation in frame with the reporter green fluorescent protein (GFP). In particular, depending on the dose used, we have observed that curcumin is able to induce both HSP27 and alphaB-crystallin, to reduce expression of both RNA and protein of endogenous GFAP, to induce autophagy and, finally, to rescue the filamentous organization of the GFAP mutant protein, thus suggesting a role of this spice in counteracting the pathogenic effects of GFAP mutations.
Assuntos
Doença de Alexander/tratamento farmacológico , Doença de Alexander/metabolismo , Curcumina/farmacologia , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Doença de Alexander/genética , Sequência de Bases , Linhagem Celular , Primers do DNA/genética , Regulação para Baixo/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/química , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico , Humanos , Chaperonas Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Multimerização Proteica/efeitos dos fármacos , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Regulação para Cima/efeitos dos fármacos , Cadeia B de alfa-Cristalina/genética , Cadeia B de alfa-Cristalina/metabolismoRESUMO
In neonates with hypoxic-ischemic encephalopathy (HIE), neuroprotection mediated by therapeutic hypothermia (TH) is the standard of care in developed nations; however TH may be not beneficial or contraindicated in developing world. Moreover, in most of the clinical trials, hypothermic neuroprotection was incomplete because many infants still die or suffer significant neurological sequelae. Therefore, finding innovative, neuroprotective compounds for this encephalopathy represents an important and urgent need. In reference to the recent review by Zhou , ACS Chem. Neurosci. 2023 14, 1-9, in this viewpoint, we discuss the therapeutic role of ketone bodies and thiamine in neonatal HIE, their possible synergistic effect, and how these micronutrients may provide additive neuroprotection to TH and improve safer and effective treatment strategies also helpful in low-middle-income countries.
Assuntos
Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Recém-Nascido , Lactente , Humanos , Hipóxia-Isquemia Encefálica/terapia , Neuroproteção , Resultado do TratamentoRESUMO
Alexander disease is a rare, untreatable and usually fatal neurodegenerative disorder caused by heterozygous mutations of the glial fibrillary acidic protein (GFAP) gene which ultimately lead to formation of aggregates, containing also alphaB-Crystallin, HSP27, ubiquitin and proteasome components. Recent findings indicate that up-regulation of alphaB-Crystallin in mice carrying GFAP mutations may temper the pathogenesis of the disease. Neuroprotective effects of ceftriaxone have been reported in various animal models and, noteworthy, we have recently shown that the chronic use of ceftriaxone in a patient affected by an adult form of Alexander disease could halt its progression and ameliorate some of the symptoms. Here we show that ceftriaxone is able to reduce the intracytoplasmic aggregates of mutant GFAP in a cellular model of Alexander disease. Underlying mechanisms include mutant GFAP elimination, concurrent with up-regulation of HSP27 and alphaB-Crystallin, polyubiquitination and autophagy. Ceftriaxone has also been shown to modulate the proteasome system, thus decreasing NF-kappaB activation and GFAP promoter transcriptional regulation, which further accounts for the down-modulation of GFAP protein levels. These mechanisms provide previously unknown neuroprotective targets of ceftriaxone and confirm its potential therapeutic role in patients with Alexander disease and other neurodegenerative disorders with astrocyte involvement.
Assuntos
Antibacterianos/farmacologia , Ceftriaxona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/genética , Proteínas de Choque Térmico HSP27/genética , Cadeia B de alfa-Cristalina/genética , Astrocitoma/tratamento farmacológico , Astrocitoma/metabolismo , Autofagia , Western Blotting , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Imunofluorescência , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Técnicas In Vitro , Luciferases/metabolismo , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Regiões Promotoras Genéticas/genética , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Multimerização Proteica , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismo , Ubiquitina/metabolismo , Cadeia B de alfa-Cristalina/metabolismoRESUMO
Alexander's disease (AxD) is a rare, usually relentlessly progressive disorder of astroglial cells in the central nervous system related to mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP). The pathophysiology of AxD is only partially understood. Available data indicate that an excessive GFAP gene expression may play a role. In particular, a "threshold hypothesis" has been reported, suggesting that mutant GFAP representing about 20% of the total cellular GFAP should be sufficient to cause disease. Thus, strategies based on reducing cellular mutant GFAP protein levels and/or activating biological processes involved in the correct protein folding could be effective in counteracting the toxic effect of misfolded GFAP. Considering that clomipramine (CLM), which has been selected by a wide small molecules screening as the greatest inhibitory potential drug against GFAP expression, is contraindicated because of its proconvulsant activity in the infantile form of AxD, which is also characterized by the occurrence of epileptic seizures, two powerful antiepileptic agents, carbamazepine (CBZ) and phenytoin (PHT), which share specific stereochemical features in common with CLM, were taken into consideration in a reliable in vitro model of AxD. In the present work, we document for the first time that CBZ and PHT have a definite inhibitory effect on pathological GFAP cellular expression and folding. Moreover, we confirm previous results of a similar beneficial effect of CLM. In addition, we have demonstrated that CBZ and CLM play a refolding effect on mutant GFAP proteins, likely ascribed at the induction of CRYAB expression, resulting in the decrease of mutant GFAP aggregates formation. As CBZ and PHT are currently approved for use in humans, their documented effects on pathological GFAP cellular expression and folding may indicate a potential therapeutic role as disease-modifying agents of these drugs in the clinical management of AxD, particularly in AxD patients with focal epilepsy with and without secondary generalization.
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Interleukin 2 (IL-2) is considered a key player in exacerbating multiple sclerosis (MS). Therapies targeting its receptor have been developed; however, a resolution of the disease and side effects are still an issue of concern. The involvement of other factors, such as Mycobacterium avium subspecies paratuberculosis (MAP) and envelope protein derived from human endogenous retrovirus type W (HERV-Wenv), in MS pathogenesis has been recently suggested. Here, we investigated the levels of antibodies (Abs) directed against IL-2 and HERV-Wenv in 108 MS patients, 34 patients affected by neuromyelitis optica spectrum disorder (NMOSD), and 137 healthy controls (HCs). Our results show increased levels of Abs specific to IL-2 and HERV-Wenv-su antigens in MS vs. HCs (p < 0.0001 for IL-2, p = 0.0004 for HERV-Wenv) and significantly decreased levels in NMOSD vs. MS. The assessment of different 12-month-long therapies on Abs against IL-2, HERV-Wenv, and MAP lipoarabinomannan (LAM) demonstrated the strongest effect on anti-LAM Abs (p = 0.018), a slight reduction of anti-IL-2 Abs, and small variations for anti-HERV-Wenv Abs. These results highlight the conclusion that the impact of therapy is more correlated with selected epitopes than with the therapeutic agent. Screening for anti-IL-2 and anti-HERV-Wenv Abs has a potential as additional future practice to distinguish between symptomatically similar MS and NMOSD.
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A point mutation (P56S) in the gene-encoding vesicle-associated membrane-protein-associated protein B (VAPB) leads to an autosomal-dominant form of amyotrophic lateral sclerosis (ALS), classified as ALS-8. The mutant VAPB is characterized by ER-associated aggregates that lead to a complete reorganization of ER structures. Growing evidences suggest VAPB involvement in ALS pathomechanisms. In fact, numerous studies demonstrated VAPB alteration also in sporadic ALS (sALS) and showed the presence of its aggregates when others ALS-related gene are mutant. Recently, the identification of new biomarkers in peripheral blood mononuclear cells (PBMCs) has been proposed as a good noninvasive option for studying ALS. Here, we evaluated VAPB as a possible ALS pathologic marker analyzing PBMCs of sALS patients. Immunofluorescence analysis (IFA) showed a peculiar pattern of VAPB aggregates in sALS, not evident in healthy control (HC) subjects and in Parkinson's disease (PD) PBMCs. This specific pattern led us to suppose that VAPB could be misfolded in sALS. The data indirectly confirmed by flow cytometry assay (FCA) showed a reduction of VAPB fluorescent signals in sALS. However, our observations were not associated with the presence of a genetic mutation or altered gene expression of VAPB. Our study brings further evidences of the VAPB role in ALS as a diagnostic biomarker.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Retículo Endoplasmático/metabolismo , Agregados Proteicos , Proteínas de Transporte Vesicular/metabolismo , Idoso , Biomarcadores/metabolismo , Feminino , Fibroblastos/metabolismo , Fluorescência , Células HeLa , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Pele/patologia , Proteínas de Transporte Vesicular/genéticaRESUMO
BACKGROUND: Transcutaneous trigeminal nerve stimulation (TNS) has antiepileptic effects in patients with drug-resistant epilepsy (DRE). However, whether and how TNS is able to modulate the electroencephalogram (EEG) background activity in patients with DRE is still unknown. OBJECTIVES: To investigate the effect of short-term TNS on EEG background activity in DRE by qualitative and quantitative analyses. METHODS: Twenty-nine DRE patients participated in the study. Twenty-two were randomly divided into a "sham-TNS" or "real-TNS" group; seven patients underwent stimulation of the median nerve (MNS) at the wrist. Real-TNS was delivered bilaterally to the infraorbital nerve (trains of 1-20â¯mA, 120â¯Hz, cyclic modality for 20â¯min). The sham-TNS protocol mimicked the real-TNS one but at a zero intensity. For MNS, the same parameters as real-TNS were used. EEG was continuously acquired for 40â¯min: 10' pre, 20' during and 10' post stimulation. EEG was visually inspected for interictal epileptiform discharge (IEDs) changes and processed by spectral analysis for changes in mean frequency and absolute power of each frequency band. RESULTS: A significant increase of EEG absolute alpha power was observed during real-TNS compared with the sham-TNS (F34,680â¯=â¯1.748; pâ¯=â¯0.006). Conversely, no significant effects were noticed either for quantitative analysis of other frequency bands or for IEDs detection. MNS proved unable to modulate EEG activity. CONCLUSIONS: Short-term TNS induces an acute and specific effect on background EEG of DRE by increasing the absolute alpha band power. EEG alpha rhythm enhancement may index a cortical functional inhibition and act as a seizure-preventing mechanism.
Assuntos
Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia Resistente a Medicamentos/terapia , Eletroencefalografia/métodos , Estimulação Elétrica Nervosa Transcutânea/métodos , Nervo Trigêmeo/fisiologia , Adulto , Idoso , Epilepsia Resistente a Medicamentos/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Parkinson's disease is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons of the substantia nigra pars compacta with a reduction of dopamine concentration in the striatum. The complex interaction between genetic and environmental factors seems to play a role in determining susceptibility to PD and may explain the heterogeneity observed in clinical presentations. The exact etiology is not yet clear, but different possible causes have been identified. Inflammation has been increasingly studied as part of the pathophysiology of neurodegenerative diseases, corroborating the hypothesis that the immune system may be the nexus between environmental and genetic factors, and the abnormal immune function can lead to disease. In this review we report the different aspects of inflammation and immune system in Parkinson's disease, with particular interest in the possible role played by immune dysfunctions in PD, with focus on autoimmunity and processes involving infectious agents as a trigger and alpha-synuclein protein (α-syn).
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OBJECTIVE: To determine the diagnostic relevance of myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) in CSF of seronegative cases by retrospectively analyzing consecutive time-matched CSF of 80 MOG-Ab-seronegative patients with demyelinating disease. METHODS: The cohort included 44 patients with NMOSD and related disorders and 36 patients with multiple sclerosis (MS). Two independent neurologists blinded to diagnosis analyzed MOG-Abs by live cell-based immunofluorescence assay with goat anti-human immunoglobulin (Ig) G (whole molecule) antibody. Sera were tested at dilutions of 1:20 and 1:40, and a cutoff of 1:160 was considered for serum positivity. CSF specimens were tested undiluted and at 1:2 dilution with further titrations in case of positivity. Anti-IgG-Fc and anti-IgM-µ secondary antibodies were used to confirm the exclusive presence of MOG-IgG in positive cases. CSF of 13 MOG-Abs seropositive cases and 36 patients with neurodegenerative conditions was analyzed as controls. RESULTS: Three seronegative cases had CSF MOG-Abs (4% of the whole cohort or 7% of cases excluding patients with MS, in which MOG-Abs seem to lack diagnostic relevance). In particular, 2 patients with neuromyelitis optica spectrum disorder (NMOSD) and 1 with acute disseminated encephalomyelitis had MOG-Abs in CSF. Analysis with anti-IgG-Fc and anti-IgM confirmed the exclusive presence of MOG-IgG in the CSF of these patients. Among the control group, MOG-Abs were detectable in the CSF of 8 of 13 MOG-Ab-seropositive cases and in none of the patients with neurodegenerative disorders. CONCLUSION: Although serum is the optimal specimen for MOG-Ab testing, analyzing CSF could improve diagnostic sensitivity in seronegative patients. This observation has relevant diagnostic impact and might provide novel insight into the biological mechanisms of MOG-Ab synthesis.
Assuntos
Aquaporina 4/imunologia , Autoanticorpos/sangue , Autoanticorpos/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico , Glicoproteína Mielina-Oligodendrócito/imunologia , Neuromielite Óptica/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/imunologia , Neuromielite Óptica/sangue , Neuromielite Óptica/líquido cefalorraquidiano , Neuromielite Óptica/imunologia , Estudos Retrospectivos , Adulto JovemRESUMO
Circulating and cerebrospinal fluid (CSF) neurofilament light chain (NfL) levels represent a reliable indicator of disease activity and axonal damage in different neuroinflammatory conditions. Recently, high CSF NfL levels have been detected in active autoimmune encephalitis, as opposed to significant lower levels after clinical improvement. The aim of the present study was to evaluate serum and CSF NfL concentration in patients with autoimmune encephalitis and to analyse the association between NfL levels and clinical, MRI, and CSF data. We retrospectively included 25 patients with neurological syndromes associated with autoantibodies to neuronal cell surface antigens and we collected clinical, MRI, CSF, and follow-up data. Using an ultrasensitive method (Simoa, Quanterix), we measured NfL levels in serum and CSF samples of all patients and in 25 sera of healthy controls. Serum NfL levels were higher in all cases, including 20 patients with inflammatory MRI/CSF features and 5 non-inflammatory cases (median 16.9 pg/ml, range 4.5-90) than in controls (median 6.9 pg/ml, range 2.7-12.8; p < 0.001). A correlation between serum and CSF NfL levels was found (r = 0.461, p = 0.023), whereas no significant association was observed between NfL levels and clinical, MRI/CSF inflammatory burden, and antibody type. In the 13 available follow-up samples, correlation between disease activity and NfL values was also observed. In conclusion, NfL levels are significantly increased in the serum of patients with antibody-mediated encephalitis, independently of the MRI/CSF inflammatory profile. These findings support the presence of ongoing axonal damage and suggest the co-occurrence of different mechanisms for neuronal/axonal involvement in antibody-associated CNS syndromes.
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Encefalite/sangue , Encefalite/líquido cefalorraquidiano , Doença de Hashimoto/sangue , Doença de Hashimoto/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Criança , Pré-Escolar , Encefalite/diagnóstico por imagem , Feminino , Seguimentos , Doença de Hashimoto/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
We studied the effects of oral levetiracetam (LEV) (500 mg twice daily) in three women with stiff-person syndrome in a single-blind, placebo-controlled study. The severity of muscle rigidity and of paroxysmal symptoms was assessed by EMG and clinically by a rating scale of 0-4 and by the Patients Global Impressions Scale. LEV was well tolerated. On active treatment all patients improved as assessed by any of the objective or subjective outcome measures. No response was noticed on placebo. Our data indicate that in patients with SPS, LEV is well tolerated and has a therapeutic role in the management of both muscle stiffness and life-threatening paroxysmal respiratory spasms.
Assuntos
Anticonvulsivantes/uso terapêutico , Piracetam/análogos & derivados , Rigidez Muscular Espasmódica/tratamento farmacológico , Idoso , Eletromiografia , Feminino , Humanos , Levetiracetam , Pessoa de Meia-Idade , Rigidez Muscular/tratamento farmacológico , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Exame Neurológico , Piracetam/uso terapêutico , Respiração/efeitos dos fármacos , Método Simples-Cego , Espasmo/tratamento farmacológicoRESUMO
We report the first instance of restless legs syndrome (RLS) associated with periodic limb movements (PLM) and disruption of sleep architecture occurring in a patient following ischemic infarction in the right lenticulostriate region. Recently, a role for the basal ganglia-brainstem system in the control of motor behaviors and in the regulation of awake-sleep states has been proposed. The purported roles of these structures may be relevant in explaining the occurrence of the RLS in our patient. The discrete brain localization observed in this patient may be a clue to a better understanding of the pathophysiology of RLS and PLM.