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Epstein-Barr virus (EBV) infection is approved as the main environmental trigger of multiple sclerosis (MS). In this path, we quantified ebv-miR-BART9-3p and ebv-miR-BART15 in exosomes of cerebrospinal fluid (CSF) of untreated relapsing-remitting MS (RRMS) patients in comparison with the control group. Interestingly, patients displayed significant upregulation of ebv-miR-BART9-3p (18.4-fold) and ebv-miR-BART15 (3.1-fold) expression in CSF exosomes. Moreover, the expression levels of hsa-miR-21-5p and hsa-miR-146a-5p were found to be significantly elevated in the CSF samples obtained from the patient group compared to those obtained from the HC group. The levels of Interferon-gamma (IFN-γ), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-23 (IL-23), transforming growth factor beta (TGF-ß), and tumor necrosis factor-alpha (TNF-α) were observed to be significantly elevated in the serum and CSF exosomes of the patients. The highest increase was observed in TGF-ß (8.5-fold), followed by IL-23 (3.9-fold) in CSF exosomes. These findings are in agreement with the association between EBV infection and inflammatory cytokines induction. Furthermore, the ratios of TGF-ß: TNF-α and TGF-ß: IFN-γ attained values of 4 to 16.4 and 1.3 to 3.6, respectively, in the CSF exosomes of the patients, in comparison to those of the control group. These findings show EBV activity in RRMS patients is different from that of healthy ones. Elevation of ebv-miR-BART9-3p, ebv-miR-BART15, and inflammatory cytokines expression in CSF exosomes in RRMS patients provides a substantial link between EBV activity and the onset of the disease, as well as the transition from EBV infection to MS.
Assuntos
Exossomos , Herpesvirus Humano 4 , MicroRNAs , Esclerose Múltipla Recidivante-Remitente , Humanos , Exossomos/metabolismo , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/virologia , Herpesvirus Humano 4/genética , Feminino , Masculino , MicroRNAs/líquido cefalorraquidiano , MicroRNAs/genética , Adulto , Citocinas/líquido cefalorraquidiano , Infecções por Vírus Epstein-Barr/líquido cefalorraquidiano , Infecções por Vírus Epstein-Barr/virologia , RNA Viral/líquido cefalorraquidiano , RNA Viral/genética , Pessoa de Meia-Idade , Interferon gama/líquido cefalorraquidianoRESUMO
BACKGROUND: Cognitive impairment is highly prevalent in multiple sclerosis (MS) with poorly understood underlying mechanisms. Lipids are considered to be associated with MS progression through the inflammatory and oxidative stress pathways, brain atrophy, cellular signaling, and tissue physiology. In addition, serum lipids are proposed as a modifiable factor affecting the neuropsychiatric condition; therefore, this study aims to assess the association between serum lipid levels and cognitive outcomes in MS. METHODS: This study was carried out following the PRISMA 2020 statement. A systematic search was conducted in PubMed, Scopus, Web of Science, and Embase in March 2023, and the Joanna Briggs Institute (JBI)'s critical appraisal tools were utilized for risk of bias (RoB) assessments in the included studies. The quantitative synthesis was performed with the comprehensive meta-analysis (CMA3) software. RESULTS: Out of 508 screened records, 7 studies were eventually found to meet our inclusion criteria. In two studies, the course of MS in the sample of the study was only Relapsing-Remitting MS (RRMS), whereas the other five studies' sample was a combination of different phenotypes. Studies utilized different scales such as Minimal Assessment of Cognitive Function in MS (MACFIMS), Brief International Cognitive Assessment for MS (BICAMS), Montreal Cognitive Assessment (MoCA), Brief Repeatable Battery of Neuropsychological Tests (BRB-N) for cognitive evaluations. Dealing with possible confounders such as age, disease duration and level of disability was the most common possible source of bias in the included studies. One study revealed an inverse relationship between serum levels of apolipoproteins (including ApoA-I, ApoB, and ApoB/ApoA-I) and Symbol Digit Modalities Test (SDMT) scores. Also, a correlation between 24S-hydroxycholesterol (24OHC) serum concentrations and SDMT score was reported in one study. The association between serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) and different aspects of cognitive function was reported in the studies; however, serum levels of high-density lipoprotein cholesterol (HDL) were not found to be associated. The quantitative synthesis revealed a significant correlation between TC and the MoCA scores (r =-0.238; 95 %CI: -0.366 to -0.100; p-value = 0.001); however, the correlation between TG levels and MoCA were not statistically significant (r:-0.070; 95 %CI: -0.209 to 0.072; p-value: 0.334). In addition, the mata-analyses were not associated with significant findings regarding the correlation between lipid profiles (including HDL, LDL, TG, and TC) and other cognitive assessment scales including SDMT, Brief Visuospatial Memory Test (BVMT), and California Verbal Learning Test (CVLT) (p-values>0.05). DISCUSSION: Available evidence suggested a link between TC and LDL with cognitive outcomes of MS patients which was not evident in our quantitative synthesis. The limited number of studies, high RoB, different cognitive assessment scales and reporting methods, and the cross-sectional design of the included studies, were the main limitations that alleviate the clinical significance of the findings of this study and suggested further investigations on this topic. FUNDING AND REGISTRATION: The research protocol was approved and supported by the Student Research Committee, Tabriz University of Medical Sciences (grant number: 71,909). This study is registered in the international prospective register of systematic reviews (PROSPERO ID: CRD42023441625).
Assuntos
Disfunção Cognitiva , Esclerose Múltipla , Humanos , Disfunção Cognitiva/sangue , Disfunção Cognitiva/etiologia , Esclerose Múltipla/sangue , Esclerose Múltipla/complicações , Lipídeos/sangueRESUMO
Extracellular vesicles (EVs) secreted by various cells offer great potential for use in the diagnosis and treatment of disease. EVs are heterogeneous membranous vesicles. Exosomes are a subtype of EVs, 40-150 nm spherical vesicles with a lipid layer derived from endosomes. Exosomes, which are involved in signal transduction and maintain homeostasis, are released from almost all cells, tissues, and body fluids. Although several methods exist to isolate and characterize EVs and exosomes, each technique has significant drawbacks and limitations that prevent progress in the field. New approaches in the biology of EVs show great potential for isolating and characterizing EVs, which will help us better understand their biological function. The strengths and limitations of conventional strategies and novel methods (microfluidic) for EV isolation are outlined in this review. We also present various exosome isolation techniques and kits that are commercially available and assess the global market demand for exosome assays.
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Exossomos , Vesículas Extracelulares , Transdução de Sinais , EndossomosRESUMO
BACKGROUND: Alzheimer's disease (AD) is a genetic and sporadic neurodegenerative disease considered by an archetypal cognitive impairment and a decrease in less common cognitive impairment. Notably, the discovery of goals in this paradigm is still a challenge, and understanding basic mechanisms is an important step toward improving disease management. Polyadenylation (PA) and alternative polyadenylation (APA) are two of the most critical RNA processing stages in 3'UTRs that influence various AD-related genes. METHODS: In this study, we assessed Cleavage and polyadenylation specificity factors 1 and 6 (CPSF1 and CPSF6), cleavage stimulation factor 1 (CSTF1), and WD Repeat Domain 33 (WDR33) genes expression in the periphery of 50 AD patients and 50 healthy individuals with age and gender-matched by quantitative real-time PCR. RESULTS: Comparing AD patients with healthy people using expression analysis revealed a substantial increase in CSTF1 (posterior beta = 0.773, adjusted P-value = 0.042). Significant positive correlations were found between CSTF1 and CPSF1 (r = 0.365, P < 0.001), WDR33 (r = 0.506, P < 0.001), and CPSF6 (r = 0.446, P < 0.001) expression levels. CONCLUSION: Although further research is required to determine their potential contribution to AD, our findings offer a fresh perspective on molecular regulatory pathways associated with AD pathogenic mechanisms associated with PA and APA.
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Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Poliadenilação , Doença de Alzheimer/genética , Doenças Neurodegenerativas/genética , Expressão Gênica , Regiões 3' não Traduzidas/genéticaRESUMO
Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system. Selenium is a trace element with significant antioxidant activity. This study aimed to seek evidence concerning selenium supplementation in MS. A systematic search was performed on PubMed, Web of Science, Scopus, and Embase databases to identify the studies assessing the consumption rate, efficacy, and safety of selenium and selenium-containing supplementations in MS patients. The meta-analysis was performed using the Comprehensive Meta-Analysis and the risk of bias was evaluated using the Joanna Briggs Institute's critical appraisal tools. A total of 9 studies were included, which consisted of six studies regarding the rate of selenium supplement consumption in MS patients, with a total sample size of 2381 patients. Based on the quantitative synthesis, 14.3% (95% CI, 12.8-16.0%; I2, 3.58%) of MS patients had current selenium supplements usage, and 11.3% (95% CI, 7.6-16.6%; I2, 81.40%) of patients had used selenium supplements previously. Although there is no evidence regarding supplementation with selenium alone, three RCT studies reported the safety of selenium-containing supplementation use in MS with improved inflammation and oxidative stress conditions. The findings of this study show that over 10% of patients with MS used selenium supplements, with no clinical significance supporting the benefits. There is a lack of evidence regarding the safety and efficacy of selenium supplements in MS patients. Due to the limited number of included studies and the lack of comprehensive and specific studies regarding selenium supplements in MS, the results must be interpreted with caution, and future clinical trials are required.
Assuntos
Suplementos Nutricionais , Esclerose Múltipla , Selênio , Humanos , Esclerose Múltipla/tratamento farmacológico , Selênio/administração & dosagem , Antioxidantes/administração & dosagem , Estresse Oxidativo/efeitos dos fármacosRESUMO
BACKGROUND: Late-onset multiple sclerosis (LOMS) is most commonly defined as the onset of the disease's presentations at age 50 or older. There is still much to discover about the radiological features of LOMS. The current study aims to assess the imaging features of LOMS, as well as the correlation between these findings and the clinical characteristics of these patients. METHOD: This study was conducted following the PRISMA statement. A systematic search was conducted through PubMed, Scopus, and EMBASE databases to identify the studies that have applied magnetic-resonance imaging (MRI) or other imaging methods to investigate the radiological findings, as well as the relationship between them and clinical findings of LOMS patients. The risk of bias was assessed using the Joanna Briggs Institute (JBI) checklists. Meta-analysis was conducted using the third version of the compressive meta-analysis software (CMA3). RESULTS: Our search identified 753 unique titles. Among them, 15 studies, including seven case-control, five case-series, and three cross-sectional studies, met the eligibility criteria. According to the quantitative synthesis, brain lesions were detected among 72.2% of LOMS patients (4 studies; 95% CI: 67.0% - 93.1%). In the context of spinal lesions, overall spinal cord involvement was 64.0% (8 studies; 95% CI: 42.5% - 81.1%). Based on the available evidence, supratentorial involvement was found in 82.7% of cases (3 studies; 95% CI: 17.4% - 99.1%), juxtacortical involvement in 34.1% (3 studies; 95% CI: 26.4% - 42.7%), infratentorial involvement in 51.3% (4 studies; 95% CI: 32.1% - 70.1%), and cerebellar involvement in 18.5% (3 studies; 95% CI: 13.9% - 24.1%). CONCLUSION: Based on the neuroimaging findings, we found that, given the heterogeneity of MS, LOMS patients have a high rate of spinal cord lesions and supratentorial involvement. The limited available evidence suggests that Barkhof criteria are the best compromise for the diagnosis of LOMS. There is still a need for future studies.
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Esclerose Múltipla , Humanos , Estudos Transversais , Progressão da Doença , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Radiografia , Idade de InícioRESUMO
Objectives: Multiple sclerosis (MS) is among the most prevalent chronic immune-mediated inflammatory diseases. If MS onset is under 18, it is defined as pediatric-onset MS (POMS). This study aimed to determine the clinical and epidemiological aspects of POMS. Materials & Methods: This population-based study was conducted in East-Azerbaijan (EA) province and concerned POMS patients. The data concerning almost all of the POMS patients of the province was gathered from the only MS registry center in the university hospital of the Tabriz University of Medical Sciences by the end of 2017. The diagnosis of patients was based on McDonald's criteria. Results: Out of 2976 total cases of MS, eighty-five (2.85%) were POMS. The overall regional prevalence of POMS was 11.67 per 100,000 (95% CI:9.43-11.43). Sixty-seven cases were female (prevalence: 18.94 per 100,000 [95% CI:14.91-24.07], and eighteen were male (prevalence: 4.80 per 100,000 [95% CI:3.03-7.62]. The crude regional incidence in 2017 was 1.37/100,000 (95% CI:0.74-2.55). The mean age of onset was 15.81±1.33 years, with a minimum age of 12. 71.76% of the patients were diagnosed in the 16- or 17-years old age group. 7.05% had a positive family history, and 87.5% of the patients diagnosed the disease promptly. The most common first clinical presentations were blurred vision (43.75%), sensory (28.12%), cerebellar (15.62%), and brainstem (9.37%) symptoms. Conclusion: POMS is not a rare condition, and it mainly affects females. POMS prevalence increases significantly after age 15 years old, and the first manifestation of the disease is usually blurred vision.
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Background: Hand tremor is a common symptom of Parkinson's disease (PD). Tremors may be resistant to drug treatments. Therefore, Botulinum toxin (BoNT) could be a good alternative. This study aimed to review and analyze studies on the efficacy and safety of BoNT injection in hand tremor intensity and upper limb function in patients with idiopathic PD. Methods: A comprehensive search was conducted for studies on the effect of local BoNT injections on tremors in PD patients from 1990 to December 2021. Electronic databases such as Cochrane Central Control Records, PubMed, Scopus, Web of Science, EMBASE, Google Scholar, Clinicaltrial.gov, ProQuest, Science Direct, CINAHL, and Psychoinfo were searched systematically. Results: Ten studies, comprising one double-blinded randomized clinical trial and nine pilot open-labeled studies with 131 participants, met eligibility criteria. The reported tremor intensity ranged from 1 to 3, and the average tremor duration of 5.93 ± 2.08 years. The injectable dose was 68-100 units of onabotulinum-toxin-A in each upper limb muscle, mostly wrist flexors. The results showed a decrease in unified Parkinson's disease rating scale (UPDRS)_20 and UPDRS_21 indices by 1.22 ± 1.1 and 1.20 ± 0.9, respectively, without causing severe side effects. The BoNT relative effectiveness in the forearm and arm muscles was reported 6-16 weeks after injection. Discussion: The kinematic, electromyography-guided, and electrical stimulation evaluations allow for accurate muscle localization and minimize the possibility of BoNT diffusion and antibody formation. More extensive randomized clinical trials with uniform measurement criteria are recommended to reduce bias and provide more accurate conclusions. Highlight: Tremor treatment in Parkinson's-disease (PD) is challenging. Drugs effect is temporary, and surgery is critical management. This study reviews the Botulinum-toxin injection efficacy in hand tremor intensity and upper limb function. The results showed a decrease in unified Parkinson's disease rating scale (UPDRS)_20 and UPDRS_21 by 1.22 ± 1.1 and 1.20 ± 0.9, respectively, 6-16 weeks after injection.
Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Tremor/tratamento farmacológico , Tremor/etiologia , Extremidade Superior , Antebraço , Bases de Dados Factuais , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Melatonin is a neurohormone secreted predominantly by the pineal gland that is demonstrated to be associated with the pathogenesis of multiple sclerosis (MS). This research desires to evaluate the tolerability and beneficial effects of exogenous melatonin supplementations in patients with MS. METHODS: This study was executed following the PRISMA 2020 statement. Both observational and interventional studies which reported the clinical effectiveness and/or safety of melatonin supplementation in patients with MS were included in this systematic review. Ovid, PubMed, Scopus, Embase, and Web of Science databases were searched and the risk of bias in included studies was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools based on study design. RESULTS: Out of 1304 results of database searches, finally, 14 articles, including 7 randomized controlled trials (RCTs), 6 case-control studies, and one quasi-experimental study, were included based on the full-text review. Included phenotypes of MS were mostly relapsing-remitting MS (RRMS) (in 11 studies); it was secondary progressive MS (SPMS) in only one study, and two other studies had a mixture of the different phenotypes. The course of treatment with melatonin supplementation was between 2 weeks and 12 months. There were no substantial safety issues. Although melatonin was associated with enhanced oxidative stress and inflammation status, concerning the clinical benefits, limited studies suggested improvements in sleep conditions, cognitive outcomes, and fatigue in MS. DISCUSSION: There are insufficient data to support the regular melatonin prescription in MS. Limitations such as the small number of included studies, the diversity of the dosage, route, and duration of melatonin administration, and the diversity of assessment tests lead to unconvincing findings in this study. There is a need for future studies to achieve a comprehensive judgment on this subject.
Assuntos
Melatonina , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Melatonina/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Resultado do Tratamento , Suplementos NutricionaisRESUMO
BACKGROUND: Progressive multiple sclerosis (PMS) is a debilitating condition characterized by progressively worsening symptoms. Monoclonal antibodies are novel therapies for MS, but their safety and efficacy in the progressive form have not been comprehensively studied. In this systematic review, we aimed to evaluate the available evidence regarding monoclonal antibody treatment for PMS. METHODS: After registration of the study protocol in PROSPERO, we systematically searched three major databases for clinical trials involving monoclonal antibodies administration for PMS treatment. All the retrieved results were imported into the EndNote reference manager. After removing the duplicates, two independent researchers did the study selection and data extraction. The risk of bias was assessed using the Joanna Briggs Institute (JBI) checklist. RESULTS: Of the 1846 studies in the preliminary search, 13 clinical trials investigating monoclonal antibodies (Ocrelizumab, Natalizumab, Rituximab, and Alemtuzumab) in PMS patients were included. Ocrelizumab was significantly effective in reducing clinical disease progression measures in primary PMS patients. The results for Rituximab were not completely reassuring and only showed significant changes for some endpoints on MRI and clinical measures. Natalizumab decreased the relapse rate and improved MRI features for secondary PMS patients, but not clinical endpoints. The studies on Alemtuzumab treatment revealed conflicting outcomes, with improvements observed in MRI endpoints but clinical worsening in patients. Additionally, among the studied adverse events, upper respiratory infections, urinary tract infections, and nasopharyngitis were frequently reported. CONCLUSION: Based on our findings, Ocrelizumab is the most efficient monoclonal antibody for primary PMS, although it is associated with a higher risk of infection. While other monoclonal antibodies did not show significant promise in treating PMS, more research is necessary.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Anticorpos Monoclonais/efeitos adversos , Rituximab/uso terapêutico , Natalizumab/uso terapêutico , Alemtuzumab , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológicoRESUMO
Exosomal microRNAs (miRNAs) are emerging diagnostic biomarkers for neurodegenerative diseases. In this study, we aimed to detect relapsing-remitting multiple sclerosis (RRMS)-specific miRNAs in cerebrospinal fluid (CSF) and serum exosomes with diagnostic potential. One ml of CSF and serum sample were collected from each of the 30 untreated RRMS patients and healthy controls (HCs). A panel of 18 miRNAs affecting inflammatory responses was applied, and qRT-PCR was conducted to detect differentially expressed exosomal miRNAs in CSF and serum of RRMS patients. We identified that 17 out of 18 miRNAs displayed different patterns in RRMS patients compared to HCs. Let-7 g-5p, miR-18a-5p, miR-145-5p, and miR-374a-5p with dual pro-inflammatory and anti-inflammatory actions and miR-150-5p and miR-342-3p with anti-inflammatory action were significantly upregulated in both CSF and serum-derived exosomes of RRMS patients compared to corresponding HCs. Additionally, anti-inflammatory miR-132-5p and pro-inflammatory miR-320a-5p were significantly downregulated in both CSF and serum-derived exosomes of RRMS patients compared to HCs. Ten of 18 miRNAs were differentially expressed in CSF and serum exosomes of the patients. Furthermore, miR-15a-5p, miR-19b-3p, and miR-432-5p were upregulated, and miR-17-5p was downregulated only in CSF exosomes. Interestingly, U6 housekeeping gene was differentially expressed in CSF and serum exosomes, in both RRMS and HCs. As the first report describing CSF exosomal miRNAs expression profile compared to that of serum exosomes in untreated RRMS patients, we showed that CSF and serum exosomes are not identical in terms of biological compounds and display different patterns in miRNAs and U6 expression.
Assuntos
Exossomos , MicroRNAs , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , MicroRNAs/metabolismo , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Exossomos/metabolismo , Esclerose Múltipla/metabolismo , BiomarcadoresRESUMO
Mild cognitive impairment (MCI) is an interstitial state between normal aging and dementia. Objective: In this study, we investigated working memory (WM) profiles of MCI patients using the Cambridge Neuropsychological Test Automated Battery (CANTAB). We also examined the diagnostic accuracy and possible associated factors as secondary outcomes of the study. Methods: We conducted an electronic search on EMBASE, PubMed, and ScienceDirect databases. Studies with MCI participants and using CANTAB battery subtests for the assessment of WM were included. Meta-analysis was conducted using the CMA2 software. Results: Out of 1537 records, 14 studies were covered in this systematic review, and 7 of them were included in the meta-analysis. There was a significant difference between MCI patients and healthy controls in spatial working memory (SWM) (SDM: 0.535; 95%CI 11-96; p-value=0.014), spatial span (SSP) (SDM: 0.649 95%CI 0.297-0.100; p-value<0.01), and rapid visual information processing (RVP) (SDM: 0.52; 95%CI 0.386-0.654; p-value<0.01). WM function of MCI patients was associated with the cerebrospinal fluid (CSF) levels of tau-protein and amyloid-beta (Aß). Conclusions: WM is an impaired cognitive domain in MCI. CANTAB WM subtests including SSP, SWM, and RVP are accurate enough to be used as a proper assessment tool for the diagnosis of MCI in clinical settings. Tau-protein and Aß are associated with lower WM scores in MCI patients; however, sex, age, psychiatric disorders, apolipoprotein 4 allele, and functional activity scores cannot affect WM.
O comprometimento cognitivo leve (CCL) é um estado intersticial entre o envelhecimento normal e a demência. Objetivo: Neste estudo, investigamos os perfis de memória de trabalho (MT) de pacientes com CCL usando a bateria automatizada de testes neuropsicológicos de Cambridge (Cambridge Neuropsychological Test Automated Battery CANTAB). Também examinamos a acurácia diagnóstica e possíveis fatores associados como desfechos secundários do estudo. Métodos: Foi realizada uma busca eletrônica nas bases de dados EMBASE, PubMed e ScienceDirect. Foram incluídos estudos com participantes com CCL e utilizando subtestes da bateria CANTAB para avaliação da MT. A meta-análise foi realizada usando o software CMA2. Resultados: Dos 1.537 registros, esta revisão sistemática abordou 14 estudos, e 7 deles foram incluídos na meta-análise. Houve uma diferença significativa entre pacientes com CCL e controles saudáveis na memória de trabalho espacial (MTE) (DPM: 0,535; IC95% 1196; valor p=0,014), spatial span (SSP) (SDM: 0,649; IC95% 0,2970,100; valor p<0,01) e processamento rápido de informação visual (PRV) (DPM: 0,52; IC95% 0,3860,654; valor p<0,01). A MT de pacientes com CCL foi associada com os níveis de proteína tau e beta-amiloide (Aß) no líquido cefalorraquidiano (CSF). Conclusões: A MT é um domínio cognitivo prejudicado no CCL. Os subtestes CANTAB WM, incluindo SSP, MTE e PRV, são precisos o suficiente para serem usados como uma ferramenta de avaliação adequada para o diagnóstico de CCL em ambientes clínicos. A proteína Tau e Aß estão associadas a pontuações de MT mais baixas em pacientes com CCL; entretanto, sexo, idade, transtornos psiquiátricos, alelo da apolipoproteína 4 e escores de atividade funcional não podem afetar a MT.
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ABSTRACT Mild cognitive impairment (MCI) is an interstitial state between normal aging and dementia. Objective: In this study, we investigated working memory (WM) profiles of MCI patients using the Cambridge Neuropsychological Test Automated Battery (CANTAB). We also examined the diagnostic accuracy and possible associated factors as secondary outcomes of the study. Methods: We conducted an electronic search on EMBASE, PubMed, and ScienceDirect databases. Studies with MCI participants and using CANTAB battery subtests for the assessment of WM were included. Meta-analysis was conducted using the CMA2 software. Results: Out of 1537 records, 14 studies were covered in this systematic review, and 7 of them were included in the meta-analysis. There was a significant difference between MCI patients and healthy controls in spatial working memory (SWM) (SDM: 0.535; 95%CI 11-96; p-value=0.014), spatial span (SSP) (SDM: 0.649 95%CI 0.297-0.100; p-value<0.01), and rapid visual information processing (RVP) (SDM: 0.52; 95%CI 0.386-0.654; p-value<0.01). WM function of MCI patients was associated with the cerebrospinal fluid (CSF) levels of tau-protein and amyloid-beta (Aβ). Conclusions: WM is an impaired cognitive domain in MCI. CANTAB WM subtests including SSP, SWM, and RVP are accurate enough to be used as a proper assessment tool for the diagnosis of MCI in clinical settings. Tau-protein and Aβ are associated with lower WM scores in MCI patients; however, sex, age, psychiatric disorders, apolipoprotein 4 allele, and functional activity scores cannot affect WM.
RESUMO O comprometimento cognitivo leve (CCL) é um estado intersticial entre o envelhecimento normal e a demência. Objetivo: Neste estudo, investigamos os perfis de memória de trabalho (MT) de pacientes com CCL usando a bateria automatizada de testes neuropsicológicos de Cambridge (Cambridge Neuropsychological Test Automated Battery - CANTAB). Também examinamos a acurácia diagnóstica e possíveis fatores associados como desfechos secundários do estudo. Métodos: Foi realizada uma busca eletrônica nas bases de dados EMBASE, PubMed e ScienceDirect. Foram incluídos estudos com participantes com CCL e utilizando subtestes da bateria CANTAB para avaliação da MT. A meta-análise foi realizada usando o software CMA2. Resultados: Dos 1.537 registros, esta revisão sistemática abordou 14 estudos, e 7 deles foram incluídos na meta-análise. Houve uma diferença significativa entre pacientes com CCL e controles saudáveis na memória de trabalho espacial (MTE) (DPM: 0,535; IC95% 11-96; valor p=0,014), spatial span (SSP) (SDM: 0,649; IC95% 0,297-0,100; valor p<0,01) e processamento rápido de informação visual (PRV) (DPM: 0,52; IC95% 0,386-0,654; valor p<0,01). A MT de pacientes com CCL foi associada com os níveis de proteína tau e beta-amiloide (Aβ) no líquido cefalorraquidiano (CSF). Conclusões: A MT é um domínio cognitivo prejudicado no CCL. Os subtestes CANTAB WM, incluindo SSP, MTE e PRV, são precisos o suficiente para serem usados como uma ferramenta de avaliação adequada para o diagnóstico de CCL em ambientes clínicos. A proteína Tau e Aβ estão associadas a pontuações de MT mais baixas em pacientes com CCL; entretanto, sexo, idade, transtornos psiquiátricos, alelo da apolipoproteína 4 e escores de atividade funcional não podem afetar a MT.
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HumanosRESUMO
This meta-analysis was conducted to determine the relationship between neutrophil to lymphocyte ratio (NLR) and febrile seizure (FS). Our study was registered with the PROSPERO (ID: CRD42021259944). Web of Science, Embase, PubMed, Scopus, and ProQuest Central were searched, and finally, 17 studies were included. Standardized mean difference (SMD) was reported with a 95% confidence interval (CI) for the NLR levels. Compared with the febrile control group, the FS patients' NLR levels were significantly higher (SMD = 0.49; 95%CI = 0.26 to 0.72, P < 0.001). Furthermore, we conducted a comparison of NLR levels between febrile controls against simple and complex FS cases separately and found that NLR levels of children with either simple or complex FS were higher compared with those of febrile controls (SMD = 0.42, 95%CI = 0.14 to 0.69, P = 0.003 and SMD = 0.90, 95%CI = 0.71 to 1.09, P < 0.001, respectively). Also, in comparison with the NLR levels of the simple FS group, the complex FS patients' NLR levels were significantly higher (SMD = 0.59, 95%CI = 0.34 to 0.85, P < 0.001). Our study indicated that NLR could be recommended as an inexpensive diagnostic biomarker for FS. In addition, it can be useful when distinguishing between simple FS and complex FS.
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Neutrófilos , Convulsões Febris , Humanos , Criança , Convulsões Febris/diagnóstico , Linfócitos , Febre , BiomarcadoresRESUMO
Non-coding RNAs including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are implicated in the regulation of gene expression at transcriptional, posttranscriptional, and epigenetic levels. Several studies in cell lines, animal models, and humans, have revealed that non-coding RNAs play crucial roles in the pathogenesis of Alzheimer's disease (AD). Detailed knowledge on their mechanism of implication in the AD pathogenesis can help to develop novel therapeutic and disease management strategies. The two main pathological hallmarks of AD are amyloid plaques resulting from the ß-amyloid accumulation, and neurofibrillary tangles (NFT) due to the phosphorylated tau accumulation. Several lncRNAs and miRNAs play crucial roles in both these hallmarks of the AD pathogenesis and other AD-related pathological procedures such as neuronal and synaptic plasticity, neuroinflammation, neuronal differentiation and neuronal apoptosis. In this review, we outlined the non-coding RNAs and further discussed how they are implicated in these AD-related pathological procedures.
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OBJECTIVES: Concerning the impact of neurogenic lower urinary tract dysfunction (NLUTD) on quality of life, besides the lack of standard psychometrically-analyzed Persian tools, the present study investigated the validity and reliability of the Persian version of the neurogenic bladder symptom score (NBSS) questionnaire. METHODS: A total of 279 multiple sclerosis (MS) or stroke/cerebrovascular accident (CVA) patients over 18 years of age with NLUTD referred to the neurology clinics entered the study in 2021-2022. After translation, back-translation, and developing a Persian version, its validity and reliability were determined. The content validity index (CVI) and content validity ratio (CVR) were calculated quantitatively. To determine the internal consistency and scale reliability, a test-retest was used. RESULTS: The Cronbach's α coefficient was 0.83 and the intraclass correlation coefficient (95% confidence interval) was 0.85 (0.82, 0.88). Cronbach's α in all domains (incontinence, storage and voiding, and consequence) was greater than 0.70. The criterion validity also showed a positive correlation of NBSS with the International Consultation on Incontinence Questionnaire-overactive bladder (p < 0.001 and r = 0.55). The face validity was acceptable according to the opinion of 10 participants. To determine the CVI and the CVR, 10 experts' panels reviewed all items related to the questionnaire in terms of necessity, clarity, transparency, and relevancy. Based on the expert panel all NBSS criteria got a high score, and all criteria were essential to assess NLUTD (CVI: 0.78-1). CONCLUSIONS: Regarding validity and reliability, the Persian version NBSS questionnaire can properly evaluate NLUTD in MS or stroke/CVA patients.
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Esclerose Múltipla , Acidente Vascular Cerebral , Bexiga Urinaria Neurogênica , Incontinência Urinária , Humanos , Adolescente , Adulto , Psicometria , Bexiga Urinaria Neurogênica/diagnóstico , Bexiga Urinaria Neurogênica/etiologia , Reprodutibilidade dos Testes , Qualidade de Vida , Esclerose Múltipla/complicações , Inquéritos e Questionários , Incontinência Urinária/diagnóstico , Acidente Vascular Cerebral/complicaçõesRESUMO
Long non-coding RNAs (lncRNA) play critical roles in pathogenesis of neurodegenerative diseases. Human plasma carries lncRNAs that are stable in the blood, and their disease-specific profile have made them valuable biomarkers for some diseases. This study reports screening of the plasma levels of 90 lncRNAs in patients with Alzheimer disease (AD) to find out plasma-based AD biomarkers. Total RNA was isolated from plasma samples of 50 AD and 50 matched healthy controls. The plasma samples of 10 advanced AD patients and 10 matched healthy controls were screened for expression levels of 90 lncRNAs using Human LncRNA Profiler qPCR Array Kit (SBI). Based on the profiling results, lncRNAs BC200, NDM29, NEAT1, FAS-AS1 and GAS5-AS1 were selected for further analysis in all samples and their biomarker potency was evaluated by ROC curve analysis. We further surveyed RNAseq data by in silico analysis. We found that the NEAT1 and BC200 levels in the plasma of the AD patients were significantly higher compared with the control group (P=0.0021, p= 0.02, respectively). ROC curve analysis showed that the plasma level of NEAT1 and BC200 discriminated AD patients from healthy controls with sensitivity of 72 % and 60 %, and specificity of 84 % and 91 % respectively. Moreover, NEAT1 discriminated MCI (60 % sensitivity and 91 % specificity) and advanced-AD patients from healthy controls (73 % sensitivity and 71 % specificity). Besides, plasma level of BC200 discriminated the pre-clinical subjects from healthy controls with 83 % sensitivity and 66 % specificity. A positive correlation was also observed between plasma levels of BC200 with the age patients (r = 0.34, p=0.02). In silico RNAseq data analysis showed that a total of 33 lncRNAs were up-regulated but 13 lncRNAs were down-regulated significantly in AD patients compared with the healthy controls. In conclusion, this study elucidated that the plasma levels of lncRNAs NEAT1 and BC200 might be considered as potential blood-based biomarkers for AD development and progression.
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Alzheimer's disease (AD) is a heterogeneous degenerative disorder of the brain that is on the rise worldwide. One of the critical processes that might be disturbed in AD is gene expression regulation. Tristetraprolin (TTP) and RC3H1 gene (ROQUIN) are two RNA-binding proteins (RBPs) that target AU-rich elements (AREs) and constitutive decay elements (CDEs), respectively. TTP and ROQUIN, members of the CCCH zinc-finger protein family, have been demonstrated to fine-tune numerous inflammatory factors. In addition, miR-16 has distinct characteristics and may influence the target mRNA through the ARE site. Interestingly, BDNF mRNA has ARE sites in the 3' untranslated region (UTR) and can be targeted by regulatory factors, such as TTP and miR-16 on MRE sequences, forming BDNF/miR-16/TTP regulatory axis. A number of two microarray datasets were downloaded, including information on mRNAs (GSE106241) and miRNAs (GSE157239) from individuals with AD and corresponding controls. R software was used to identify BDNF, TTP, ROQUIN, and miR-16 expression levels in temporal cortex (TC) tissue datasets. Q-PCR was also used to evaluate the expression of these regulatory factors and the expression of BDNF in the blood of 50 patients with AD and 50 controls. Bioinformatic evaluation showed that TTP and miR-16 overexpression might act as post-transcriptional regulatory factors to control BDNF expression in AD in TC samples. Instead, this expression pattern was not found in peripheral blood samples from patients with AD compared to normal controls. ROQUIN expression was increased in the peripheral blood of patients with AD. Hsa-miR-16-5p levels did not show significant differences in peripheral blood samples. Finally, it was shown that TTP and BDNF, based on evaluating the receiver operating characteristic (ROC), effectively identify patients with AD from healthy controls. This study could provide a new perspective on the molecular regulatory processes associated with AD pathogenic mechanisms linked to the BDNF growth factor, although further research is needed on the possible roles of these factors in AD.
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BACKGROUND: Multiple sclerosis (MS) is a neuroinflammatory disorder commonly seen in young female adults. Cognitive impairment is one of the widespread symptoms of MS. In recent years multiple studies sought the possible risk factors for MS-related cognitive deficit. Apolipoprotein E (ApoE) genotype is one of the genetic factors which correlated significantly with cognitive status and it is a well-known risk factor for Alzheimer's Disease. In this systematic review and meta-analysis, we collected the current evidence to evaluate the association between the ApoE genotype and the cognitive outcomes in patients with MS. METHOD: Results of searches through Medline via PubMed, Scopus, and ISI web of science, as well as hand searching, were screened in the title/abstract and full-text stages. English observational studies in which the association between ApoE and cognitive outcomes, in patients with MS were included in this systematic review. Animal studies, conference abstracts, reviews, clinical trials, case reports, letters and withdrawn studies, were not included. Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools and the meta-analysis was conducted with Comprehensive Meta-Analysis (CMA.2) software. The numbers of patients with impairment in both ApoE4+ and ApoE4- groups were utilized for the calculation of the odds ratios (ORs) with 95% confidence intervals (CI) and a 0.05 level of significance for p-value. RESULT: Out of 224 results of searching, 13 studies met the eligibility criteria and were included in our systematic review, and 5 of them were included in the quantitative synthesis. Eleven studies assessed the cognitive status of patients with MS in two groups of ApoE4+ and ApoE4- while 2 rests, reported the rate of ApoE4+ patients in cognitively impaired and non-impaired groups. The phenotype of MS was only Relapsing-remitting multiple sclerosis (RRMS) in 3 studies and in the other 10 studies, it was a mixture of RRMS, clinically isolated syndrome (CIS), and progressive MS. Most of the reports did not find a significant association between ApoE genotype and cognitive outcomes in patients with MS. Contrary to the expectations, patients in ApoE4- group were more likely to have impairment in Judgment of Line Orientation (JLO) (OR: 0.405; 95% CI: 0.173 to 0.949, p-value:0.038), while ApoE4+ patients had more rate of impairment in SRT (OR:1.901; 95%CI: 1.237 to 2.920; p-value:0.003). Appropriate identifying and dealing with cofounding factors were the most common source of bias in our included studies. CONCLUSION: ApoE may have a domain-specific association with cognitive impairment in MS patients. ApoE4 patients had more delayed responses to stimuli, but the rate of impaired visuospatial perception is lower in these patients. Based on the current evidence, there is a doubt about the clinical significance of this association.
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Apolipoproteínas E/genética , Disfunção Cognitiva , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Apolipoproteína E4/genética , Apolipoproteína E4/uso terapêutico , Cognição , Disfunção Cognitiva/genética , Feminino , Genótipo , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/genética , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológicoRESUMO
Multiple sclerosis (MS) remains a challenging disease that requires timely diagnosis. Therefore, an ultrasensitive optical biosensor based on hybridization chain reaction (HCR) was developed to detect microRNA-145 (miRNA-145) as an MS biomarker. To construct such a sensor, HCR occurred between specific hairpin probes, as MB1 contains a poly-cytosine nucleotide loop and MB2 has a poly-guanine nucleotide sticky end. By introducing miR-145 as a target sequence, long-range dsDNA polymers are formed. Then, positively charged gold nanoparticles (AuNPs) were incubated with the HCR product, which adsorbed onto the dsDNA polymers due to electrostatic adsorption. This resulted in the precipitation of the AuNPs. By incubating different concentrations of miR-145 with AuNPs, the changes in the UV-vis spectrum of the supernatant were analyzed. The proposed biosensor showed a great ability to detect miR-145 in a wide linear range from 1 pM-1 nM with an excellent detection limit (LOD) of 0.519 nM. Furthermore, the developed biosensor indicated considerable selectivity in discriminating between miR-145 and mismatched sequences. It shows high selectivity in differentiating targets. Interestingly, the proposed method was also able to detect miRNA-145 in the diluted serum samples. In conclusion, this sensing platform exhibits high selectivity and specificity for the detection of circulating microRNAs, which holds great promise for translation to routine clinical applications.