Early diagnosis and treatment of Alzheimers disease: new definitions and challenges

The prevalence of Alzheimer's disease (AD), a progressive neurodegenerative disorder, is expected to more than double by 2050. Studies on the pathophysiology of AD have been changing our understanding of this disorder and setting a new scenario for drug development and other therapies. Concepts like the "amyloid cascade" and the "continuum of AD," discussed in this article, are now well established. From updated classifications and recommendations to advances in biomarkers of AD, we aim to critically assess the literature on AD, addressing new definitions and challenges that emerged from recent studies on the subject. Updates on the status of major clinical trials are also given, and future perspectives are discussed.

Schizophrenia TreAtment with electRic Transcranial Stimulation (STARTS): design, rationale and objectives of a randomized, double-blinded, sham-controlled trial / Tratamento da esquizofrenia com estimulação transcraniana por corrente contínua (ETCC): fundamentação teórica e objetivos de um ensaio clínico randomizado, duplo-cego, controlado por simulação

Abstract Introduction Schizophrenia is a severe mental disorder. While some antipsychotic medications have demonstrated efficacy in treating positive symptoms, there is no widely recognized treatment for negative symptoms, which can cause significant distress and impairment for patients with schizophrenia. Here we describe the rationale and design of the STARTS study (Schizophrenia TreAtment with electRic Transcranial Stimulation), a clinical trial aimed to test the efficacy of a non-pharmacological treatment known as transcranial direct current stimulation (tDCS) for treating the negative symptoms of schizophrenia Methods The STARTS study is designed as a randomized, sham-controlled, double-blinded trial evaluating tDCS for the treatment of the negative symptoms of schizophrenia. One-hundred patients will be enrolled and submitted to 10 tDCS sessions over the left dorsolateral prefrontal cortex (anodal stimulation) and left temporoparietal junction (cathodal stimulation) over 5 consecutive days. Participants will be assessed using clinical and neuropsychological tests before and after the intervention. The primary outcome is change in the Positive and Negative Syndrome Scale (PANSS) negative subscale score over time and across groups. Biological markers, including blood neurotrophins and interleukins, genetic polymorphisms, and motor cortical excitability, will also be assessed. Results The clinical results will provide insights about tDCS as a treatment for the negative symptoms of schizophrenia, and the biomarker investigation will contribute towards an improved understanding of the tDCS mechanisms of action. Conclusion Our results could introduce a novel therapeutic technique for the negative symptoms of schizophrenia. Clinical trial registration: ClinicalTrials.gov, NCT02535676 .

Resumo Introdução A esquizofrenia é um transtorno mental grave. Embora alguns medicamentos antipsicóticos tenham demonstrado eficácia no tratamento de sintomas positivos, não há tratamento amplamente reconhecido para sintomas negativos, o que pode causar sofrimento e prejuízo significativos para pacientes com esquizofrenia. Aqui descrevemos a fundamentação teórica e o design do estudo STARTS (Schizophrenia TreAtment with electRic Transcranial Stimulation), um ensaio clínico destinado a testar a eficácia de um tratamento não farmacológico conhecido como estimulação transcraniana por corrente contínua (ETCC) para tratar os sintomas negativos da esquizofrenia. Métodos O estudo STARTS foi concebido como um ensaio clínico randomizado, controlado por simulação, duplo-cego, avaliando a ETCC para o tratamento dos sintomas negativos da esquizofrenia. Cem pacientes serão incluídos e submetidos a 10 sessões de ETCC sobre o córtex pré-frontal dorsolateral esquerdo (estimulação anódica) e a junção temporoparietal esquerda (estimulação catodal) durante 5 dias consecutivos. Os participantes serão avaliados através de testes clínicos e neuropsicológicos antes e após a intervenção. O desfecho primário é a mudança na pontuação da subescala negativa da Escala da Síndrome Positiva e Negativa (Positive and Negative Syndrome Scale [PANSS]) ao longo do tempo e entre os grupos. Marcadores biológicos, incluindo neurotrofinas e interleucinas do sangue, polimorfismos genéticos e excitabilidade cortical motora, também serão avaliados. Resultados Os resultados clínicos fornecerão informações sobre a ETCC como um tratamento para os sintomas negativos da esquizofrenia, e a investigação dos biomarcadores contribuirá para uma melhor compreensão dos mecanismos de ação da ETCC. Conclusão Nossos resultados podem trazer uma nova técnica terapêutica para o tratamento dos sintomas negativos da esquizofrenia. Registro do ensaio clínico: ClinicalTrials.gov, NCT02535676.

Noninvasive brain stimulation in psychiatric disorders: a primer

Objective: Noninvasive brain stimulation (NIBS) techniques, such as transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), are increasingly being used to treat mental disorders, particularly major depression. The aim of this comprehensive review is to summarize the main advances, limitations, and perspectives of the field. Methods: We searched PubMed and other databases from inception to July 2017 for articles, particularly systematic reviews and meta-analyses, evaluating the use of NIBS in psychiatric disorders. Results: We reviewed the mechanisms of action, safety, tolerability, efficacy, and relevant clinical parameters of NIBS. Repetitive TMS is already an established technique for the treatment of depression, and there is theoretically room for further methodological development towards a high-end therapeutic intervention. In contrast, tDCS is a technically easier method and therefore potentially suitable for wider clinical use. However the evidence of its antidepressant efficacy is less sound, and a recent study found tDCS to be inferior to antidepressant pharmacotherapy. Clinical trials using rTMS for other mental disorders produced mixed findings, whereas tDCS use has not been sufficiently appraised. Conclusion: The most promising results of NIBS have been obtained for depression. These techniques excel in safety and tolerability, although their efficacy still warrants improvement.

Epistasis between COMT Val158Met and DRD3 Ser9Gly polymorphisms and cognitive function in schizophrenia: genetic influence on dopamine transmission

Objective:To assess the relationship between cognitive function, a proposed schizophrenia endophenotype, and two genetic polymorphisms related to dopamine function, catechol-O-methyl transferase (COMT) Val158Met and dopamine receptor 3 (DRD3) Ser9Gly.Methods:Fifty-eight outpatients with schizophrenia/schizoaffective disorder and 88 healthy controls underwent neurocognitive testing and genotyping. Analyses of covariance (ANCOVAs) using age, sex, and years of education as covariates compared cognitive performance for the proposed genotypes in patients and controls. ANCOVAs also tested for the epistatic effect of COMT and DRD3 genotype combinations on cognitive performance.Results:For executive functioning, COMT Val/Val patients performed in a similar range as controls (30.70-33.26 vs. 35.53-35.67), but as COMT Met allele frequency increased, executive functioning worsened. COMT Met/Met patients carrying the DRD3 Ser/Ser genotype performed poorest (16.184 vs. 27.388-31.824). Scores of carriers of this COMT/DRD3 combination significantly differed from all DRD3 Gly/Gly combinations (p < 0.05), from COMT Val/Met DRD3 Ser/Gly (p = 0.02), and from COMT Val/Val DRD3 Ser/Ser (p = 0.01) in patients. It also differed significantly from all control scores (p < 0.001).Conclusion:Combined genetic polymorphisms related to dopamine neurotransmission might influence executive function in schizophrenia. Looking at the effects of multiple genes on a single disease trait (epistasis) provides a comprehensive and more reliable way to determine genetic effects on endophenotypes.

Tratamento do transtorno depressivo maior pós acidente vascular cerebral com Estimulação Transcraniana por Corrente Contínua (ETCC): ensaio-clínico, randomizado, duplo-cego / Transcranial direct current stimulation for the treatment of poststroke depression: results from a randomized, sham-controlled, double-blinded trial

A depressão pós Acidente Vascular Cerebral (AVC) é uma condição desabilitante que ocorre em um terço dos casos. Há uma dificuldade no tratamento farmacológico devido a efeitos adversos e eficácia limitada. Recentemente, a estimulação trasncraniana por corrente contínua (ETCC) tem demonstrado eficácia no tratamento da depressão unipolar, apesar dos seus efeitos em depressões secundárias serem desconhecidos. O objetivo do estudo foi avaliar a eficácia e segurança da ETCC, uma intervenção não farmacológica, para depressão pós AVC (DPA), através de um ensaio clínico, randomizado, duplo-cego, sham-controlado. Foram incluídos quarenta e oito pacientes sem uso de antidepressivos com DPA foram igualmente divididos em 2 grupos que não diferiram em gênero, idade, gravidade do AVC ou da depressão e nem em outras variáveis clínicas. Foram realiadas 12 sessões de 30 minutos de ETCC com 2mA de corrente com ânodo à esquerda e cátodo à direita em córtex pré-frontal dorsolateral. Para a ETCC sham foi feita um minuto de estimulação somente, seguida por desligamento da máquina até um total de 30 minutos. Foi feita uma análise por intenção de tratamento, na qual o desfecho primário foi mudança na Hamilton Depression Rating Scale na sexta-semana (final). Resposta clínica e remissão foram desfechos secundários. Segurança foi avaliada usando um questionário de efeitos adversos, avaliação da cognição e a escala de mania de Young. A ETCC ativa foi significantemente superior a sham no desfecho final (diferença de médias de 4.7 pontos, IC95% de 2.1 a 7.3, P < 0.001). Taxas de resposta e remissão também foram estatisticamente maior no grupo ativo (37.5% e 20.8%, respectivamente) em relação ao grupo sham (4.1% e 0). O número necessário para tratar para resposta e remissão foi, respectivamente, 3 e 5. A região ou lado do AVC não predisse resposta. Nenhum efeito adverso grave foi relatado e a frequência dos efeitos adversos foi semelhante em ambos grupos. Pacientes...

Depression after a stroke is a disabling condition that occurs in up to one-third of cases. Pharmacological treatment is challenging due to adverse effects and presents limited efficacy. Recently, transcranial direct current stimulation (tDCS) has shown efficacy in the treatment of unipolar depression, although its antidepressant effects in secondary depressions are unknown. The objective of the study was to assess the efficacy and safety of tDCS, a nonpharmacological intervention, for post-stroke depression (PSD) in a prospective, randomized, double blind, sham-controlled trial. Forty-eight antidepressant-free patients with PSD were equally divided in two groups that did not differ in gender, age, stroke and depression severity and other clinical variables. Twelve 30-minute sessions of 2-mA anodal left/cathodal right dorsolateral prefrontal tDCS applied over 6 weeks. For sham tDCS we performed 1-min of stimulation only, followed by no stimulation during the remaining period. Intention-to-treat analysis, in which the primary outcome measure was the change in Hamilton Depression Rating scale score at 6 weeks (endpoint). Clinical response and remission were secondary outcomes. Safety was assessed using an adverse effects questionnaire, cognitive assessment and the Young mania rating scale. Active tDCS was significantly superior to sham at endpoint (mean difference, 4.7 points; 95% CI, 2.1 to 7.3; P <.001). Response and remission rates were also statistically higher in active (37.5% and 20.8%, respectively) vs. sham (4.1% and 0) groups. The number needed to treat for response and remission was, respectively, 3 and 5. Stroke region or side did not predict response. No serious adverse effects were reported and the frequency of common adverse effects was similar in both groups. Patients and raters were effectively blinded. This is the first controlled study that demonstrates the safety and clinically meaningful efficacy of tDCS in patients...

Lithium safety and tolerability in mood disorders: a critical review / Tolerabilidade e segurança do lítio em transtornos do humor: uma revisão crítica

Background: Lithium is a first-line treatment for bipolar disorder in all phases, also indicated as add-on drug for unipolar depression and suicide prevention. This study encompasses a broad critical review on the safety and tolerability of lithium for mood disorders. Methods: A computerized search for English written human studies was made in MEDLINE, using the keywords “lithium” and “mood disorders”, starting from July 1993 through July 2013 (n = 416). This initial search aimed to select clinical trials, prospective data, and controlled design studies of lithium treatment for mood disorders reporting adverse effects (n = 36). The final selection yielded 91 studies. Results: The most common general side effects in patients on lithium treatment were thirst, frequent urination, dry mouth, weight gain, fatigue and cognitive complaints. Lithium users showed a high prevalence of hypothyroidism, hyperparathyroidism, and decrease in urinary concentration ability. Reduction of glomerular filtration rate in patients using lithium was also observed, but in a lesser extent. The evidence of teratogenicity associated with lithium use is not well established. Anti-inflammatory non-steroidal drugs, thiazide diuretics, angiotensin-converting enzyme inhibitors, and alprazolam may increase serum lithium and the consequent risk for intoxication. Discussion: Short-term lithium treatment is associated with mild side effects. Medium and long-term lithium treatment, however, might have effects on target organs which may be prevented by periodical monitoring. Overall, lithium is still a safe option for the treatment of mood disorders...

Contexto: O lítio é um tratamento de primeira linha para o transtorno bipolar, em todas as fases, e também é indicado como terapia adjunta para a depressão unipolar e prevenção do suicídio. Este estudo abrange uma ampla revisão crítica sobre a segurança e a tolerabilidade do lítio para transtornos do humor. Métodos: Uma busca informatizada para estudos com humanos escritos em inglês foi feita no MEDLINE, usando as palavras-chave “lítio” e “transtornos de humor”, a partir de julho de 1993 a julho de 2013 (n = 416). Esta pesquisa inicial teve como objetivo selecionar ensaios clínicos, estudos prospectivos e estudos controlados com tratamento com lítio para transtornos de humor, relatando efeitos adversos (n = 36). A seleção final identificou 91 estudos. Resultados: Os efeitos colaterais mais comuns nos pacientes em tratamento com lítio foram sede, micção frequente, boca seca, ganho de peso, fadiga e queixas cognitivas. Usuários de lítio mostraram uma alta prevalência de hipotireoidismo, hiperparatireoidismo e diminuição da capacidade de concentração urinária. Também foi observada redução da taxa de filtração glomerular em pacientes utilizando lítio, mas em menor grau. A evidência de teratogenicidade associada com o uso de lítio não está bem estabelecida. Os medicamentos anti-inflamatórios não esteroides, diuréticos, inibidores da enzima de conversão da angiotensina e alprazolam podem aumentar o lítio sérico e o consequente risco de intoxicação. Conclusões: O tratamento de curto prazo com lítio está associado com efeitos colaterais leves. No entanto, tratamentos de médio a longo prazo com lítio podem ter efeitos sobre órgãos-alvo que podem ser prevenidos por acompanhamento periódico. Em geral, o lítio é ainda uma alternativa segura para o tratamento dos transtornos de humor...

Novel neurotherapeutics in psychiatry: use and rationale of transcranial direct current stimulation in major depressive disorder / Novas neuroterapêuticas em psiquiatria: racional e uso da estimulação transcraniana por corrente contínua no transtorno depressivo maior

Background: Transcranial direct current stimulation (tDCS) is a novel non-pharmacological intervention being investigated for the treatment of major depressive disorder (MDD). Objective: To perform an updated review of tDCS for MDD. Method: Systematic review in Medline/PubMed and other databases of all clinical studies evaluating the clinical efficacy of tDCS in MDD, from the first date available to December/2013. Results: Out of 55 articles, 24 were included, being 6 open-label studies; 8 randomized, double-blind, sham-controlled trials; 2 follow-up studies; 2 meta-analyses and 6 case reports. We observed an improvement of 20-40% in depressive symptoms, being slightly better in open studies. Five randomized clinical trials displayed positive results. The meta-analyses presented mixed results; although none included the study of Brunoni et al. (2013) that represents almost 50% of the evaluated sample. Open-label studies and case reports also investigated tDCS in bipolar depression, post-stroke depression and employed different parameters of stimulation. Discussion: TDCS is a novel, promising treatment for MDD. Definite evidence from large, ongoing clinical trials will be available in the next years...

Contexto: A estimulação transcraniana por corrente contínua (ETCC) é uma nova intervenção não farmacológica investigada como tratamento no transtorno depressivo maior (TDM). Objetivo: Apresentar uma revisão atualizada da ETCC no TDM. Método: Revisão sistemática no banco de dados Medline/PubMed e outros de todos os estudos clínicos publicados avaliando a eficácia da ETCC no TDM, da primeira data disponível a dezembro/2013. Resultados : De 55 artigos, 24 foram incluídos, sendo 6 estudos abertos; 8 ensaios clínicos randomizados, duplo-cego, placebo controlados; 2 estudos de seguimento; 2 metanálises e 6 relatos de caso. Observa-se uma melhora de 20-40% nos sintomas depressivos, sendo ligeiramente maior nos estudos abertos. Entre os ensaios controlados, 5 demonstraram eficácia da técnica. As metanálises divergiram quanto aos resultados, mostrando presença e ausência de eficácia e ausência da ETCC. Porém, nenhuma incluiu o estudo de Brunoni et al. (2013), que representa quase 50% da população estudada. Estudos abertos e relatos de caso também investigaram o uso da ETCC na depressão bipolar, na depressão pós-AVC e usaram variações nos parâmetros de estimulação. Conclusões: A ETCC é uma técnica promissora no tratamento da TDM. Evidências definitivas devem estar disponíveis nos próximos anos, com a divulgação de resultados de grandes ensaios clínicos em andamento...

Espondilodiscite causada por Candida parapsilosis: relato de caso e revisão de literatura / Spondilodiscit caused bay Candida parapsilosis: case report and literature review

São raras as espondilodiscites fúngicas decorrentes de espéciesdo gênero Candida, sendo que até 2004 foram descritos menos de 75 casos. RELATO DE CASO: Homem, 42 anos, com história de etilismo por 35 anos, foi admitido com quadro de dorem abdome inferior com irradiação para membros inferiores e fraqueza dos mesmos nos últimos 3 meses. Os achados do exame físico foram: atrofia muscular em região glútea, dor àmobilização da articulação coxo-femoral, lombalgia em níveis L4 e L5 e força muscular grau II de parte distal de membros inferiores. O paciente foi internado e introduziu-se empiracamenteclindamicina e ciprofloxacina por suspeita de espondilodiscite, confirmada por meio do exame de Ressonância Magnética (RM)...

Fungic Spondilodiscit decorrent of Candida generus species arerare, being less than 75 cases described until 2004. Case Report: Man, 42 years old, with 35 years history of alcohol abuse, was admitted with a lower abdomen pain with irradiation toinferior members and weakness of them in the past 3 months. The physical exam were: gluteus muscular atrophy, mobilization pain of the coxo-femoral articulation, L4 and L5 back pain andmuscle strength grade II in the inferior member distal part. The patient was admitted and initiated clindamicin and ciprofloxacin with the suspect of spondilodiscit, confirmed by MagneticRessonance (RM)..

Intracranial arterial aneurysms in childhood: case report / Aneurismas arteriais intracranianos na infância: relato de caso

A case of an intracranial arterial aneurysm at internal carotid bifurcation in a 10-year-old girl is described with the special features of cerebral aneurysm which occur in children, comparing with the adults. We alert for the necessity of carefully operative technique in order to avoid damage and intraoperative rupture of the aneurysm due to the very thin vessel wall that this population can develop. Our recommendation is early surgery in these patients.

Relatamos o caso de aneurisma arterial intracraniano na bifurcação da carótida interna em menina de 10 anos de idade. As características especiais dos aneurismas intracranianos que acometem a faixa etária pediátrica são descritas, comparando com a faixa etária adulta. Alertamos a necessidade de emprego de técnica operatória microcirúrgica cautelosa para evitar lesão e ruptura intraoperatória do aneurisma, devido a parede do aneurisma geralmente ser muito fina na faixa etária pediátrica. Recomendamos cirurgia precoce nestes pacientes.

Genetic therapy in gliomas: historical analysis and future perspectives.

High-grade gliomas are relatively frequent in adults, and consist of the most malignant kind of primary brain tumor. Being resistant to standard treatment modalities such as surgery, radiation, and chemotherapy, it is fatal within 1 to 2 years of onset of symptoms. Although several gene therapy systems proved to be efficient in controlling or eradicating these tumors in animal models, the clinical studies performed so far were not equally successful. Most clinical studies showed that methodologies that increase tumor infection/transduction and, consequently confer more permanent activity against the tumor, will lead to enhanced therapeutic results. Due to the promising practical clinical benefits that can be expected for the near future, an exposition to the practicing neurosurgeon about the basic issues in genetic therapy of gliomas seems convenient. Among the main topics, we shall discuss anti-tumoral mechanisms of various genes that can be transfected, the advantages and drawbacks of the different vectors utilized, the possibilities of tumor targeting by modifications in the native tropism of virus vectors, as well as the different physical methods for vector delivery to the tumors. Along with the exposition we will also review of the history of the genetic therapy for gliomas, with special focus on the main problems found during the advancement of scientific discoveries in this area. A general analysis is also made of the present state of this promising therapeutic modality, with reference to the problems that still must be solved and the new paradigms for future research in this area.