1,721,218 research outputs found
Catechol-O-methyl transferase modulates cognition in late life: Evidence and implications for cognitive enhancement
No full textAging is associated with deficits in several cognitive domains as well as a decline in brain dopamine activity. Catechol-O-methyl transferase (COMT), an enzyme involved in the degradation of dopamine, is a critical determinant of the availability of this neurotransmitter in the prefrontal cortex. A functional single nucleotide polymorphism in the COMT gene, Val158Met, modulates the activity of this enzyme and affects cognition and the brain regions underlying this function. The effects of COMT Val158Met polymorphism are magnified in the aging brain. Here, we review the evidence supporting a role of COMT genetic variation in cognitive as well as structural and functional brain changes associated with senescence. We will address the potential modulatory role of genetic and non-genetic factors on the neural and cognitive effects of COMT Val158Met in late life. Furthermore, we will discuss the viability of a COMT-targeted treatment for improving cognitive efficiency in aging
Cell-autonomous and non-cell-autonomous toxicity in polyglutamine diseases
No full textPolyglutamine diseases are neurodegenerative disorders caused by expansion of polyglutamine tracts in the coding regions of specific genes. One of the most important features of polyglutamine diseases is that, despite the widespread and in some cases ubiquitous expression of the polyglutamine proteins, specific populations of neurons degenerate in each disease. This finding has led to the idea that polyglutamine diseases are cell-autonomous diseases, in which selective neuronal dysfunction and death result from damage caused by the mutant protein within the targeted neuronal population itself. Development of animal models for conditional expression of polyglutamine proteins, along with new pharmacologic manipulation of polyglutamine protein expression and toxicity, has led to a remarkable change of the current view of polyglutamine diseases as cell-autonomous disorders. It is becoming evident that toxicity in the neighboring non-neuronal cells contributes to selective neuronal damage. This observation implies non-cell-autonomous mechanisms of neurodegeneration in polyglutamine diseases. Here, we describe cell-autonomous and non-cell-autonomous mechanisms of polyglutamine disease pathogenesis, including toxicity in neurons, skeletal muscle, glia, germinal cells, and other cell type
Post-translational Modifications and Protein Quality Control in Motor Neuron and Polyglutamine Diseases
Full text linkNeurodegenerative diseases, including motor neuron and polyglutamine (polyQ) diseases, are a broad class of neurological disorders. These diseases are characterized by neuronal dysfunction and death, and by the accumulation of toxic aggregation-prone proteins in the forms of inclusions and micro-aggregates. Protein quality control is a cellular mechanism to reduce the burden of accumulation of misfolded proteins, a function that results from the coordinated actions of chaperones and degradation systems, such as the ubiquitin-proteasome system (UPS) and autophagy-lysosomal degradation system. The rate of turnover, aggregation and degradation of the disease-causing proteins is modulated by post-translational modifications (PTMs), such as phosphorylation, arginine methylation, palmitoylation, acetylation, SUMOylation, ubiquitination, and proteolytic cleavage. Here, we describe how PTMs of proteins linked to motor neuron and polyQ diseases can either enhance or suppress protein quality control check and protein aggregation and degradation. The identification of molecular strategies targeting these modifications may offer novel avenues for the treatment of these yet incurable diseases
Whole-brain structural and functional neuroimaging of individuals who attempted suicide and people who did not: A systematic review and exploratory coordinate-based meta-analysis
Full text linkSuicide is the cause of death of approximately 800,000 people a year. Despite the relevance of this behaviour, risk assessment tools rely on clinician experience and subjective ratings. Given that previous suicide attempts are the single strongest predictors of future attempts, we designed a systematic review and coordinate-based meta-analysis to demonstrate whether neuroimaging features can help distinguish individuals who attempted suicide from subjects who did not. Out of 5,659 publications from PubMed, Scopus, and Web of Science, we summarised 102 experiments and meta-analysed 23 of them. A cluster in the right superior temporal gyrus, a region implicated in emotional processing, might be functionally hyperactive in individuals who attempted suicide. No statistically significant differences in brain morphometry were evidenced. Furthermore, we used JuSpace to show that this cluster is enriched in 5-HT1A heteroreceptors in the general population. This exploratory meta-analysis provides a putative neural substrate linked to previous suicide attempts. Heterogeneity in the analytical techniques and weak or absent power analysis of the studies included in this review currently limit the applicability of the findings, the replication of which should be prioritised
The effect of polygenic risk scores for major depressive disorder, bipolar disorder and schizophrenia on morphological brain measures: A systematic review of the evidence
No full textBackground: Major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SCZ) share clinical features and genetic bases. Magnetic Resonance Imaging (MRI) studies assessing the effect of polygenic risk score (PRS) for psychiatric disorders on brain structure show heterogeneous results. Therefore, we provided an overview of the existing evidence on the association between PRS for MDD, BD and SCZ and MRI abnormalities in clinical and healthy populations. Methods: A search on PubMed, Web of Science and Scopus was performed to identify the studies exploring the effect of PRS for MDD, BD and SCZ on MRI measures. A total of 25 studies were included (N = 13 on healthy individuals and N = 12 on clinical populations). Results: Both in affected and unaffected individuals, PRS for BD and SCZ showed either positive or negative correlations with cortical thickness (CT), mostly involving fronto-temporal areas, whereas PRS for MDD was associated with cortical alterations in prefrontal regions in healthy subjects. Limitations: The heterogeneity in the methods limits the conclusions of this review. Conclusions: Overall the evidence on the effect of PRS for MDD, BD and SCZ on brain is considerably heterogeneous and far to be conclusive. However, from the results emerged that PRS for MDD, BD and SCZ were associated with widespread cortical abnormalities in all the populations explored, suggesting that genetic risk for MDD, BD and SCZ might affect neurodevelopmental processes, resulting in cortical alterations that transcend diagnostic boundaries and seem to be independent from the clinical status
Structural and functional features of treatment-resistant depression: A systematic review and exploratory coordinate-based meta-analysis of neuroimaging studies
Full text linkObjectives: A third of people suffering from major depressive disorder do not experience a significant improvement in their symptoms even after adequate treatment with two different antidepressant medications. This common condition, termed treatment-resistant depression (TRD), severely affects the quality of life of millions of people worldwide, causing long-lasting interpersonal problems and social costs. Given its epidemiological and clinical relevance and the little consensus on whether the neurobiological underpinnings of TRD differ from treatment-sensitive depression (TSD), we sought to highlight the convergent morphometric and functional neuroimaging correlates of TRD. Methods: We systematically reviewed the published literature on structural and resting-state functional neuroimaging of TRD compared to TSD and healthy controls (HC) and performed exploratory coordinate-based meta-analyses (CBMA) of significant results separately for each modality and multimodally ("all-effects"). CBMAs were also performed for each direction and combining both directions of group contrasts. Results: Out of the initial 1929 studies, only eight involving 555 participants (189 patients with TRD, 156 with TSD, and 210 HC) were included. In all-effects CBMA, precentral/superior frontal gyrus showed a significant difference between TRD and HC. Functional and structural imaging meta-analyses did not yield statistically significant results. A marginally significant cluster of altered intrinsic activity was found between TRD and HC in the cerebellum/pons. Conclusions: Frontal, cerebellar, and brainstem functions can be involved in the pathophysiology of TRD. However, the design and heterogeneity of the (scarce) published literature hinder the generalizability of the findings. This article is protected by copyright. All rights reserved
Melatonin and melatonin‐agonists for metabolic syndrome components in patients treated with antipsychotics: A systematic review and meta‐analysis
No full textObjective: Metabolic side effects are a limiting factor in the use of antipsychotics, which remain the cornerstone of long-term management of patients with severe mental illness. There is contrasting evidence on a possible role of melatonin and melatonin-agonists in attenuating antipsychotic-induced metabolic abnormalities. Design: We conducted a systematic review (PubMed, PsycInfo, Cochrane databases, up to August 2020) and a random-effect meta-analysis of double-blind, randomized placebo-controlled trials (RCTs) involving melatonin and melatonin-agonists in the treatment of antipsychotic-induced metabolic changes. The primary outcome was the standardized mean difference (SMD) of composite metabolic outcomes built with metabolic syndrome components. Secondary outcomes were individual metabolic syndrome components, and other anthropometric, glucose metabolism, lipid profile, and psychopathology measures. Results: Out of the initial 41 studies, six documented five separate RCTs randomizing 248 patients (126 to melatonin/ramelteon, 122 to placebo) affected by schizophrenia-spectrum disorders and bipolar disorder. Melatonin/ramelteon outperformed placebo on the primary outcome (SMD -0.28, 95% CI = -0.39 ÷ -0.168), as well as on all individual components of metabolic syndrome (systolic blood pressure MD -3.266, 95% CI = -6.020 ÷ -0.511; fasting glucose MD -3.766, 95% CI = -5.938 ÷ -1.593; triglycerides MD -9.800, 95% CI = -19.431 ÷ -0.169; HDL MD 2.995, 95% CI = 0.567 ÷ 5.423), except waist circumference. Conclusions: Melatonin/ramelteon augmentation may be beneficial for non-anthropometric metabolic syndrome components in patients treated with antipsychotics
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