Effects of non-pharmacological or pharmacological interventions on cognition and brain plasticity of aging individuals.

Brain aging and aging-related neurodegenerative disorders are major health challenges faced by modern societies. Brain aging is associated with cognitive and functional decline and represents the favourable background for the onset and development of dementia. Brain aging is associated with early and subtle anatomo-functional physiological changes that often precede the appearance of clinical signs of cognitive decline. Neuroimaging approaches unveiled the functional correlates of these alterations and helped in the identification of therapeutic targets that can be potentially useful in counteracting age-dependent cognitive decline. A growing body of evidence supports the notion that cognitive stimulation and aerobic training can preserve and enhance operational skills in elderly individuals as well as reduce the incidence of dementia. This review aims at providing an extensive and critical overview of the most recent data that support the efficacy of non-pharmacological and pharmacological interventions aimed at enhancing cognition and brain plasticity in healthy elderly individuals as well as delaying the cognitive decline associated with dementia

Elevated plasma ceramide levels in post-menopausal women: a cross-sectional study.

Circulating ceramide levels are abnormally elevated in age-dependent pathologies such as cardiovascular diseases, obesity and Alzheimer's disease. Nevertheless, the potential impact of age on plasma ceramide levels has not yet been systematically examined. In the present study, we quantified a focused panel of plasma ceramides and dihydroceramides in a cohort of 164 subjects (84 women) 19 to 80 years of age. After adjusting for potential confounders, multivariable linear regression analysis revealed a positive association between age and ceramide (d18:1/24:0) (β (SE) = 5.67 (2.38); p = .0198) and ceramide (d18:1/24:1) (β (SE) = 2.88 (.61); p < .0001) in women, and between age and ceramide (d18:1/24:1) in men (β (SE) = 1.86 (.77); p = .0179). In women of all ages, but not men, plasma ceramide (d18:1/24:1) was negatively correlated with plasma estradiol (r = -0.294; p = .007). Finally, in vitro experiments in human cancer cells expressing estrogen receptors showed that incubation with estradiol (10 nM, 24 h) significantly decreased ceramide accumulation. Together, the results suggest that aging is associated with an increase in circulating ceramide levels, which in post-menopausal women is at least partially associated with lower estradiol levels

The mitochondrial Na+/Ca2+ exchanger upregulates glucose dependent Ca2+ signalling linked to insulin secretion.

Mitochondria mediate dual metabolic and Ca(2+) shuttling activities. While the former is required for Ca(2+) signalling linked to insulin secretion, the role of the latter in β cell function has not been well understood, primarily because the molecular identity of the mitochondrial Ca(2+) transporters were elusive and the selectivity of their inhibitors was questionable. This study focuses on NCLX, the recently discovered mitochondrial Na(+)/Ca(2+) exchanger that is linked to Ca(2+) signalling in MIN6 and primary β cells. Suppression either of NCLX expression, using a siRNA construct (siNCLX) or of its activity, by a dominant negative construct (dnNCLX), enhanced mitochondrial Ca(2+) influx and blocked efflux induced by glucose or by cell depolarization. In addition, NCLX regulated basal, but not glucose-dependent changes, in metabolic rate, mitochondrial membrane potential and mitochondrial resting Ca(2+). Importantly, NCLX controlled the rate and amplitude of cytosolic Ca(2+) changes induced by depolarization or high glucose, indicating that NCLX is a critical and rate limiting component in the cross talk between mitochondrial and plasma membrane Ca(2+) signalling. Finally, knockdown of NCLX expression was followed by a delay in glucose-dependent insulin secretion. These findings suggest that the mitochondrial Na(+)/Ca(2+) exchanger, NCLX, shapes glucose-dependent mitochondrial and cytosolic Ca(2+) signals thereby regulating the temporal pattern of insulin secretion in β cells

The pharmacological perturbation of brain zinc impairs BDNF-related signaling and the cognitive performances of young mice.

Zinc (Zn2+) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn2+ levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn2+ affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn2+ levels, we employed the Zn2+ (and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signaling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn2+ was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine density in vivo. Our study highlights the importance of choosing "when", "where", and "how much" in the modulation of brain Zn2+ levels. Our findings confirm the importance of targeting Zn2+ as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn2+ availability upon the early stages of development

Inhibition of de novo ceramide biosynthesis affects aging phenotype in an in vitro model of neuronal senescence.

Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be counteracted. Intracellular calcium (Ca2+i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a pleiotropic class of sphingolipids, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored. In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of thede novoceramide biosynthesis, on the aging phenotype of cortical neurons cultured for 22 days, a setting employed as anin vitromodel of senescence. Our findings indicate that, compared to control cultures, 'aged' neurons display dysregulation of [Ca2+]ilevels, mitochondrial dysfunction, increased generation of reactive oxygen species (ROS), altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS positively affected the senescent phenotype, a result associated with recovery of neuronal [Ca2+]isignaling and reduction of mitochondrial dysfunction and ROS generation. The results suggest that thede novoceramide biosynthesis represents a critical intermediate in the molecular and functional cascade leading to neuronal senescence and identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease age-related neuronal dysfunctions

Microarray Analysis on Human Neuroblastoma Cells Exposed to Aluminum, β1–42-Amyloid or the β1–42-Amyloid Aluminum Complex

BACKGROUND: A typical pathological feature of Alzheimer's disease (AD) is the appearance in the brain of senile plaques made up of β-amyloid (Aβ) and neurofibrillary tangles. AD is also associated with an abnormal accumulation of some metal ions, and we have recently shown that one of these, aluminum (Al), plays a relevant role in affecting Aβ aggregation and neurotoxicity. METHODOLOGY: In this study, employing a microarray analysis of 35,129 genes, we investigated the effects induced by the exposure to the Aβ(1-42)-Al (Aβ-Al) complex on the gene expression profile of the neuronal-like cell line, SH-SY5Y. PRINCIPAL FINDINGS: The microarray assay indicated that, compared to Aβ or Al alone, exposure to Aβ-Al complex produced selective changes in gene expression. Some of the genes selectively over or underexpressed are directly related to AD. A further evaluation performed with Ingenuity Pathway analysis revealed that these genes are nodes of networks and pathways that are involved in the modulation of Ca(2+) homeostasis as well as in the regulation of glutamatergic transmission and synaptic plasticity. CONCLUSIONS AND SIGNIFICANCE: Aβ-Al appears to be largely involved in the molecular machinery that regulates neuronal as well as synaptic dysfunction and loss. Aβ-Al seems critical in modulating key AD-related pathways such as glutamatergic transmission, Ca(2+) homeostasis, oxidative stress, inflammation, and neuronal apoptosis

GLP-1 Receptor Agonists and Related Mental Health Issues; Insights from a Range of Social Media Platforms Using a Mixed-Methods Approach

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/The emergence of glucagon-like peptide-1 receptor agonists (GLP-1 RAs; semaglutide and others) now promises effective, non-invasive treatment of obesity for individuals with and without diabetes. Social media platforms’ users started promoting semaglutide/Ozempic as a weight-loss treatment, and the associated increase in demand has contributed to an ongoing worldwide shortage of the drug associated with levels of non-prescribed semaglutide intake. Furthermore, recent reports emphasized some GLP-1 RA-associated risks of triggering depression and suicidal thoughts. Consistent with the above, we aimed to assess the possible impact of GLP-1 RAs on mental health as being perceived and discussed in popular open platforms with the help of a mixed-methods approach. Reddit posts yielded 12,136 comments, YouTube videos 14,515, and TikTok videos 17,059, respectively. Out of these posts/entries, most represented matches related to sleep-related issues, including insomnia (n = 620 matches); anxiety (n = 353); depression (n = 204); and mental health issues in general (n = 165). After the initiation of GLP-1 RAs, losing weight was associated with either a marked improvement or, in some cases, a deterioration, in mood; increase/decrease in anxiety/insomnia; and better control of a range of addictive behaviors. The challenges of accessing these medications were a hot topic as well. To the best of our knowledge, this is the first study documenting if and how GLP-1 RAs are perceived as affecting mood, mental health, and behaviors. Establishing a clear cause-and-effect link between metabolic diseases, depression and medications is difficult because of their possible reciprocal relationship, shared underlying mechanisms and individual differences. Further research is needed to better understand the safety profile of these molecules and their putative impact on behavioral and non-behavioral addictions.Peer reviewe

The factitious/malingering continuum and its burden on public health costs: a review and experience in an Italian neurology setting

Abstract: Factitious disorder is classified as one of the five aspects of somatic symptom disorders. The fundamental element of factitious disorder is deception, i.e., pretending to have a medical or psychiatric disorder, but the enactment of deception is considered unconscious. Indeed, volition, i.e., the perception of deliberate deception, is blurred in patients presenting with factitious disorder. In the USA and the UK, factitious disorder has received constant media attention because of its forensic implications and outrageous costs for the National Health Systems. Unfortunately, a comparable level of attention is not present in Italian National Health System or the Italian mass media. The review analyzes the classifications, disorder mechanisms, costs, and medico-legal implications in the hope of raising awareness on this disturbing issue. Moreover, the review depicts 13 exemplification cases, anonymized and fictionalized by expert writers. Finally, our paper also evaluates the National Health System’s expenditures for each patient, outlandish costs in the range between 50,000 and 1 million euros.Peer reviewe