Manuel Jose Rodriguez

Background: Scientific attention is increasingly being drawn to the emotional impact and neurodevelopmental difficulties experienced by children and adolescents with heart disease. Therefore, this article aimed to review the literature from the last decade on health-related quality of life (HR-QoL) and cognitive functions (CFs) in children and adolescents with heart disease, highlighting its implications for these populations. Methods: This rapid systematic review and meta-analysis were conducted using the Web of Science (WoS) database. We used the Scale for the Assessment of Narrative Review Articles (SANRA) as a quality control check and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Two meta-analyses were conducted to synthesize intelligence quotient (IQ) and QoL outcomes using data extracted from eligible studies. Random-effects models, Hedges’ G or mean differences, and I2 statistics derived from Cochran’s Q were applied to assess effect sizes and between-study heterogeneity. Results: A total of 133 articles were identified, and 23 were eligible. The main results suggested a relationship between the characteristics and consequences of heart disease and neurodevelopment, which influence QoL and functional areas. The meta-analysis revealed a significant decrease in total IQ in patients compared to controls. We also found that the psychosocial QoL of the patient was significantly lower than the physical QoL. Conclusions: Neurodevelopment and QoL are fundamental aspects that must be addressed in a preventive manner.This review responds to the challenges faced by children and adolescents with congenital heart disease (CHD) who have undergone one or more surgical interventions, particularly regarding neurodevelopmental outcomes and executive function deficits, as examined through cohort and cross-sectional studies. However, a critical gap remains in the literature regarding longitudinal studies that evaluate the impact of short-, medium-, and long-term interventions specifically designed for this population.

The rare conditions XK disease (McLeod syndrome) and VPS13A disease (chorea-acanthocytosis), 25 have historically been termed "neuroacanthocytosis", due to the association of neurodegeneration, 26 particularly of the basal ganglia, with spiky deformed red blood cells (acanthocytes). Even more 27 obsolete is the 1960s' designation "Levine-Critchley syndrome": genetic analyses of the reported 28 families have determined that Levine´s patients were affected by mutations of XK and those of 29Critchley by VPS13A variants. Two multi-author books summarize early developments (Danek,30 2004; The articles collected here represent a number of recent advances in this rapidly-evolving field. The 94 ultimate goal is to develop and validate therapies for these devasting neurological and multi-organ 95 disorders, and additionally to add to understanding of cellular processes which may benefit other 96 fields. 97

INTRODUCTION: Alzheimer's disease (AD) pathogenesis involves astrocytic responses to extracellular amyloid beta deposits and phospho‐tau neurofibrillary tangles, which drive inflammatory activation. RTP801, a stress‐responsive protein, has been implicated in mediating neuroinflammation. Its levels are increased in AD hippocampal samples, correlating with disease severity and cognitive decline.METHODS: Using astrocyte‐specific RTP801 silencing in the hippocampus of 5xFAD mice, we evaluated cognition, neuroinflammation, and hippocampal connectivity by magnetic resonance spectroscopy (MRS) and resting‐state functional connectivity analyses. Histological and biochemical analyses assessed microgliosis, astrogliosis, and inflammasome‐related protein levels.RESULTS: Astrocytic RTP801 silencing in 5xFAD mice preserved spatial memory, maintained hippocampal γ‐aminobutyric acid (GABA) levels, and preserved resting‐state brain networks. In addition, RTP801 silencing significantly reduced markers of microgliosis, astrogliosis, and inflammasome effectors.DISCUSSION: Astrocytic RTP801 contributes to AD‐associated cognitive decline by disrupting GABAergic‐regulated connectivity and amplifying inflammatory responses. Targeting astrocytic RTP801 may therefore offer therapeutic potential to mitigate AD progression by preserving neural connectivity and reducing neuroinflammation.Highlights: The 5xFAD mouse model of Alzheimer's disease presents higher levels of RTP801 in hippocampal astrocytes. Normalizing the levels of astrocytic RTP801 prevents cognitive decline and restores anxiety‐like behavior in the 5xFAD mouse model. Knocking down astrocytic RTP801 preserves the resting‐state functional connectivity in the 5xFAD mouse model. Astrocytic RTP801 mediates the loss of Parvalbumin+ interneurons, negatively affecting the levels of γ‐aminobutyric acid (GABA) in the 5xFAD mouse model. Astrocytic RTP801 contributes to astro‐ and microgliosis and inflammasome expression in the 5xFAD mouse model.

VPS13A disease and Huntington’s disease (HD) are two basal ganglia disorders that may be difficult to distinguish clinically because they have similar symptoms, neuropathological features, and cellular dysfunctions with selective degeneration of the medium spiny neurons of the striatum. However, their etiology is different. VPS13A disease is caused by a mutation in the VPS13A gene leading to a lack of protein in the cells, while HD is due to an expansion of CAG repeat in the huntingtin (Htt) gene, leading to aberrant accumulation of mutant Htt. Considering the similarities of both diseases regarding the selective degeneration of striatal medium spiny neurons, the involvement of VPS13A in the molecular mechanisms of HD pathophysiology cannot be discarded. We analyzed the VPS13A distribution in the striatum, cortex, hippocampus, and cerebellum of a transgenic mouse model of HD. We also quantified the VPS13A levels in the human cortex and putamen nucleus; and compared data on mutant Htt-induced changes in VPS13A expression from differential expression datasets. We found that VPS13A brain distribution or expression was unaltered in most situations with a decrease in the putamen of HD patients and small mRNA changes in the striatum and cerebellum of HD mice. We concluded that the selective susceptibility of the striatum in VPS13A disease and HD may be a consequence of disturbances in different cellular processes with convergent molecular mechanisms already to be elucidated.