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HIV-associated neurocognitive disorders (HANDs) still persist despite improved life expectancy, reduced viral loads, and decreased infection severity. The number of patients affected by HANDs ranges from (30 to 50) % of HIV-infected individuals. The pathological mechanisms contributing to HANDs and the most serious manifestation of the disease, HIV-associated dementia (HAD), are not yet well understood. Evidence suggests that these mechanisms are likely multifactorial, producing neurocognitive complications involving disorders such as neurogenesis, autophagy, neuroinflammation, and mitochondrial dysfunction. Over the years, multiple pharmacological approaches with specific mechanisms of action acting upon distinct targets have been approved. Although these therapies are effective in reducing viral loading to undetectable levels, they also present some disadvantages such as common side effects, the need for administration with a very high frequency, and the possibility of drug resistance. Genetic studies on HANDs provide insights into the biological pathways and mechanisms that contribute to cognitive impairment in people living with HIV-1. Furthermore, they also help identify genetic variants that increase susceptibility to HANDs and can be used to tailor treatment approaches for HIV-1 patients. Identification of the genetic markers associated with disease progression can help clinicians predict which individuals require more aggressive management and by understanding the genetic basis of the disorder, it will be possible to develop targeted therapies to mitigate cognitive impairment. The main goal of this review is to provide details on the epidemiological data currently available and to summarise the genetic (specifically, the genetic makeup of the immune system), transcriptomic, and epigenetic studies available on HANDs to date. In addition, we address the potential pharmacological therapeutic strategies currently being investigated. This will provide valuable information that can guide clinical care, drug development, and our overall understanding of these diseases.
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Complexo AIDS Demência , Infecções por HIV , HIV-1 , Humanos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Genômica , Transtornos Neurocognitivos/etiologia , Transtornos Neurocognitivos/genética , Complexo AIDS Demência/tratamento farmacológico , Complexo AIDS Demência/genéticaRESUMO
The Insulin-like growth factor 2 (IGF-2) has been recently proven to alleviate depressive-like behaviors in both rats and mice models. However, its potential role as a peripheral biomarker has not been evaluated in depression. To do this, we measured plasma IGF-2 and other members of the IGF family such as Binding Proteins (IGFBP-1, IGFBP-3, IGFBP-5 and IGFBP-7) in a depressed group of patients (n = 51) and in a healthy control group (n = 48). In some of these patients (n = 15), we measured these proteins after a period (19 ± 6 days) of treatment with antidepressants. The Hamilton Depressive Rating Scale (HDRS) and the Self-Assessment Anhedonia Scale (SAAS) were used to measure depression severity and anhedonia, respectively. The general cognition state was assessed by the Mini-Mental State Examination (MMSE) test and memory with the Free and Cued Selective Reminding Test (FCSRT). The levels of both IGF-2 and IGFBP-7 were found to be significantly increased in the depressed group; however, only IGF-2 remained significantly elevated after correction by age and sex. On the other hand, the levels of IGF-2, IGFBP-3 and IGFBP-5 were significantly decreased after treatment, whereas only IGFBP-7 was significantly increased. Therefore, peripheral changes in the IGF family and their response to antidepressants might represent alterations at the brain level in depression.
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Transtorno Depressivo Maior , Fator de Crescimento Insulin-Like II , Humanos , Ratos , Animais , Camundongos , Fator de Crescimento Insulin-Like II/metabolismo , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina , Transtorno Depressivo Maior/tratamento farmacológico , Fator de Crescimento Insulin-Like I/metabolismo , Anedonia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Proteína 2 de Ligação a Fator de Crescimento Semelhante à InsulinaRESUMO
OBJECTIVES: To analyze the frequency and demographic characteristics of multiple sclerosis (MS) in the Council of Santiago de Compostela (SPAIN). MATERIAL AND METHODS: The patients diagnosed with MS according to the McDonald 2010 diagnostic criteria were identified within the population of the District of Santiago de Compostela. Several sources were used (records and databases from Hospital, General Practitioners, Private Clinics, and the MS Patients Association). Demographic and clinical data were obtained from the electronic files. RESULTS: The incidence of MS between 2010 and 2015 was 8/100 000/year (95% CI: 6-10), and the prevalence on December 31, 2015, was 152/100 000 (95% CI: 127-176). The age-standardized prevalence (using the European Standard Population 2013) was 137 (95% CI: 114-159) and the incidence of 7 (95% CI: 2-12). The female:male ratio was 1.84, the mean age at the first symptom was 32.23 years, the diagnosis was delayed 3.12 years, and the mean EDSS was 2.82. 71.17% had relapsing-remitting MS, 16.55% secondary progressive MS, 7.59% primary progressive MS, and 0.69% progressive relapsing MS. A disease-modifying treatment was established in 62.76% of patients in a mean of 1.96 years after the diagnosis. CONCLUSIONS: The northwest of Spain is a high-risk area for MS, with frequencies similar to other Atlantic regions and higher than the rest of the country.
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Esclerose Múltipla/epidemiologia , Adolescente , Adulto , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , Bases de Dados Factuais , Diagnóstico Tardio , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/mortalidade , Esclerose Múltipla Crônica Progressiva/epidemiologia , Esclerose Múltipla Crônica Progressiva/mortalidade , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Esclerose Múltipla Recidivante-Remitente/mortalidade , Prevalência , Fatores Sexuais , Espanha/epidemiologia , Adulto JovemRESUMO
Introduction: Bipolar disorder (BD) is a recurrent and disabling psychiatric disorder related to low-grade peripheral inflammation and altered levels of the members of the insulin-like growth factor (IGF) family. The aim of this study was to evaluate the plasma levels of IGF-2, insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-3, IGFBP-5, IGFBP-7, and inflammatory markers such as tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1ß (MIP-1ß). Methods: We used the Young Mania Rating Scale (YMRS) to determine the severity of the symptomatology, while proteins were measured by enzyme-linked immunosorbent assay (ELISA). We included 20 patients with BD who suffered a manic episode and 20 controls. Some BD patients (n = 10) were evaluated after a period (17 ± 8 days) of pharmacological treatment. Results: No statistical difference was found in IGF-2, IGFBP-1, IGFBP-7, TNF-α, and MIP-1ß levels. However, IGFBP-3 and IGFBP-5 levels were found to be statistically decreased in BD patients. Conversely, the MCP-1 level was significantly increased in BD patients, but their levels were normalized after treatment. Intriguingly, only IGFBP-1 levels were significantly decreased after treatment. No significant correlation was found between the YMRS and any of the proteins studied either before or after treatment or between IGF proteins and inflammatory markers. Discussion: To some extent, IGFBP-3 and IGFBP-5 might be further explored as potential indicators of treatment responsiveness or diagnosis biomarkers in BD.
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Multiple sclerosis (MS) is a multifaceted neurological condition characterized by challenges in timely diagnosis and personalized patient management. The application of Artificial Intelligence (AI) to MS holds promises for early detection, accurate diagnosis, and predictive modeling. The objectives of this study are: 1) to propose new MS trajectory descriptors that could be employed in Machine Learning (ML) regressors and classifiers to predict patient evolution; 2) to explore the contribution of ML models in discerning MS trajectory descriptors using only baseline Magnetic Resonance Imaging (MRI) studies. This study involved 446 MS patients who had a baseline MRI, at least two measurements of Expanded Disability Status Scale (EDSS), and a 1-year follow-up. Patients were divided into two groups: 1) for model development and 2) for evaluation. Three descriptors: ß1, ß2, and EDSS(t), were related to baseline MRI parameters using regression and classification XGBoost models. Shapley Additive Explanations (SHAP) analysis enhanced model transparency by identifying influential features. The results of this study demonstrate the potential of AI in predicting MS progression using the proposed patient trajectories and baseline MRI scans, outperforming classic Multiple Linear Regression (MLR) methods. In conclusion, MS trajectory descriptors are crucial; incorporating AI analysis into MRI assessments presents promising opportunities to advance predictive capabilities. SHAP analysis enhances model interpretation, revealing feature importance for clinical decisions.
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Progressão da Doença , Aprendizado de Máquina , Imageamento por Ressonância Magnética , Esclerose Múltipla , Humanos , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico por imagem , Feminino , Masculino , Adulto , Pessoa de Meia-IdadeRESUMO
Introduction: The Spasticity-Plus Syndrome (SPS) in multiple sclerosis (MS) refers to a combination of spasticity and other signs/symptoms such as spasms, cramps, bladder dysfunction, tremor, sleep disorder, pain, and fatigue. The main purpose is to develop a user-friendly tool that could help neurologists to detect SPS in MS patients as soon as possible. Methods: A survey research based on a conjoint analysis approach was used. An orthogonal factorial design was employed to form 12 patient profiles combining, at random, the eight principal SPS signs/symptoms. Expert neurologists evaluated in a survey and a logistic regression model determined the weight of each SPS sign/symptom, classifying profiles as SPS or not. Results: 72 neurologists participated in the survey answering the conjoint exercise. Logistic regression results of the survey showed the relative contribution of each sign/symptom to the classification as SPS. Spasticity was the most influential sign, followed by spasms, tremor, cramps, and bladder dysfunction. The goodness of fit of the model was appropriate (AUC = 0.816). Concordance between the experts' evaluation vs. model estimation showed strong Pearson's (r = 0.936) and Spearman's (r = 0.893) correlation coefficients. The application of the algorithm provides with a probability of showing SPS and the following ranges are proposed to interpret the results: high (> 60%), moderate (30-60%), or low (< 30%) probability of SPS. Discussion: This study offers an algorithmic tool to help healthcare professionals to identify SPS in MS patients. The use of this tool could simplify the management of SPS, reducing side effects related with polypharmacotherapy.
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BACKGROUND: People with secondary progressive multiple sclerosis (pwSPMS) experience increasing disability, which impacts negatively on their health-related quality of life (HRQoL). Our aims were to assess the impact of secondary progressive multiple sclerosis (SPMS) on functional status and HRQoL and describe the clinical profile in this population. METHODS: DISCOVER is an observational, cross-sectional, multicenter study with retrospective data collection in real-world clinical practice in Spain. Sociodemographic and clinical variables, functional and cognitive scales, patient-reported outcomes (PROs), and direct healthcare, and non-healthcare and indirect costs were collected. RESULTS: A total of 297 evaluable pwSPMS with a EDSS score between 3-6.5 participated: 62.3 % were female and 18.9 % had active SPMS. At the study visit, 77 % of them presented an Expanded Disability Scale Score (EDSS) of 6-6.5. Nearly 40 % did not receive any disease-modifying treatment. Regarding the working situation, 61.6 % were inactive due to disability. PROs: 99.3 % showed mobility impairment in EuroQoL-5 Dimensions-5 Levels, and about 60 % reported physical impact on the Multiple Sclerosis Impact Scale-29. Fatigue was present in 76.1 %, and almost 40 % reported anxiety or depression. The Symbol Digit Modalities Test was used to assess cognitive impairment; 80 % of the patients were below the mean score. Participants who presented relapses two years before and had high EDSS scores had a more negative impact on HRQoL. PwSPMS with a negative impact on HRQoL presented a higher cost burden, primarily due to indirect costs. CONCLUSIONS: PwSPMS experience a negative impact on their HRQoL, with a high physical impact, fatigue, cognitive impairment, and a high burden of indirect costs.
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INTRODUCTION AND OBJECTIVES: Recently, neurologists have begun to perform focused cardiac ultrasound for the detection of a cardiac source of embolism in stroke patients, requiring them to undergo a prior accredited training process. We designed a prospective study to analyze the incidence of heart disease detected by a focused cardiac ultrasound program within a stroke care network with cardiac imaging units and to identify the outcomes of detected structural heart disease at 1 year of follow-up. METHODS: We included patients admitted to a university hospital for ischemic stroke or a transient ischemic attack between 2017 and 2021 who were evaluated by focused cardiac ultrasound. We studied the presence of structural heart disease and cardioembolic sources. We analyzed cardiovascular events (CVE) during the first year of follow-up. RESULTS: Focused cardiac ultrasound was performed in 706 patients. Structural heart disease was detected in 52.1% and a cardioembolic source in 31.9%. Adverse CVE occurred in 5.49% of the patients in the first year of follow-up. The presence of de novo structural heart disease was independently associated with a higher probability of adverse CVE (HR, 1.72; 95%CI, 1.01- 2.91; P=.046). CONCLUSIONS: Focused cardiac ultrasound within a stroke care network with cardiac imaging units is an accessible technique with high diagnostic yield. Its use allows clinical and therapeutic actions in the prevention of stroke recurrences and other CVEs in this group of patients.
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Cardiopatias , Acidente Vascular Cerebral , Humanos , Estudos Prospectivos , Neurologistas , Ecocardiografia Transesofagiana , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Cardiopatias/diagnóstico , Cardiopatias/epidemiologia , Cardiopatias/complicaçõesRESUMO
Background: Multiple sclerosis (MS) treatment has radically improved over the last years; however, MS symptom management is still challenging. The novel Spasticity-Plus syndrome was conceptualized to frame several spasticity-related symptoms that can be addressed together with broad-spectrum medication, such as certain cannabinoid-based drugs. The aim of this project was to gain insight into Spanish neurologists' clinical experience on MS spasticity and associated symptoms, and to assess the acknowledgment and applicability of the Spasticity-Plus syndrome concept in patients with MS. Methods: Ten online meetings were conducted using the Workmat® methodology to allow structured discussions. Fifty-five Spanish neurologists, experts in MS management, completed and discussed a set of predefined exercises comprising MS symptom assessment and its management in clinical practice, MS symptoms clustering in clinical practice, and their perception of the Spasticity-Plus syndrome concept. This document presents the quantitative and qualitative results of these discussions. Results: The specialists considered that polytherapy is a common concern in MS and that simplifying the management of MS spasticity and associated manifestations could be useful. They generally agreed that MS spasticity should be diagnosed before moderate or severe forms appear. According to the neurologists' clinical experience, symptoms commonly associated with MS spasticity included spasms/cramps (100% of the specialists), pain (85%), bladder dysfunction (62%), bowel dysfunction (42%), sleep disorders (42%), and sexual dysfunction (40%). The multiple correspondence analysis revealed two main symptom clusters: spasticity-spasms/cramps-pain, and ataxia-instability-vertigo. Twelve out of 16 symptoms (75%) were scored >7 in a 0-10 QoL impact scale by the specialists, representing a moderate-high impact. The MS specialists considered that pain, spasticity, spasms/cramps, bladder dysfunction, and depression should be a treatment priority given their frequency and chance of therapeutic success. The neurologists agreed on the usefulness of the new Spasticity-Plus syndrome concept to manage spasticity and associated symptoms together, and their experience with treatments targeting the cannabinoid system was satisfactory. Conclusions: The applicability of the new concept of Spasticity-Plus in MS clinical practice seems possible and may lead to an integrated management of several MS symptoms, thus reducing the treatment burden of disease symptoms.
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Introduction: Nabiximols, a cannabinoid-based oromucosal spray, is indicated as add-on therapy for symptomatic relief of spasticity in persons with multiple sclerosis (MS). This review compiles tolerability and safety data from clinical trials that investigated nabiximols for spasticity and/or chronic pain.Areas covered: Systematic searches identified 38 placebo-controlled randomized controlled trials (RCTs) or post-RCT open-label studies reporting safety data: 15 in spasticity; 16 in neuropathic pain; six in chronic cancer pain; and one in rheumatoid arthritis pain. In RCTs, discontinuation rates due to adverse events (AEs) for nabiximols and placebo were lower in spasticity studies (5.4% and 2.8%) than in neuropathic pain (12.9% and 5.3%) or cancer pain (19.5% and 16.6%) studies. The most consistently identified AEs were dizziness, nausea and fatigue in spasticity or neuropathic pain studies; and dizziness, nausea, vomiting and somnolence in cancer pain studies. Serious AE (SAE) rates for nabiximols and placebo were higher in cancer pain (21.8% and 16.9%) than in MS spasticity (4.7% vs. 0.8%) and neuropathic pain (4.1% vs. 3.1%) studies despite similar dose ranges. Treatment-related SAEs showed no particular pattern.Expert opinion: More than 15 years of investigation of nabiximols oromucosal spray in spasticity and chronic pain conditions indicates an acceptable overall safety profile.
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Canabidiol , Esclerose Múltipla , Neuralgia , Canabidiol/efeitos adversos , Dronabinol/efeitos adversos , Combinação de Medicamentos , Humanos , Esclerose Múltipla/tratamento farmacológico , Espasticidade Muscular/tratamento farmacológico , Neuralgia/tratamento farmacológicoRESUMO
INTRODUCTION: : Nabiximols oromucosal spray,a cannabis-based medicine containing a balanced ratio of Δ-9-tetrahydrocannabinol and cannabidiol, is approved widely as an add-on therapy for symptomatic relief of spasticity in people with multiple sclerosis (MS). Most safety data for nabiximols derive from use in MS spasticity, with some data available from the analgesia area. AREAS COVERED: : This review compiles safety and tolerability data from all published observational studies, registry analyses, and case reports identified in systematic searches in which nabiximols oromucosal spray was investigated for spasticity (n = 20) and/or chronic non-cancer pain (n = 4). Aligning with the known safety profile of nabiximols as demonstrated in randomized controlled trials, common adverse events reported consistently across studies conducted under clinical practice conditions were dizziness, fatigue and somnolence. The serious adverse event (SAE) rate with nabiximols in MS spasticityobservational studies was 3.1% (137/4351). A total of 39 treatment-related SAEs were reported in 32 patients with spasticity, all of which (where specified) were resolved. No treatment-related SAEs were recorded in nabiximols pain studies. EXPERT OPINION: : Real-world experience with nabiximols oromucosal spray in treating spasticity and chronic pain indicates that, overall, it is well tolerated and has a good safety profile.
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Canabidiol , Dor Crônica , Esclerose Múltipla , Analgésicos Opioides , Canabidiol/uso terapêutico , Dronabinol/efeitos adversos , Combinação de Medicamentos , Humanos , Esclerose Múltipla/tratamento farmacológico , Espasticidade Muscular/tratamento farmacológico , Sistema de RegistrosRESUMO
In the last few years, there has been an explosion of new drugs acting on the clinical course of multiple sclerosis (MS) but less attention has been paid to better knowledge of the symptoms of this disease and their pathogenesis and treatment, which is essential to improve patients' quality of life. Because many patients have numerous concurrent symptoms during their clinical course, their management is complex and consequently it is important to know which symptoms are a direct result of the degenerative lesions of MS. The present article describes all the therapeutic options available for spasticity and its associated pain, paroxystic symptoms, fatigue, genitourinary disorders and sexual dysfunction, tremor, ataxia, gait disorder and cognitive impairment, with special emphasis on novel treatments. The article also defines exacerbations, how to recognize them and the available treatments, mainly oral administration of high-dose methylprednisolone and plasmapheresis.
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Esclerose Múltipla/terapia , Progressão da Doença , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnósticoRESUMO
There is a need for a study of the complex diseases due to their important impact on our society. One of the solutions involves the theoretical methods which are fast and efficient tools that can lead to the discovery of new active drugs specially designed for these diseases. The Quantitative Structure - Activity Relationship models (QSAR) and the complex network theory become important solutions for screening and designing efficient pharmaceuticals by coding the chemical information of the molecules into molecular descriptors. This review presents the most recent studies on drug discovery and design using QSAR of several complex diseases in the fields of Neurology, Cardiology and Oncology.