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1.
Neurobiol Dis ; : 106579, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38936435

RESUMEN

BACKGROUND: The diagnosis of amyotrophic lateral sclerosis (ALS) is primarily clinical, supported by the electromyographic examination to reveal signs of lower motor neuron damage. Identifying reliable markers of upper motor neuron (UMN) involvement is challenging. On this regard, the role of transcranial magnetic stimulation-induced motor-evoked potentials (TMS-MEPs), and its relationship with UMN burden, is still under investigation. OBJECTIVE: To evaluate the ability of TMS-MEPs in delineating the neurophysiological UMN damage, and to determine the relationship between TMS-MEPs and [18F]FDG-PET measures of neural dysfunction. METHODS: We retrospectively selected 13 ALS patients who underwent, during the diagnostic process, the TMS-MEPs and [18F]FDG-PET scans. Demographic and clinical data were collected. For the MEP evaluation, we considered normal MEP, absent MEP, or significantly increased central-motor-conduction-time. For [18F]FDG-PET, we conducted voxel-wise analyses, both at single-subject and group levels, exploring hypometabolism and hypermetabolism patterns in comparison with a large dataset of healthy controls (HC). RESULTS: Based on TMS-MEPs, we identified 4/13 patients with normal MEP in all limbs (GROUP-NO), while 9/13 had an abnormal MEP in at least one limb (GROUP-AB). Despite the [18F]FDG-PET single-subject analysis revealed heterogenous expression of regional hypo- and hyper-metabolism patterns in the patients, the group-level analysis revealed a common hypometabolism, involving the precentral gyrus and the supplementary motor area, the paracentral lobule and the anterior cingulate cortex in the GROUP-AB. Moreover, exclusively for the GROUP-AB compared with HC, a relative hypermetabolism was observed in the right cerebellum, right inferior and middle temporal gyrus. The GROUP-NO showed no specific cluster of hypo- and hyper-metabolism compared to HC. CONCLUSION: This study showed altered brain metabolism only in the ALS group with abnormal MEPs, suggesting an association between the two biomarkers in defining the UMN damage.

2.
Int J Mol Sci ; 25(8)2024 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-38673915

RESUMEN

Parkinson's disease (PD) is a chronic, age-related, progressive multisystem disease associated with neuroinflammation and immune dysfunction. This review discusses the methodological approaches used to study the changes in central and peripheral immunity in PD, the advantages and limitations of the techniques, and their applicability to humans. Although a single animal model cannot replicate all pathological features of the human disease, neuroinflammation is present in most animal models of PD and plays a critical role in understanding the involvement of the immune system (IS) in the pathogenesis of PD. The IS and its interactions with different cell types in the central nervous system (CNS) play an important role in the pathogenesis of PD. Even though culture models do not fully reflect the complexity of disease progression, they are limited in their ability to mimic long-term effects and need validation through in vivo studies. They are an indispensable tool for understanding the interplay between the IS and the pathogenesis of this disease. Understanding the immune-mediated mechanisms may lead to potential therapeutic targets for the treatment of PD. We believe that the development of methodological guidelines for experiments with animal models and PD patients is crucial to ensure the validity and consistency of the results.


Asunto(s)
Modelos Animales de Enfermedad , Enfermedad de Parkinson , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/etiología , Animales , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/patología
3.
Int J Mol Sci ; 24(12)2023 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-37373343

RESUMEN

Hepatitis C virus (HCV) patients are at increased risk of cardiovascular disease (CVD). In this study, we aimed to evaluate the role of extracellular vesicles (EVs) as pathogenic factors for the onset of HCV-related endothelial dysfunction. Sixty-five patients with various stages of HCV-related chronic liver disease were enrolled in this case series. Plasma EVs were characterized and used to stimulate human vascular endothelial cells (HUVEC), which were examined for cell viability, mitochondrial membrane potential, and reactive oxygen species (ROS) release. The results showed that EVs from HCV patients were mainly of endothelial and lymphocyte origin. Moreover, EVs were able to reduce cell viability and mitochondrial membrane potential of HUVEC, while increasing ROS release. Those harmful effects were reduced by the pretreatment of HUVEC with the NLR family pyrin domain containing 3 (NLRP3)/AMP-activated protein kinase and protein kinase B blockers. In conclusion, in HCV patients, we could highlight a circulating pattern of EVs capable of inducing damage to the endothelium. These data represent a novel possible pathogenic mechanism underlying the reported increase of CVD occurrence in HCV infection and could be of clinical relevance also in relation to the widespread use of antiviral drugs.


Asunto(s)
Vesículas Extracelulares , Hepatitis C , Humanos , Células Endoteliales/patología , Hepacivirus , Especies Reactivas de Oxígeno/metabolismo , Hepatitis C/metabolismo , Vesículas Extracelulares/metabolismo
4.
Int J Mol Sci ; 24(19)2023 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-37834361

RESUMEN

Circulating extracellular vesicles (EVs) may play a pathophysiological role in the onset of complications of subarachnoid hemorrhage (SAH), potentially contributing to the development of vasospasm (VP). In this study, we aimed to characterize circulating EVs in SAH patients and examine their effects on endothelial and smooth muscle cells (SMCs). In a total of 18 SAH patients, 10 with VP (VP), 8 without VP (NVP), and 5 healthy controls (HC), clinical variables were recorded at different time points. EVs isolated from plasma samples were characterized and used to stimulate human vascular endothelial cells (HUVECs) and SMCs. We found that EVs from SAH patients expressed markers of T-lymphocytes and platelets and had a larger size and a higher concentration compared to those from HC. Moreover, EVs from VP patients reduced cell viability and mitochondrial membrane potential in HUVECs and increased oxidants and nitric oxide (NO) release. Furthermore, EVs from SAH patients increased intracellular calcium levels in SMCs. Altogether, our findings reveal an altered pattern of circulating EVs in SAH patients, suggesting their pathogenic role in promoting endothelial damage and enhancing smooth muscle reactivity. These results have significant implications for the use of EVs as potential diagnostic/prognostic markers and therapeutic tools in SAH management.


Asunto(s)
Vesículas Extracelulares , Hemorragia Subaracnoidea , Vasoespasmo Intracraneal , Humanos , Hemorragia Subaracnoidea/complicaciones , Células Endoteliales/metabolismo , Vesículas Extracelulares/metabolismo , Plaquetas/metabolismo , Vasoespasmo Intracraneal/metabolismo
5.
Neurol Sci ; 43(8): 4769-4776, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35386018

RESUMEN

INTRODUCTION: Dopamine is involved in sexual behavior, but dopaminergic imaging studies establishing the relationship between nigrostriatal dopaminergic degeneration and sexual dysfunction (SD) in Parkinson's disease (PD) are lacking. METHODS: We retrospectively analyzed clinical and 123I-FP-CIT SPECT data of 43 drug-naïve PD patients. Based on the sexual function domain of the Non-Motor Symptoms Scale (NMSS), we identified 23 patients with sexual concerns (WSC), reporting a score ≥ 2 due to hyposexuality, and 20 patients without sexual concerns (NoSC). Dopamine transporter (DAT) uptake was assessed through semi-quantitative analysis in the most and least affected putamen (maP, laP), and most and least affected caudate (maC, laC). Total putamen-to-caudate ratio and total striatal binding ratio (tSBR) were also quantified. RESULTS: WSC and NoSC had similar demographic and disease-related characteristics. WSC displayed lower uptake values in maC (p = 0.016), maP (p = 0.004), laC (p = 0.019), laP (p = 0.009), and tSBR (p = 0.006). Pearson correlation analysis revealed, in the WSC group, moderate inverse correlations between the log-transformed SD scores and the uptake in maP (r = - 0.473, p = 0.023), maC (r = - 0.428, p = 0.042), laP (r = -0.437, p = 0.037), and tSBR (r = - 0.460, p = 0.027). After controlling in a two-way ANCOVA model for age and sex, between-group differences,between WSC and NoSC remained statistically significant only for dopaminergic denervation in maP [F(1,38) = 7.478, p = 0.009)], laP [F(1,38) = 4.684, p = 0.037)], and tSBR [F(1,38) = 5.069, p = 0.030]. CONCLUSION: To the best of our knowledge, this is the first study reporting the relationship between the severity of SD and specific patterns of nigrostriatal dopaminergic denervation (especially involving both putamina) in newly diagnosed drug-naïve PD patients.


Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Enfermedad de Parkinson , Disfunciones Sexuales Fisiológicas , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Estudios Retrospectivos , Disfunciones Sexuales Fisiológicas/etiología , Tomografía Computarizada de Emisión de Fotón Único/métodos , Tropanos/metabolismo
6.
Neurol Sci ; 43(6): 3919-3922, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35006444

RESUMEN

A 35-year-old Caucasian woman presented an abrupt onset of bilateral impaired vision, and arrived to our attention two weeks later. She had a previous episode of mild dizziness. She underwent a fluorescein angiography showing branch retinal artery occlusions and a brain magnetic resonance imaging (MRI) revealing several supraand infratentorial FLAIR-hyperintense white matter lesions, two with contrast enhancement. Thrombophilic, autoimmune and infective (including Human Immunodeficiency Virus, Borrelia burgdorferi, Hepatitis B Virus, Hepatitis C Virus, Herpes Simplex Virus 1-2, Varicella Zoster Virus) screening was negative. Cerebrospinal fluid analysis showed intrathecal IgG synthesis. We suspected a Primary Central Nervous System Vasculitis, and intravenous steroids were started. Three months later a second brain MRI showed seven new lesions without contrast enhancement, and she revealed a cognitive impairment and bilateral hearing loss. Reviewing the clinical history and MRI, she fulfilled diagnostic criteria for Susac syndrome. She had two cycles of cyclophosphamide, and recovered in 6 months and then remained stable with metotrexate.


Asunto(s)
Oclusión de la Arteria Retiniana , Síndrome de Susac , Adulto , Encéfalo/patología , Femenino , Humanos , Imagen por Resonancia Magnética/efectos adversos , Oclusión de la Arteria Retiniana/diagnóstico , Oclusión de la Arteria Retiniana/etiología , Oclusión de la Arteria Retiniana/patología , Síndrome de Susac/diagnóstico , Síndrome de Susac/diagnóstico por imagen , Vértigo/etiología
7.
Int J Mol Sci ; 23(7)2022 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-35408836

RESUMEN

Parkinson's disease (PD) is a common neurodegenerative disease characterized by loss of dopaminergic neurons in the pars compacta of the midbrain substantia nigra. PD pathophysiology is complex, multifactorial, and not fully understood yet. Nonetheless, recent data show that immune system hyperactivation with concomitant production of pro-inflammatory cytokines, both in the central nervous system (CNS) and the periphery, is a signature of idiopathic PD. About 5% of PD patients present an early onset with a determined genetic cause, with either autosomal dominant or recessive inheritance. The involvement of immunity in the genetic forms of PD has been a matter of interest in several recent studies. In this review, we will summarize the main findings of this new and promising field of research.


Asunto(s)
Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Neuronas Dopaminérgicas/metabolismo , Humanos , Inmunidad , Enfermedad de Parkinson/genética , Sustancia Negra/metabolismo , alfa-Sinucleína/metabolismo
8.
Neurogenetics ; 22(1): 65-70, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33471268

RESUMEN

Primary familial brain calcification (PFBC) is a neurological condition characterized by the presence of intracranial calcifications, mainly involving basal ganglia, thalamus, and dentate nuclei. So far, six genes have been linked to this condition: SLC20A2, PDGFRB, PDGFB, and XPR1 inherited as autosomal-dominant trait, while MYORG and JAM2 present a recessive pattern of inheritance. Patients mainly present with movement disorders, psychiatric disturbances, and cognitive decline or are completely asymptomatic and calcifications may represent an occasional finding. Here we present three variants in SLC20A2, two exonic and one intronic, which we found in patients with PFBC associated to three different clinical phenotypes. One variant is novel and two were already described as variants of uncertain significance. We confirm the pathogenicity of these three variants and suggest a broadening of the phenotypic spectrum associated with mutations in SLC20A2.


Asunto(s)
Encefalopatías/genética , Mutación/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/genética , Anciano , Encéfalo/metabolismo , Encéfalo/patología , Encefalopatías/diagnóstico , Encefalopatías/patología , Exones/genética , Femenino , Humanos , Linaje , Fenotipo , Receptor de Retrovirus Xenotrópico y Politrópico
9.
Mov Disord ; 36(1): 225-229, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32649001

RESUMEN

BACKGROUND: CD4+ T-cell dysregulation occurs in Parkinson's disease (PD); however, it is unknown whether it contributes to PD development. The objective of this study was to investigate transcription factor gene expression in CD4+ T cells in idiopathic rapid eye movement sleep behavior disorder, the strongest risk factor for prodromal PD. METHODS: Expression of transcription factors (TBX21, STAT1, STAT3, STAT4, STAT6, RORC, GATA3, FOXP3, and NR4A2) was measured in CD4+ T cells from 33 polysomnographically confirmed idiopathic rapid eye movement sleep behavior disorder subjects and compared with expression in cells from matched healthy subjects and antiparkinson drugs-naive PD patients. RESULTS: Compared with healthy subjects, idiopathic rapid eye movement sleep behavior disorder subjects and PD patients had lower TBX21, STAT3, and STAT4, and higher FOXP3 expression. TBX21 expression discriminated healthy subjects from idiopathic rapid eye movement sleep behavior disorder subjects and PD patients, but not idiopathic rapid eye movement sleep behavior disorder subjects with PD. CONCLUSIONS: In idiopathic rapid eye movement sleep behavior disorder subjects CD4+ T cells exhibit a peculiar molecular signature strongly resembling cells from PD patients, suggesting early involvement of peripheral immunity in PD. © 2020 International Parkinson and Movement Disorder Society.


Asunto(s)
Enfermedad de Parkinson , Trastorno de la Conducta del Sueño REM , Linfocitos T CD4-Positivos , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/genética , Trastorno de la Conducta del Sueño REM/genética , Factores de Transcripción TCF
10.
Neurol Sci ; 42(6): 2519-2522, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33506301

RESUMEN

Aquaporin-4 antibody (AQP4-IgG) neuromyelitis optica spectrum disorders (NMOSD) are rare idiopathic autoimmune diseases, presenting with optic neuritis (ON), longitudinally extensive transverse myelitis (LETM), and brainstem syndromes and a prevalence range between 0.5 and 4/100,000. Only 3% to 25% of NMOSD have been described as a paraneoplastic (PN) syndrome (PNNMOSD). Both idiopathic NMOSD (INMOSD) and PNNMOSD cases mostly affect females, but PNNMOSD usually presents with a spinal cord or brainstem involvement in elderly patients. Few cases of both malignancies (for the majority breast or lung cancer) and benign tumors (monoclonal gammopathy) were previously reported. Currently, there is no consensus on treatment approach for PNNMOSD (only surgical removal or surgery combined with chronic immunosuppression). Here, we present a series of three newly diagnosed PNNMOSD cases, who differ from each other for demographic and clinical features, tumor association, long-term treatment, and outcome. We propose that a PN etiology should be considered always whenever a new diagnosis of NMOSD is made, not only in patients over 50 years old or in spinal cord/brainstem lesions presentations. Our findings add to existing evidence and raise awareness on PNNMOSD. We enhance the importance for the clinicians of recognizing tumor symptoms and signs whenever a NMOSD is newly diagnosed.


Asunto(s)
Mielitis Transversa , Neuromielitis Óptica , Anciano , Acuaporina 4 , Autoanticuerpos , Femenino , Humanos , Persona de Mediana Edad , Neuromielitis Óptica/complicaciones , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/terapia
11.
Int J Mol Sci ; 22(7)2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33917417

RESUMEN

Parkinson's disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the midbrain. PD is clinically characterized by a variety of motor and nonmotor symptoms, and treatment relies on dopaminergic replacement. Beyond a common pathological hallmark, PD patients may present differences in both clinical progression and response to drug therapy that are partly affected by genetic factors. Despite extensive knowledge on genetic variability of dopaminergic receptors (DR), few studies have addressed their relevance as possible influencers of clinical heterogeneity in PD patients. In this review, we summarized available evidence regarding the role of genetic polymorphisms in DR as possible determinants of PD development, progression and treatment response. Moreover, we examined the role of DR in the modulation of peripheral immunity, in light of the emerging role of the peripheral immune system in PD pathophysiology. A better understanding of all these aspects represents an important step towards the development of precise and personalized disease-modifying therapies for PD.


Asunto(s)
Enfermedad de Parkinson/genética , Polimorfismo Genético , Receptores Dopaminérgicos/genética , Humanos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/terapia , Receptores Dopaminérgicos/metabolismo
12.
Brain Behav Immun ; 89: 668-674, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32688028

RESUMEN

INTRODUCTION: Parkinson's disease (PD) is characterized by loss of dopaminergic neurons. Neuroinflammation may represent an important factor in the pathophysiology of PD and recent findings indicate that PD patients present a pro-inflammatory peripheral profile of CD4+ T lymphocytes, which may correlate with motor disability. However, no data are currently available on the relationship between CD4+ T lymphocytes and cognitive function in PD. The aim of our study is to evaluate the relationship between cognitive profile and circulating CD4+ T lymphocyte subsets in PD patients. METHODS: PD patients underwent blood withdrawal and CD4+ T lymphocyte subpopulations, including CD4+ T naïve and memory cells, Th1, Th2, Th17, Th1/17 and T regulatory (Treg) cells were evaluated by flow cytometry. Cognitive evaluation was performed using Addenbrooke Cognitive Examination (ACE-R). RESULTS: 43 consecutive PD patients (31 males; age [mean ± SD]: 68.9 ± 8.4 years) were enrolled. 14/43 (32.6%) were drug naïve. Based on the ACE-R score, patients were divided in two groups using defined cutoff values. In comparison to patients with normal cognitive profile, patients with cognitive impairment had a higher number of circulating lymphocytes. Moreover, drug naïve patients with a worse cognitive outcome had a lower number of resting Treg and higher number of activated Treg. Furthermore, we found a correlation between pro-inflammatory peripheral immune phenotype and worse cognitive outcome in the ACE-R total and sub-items scores. CONCLUSIONS: In our cohort of PD patients, cognitive impairment was associated with higher number of circulating lymphocytes, and - at least in drug naïve patients - with dysregulation of the Treg compartment. Further studies are needed to assess whether and to what extent peripheral immunity mechanistically contributes to cognitive decline in PD.


Asunto(s)
Disfunción Cognitiva , Personas con Discapacidad , Trastornos Motores , Enfermedad de Parkinson , Anciano , Linfocitos T CD4-Positivos , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Linfocitos T Reguladores , Células Th17
13.
J Neural Transm (Vienna) ; 127(6): 881-891, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32212015

RESUMEN

The TANDEM investigation was carried out in 17 Italian Movement Disorder centers on behalf of a joint initiative of neurologist members of the Italian Academy for Parkinson's disease and Movement Disorders (LIMPE-DISMOV Academy) and gastroenterologist members of the Italian Society of Digestive Endoscopy (SIED) to evaluate the efficacy and tolerability of levodopa-carbidopa intestinal gel (LCIG) in patients with advanced Parkinson's disease (PD) in routine medical care. Motor scores in "ON" and OFF" state (UPDRS-III), complications of therapy (UPDRS-IV), activities of daily living, sleep disorders and quality of life were evaluated at baseline and at two follow-up assessments (FUV1 and FUV2) within the initial 12-month LCIG treatment. In 159 patients (55% males) with a mean age of 69.1 ± 6.6 years and a diagnosis of PD since 13.6 ± 5.5 years, the UPDRS-III total score (in "OFF") decreased from baseline (45.8 ± 13.2) to FUV1 (41.0 ± 17.4; p < 0.001) and FUV2 (40.5 ± 15.5; p < 0.001), the UPDRS-IV total score decreased from baseline (8.8 ± 2.9) to FUV1 (5.1 ± 3.4; p < 0.001) and FUV2 (5.5 ± 3.2; p < 0.001). The percentage of patients exhibiting freezing, dystonia, gait/walking disturbances, falls, pain and sleep disorders was significantly reduced. Twenty-eight device complications were reported and 11 (6.9%) patients prematurely terminated the study. LCIG after 12-month treatment led to sustained improvement of time spent in "OFF", complications of therapy, PD-associated symptoms and sleep disorders. LCIG tolerability was consistent with the established safety profile of LCIG.


Asunto(s)
Carbidopa , Enfermedad de Parkinson , Actividades Cotidianas , Antiparkinsonianos/efectos adversos , Carbidopa/efectos adversos , Combinación de Medicamentos , Femenino , Geles , Humanos , Recién Nacido , Levodopa/efectos adversos , Masculino , Enfermedad de Parkinson/tratamiento farmacológico , Calidad de Vida
14.
Neurol Sci ; 40(4): 759-762, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30666473

RESUMEN

BACKGROUND: Lumbar puncture (LP) is a safe procedure commonly performed in the diagnostic work-up of multiple sclerosis (MS), and its main adverse event is post-LP headache (PLPH). Predictors for PLPH in MS are not established. AIMS: To describe the occurrence of, and, factors related to PLPH in patients with suspected MS, studied on a daily-basis admission. PATIENTS AND METHODS: One hundred patients (70 females) were admitted for a diagnostic LP (standardized with a traumatic 19-G needle), observed for 6 h, and evaluated for adverse events 2 and 7 days later. Descriptive statistics and a multivariate analysis (for PLPH) were performed. RESULTS: Fifty-seven (57%) patients had PLPH at 48 h, which persisted 1 week in 31, and only two presented beyond the first 2 days. Other adverse events were tinnitus and neck stiffness. None required investigations or was hospitalized. Age was the only predictor for PLPH at day 2, whereas the onset of headache within 48 h and female gender were predictors for PLPH at day 7. CONCLUSION: PLPH is a frequent complication of LP performed on daily-basis admission in MS work-up. The maximum onset is within the first 48 h. Age and gender seem the only predictors for the appearance and persistence of PLPH.


Asunto(s)
Esclerosis Múltiple/diagnóstico , Cefalea Pospunción de la Duramadre/etiología , Punción Espinal/efectos adversos , Punción Espinal/estadística & datos numéricos , Adolescente , Adulto , Factores de Edad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Adulto Joven
15.
Int J Mol Sci ; 20(1)2019 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-30626016

RESUMEN

Tolerogenic vaccines are aimed at inhibiting antigen-specific immune responses. Antigen-loaded nanoparticles (NPs) have been recently emerged as ideal tools for tolerogenic vaccination because their composition, size, and capability of loading immunomodulatory molecules can be readily exploited to induce peripheral tolerance. Among polymeric NPs, poly(lactic-co-glycolic acid) (PLGA) NPs have the advantage of currently holding approval for several applications in drug delivery, diagnostics, and other clinical uses by the Food and Drug Administration (FDA). PLGA-NPs are non-toxic and display excellent biocompatibility and biodegradability properties. Moreover, surface functionalization may improve their interaction with biological materials, thereby optimizing targeting and performance. PLGA-NPs are the most extensively studied in pre-clinical model in the field of tolerogenic vaccination. Thus, this review describes their potential applications in the treatment of autoimmune diseases.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Materiales Biocompatibles/química , Tolerancia Inmunológica , Nanopartículas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Vacunas/inmunología , Animales , Humanos
16.
J Neuroinflammation ; 15(1): 205, 2018 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-30001736

RESUMEN

BACKGROUND: Parkinson's disease (PD) affects an estimated 7 to 10 million people worldwide, and only symptomatic treatments are presently available to relieve the consequences of brain dopaminergic neurons loss. Neuronal degeneration in PD is the consequence of neuroinflammation in turn influenced by peripheral adaptive immunity, with CD4+ T lymphocytes playing a key role. CD4+ T cells may however acquire proinflammatory phenotypes, such as T helper (Th) 1 and Th17, as well as anti-inflammatory phenotypes, such as Th2 and the T regulatory (Treg) one, and to what extent the different CD4+ T cell subsets are imbalanced and their functions dysregulated in PD remains largely an unresolved issue. METHODS: We performed two cross-sectional studies in antiparkinson drug-treated and drug-naïve PD patients, and in age- and sex-matched healthy subjects. In the first one, we examined circulating Th1, Th2, Th17, and in the second one circulating Treg. Number and frequency of CD4+ T cell subsets in peripheral blood were assessed by flow cytometry and their functions were studied in ex vivo assays. In both studies, complete clinical assessment, blood count and lineage-specific transcription factors mRNA levels in CD4+ T cells were independently assessed and thereafter compared for their consistency. RESULTS: PD patients have reduced circulating CD4+ T lymphocytes, due to reduced Th2, Th17, and Treg. Naïve CD4+ T cells from peripheral blood of PD patients preferentially differentiate towards the Th1 lineage. Production of interferon-γ and tumor necrosis factor-α by CD4+ T cells from PD patients is increased and maintained in the presence of homologous Treg. This Th1-biased immune signature occurs in both drug-naïve patients and in patients on dopaminergic drugs, suggesting that current antiparkinson drugs do not affect peripheral adaptive immunity. CONCLUSIONS: The complex phenotypic and functional profile of CD4+ T cell subsets in PD patients strengthen the evidence that peripheral adaptive immunity is involved in PD, and represents a target for the preclinical and clinical assessment of novel immunomodulating therapeutics.


Asunto(s)
Citocinas/metabolismo , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/patología , Células TH1/patología , Células Th17/patología , Células Th2/patología , Anciano , Linfocitos T CD4-Positivos , Estudios Transversales , Citocinas/genética , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/sangre , ARN Mensajero/metabolismo
17.
Neurol Sci ; 39(4): 733-739, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29441484

RESUMEN

In this retrospective study, we evaluated both efficacy and effectiveness of safinamide 50 and 100 mg in the treatment of motor fluctuations and disabling dyskinesias in a cohort of patients with idiopathic Parkinson's disease (PD). Ninety-one PD patients were evaluated during the first year of commercialization of the drug, both prior to starting safinamide and at the last available follow-up. Evaluations were based on the Unified Parkinson's Disease Scale part III (UPDRS III), Hoehn & Yahr (HY), Unified Dyskinesia Rating Scale (UDysRS) walking and balance item 9 score, daily time spent in OFF and in ON with disabling dyskinesias (1 week diary), mean daily dose of levodopa (LD), dopamine-agonists (DA), catechol-O-methyl transferase inhibitor (COMT-I), monoamine oxidase B inhibitor (MAOB-I), and their LD equivalent dose (LEDD). Eight patients withdrew safinamide within the first month for minor side effects. At the follow-up evaluation, after a mean time with safinamide of 7.5 months ± 3.4, all patients showed a significant improvement of all the scale scores, except for HY, and of the daily dosages of the drugs and the LEDD. The same results were shown by PD patients treated with safinamide 50 mg and patients who started safinamide without switching from a previous MAOBI. PD patients with safinamide 100 mg and patients who started safinamide switching from a previous MAOBI significantly improved in time spent in OFF and LEDD. In conclusion, safinamide is safe and effective in improving motor complications in patients with idiopathic PD and can be considered a useful levodopa sparing strategy.


Asunto(s)
Alanina/análogos & derivados , Antiparkinsonianos/uso terapéutico , Bencilaminas/farmacología , Inhibidores de la Monoaminooxidasa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Alanina/farmacología , Agonistas de Dopamina/uso terapéutico , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada/métodos , Femenino , Humanos , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento
18.
Neurol Sci ; 39(9): 1585-1589, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29931515

RESUMEN

BACKGROUND AND AIM: Chronic obstructive pulmonary disease (COPD) may be associated with worsening of cognitive performance. We studied patients with Alzheimer's disease (AD) with and without COPD, and we analyzed, in a retrospective way, clinical and neuropsychological variables to verify if COPD plays a pejorative role on cognitive or functional autonomy in patients with dementia. METHODS: We enrolled 23 adult patients (AD-COPD) with probable AD and COPD and 23 with AD only (AD-only); they were matched for sex, age, educational level, and Mini Mental State Examination (MMSE) at the disease onset. Global cognitive status was estimated using MMSE at the first assessment and after 24 months. Memory, executive functions, praxia, and language were the other cognitive domains analyzed. The two groups were also compared for the presence of behavioral disorders (anxiety, depression). RESULTS: AD-COPD had worse results in executive functions screening than AD-only; no significant differences were found comparing other cognitive domains; moreover, there was no significant difference between the two groups considering the decrease in MMSE scores. AD-COPD also showed a higher presence of depression. DISCUSSION: COPD is known to be associated with the development of cognitive deficits, in particular, regarding for executive functions and attention, memory and logical reasoning. In this context, MMSE has a low diagnostic accuracy to underline effective cognitive impairment in AD-COPD. Our study shows a higher frequency of frontal deficits and behavioral disturbances in patients with AD and COPD than patients with AD-only. COPD could complicate the management of AD patients, thus necessitating a closer and multidisciplinary monitoring.


Asunto(s)
Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Anciano , Enfermedad de Alzheimer/psicología , Comorbilidad , Depresión/epidemiología , Función Ejecutiva , Femenino , Humanos , Masculino , Pruebas de Estado Mental y Demencia , Enfermedad Pulmonar Obstructiva Crónica/psicología
19.
Br J Haematol ; 176(2): 258-267, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27391055

RESUMEN

A defective switching off of the immune response is involved in several autoimmune diseases. This switching off involves Fas-mediated apoptosis, perforin-mediated fratricide of activated lymphocytes, and the suppressive activity of regulatory T (Treg) cells. These mechanisms are altered in autoimmune lymphoproliferative syndrome that often displays autoimmune thrombocytopenia. The aim of this research was to evaluate these mechanisms in adult patients with primary immune thrombocytopenia (ITP), compared with healthy controls. The results show that a substantial subgroup of the ITP patients displayed a defective Fas function; most of them displayed decreased Fas expression in T cells activated in vitro. Moreover, ITP patients displayed an increased frequency of rare missense variations of the PRF1 gene and decreased levels of Treg. Immunological analysis showed that levels of Interleukin (IL)10 and IL17 were decreased and marginal zone B cells were increased. Moreover, myeloid and plasmacytoid dendritic cells were decreased in ITP patients. In conclusion, in adult ITP patients, several mechanisms involved in shutting off the immune response are defective and several immunological parameters are dysregulated; these alterations may play a role in the clinical heterogeneity of the disease.


Asunto(s)
Perforina/genética , Púrpura Trombocitopénica Idiopática/inmunología , Receptor fas/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/patología , Células Dendríticas/patología , Femenino , Humanos , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Masculino , Persona de Mediana Edad , Mutación Missense , Células Mieloides/patología , Púrpura Trombocitopénica Idiopática/patología , Linfocitos T Reguladores/patología , Adulto Joven , Receptor fas/fisiología
20.
Clin Lab ; 63(3): 551-559, 2017 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-28271695

RESUMEN

BACKGROUND: Isoelectrofocusing (IEF) to detect oligoclonal bands (OBCs) in cerebrospinal fluid (CSF) is the gold standard approach for evaluating intrathecal immunoglobulin synthesis in multiple sclerosis (MS) but the kappa free light chain index (KFLCi) is emerging as an alternative marker, and the combined/sequential uses of IEF and KFLCi have never been challenged. METHODS: CSF and serum albumin, IgG, kFLC and lFLC were measured by nephelometry; albumin, IgG and kFLC quotients as well as Link and kFLC indexes were calculated; OCBs were evaluated by immunofixation. A total of 150 consecutive patients: 48 with MS, 32 with other neurological inflammatory diseases (NID), 62 with neurological non-inflammatory diseases (NNID), and 8 without any detectable neurological disease (NND) were investigated. RESULTS: Both IEF and KFLCi showed a similar accuracy as diagnostic tests for multiple sclerosis. The high sensitivity and specificity associated with the lower cost of KFLCi suggested to use this test first, followed by IEF as a confirmative procedure. The sequential use of IEF and KFLCi showed high diagnostic efficiency with cost reduction of 43 and 21%, if compared to the contemporary use of both tests, or the unique use of IEF in all patients. CONCLUSIONS: The "sequential testing" using KFLCi followed by IEF in MS represents an optimal procedure with accurate performance and lower costs.


Asunto(s)
Esclerosis Múltiple , Biomarcadores , Humanos , Inmunoglobulina G , Cadenas kappa de Inmunoglobulina , Nefelometría y Turbidimetría , Bandas Oligoclonales
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