nNOS(+) striatal neurons, a subpopulation spared in Huntington's Disease, possess functional NMDA receptors but fail to generate mitochondrial ROS in response to an excitotoxic challenge.

Huntington's disease (HD) is a neurodegenerative condition characterized by severe neuronal loss in the cortex and striatum that leads to motor and behavioral deficits. Excitotoxicity is thought to be involved in HD and several studies have indicated that NMDA receptor (NMDAR) overactivation can play a role in the selective neuronal loss found in HD. Interestingly, a small subset of striatal neurons (less than 1% of the overall population) is found to be spared in post-mortem HD brains. These neurons are medium-sized aspiny interneurons that highly express the neuronal isoform of nitric oxide synthase (nNOS). Intriguingly, neurons expressing large amounts of nNOS [hereafter indicated as nNOS(+) neurons] show reduced vulnerability to NMDAR-mediated excitotoxicity. Mechanisms underlying this reduced vulnerability are still largely unknown and may shed some light on pathogenic mechanisms involved in HD. One untested possibility is that nNOS(+) neurons possess fewer or less functioning NMDARs. Employing single cell calcium imaging we challenged this hypothesis and found that cultured striatal nNOS(+) neurons show NMDAR-evoked responses that are identical to the ones observed in the overall population of neurons that express lower levels of nNOS [nNOS(-) neurons]. NMDAR-dependent deregulation of intraneuronal Ca(2+) is known to generate high levels of reactive oxygen species of mitochondrial origin (mt-ROS), a crucial step in the excitotoxic cascade. With confocal imaging and dihydrorhodamine (DHR; a ROS-sensitive probe) we compared mt-ROS levels generated by NMDAR activation in nNOS(+) and (-) cultured striatal neurons. DHR experiments revealed that nNOS(+) neurons failed to produce significant amounts of mt-ROS in response to NMDA exposure, thereby providing a potential mechanism for their reduced vulnerability to excitotoxicity and decreased vulnerability in HD

Modafinil-Induced changes in functional connectivity in the cortex and cerebellum of healthy elderly subjects

In the past few years, cognitive enhancing drugs (CEDs) have gained growing interest and the focus of investigations aimed at exploring their use to potentiate the cognitive performances of healthy individuals. Most of this exploratory CED-related research has been performed on young adults. However, CEDs may also help to maintain optimal brain functioning or compensate for subtle and or subclinical deficits associated with brain aging or early-stage dementia. In this study, we assessed effects on resting state brain activity in a group of healthy elderly subjects undergoing acute administration of modafinil, a wakefulness-promoting agent. To that aim, participants (n = 24) were investigated with resting state functional Magnetic Resonance Imaging (rs-fMRI) before and after the administration of a single dose (100 mg) of modafinil. Effects were compared to age and size-matched placebo group. Rs-fMRI effects were assessed, employing a graph-based approach and Eigenvector Centrality (EC) analysis, by taking in account topological changes occurring in functional brain networks. The main finding of the study is that modafinil promotes enhanced centrality, a measure of the importance of nodes within functional networks, of the bilateral primary visual (V1) cortex. EC analysis also revealed that modafinil-treated subjects show increased functional connectivity between the V1 and specific cerebellar (Crus I, Crus II, VIIIa lobule) and frontal (right inferior frontal sulcus and left middle frontal gyrus) regions. Present findings provide functional data supporting the hypothesis that modafinil can modulate the cortico-cerebellar connectivity of the aging brai

Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer's disease mouse model.

Altered neuronal excitability is emerging as an important feature in Alzheimer's disease (AD). Kv2.1 potassium channels are important modulators of neuronal excitability and synaptic activity. We investigated Kv2.1 currents and its relation to the intrinsic synaptic activity of hippocampal neurons from 3xTg-AD (triple transgenic mouse model of Alzheimer's disease) mice, a widely employed preclinical AD model. Synaptic activity was also investigated by analyzing spontaneous [Ca(2+)]i spikes. Compared with wild-type (Non-Tg (non-transgenic mouse model)) cultures, 3xTg-AD neurons showed enhanced spike frequency and decreased intensity. Compared with Non-Tg cultures, 3xTg-AD hippocampal neurons revealed reduced Kv2.1-dependent Ik current densities as well as normalized conductances. 3xTg-AD cultures also exhibited an overall decrease in the number of functional Kv2.1 channels. Immunofluorescence assay revealed an increase in Kv2.1 channel oligomerization, a condition associated with blockade of channel function. In Non-Tg neurons, pharmacological blockade of Kv2.1 channels reproduced the altered pattern found in the 3xTg-AD cultures. Moreover, compared with untreated sister cultures, pharmacological inhibition of Kv2.1 in 3xTg-AD neurons did not produce any significant modification in Ik current densities. Reactive oxygen species (ROS) promote Kv2.1 oligomerization, thereby acting as negative modulator of the channel activity. Glutamate receptor activation produced higher ROS levels in hippocampal 3xTg-AD cultures compared with Non-Tg neurons. Antioxidant treatment with N-Acetyl-Cysteine was found to rescue Kv2.1-dependent currents and decreased spontaneous hyperexcitability in 3xTg-AD neurons. Analogous results regarding spontaneous synaptic activity were observed in neuronal cultures treated with the antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Our study indicates that AD-related mutations may promote enhanced ROS generation, oxidative-dependent oligomerization, and loss of function of Kv2.1 channels. These processes can be part on the increased neuronal excitability of these neurons. These steps may set a deleterious vicious circle that eventually helps to promote excitotoxic damage found in the AD brain

Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO

Right-sided metastatic colorectal cancer (mCRC) patients have poor prognosis and achieve limited benefit from first-line doublets plus a targeted agent. In this unplanned analysis of the TRIBE study, we investigated the prognostic and predictive impact of primary tumor sidedness in mCRC patients and the differential impact of the intensification of the chemotherapy in subgroups defined according to both primary tumor sidedness and RAS and BRAF mutational status

Cognitive reserve in granulin-related frontotemporal dementia: from preclinical to clinical stages

OBJECTIVE Consistent with the cognitive reserve hypothesis, higher education and occupation attainments may help persons with neurodegenerative dementias to better withstand neuropathology before developing cognitive impairment. We tested here the cognitive reserve hypothesis in patients with frontotemporal dementia (FTD), with or without pathogenetic granulin mutations (GRN+ and GRN-), and in presymptomatic GRN mutation carriers (aGRN+). METHODS Education and occupation attainments were assessed and combined to define Reserve Index (RI) in 32 FTD patients, i.e. 12 GRN+ and 20 GRN-, and in 17 aGRN+. Changes in functional connectivity were estimated by resting state fMRI, focusing on the salience network (SN), executive network (EN) and bilateral frontoparietal networks (FPNs). Cognitive status was measured by FTD-modified Clinical Dementia Rating Scale. RESULTS In FTD patients higher level of premorbid cognitive reserve was associated with reduced connectivity within the SN and the EN. EN was more involved in FTD patients without GRN mutations, while SN was more affected in GRN pathology. In aGRN+, cognitive reserve was associated with reduced SN. CONCLUSIONS This study suggests that cognitive reserve modulates functional connectivity in patients with FTD, even in monogenic disease. In GRN inherited FTD, cognitive reserve mechanisms operate even in presymptomatic to clinical stages

Treatment challenges in and outside a network setting: Head and neck cancers

Head and neck cancer (HNC) is a rare disease that can affect different sites and is characterized by variable incidence and 5-year survival rates across Europe. Multiple factors need to be considered when choosing the most appropriate treatment for HNC patients, such as age, comorbidities, social issues, and especially whether to prefer surgery or radiation-based protocols. Given the complexity of this scenario, the creation of a highly specialized multidisciplinary team is recommended to guarantee the best oncological outcome and prevent or adequately treat any adverse effect. Data from literature suggest that the multidisciplinary team-based approach is beneficial for HNC patients and lead to improved survival rates. This result is likely due to improved diagnostic and staging accuracy, a more efficacious therapeutic approach and enhanced communication across disciplines. Despite the benefit of MTD, it must be noted that this approach requires considerable time, effort and financial resources and is usually more frequent in highly organized and high-volume centers. Literature data on clinical research suggest that patients treated in high-accrual centers report better treatment outcomes compared to patients treated in low-volume centers, where a lower radiotherapy-compliance and worst overall survival have been reported. There is general agreement that treatment of rare cancers such as HNC should be concentrated in high volume, specialized and multidisciplinary centers. In order to achieve this goal, the creation of international collaboration network is fundamental. The European Reference Networks for example aim to create an international virtual advisory board, whose objectives are the exchange of expertise, training, clinical collaboration and the reduction of disparities and enhancement of rationalize migration across Europe. The purpose of our work is to review all aspects and challenges in and outside this network setting planned for the management of HNC patients

Standardized evaluation of algorithms for computer-aided diagnosis of dementia based on structural MRI: the CADDementia challenge

Algorithms for computer-aided diagnosis of dementia based on structural MRI have demonstrated high performance in the literature, but are difficult to compare as different data sets and methodology were used for evaluation. In addition, it is unclear how the algorithms would perform on previously unseen data, and thus, how they would perform in clinical practice when there is no real opportunity to adapt the algorithm to the data at hand. To address these comparability, generalizability and clinical applicability issues, we organized a grand challenge that aimed to objectively compare algorithms based on a clinically representative multi-center data set. Using clinical practice as the starting point, the goal was to reproduce the clinical diagnosis. Therefore, we evaluated algorithms for multi-class classification of three diagnostic groups: patients with probable Alzheimer's disease, patients with mild cognitive impairment and healthy controls. The diagnosis based on clinical criteria was used as reference standard, as it was the best available reference despite its known limitations. For evaluation, a previously unseen test set was used consisting of 354 T1-weighted MRI scans with the diagnoses blinded. Fifteen research teams participated with a total of 29 algorithms. The algorithms were trained on a small training set (n = 30) and optionally on data from other sources (e.g., the Alzheimer's Disease Neuroimaging Initiative, the Australian Imaging Biomarkers and Lifestyle flagship study of aging). The best performing algorithm yielded an accuracy of 63.0% and an area under the receiver-operating-characteristic curve (AUC) of 78.8%. In general, the best performances were achieved using feature extraction based on voxel-based morphometry or a combination of features that included volume, cortical thickness, shape and intensity. The challenge is open for new submissions via the web-based framework: http://caddementia.grand-challenge.org