From the periphery to the brain: Lipocalin-2, a friend or foe?

Lipocalin-2 (LCN2) is an acute-phase protein that, by binding to iron-loaded siderophores, acts as a potent bacteriostatic agent in the iron-depletion strategy of the immune system to control pathogens. The recent identification of a mammalian siderophore also suggests a physiological role for LCN2 in iron homeostasis, specifically in iron delivery to cells via a transferrin-independent mechanism. LCN2 participates, as well, in a variety of cellular processes, including cell proliferation, cell differentiation and apoptosis, and has been mostly found up-regulated in various tissues and under inflammatory states, being its expression regulated by several inducers. In the central nervous system less is known about the processes involving LCN2, namely by which cells it is produced/secreted, and its impact on cell proliferation and death, or in neuronal plasticity and behaviour. Importantly, LCN2 recently emerged as a potential clinical biomarker in multiple sclerosis and in ageing-related cognitive decline. Still, there are conflicting views on the role of LCN2 in pathophysiological processes, with some studies pointing to its neurodeleterious effects, while others indicate neuroprotection. Herein, these various perspectives are reviewed and a comprehensive and cohesive view of the general function of LCN2, particularly in the brain, is provided.

Assessing the application of polypropylene multifilament yarns in brain phantoms

The currently available clinical imaging methods do not provide highly detailed information about location and severity of axonal injury or the expected recovery time of patients with traumatic brain injury [1]. High-Definition Fiber Tractography (HDFT) is a novel imaging modality that allows visualizing and quantifying, directly, the degree of axons damage, predicting functional deficits due to traumatic axonal injury and loss of cortical projections. This imaging modality is based on diffusion technology [2]. The inexistence of a phantom able to mimic properly the human brain hinders the possibility of testing, calibrating and validating these medical imaging techniques. Most research done in this area fails in key points, such as the size limit reproduced of the brain fibers and the quick and easy reproducibility of phantoms [3]. For that reason, it is necessary to develop similar structures matching the micron scale of axon tubes. Flexible textiles can play an important role since they allow producing controlled packing densities and crossing structures that match closely the human crossing patterns of the brain. To build a brain phantom, several parameters must be taken into account in what concerns to the materials selection, like hydrophobicity, density and fiber diameter, since these factors influence directly the values of fractional anisotropy. Fiber cross-section shape is other important parameter. Earlier studies showed that synthetic fibrous materials are a good choice for building a brain phantom [4]. The present work is integrated in a broader project that aims to develop a brain phantom made by fibrous materials to validate and calibrate HDFT. Due to the similarity between thousands of hollow multifilaments in a fibrous arrangement, like a yarn, and the axons, low twist polypropylene multifilament yarns were selected for this development. In this sense, extruded hollow filaments were analysed in scanning electron microscope to characterize their main dimensions and shape. In order to approximate the dimensional scale to human axons, five types of polypropylene yarns with different linear density (denier) were used, aiming to understand the effect of linear density on the filament inner and outer areas. Moreover, in order to achieve the required dimensions, the polypropylene filaments cross-section was diminished in a drawing stage of a filament extrusion line. Subsequently, tensile tests were performed to characterize the mechanical behaviour of hollow filaments and to evaluate the differences between stretched and non-stretched filaments. In general, an increase of the linear density causes the increase in the size of the filament cross section. With the increase of structure orientation of filaments, induced by stretching, breaking tenacity increases and elongation at break decreases. The production of hollow fibers, with the required characteristics, is one of the key steps to create a brain phantom that properly mimics the human brain that may be used for the validation and calibration of HDFT, an imaging approach that is expected to contribute significantly to the areas of brain related research.

Biological markers in noninvasive brain stimulation trials in major depressive disorder: a systematic review

Objectives: The therapeutic effects of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation in patients with major depression have shown promising results; however, there is a lack of mechanistic studies using biological markers (BMs) as an outcome. Therefore, our aim was to review noninvasive brain stimulation trials in depression using BMs. Methods: The following databases were used for our systematic review: MEDLINE, Web of Science, Cochrane, and SCIELO. We examined articles published before November 2012 that used TMS and transcranial direct current stimulation as an intervention for depression and had BM as an outcome measure. The search was limited to human studies written in English. Results: Of 1234 potential articles, 52 articles were included. Only studies using TMS were found. Biological markers included immune and endocrine serum markers, neuroimaging techniques, and electrophysiological outcomes. In 12 articles (21.4%), end point BM measurements were not significantly associated with clinical outcomes. All studies reached significant results in the main clinical rating scales. Biological marker outcomes were used as predictors of response, to understand mechanisms of TMS, and as a surrogate of safety. Conclusions: Functional magnetic resonance imaging, single-photon emission computed tomography, positron emission tomography, magnetic resonance spectroscopy, cortical excitability, and brain-derived neurotrophic factor consistently showed positive results. Brain-derived neurotrophic factor was the best predictor of patients’ likeliness to respond. These initial results are promising; however, all studies investigating BMs are small, used heterogeneous samples, and did not take into account confounders such as age, sex, or family history. Based on our findings, we recommend further studies to validate BMs in noninvasive brain stimulation trials in MDD.

Cognitive rehabilitation in a visual variant of Alzheimer's disease

Alzheimer's disease (AD) is commonly associated with marked memory deficits; however, nonamnestic variants have been consistently described as well. Posterior cortical atrophy (PCA) is a progressive degenerative condition in which posterior regions of the brain are predominantly affected, therefore resulting in a pattern of distinctive and marked visuospatial symptoms, such as apraxia, alexia, and spatial neglect. Despite the growing number of studies on cognitive and neural bases of the visual variant of AD, intervention studies remain relatively sparse. Current pharmacological treatments offer modest efficacy. Also, there is a scarcity of complementary nonpharmacological interventions with only two previous studies of PCA. Here we describe a highly educated 57-year-old patient diagnosed with a visual variant of AD who participated in a cognitive intervention program (comprising reality orientation, cognitive stimulation, and cognitive training exercises). Neuropsychological assessment was performed across moments (baseline, postintervention, follow-up) and consisted mainly of verbal and visual memory. Baseline neuropsychological assessment showed deficits in perceptive and visual-constructive abilities, learning and memory, and temporal orientation. After neuropsychological rehabilitation, we observed small improvements in the patient's cognitive functioning, namely in verbal memory, attention, and psychomotor abilities. This study shows evidence of small beneficial effects of cognitive intervention in PCA and is the first report of this approach with a highly educated patient in a moderate stage of the disease. Controlled studies are needed to assess the potential efficacy of cognition-focused approaches in these patients, and, if relevant, to grant their availability as a complementary therapy to pharmacological treatment and visual aids.

[Letter to the editor] Sustained effects of a neural-based intervention in a refractory case of Tourette syndrome

There are only a few treatments available for Tourette syndrome (TS). These treatments frequently do notwork in patients with moderate to severe TS [1]. Neuroimaging studies show a correlation between tics severity and increased activation over motor pathways, along with reduced activation over the control areas of the cortico-striato-thalamo-cortical circuits [2]. Moreover, the temporal pattern of tic generation suggests that cortical activation especially in the SMA precedes subcortical activation [3]. Following this assumption, here we explored the brain effects of 10-daily sessions of cathodal transcranial Direct Current Stimulation (tDCS) delivered over the pre-SMA in a patient with refractory and severe TS and also assessed whether those changes were long lasting (up to 6 months).

Evaluating balance, stability and gait symmetry of stroke patients using kinematic and dynamic gait lab data

Dissertação de mestrado integrado em Engenharia Biomédica

Pervasive patient timeline

Dissertação de mestrado integrado em Engenharia e Gestão de Sistemas de Informação

Neurocognitive profile and cognitive intervention in Alzheimer's disease

Tese de Doutoramento em Psicologia (Especialidade de Psicologia Clínica)

A network approach to brain aging through multimodal neuroimaging

Tese de Doutoramento em Ciências da Saúde.

Nanotechnological approaches using curcumin and Withania somnifera: neuroprotection and antimicrobial activities

Tese de Doutoramento em Biologia de Plantas

Psychosis associated with methimazole-induced hypothyroidism: a case report

INTRODUCTION: Thyroid dysfunction has often been associated with several psychiatric manifestations. Previous case reports/series suggest the possible role played by acute alteration of thyroid status in the onset of psychotic symptoms. METHODS: Case report and literature review. RESULTS: A 45-year-old woman with no psychiatric antecedents was brought to the ER with a full-blown psychotic episode, marked by paranoid delusions, which developed gradually over two months. She had been treated elsewhere for hyperthyroidism for five years with methimazole 40 mg/d, with poor compliance. One month before the beginning of the psychotic symptoms, methimazole was raised to 60 mg/d and she started taking it correctly. Five months earlier she had TSH: 0.074 uUI/ml and free T4: 1.3 ng/dl. At admission we found a diffuse thyroid goiter, TSH: 70.9 uUI/ml and free T4: 0.03 ng/dl. Brain CT was normal. We hospitalized her with the diagnosis of a psychosis secondary to hypothyroidism, suspended methimazole, and gave her levothyroxine (up to 75 µg/d) and risperidone (2 mg/d). The patient had a quick remission and was discharged after 15 days. Within one month she had TSH: 0.7 uUI/ml and was completely recovered psychiatrically. She has been well since then, with risperidone in the first 8 months, and without it for 10 months now. CONCLUSION: This case report is a reminder of the necessity of checking thyroid status as part of clinical assessment of psychoses. It also supports the hypothesis that antithyroid drugs may have severe psychiatric consequences, especially when they lead to an acute change of thyroid status.

Impact of TGF-ß1 -509C/T and 869T/C polymorphisms on glioma risk and patient prognosis

Transforming growth factor beta (TGF-ß) plays an important role in carcinogenesis. Two polymorphisms in the TGF-ß1 gene (-509C/T and 869T/C) were described to influence susceptibility to gastric and breast cancers. The 869T/C polymorphism was also associated with overall survival in breast cancer patients. In the present study, we investigated the relevance of these TGF-ß1 polymorphism in glioma risk and prognosis. A case-control study that included 114 glioma patients and 138 cancer-free controls was performed. Single nucleotide polymorphisms (SNPs) were evaluated by polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP). Univariate and multivariate logistic regression analyses were used to calculate odds ratio (OR) and 95 % confidence intervals (95 % CI). The influence of TGF-ß1 -509C/T and 869T/C polymorphisms on glioma patient survival was evaluated by a Cox regression model adjusted for patients' age and sex and represented in Kaplan-Meier curves. Our results demonstrated that TGF-ß1 gene polymorphisms -509C/T and 869T/C are not significantly associated with glioma risk. Survival analyses showed that the homozygous -509TT genotype associates with longer overall survival of glioblastoma (GBM) patients when compared with patients carrying CC + CT genotypes (OR, 2.41; 95 % CI, 1.06-5.50; p = 0.036). In addition, the homozygous 869CC genotype is associated with increased overall survival of GBM patients when compared with 869TT + TC genotypes (OR, 2.62; 95 % CI, 1.11-6.17; p = 0.027). In conclusion, this study suggests that TGF-ß1 -509C/T and 869T/C polymorphisms are not significantly associated with risk for developing gliomas but may be relevant prognostic biomarkers in GBM patients.

Cotard syndrome without depressive symptoms in a schizophrenic patient

Cotard Syndrome without Depressive Symptoms in a Schizophrenic Patient

The bounds of education in the human brain connectome

Inter-individual heterogeneity is evident in aging; education level is known to contribute for this heterogeneity. Using a cross-sectional study design and network inference applied to resting-state fMRI data, we show that aging was associated with decreased functional connectivity in a large cortical network. On the other hand, education level, as measured by years of formal education, produced an opposite effect on the long-term. These results demonstrate the increased brain efficiency in individuals with higher education level that may mitigate the impact of age on brain functional connectivity.