The Involvement of Neuroinflammation and Kynurenine Pathway in Parkinson's Disease

Parkinson's disease (PD) is a common neurodegenerative disorder characterised by loss of dopaminergic neurons and localized neuroinflammation occurring in the midbrain several years before the actual onset of symptoms. Activated microglia themselves release a large number of inflammatory mediators thus perpetuating neuroinflammation and neurotoxicity. The Kynurenine pathway (KP), the main catabolic pathway for tryptophan, is one of the major regulators of the immune response and may also be implicated in the inflammatory response in parkinsonism. The KP generates several neuroactive compounds and therefore has either a neurotoxic or neuroprotective effect. Several of these molecules produced by microglia can activate the N-methyl-D-aspartate (NMDA) receptor-signalling pathway, leading to an excitotoxic response. Previous studies have shown that NMDA antagonists can ease symptoms and exert a neuroprotective effect in PD both in vivo and in vitro. There are to date several lines of evidence linking some of the KP intermediates and the neuropathogenesis of PD. Moreover, it is likely that pharmacological modulation of the KP will represent a new therapeutic strategy for PD

A new perspective for the training assessment: Machine learning-based neurometric for augmented user's evaluation

Inappropriate training assessment might have either high social costs and economic impacts, especially in high risks categories, such as Pilots, Air Traffic Controllers, or Surgeons. One of the current limitations of the standard training assessment procedures is the lack of information about the amount of cognitive resources requested by the user for the correct execution of the proposed task. In fact, even if the task is accomplished achieving the maximum performance, by the standard training assessment methods, it would not be possible to gather and evaluate information about cognitive resources available for dealing with unexpected events or emergency conditions. Therefore, a metric based on the brain activity (neurometric) able to provide the Instructor such a kind of information should be very important. As a first step in this direction, the Electroencephalogram (EEG) and the performance of 10 participants were collected along a training period of 3 weeks, while learning the execution of a new task. Specific indexes have been estimated from the behavioral and EEG signal to objectively assess the users' training progress. Furthermore, we proposed a neurometric based on a machine learning algorithm to quantify the user's training level within each session by considering the level of task execution, and both the behavioral and cognitive stabilities between consecutive sessions. The results demonstrated that the proposed methodology and neurometric could quantify and track the users' progresses, and provide the Instructor information for a more objective evaluation and better tailoring of training programs. © 2017 Borghini, Aricò, Di Flumeri, Sciaraffa, Colosimo, Herrero, Bezerianos, Thakor and Babiloni

Increased mRNA expression of cytochrome oxidase in dorsal raphe nucleus of depressive suicide victims

Suicidal behavior is a problem with important social repercussions. Some groups of the population show a higher risk of suicide; for example, depression, alcoholism, psychosis or drug abuse frequently precedes suicidal behavior. However, the relationship between metabolic alterations in the brain and premorbid clinical symptoms of suicide remains uncertain. The serotonergic and noradrenergic systems have frequently been, implicated in suicidal behavior and the amount of serotonin in the brain and CSF of suicide victims has been found to be low compared with normal subjects. However, there are contradictory results regarding the role of noradrenergic neurons in the mediation of suicide attempts, possibly reflecting the heterogeneity of conditions that lead to a common outcome. In the present work we focus on the subgroup of suicide victims that share a common diagnosis of major depression. Based on post-mortem studies analyzing mRNA expression by in situ hybridization, serotonergic neurons from the dorsal raphe nucleus (DRN) from depressive suicide victims are seen to over-express cytochrome oxidase mRNA. However, no corresponding changes were found in the expression of tyrosine hydroxylase (TH) mRNA in the noradrenergic neurons of the Locus Coeruleus (LC). These results suggest that, despite of the low levels of serotonin described in suicide victims, the activity of DRN neurons could increase in the suicidally depressed, probably due to the over activation of serotonin re-uptake. No alteration was found in noradrenergic neurons, suggesting that they play no crucial role in the suicidal behavior of depressive patients

Eeg frontal asymmetry related to pleasantness of olfactory stimuli in young subjects

It is widely known, in neuroscientific literature, that the brain prefrontal cortex activity asymmetry is closely linked with the pleasantness emotion experienced by the subject during a sensorial stimulation. Thus, from the electroencephalographic (EEG) signal it is possible to estimate the approach/withdrawal index, and this index has been largely investigated and validated in scientific literature, regarding visual and acoustic stimuli. In this work, we present an innovative study aimed to prove, in a systematic way, that such brain AW index is actually correlated with the “pleasant” or “no-pleasant” perception also of olfactory stimuli, conveniently produced by standardised methods in the sensory specific scientific literature. In particular, we recorded the electroencephalographic (EEG) signal from a group, gender balanced, of 24 healthy and no-smokers subjects during the perception of ten different smells, presented by means of the “Screening test-odour identification” set (Sniffin’ sticks, Burghart). The cerebral AW indexes of all the subjects, for each odorous stimulus, were compared with the appreciation numeric score assessed by the subject during the experiment, by performing a statistical correlation test. Findings show that it is possible to evaluate the pleasantness or no-pleasantness of odorous substances by means of the analysis of EEG signals collected during the presentation of such substances, making way for new applications of such measure kind in experimental environments more and more ecological, as the typical ones of the marketing research areas

Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism

Inflammation is a predominant aspect of neurodegenerative diseases, manifested by glia activation and expression of pro-inflammatory mediators. Studies on animal models of Parkinson’s disease (PD) suggest that sustained neuroinflammation exacerbates degeneration of the dopaminergic (DA) nigro-striatal pathway. Therefore, insights into the inflammatory mechanisms of PD may help the development of novel therapeutic strategies against this disease. As extracellular matrix metalloproteinases (MMPs) could be major players in the progression of Parkinsonism, we investigated, in the substantia nigra and striatum of mice acutely injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), changes in mRNA expression, protein levels, and cell localization of MMP-9. This protease is mainly neuronal, but early after MPTP injection its mRNA and protein levels, as well as the number of MMP-9-expressing microglia and astrocytes, increase concomitantly to a prominent inflammation. Neuroinflammation and MMP-9+ glia begin to decline within 2 weeks, although protein levels remain higher than control, in association with a partial recovery of DA nigro-striatal circuit. Comparable quantitative studies on MMP-9 knock-out mice, show a significant decrease in both glia activation and loss of DA neurons and fibers, with respect to wild-type. Moreover, in a parallel study on chronically MPTP-injected macaques, we observed that perpetuation of inflammation and high levels of MMP-9 are associated to DA neuron loss. Our data suggest that MMP-9 released by injured neurons favors glia activation; glial cells in turn reinforce their reactive state via autocrine MMP-9 release, contributing to nigro-striatal pathway degeneration. Specific modulation of MMP-9 activity may, therefore, be a strategy to ameliorate harmful inflammatory outcomes in Parkinsonism

Evidence of oligodendrogliosis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism

Aims: Mice and nonhuman primates administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) represent elective experimental models of Parkinsonism, in which degeneration of the nigrostriatal dopaminergic pathway is associated with prominent neuroinflammation, characterized by activated microglia and astrocytes in both substantia nigra (SN) and striatum. To date, it is unknown whether oligodendrocytes play a role in these events. Methods: We performed a detailed qualitative and quantitative analysis of oligodendrocyte-associated changes induced by acute and chronic MPTP treatment, in the SN and striatum of mice and macaques respectively. Oligodendrocytes were immunolabelled by cell-specific markers and analysed by confocal microscopy. Results: In both experimental models, MPTP treatment induces an increase in oligodendrocyte cell number and average size, as well as in the total area occupied by this cell type per tissue section, accompanied by evident morphological changes. This multifaceted array of changes, herein referred to as oligodendrogliosis, significantly correlates with the reduction in the level of dopaminergic innervation to the striatum. Conclusions: This event, associated with early damage of the dopaminergic neurone axons and of the complex striatal circuits of which they are part, may result in an important, although neglected, aspect in the onset and progression of Parkinsonism

CCL2-Expressing Astrocytes Mediate the Extravasation of T Lymphocytes in the Brain. Evidence from Patients with Glioma and Experimental Models In Vivo

CCL2 is a chemokine involved in brain inflammation, but the way in which it contributes to the entrance of lymphocytes in the parenchyma is unclear. Imaging of the cell type responsible for this task and details on how the process takes place in vivo remain elusive. Herein, we analyze the cell type that overexpresses CCL2 in multiple scenarios of T-cell infiltration in the brain and in three different species. We observe that CCL2+ astrocytes play a part in the infiltration of T-cells in the brain and our analysis shows that the contact of T-cells with perivascular astrocytes occurs, suggesting that may be an important event for lymphocyte extravasation

A New Perspective for the Training Assessment: Machine Learning-Based Neurometric for Augmented User's Evaluation

Inappropriate training assessment might have either high social costs and economic impacts, especially in high risks categories, such as Pilots, Air Traffic Controllers, or Surgeons. One of the current limitations of the standard training assessment procedures is the lack of information about the amount of cognitive resources requested by the user for the correct execution of the proposed task. In fact, even if the task is accomplished achieving the maximum performance, by the standard training assessment methods, it would not be possible to gather and evaluate information about cognitive resources available for dealing with unexpected events or emergency conditions. Therefore, a metric based on the brain activity (neurometric) able to provide the Instructor such a kind of information should be very important. As a first step in this direction, the Electroencephalogram (EEG) and the performance of 10 participants were collected along a training period of 3 weeks, while learning the execution of a new task. Specific indexes have been estimated from the behavioral and EEG signal to objectively assess the users' training progress. Furthermore, we proposed a neurometric based on a machine learning algorithm to quantify the user's training level within each session by considering the level of task execution, and both the behavioral and cognitive stabilities between consecutive sessions. The results demonstrated that the proposed methodology and neurometric could quantify and track the users' progresses, and provide the Instructor information for a more objective evaluation and better tailoring of training programs

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe