Search Results (73)

The cerebellum plays a key role in regulating movement, coordination, and certain cognitive functions. Purkinje cells are the principal neurons of the cerebellum, essential for integrating information and modulating output to other parts of the central nervous system. Physical exercise is crucial for maintaining psychophysical well-being and improving quality of life. Moreover, its beneficial effects on brain health are well established. After a brief overview of cerebellar anatomy, this narrative review aims to summarize current experimental evidence on the effects of physical activity on Purkinje cells, particularly in the context of neuronal plasticity and neuroprotection. Special attention is given to structural and functional adaptations under both physiological and pathological conditions, including neurodegenerative diseases, neurodevelopmental disorders, traumatic brain injury, and aging. Overall, the available findings suggest that Purkinje cells represent a key cellular target of exercise-induced cerebellar plasticity. Physical activity may therefore contribute to preserving cerebellar function and promoting neuroprotection through mechanisms involving structural remodeling and synaptic adaptation of Purkinje cells. Full article

Understanding how brain activity varies across neurological and neurodevelopmental disorders requires tools capable of revealing patterns hidden in complex electroencephalographic (EEG) data. Conditions such as epilepsy, Alzheimer’s disease, dementia, and autism exhibit distinct alterations in neural oscillations and connectivity, which remain difficult to interpret in real time; therefore, this study proposes an interactive interface for intuitive exploration and analysis of disease-specific EEG dynamics. The system integrates classical signal processing techniques and computational modeling to extract spectral features, inter-electrode coherence, and spatial activation patterns, which are visualized through spectrograms, topographic maps, and connectivity graphs that update continuously. In addition, a web-based platform is incorporated to enable clinicians and technicians to store and manage patient information, including diagnosis, severity level, number of recordings, sampling frequency, recording duration, and acquisition dates, supporting structured data organization and longitudinal monitoring. The results demonstrate that the interface captures meaningful differences between disorders, with epileptic patterns showing strong synchronization and burst activity, while neurodegenerative conditions exhibit spectral slowing and reduced connectivity. Overall, the proposed framework provides an effective and accessible tool for EEG visualization, combining interactive analysis with clinical data management to support research, education, and potential clinical applications. Full article

Rare genetic disorders of the central nervous system (CNS) remain some of the most complex and challenging diseases to treat for several reasons. Targeting the CNS, especially the brain, presents one of the greatest obstacles in gene therapy using adeno-associated virus (AAV) vectors. Although various AAVs have been identified for their ability to transduce different cells in the CNS, their effectiveness and efficiency are significantly limited by the presence of neutralising antibodies (NAbs) and restricted cargo capacity. Despite these challenges, our understanding of AAV structure and technological advances continue to enable researchers to develop innovative strategies that have resulted in groundbreaking, FDA-approved therapeutic products now available for Leber congenital amaurosis (LCA) (Luxturna^®), spinal muscular atrophy (SMA) (Zolgensma^®), and the two recent gene therapy products for aromatic L-amino acid decarboxylase (AADC) deficiency, Kebilidi^® and Upstaza^®, which currently hold FDA and EMA approval, respectively. This review aims to highlight recent advances in the field of AAV gene therapy for neurological disorders, identify research gaps, and suggest areas for future investigation to enable potential breakthroughs particularly in neurodegenerative, neurodevelopmental, and neuromuscular disorders. We foresee that more tissue- and cell-specific AAV vectors designed using AI-powered platforms will emerge to precisely and efficiently target specific brain regions, transforming how CNS disorders are treated. Full article

Background/Objectives: Autophagy is a highly conserved eukaryotic cellular process whose dysfunction results in human pathologies including cancer and neurodegenerative disease. First identified in yeast, ATG genes are central players in autophagy. Mutations in core autophagy genes ATG5 and ATG7 have been previously reported to cause rare genetic disorders with autosomal recessive inheritance. Methods: Here we report, for the first time, variants in human ATG9B gene as causative factors for a rare neurodevelopmental disease with autosomal recessive inheritance. Three distinct mutations were detected in three independent families with consanguinity, five patients affected in total. Results: The first variant is an 11-nucleotide deletion resulting in a frameshift. A premature stop codon is added and the C-terminal cytosolic domain of ATG9B protein is truncated. The second one is a point mutation that changes a critical amino acid in the transmembrane domain. The third variant is a 2-nucleotide deletion causing a different truncation product. Patients presented with diverse neurodevelopmental anomalies including intellectual disability, behavioral abnormalities, congenital cerebellar ataxia, mild cerebellar atrophy, and microcephaly. Since human ATG9B is expressed specifically in the placenta, we hypothesized that the disease pathology originates during placental development. To characterize the effects of the first frameshift mutation and gain insight into the specific functions of ATG9B in a physiological setting, we used mammalian cells and a knock-in mouse model. Truncated ATG9B was not stable when expressed in cells. It was localized to perinuclear vesicles like the WT protein, but not to peripheral vesicles. Homozygous knock-in mice were viable, fertile, and displayed no gross phenotypical abnormalities. Histomorphometry analysis of the placenta layers did not reveal a significant difference between mutant and control embryos. The assessments of neurobehavioral tests were similar in wild-type and homozygous knock-in mice. However, knock-in mice had a reduced fear memory trend, which is an amygdala-involved response. Conclusions: In this study, we describe a new rare disease linked to ATG9, including cerebellar ataxia and atrophy, as described for ATG5 and ATG7. Full article

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants associated with neurodevelopmental and neurodegenerative disorders. PCB 118 is one of the most abundant congeners and exerts neurotoxic effects, yet the molecular mechanisms underlying its impact on human neurons remain poorly understood. We investigated the molecular response of retinoic acid-differentiated, neuron-like SH-SY5Y cells exposed to 5 µM PCB 118 for 24 h, a concentration that did not affect cell viability. RNA sequencing identified 1239 differentially expressed genes. Functional enrichment and protein-protein interaction analyses identified upregulation of histone and chromatin structural genes, indicative of substantial chromatin remodeling. In parallel, a significant downregulation of genes involved in ribosome biogenesis and rRNA processing was observed, potentially indicating impairment of the protein synthesis machinery. These transcriptional changes point to a coordinated reprogramming of nuclear architecture and translational machinery, potentially compromising neuronal homeostasis. The modulation of proteostasis-related pathways further supports a mechanistic link between PCB 118 exposure and neuronal dysfunction. Our results provide a comprehensive transcriptional framework connecting PCB 118 to chromatin-mediated gene regulation and suppression of ribosome biogenesis in human neuron-like cells. This study offers mechanistic insights into how environmental PCB exposure may contribute to neurotoxicity and highlights molecular pathways potentially implicated in the development of neurodegenerative disorders. Full article

Advanced Glycation End Products (AGEs) are reactive compounds formed through the non-enzymatic glycation of proteins, lipids, or nucleic acids due to exposure to reducing sugars. They accumulate through endogenous metabolic dysregulation and exogenous dietary intake, particularly high-fat and high-sugar foods prepared at high temperatures. The interaction between AGEs and their receptor, RAGE (receptor for Advanced Glycation End Products), has been implicated in a range of pathological conditions, including diabetes and metabolic syndrome. However, the impact of AGEs accumulation on neurodevelopment remains poorly understood. In this study, we investigated the effects of AGEs on human-induced pluripotent stem cell (iPSC)-derived cerebral organoids comprising neurons, astrocytes, and microglia. Our findings reveal that AGEs induce RAGE expression, leading to microglial activation, increased deposition of amyloid-beta (Aβ) aggregates, and impaired neurodevelopment. Additionally, elevated levels of AGE-modified proteins, along with altered microglial polarization, were observed in cerebral organoids modeling Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism–Dementia Complex (ALS-PDC). These findings demonstrate AGEs as active drivers of neurodevelopmental disruption and establish a mechanistic link between metabolic stress and increased susceptibility to neurodegenerative disease. Full article

Background: Neurodegenerative diseases are a major health problem, and the neuropsychiatric symptoms seen in these diseases adversely impact the lives of patients, families, and caregivers. Inappropriate aggressive behavior is a highly disruptive symptom and a leading cause of institutionalization. There are no approved drugs specifically for the treatment of problematic aggression, and the off-label use of antipsychotics has limited benefit with significant side effects and safety risks. This review discusses dysregulated arginine vasopressin (AVP) signaling in fear–threat circuitry as a key driver of inappropriate aggression. Because the AVP 1a receptor (V1aR) is the dominant subtype in the CNS, the selective antagonism of this receptor represents a well-rationalized target for the treatment of aggression across neurodegenerative, psychiatric, and neurodevelopmental disorders. Objectives: Our goal was to summarize the basis for using V1aR antagonists as a treatment for irritability and aggressive behavior. We describe its discovery, biosynthesis, receptor pharmacology, and CNS distribution, emphasizing V1aR localization in central fear–threat circuits. Translational evidence from animal studies, pharmacological neuroimaging, and lesion network mapping is presented. These data support the suggestion that heightened vasopressinergic tone biases socioemotional information processing toward negative valence, increasing threat sensitivity and the likelihood of inappropriate aggressive responses. Emerging clinical data support this framework. Highly selective, CNS-penetrant V1aR antagonists reduced aggressive behavior and had an excellent safety profile in phase 2 studies in Huntington’s disease and intermittent explosive disorder, with efficacy signals across caregiver-reported, clinician-rated, and incident-based measures. Furthermore, pharmacological neuroimaging showed that V1aR antagonism normalizes AVP-induced alterations in activity within fear–threat circuitry. Conclusions and Future Directions: Preclinical, translational, and clinical findings to date support V1aR antagonism as a promising strategy for treating pathological aggression across disorders. Additional experimental medicine studies and clinical trials are needed to conclusively establish efficacy in various disease populations, and we note the need for improved trial designs and analytical methods as part of the development process. Full article

Neuromechanobiology has emerged as a multidisciplinary field at the interface of neuroscience and mechanobiology, aiming to elucidate how mechanical forces influence the development, organization, and function of the nervous system. This review offers a comprehensive overview of the historical evolution of the discipline, its molecular and biophysical foundations, and the experimental strategies employed to investigate it. Recent advances have revealed the pivotal roles of substrate stiffness, mechanical signaling, and force transduction in neural stem proliferation, axon guidance, synapse formation, and neural circuit maturation. All these effects originate at the molecular level and extend to the mesoscopic scale. Disrupted mechanotransduction has been increasingly implicated in neurodevelopmental disorders and neurodegenerative diseases, underscoring its clinical relevance. Key unresolved questions and future directions are also highlighted, with emphasis on the need for integrative approaches to decipher the complex interplay between mechanical forces and neural function. Full article

Flavonoids are a class of natural plant compounds that are categorised within the polyphenolic group. It is widely acknowledged that their structural diversity results in a wide distribution within food sources, thus leading to a concomitant wide spectrum of biological activity. This review provides an updated overview of the main flavonoid subclasses, including flavonols, flavones, flavanones, flavanols, anthocyanins, and isoflavones, and includes an examination of their chemical properties and biosynthetic pathways. The present study will discuss the influence of biotic and abiotic factors on flavonoid function in plants, including their role in ultraviolet protection, stress tolerance, and defence signalling. The regular consumption of foods rich in flavonoids has been demonstrated to be associated with a reduced risk of chronic diseases, including cardiovascular, metabolic diseases, neurodegenerative and neurodevelopmental disorders. This observation underscores the significance of flavonoids in a balanced diet. Medicinal plants play an important role in this task. The mechanisms of action of this substance include antioxidant and anti-inflammatory effects, modulation of signalling pathways, and neuroprotective functions. The present findings underscore the significance of flavonoids as multifunctional bioactive molecules, which hold considerable potential for preventive and therapeutic applications. However, further well-designed human studies are necessary to determine effective dosage, long-term safety, and clinical relevance. Full article

Background: The insulin-like growth factor 2 receptor (IGF-2R), also known as the cation-independent mannose 6-phosphate receptor (CI-M6PR), is emerging as a critical receptor for brain function and disease. IGF-2R, in fact, plays a key role in long-term memory, and its activation by several ligands shows beneficial effects in multiple neurodevelopmental and neurodegenerative disease models. Thus, its targeting is very promising for neuropsychiatric therapeutic interventions. IGF-2R’s main known functions are transport of lysosomal enzymes and regulation of developmental tissue growth, but in the brain, it also controls learning-dependent protein synthesis underlying long-term memory. However, little is known about this receptor in brain cells, including its cell-type-specific and subcellular expression. Methods: We conducted a comprehensive investigation to comparatively assess IGF-2R protein levels in different brain cell types across various brain regions in adult male C57BL/6J mice using dual and multiplex immunofluorescent staining with cell-type-specific markers. The IGF-2R protein distribution was also compared with Igf2r mRNA expression in publicly available single-cell RNA sequencing databases. Results: A ranking of IGF-2R levels in the soma of various cell types in the hippocampus and cortical regions revealed that the highest enrichment is, by far, in excitatory and inhibitory neurons, followed by vascular mural cells and subpopulations of oligodendrocyte lineage cells, with low to undetectable levels in astrocytes, microglia, vascular endothelial cells, and perivascular fibroblasts. High levels of IGF-2R were also found in ependymal cells, choroid plexus epithelial cells, and a subpopulation of meningeal fibroblast-like cells. IGF-2R was found in dendritic and putative axonal compartments throughout the brain, with particularly high levels in the stratum lucidum. The receptor’s protein distribution aligned with that of the mRNA in mouse brain databases. Conclusions: These results suggest that IGF-2R-mediated functions in the brain vary across different cell types and subcellular compartments, with the most active roles in specific subpopulations of neurons, mural cells, ependymal cells, meningeal cells, and cells of the oligodendrocyte lineage. This study advances our understanding of IGF-2R’s distribution in the brain, which is essential for formulating new hypotheses about its functions and therapeutic targeting. Full article

Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in clinical development for Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). The S1R is a ubiquitous chaperone protein enriched in the central nervous system and regulates multiple pathways critical for neuronal cell function and survival, including cellular stress responses, mitochondrial function, calcium signaling, protein folding, and autophagy. S1R has a crucial role in the ER mitochondria-associated membrane (MAM), whose dysfunction is implicated in several neurodegenerative diseases. By activating the S1R, pridopidine corrects multiple cellular pathways necessary to the cell’s ability to respond to stress, which are disrupted in neurodegenerative diseases. Pridopidine restores MAM integrity; rescues Ca²⁺ homeostasis and autophagy; mitigates ER stress, mitochondrial dysfunction, and oxidative damage; and enhances brain-derived neurotrophic factor (BDNF) axonal transport and secretion, synaptic plasticity, and dendritic spine density. Pridopidine demonstrates neuroprotective effects in in vivo models of neurodegenerative diseases (NDDs). Importantly, pridopidine demonstrates the biphasic dose response characteristic of S1R agonists. In clinical trials in HD and ALS, pridopidine has shown benefits across multiple endpoints. Pridopidine’s mechanism of action, modulating core cellular survival pathways, positions it as a promising candidate for disease modification for different nervous system disorders. Its broad therapeutic potential includes neurodevelopmental disorders, and rare diseases including Wolfram syndrome, Rett syndrome, and Vanishing White Matter Disease. Here, we review the experimental data demonstrating pridopidine’s S1R-mediated neuroprotective effects. These findings underscore the therapeutic relevance of S1R activation and support further investigation of pridopidine for the treatment of different neurodegenerative diseases including ALS and HD. Full article

Event-Related Potentials (ERPs) are low-amplitude neural responses elicited by sensory or cognitive stimuli, widely exploited as biomarkers in the early diagnosis of neurodevelopmental and neurodegenerative disorders such as autism spectrum disorder and Alzheimer’s disease, and as control signals in brain–computer interface (BCI) systems for severely disabled individuals. However, their extremely low signal-to-noise ratio (SNR) necessitates robust denoising, especially in real-time BCI applications where low latency, minimal computational overhead, and single-channel operation are critical constraints. While advanced offline methods like Independent Component Analysis (ICA) and wavelet-based thresholding offer effective denoising in multichannel settings, they are ill-suited for embedded, causal, and resource-constrained environments. To address this gap, we propose a Partial-Update Variable Step-Size LMS (PU-VSS-LMS) algorithm that complementarily combines dynamic step-size adaptation with a magnitude-driven partial-update strategy. Evaluated on synthetic ERP-like signals embedded in realistic EEG noise (SNR = 6 dB and 0 dB), PU-VSS-LMS achieves lower mean squared error (MSE: 0.0780 vs. 0.0850 at 6 dB) and higher output SNR (8.10 dB vs. 7.80 dB) than standard VSS-LMS, while outperforming ICA in waveform preservation and noise suppression. Importantly, it reduces computational load by 75% (updating only 4 of 16 coefficients), enabling faster execution without sacrificing accuracy. These results establish PU-VSS-LMS as a highly efficient and effective solution for real-time ERP denoising in embedded, single-channel biomedical systems. Full article

Background/Objectives: Down syndrome (DS) is a neurodevelopmental and neurodegenerative disorder typically caused by trisomy 21. We recently concluded a two-site (Ohio, USA and São Paulo, Brazil), phase-2, randomized trial to evaluate the efficacy, tolerability, and safety of the drug memantine in enhancing cognitive abilities of adolescents and young adults with DS. This trial was a follow-up study to a pilot trial performed in Colorado, USA. Results of these two clinical trials have been published elsewhere. Here, we present a comparative analysis of the baseline neuropsychological assessments at the three sites of these two studies, including their psychometric properties, and an account of the considerations involved in the test battery design. We compared test results in the different sites as a way of evaluating the replicability and generalizability of the test results. The distribution of the test results at each site was analyzed and combined when no differences were detected between the mean values of these results. We used post-treatment data from the placebo arms of these studies to quantify test–retest reliability. Results: Most measures had comparable mean values across test sites, and had good-to-excellent feasibility, few floor effects, and good-to-excellent test–retest reliability. A few measures, however, were deemed unsuitable for use in future studies. Conclusions: This study demonstrated remarkable consistency of results across studies in two countries with significantly different cultures and levels of socioeconomic development, which provides supporting evidence for the future design and implementation of similar multicenter, international clinical studies involving participants with DS. Full article

Background: attention-deficit/hyperactivity disorder (ADHD) and Alzheimer’s disease (AD) are distinct neurological conditions that may share genetic and molecular underpinnings. ADHD, a neurodevelopmental disorder, affects approximately 5% of children and 3% of adults globally, while AD, a neurodegenerative disorder, is the leading cause of dementia in older adults. Emerging evidence suggests potential overlapping contributors, including pathways related to synaptic plasticity, neuroinflammation, and oxidative stress. Methods: this systematic review investigated potential genetic predispositions linking Attention-Deficit/Hyperactivity Disorder (ADHD) and Alzheimer’s Disease (AD). Following PRISMA guidelines, a search was conducted in Web of Science, Embase, PsycINFO, and PubMed using keywords related to ADHD, AD, and genetic factors. Studies included were original human studies utilizing genetic analyses and ADHD polygenic risk scores (PRS), with AD confirmed using established diagnostic criteria. Exclusion criteria comprised non-original studies, animal research, and articles not addressing genetic links between ADHD and AD. Screening was conducted with Rayyan software (version 1.4.3), assessing relevance based on titles, abstracts, and full texts. Results:. The search identified 1450 records, of which 1092 were screened after duplicates were removed. Following exclusions, two studies met inclusion criteria. One study analyzed ADHD-PRS in 212 cognitively unimpaired older adults using amyloid-beta (Aβ) PET imaging and tau biomarkers. The findings revealed that ADHD-PRS was associated with progressive cognitive decline, increased tau pathology, and frontoparietal atrophy in Aβ-positive individuals, suggesting that ADHD genetic liability may exacerbate AD pathology. Another study assessed ADHD-PRS in a cohort of 10,645 Swedish twins, examining its association with 16 somatic conditions. The results showed modest risk increases for cardiometabolic, autoimmune, and neurological conditions, with mediation effects through BMI, education, tobacco use, and alcohol misuse, but no direct link between ADHD-PRS and dementia. Discussion and conclusions: this review highlights preliminary but conflicting evidence for a genetic intersection between ADHD and AD. One study suggests that ADHD genetic liability may exacerbate AD-related pathology in Aβ-positive individuals, whereas another large registry-based study finds no direct link to dementia, with associations largely mediated by lifestyle factors. The potential ADHD–AD relationship is likely complex and context-dependent, influenced by biomarker status and environmental confounders. Longitudinal studies integrating genetics, biomarkers, and detailed lifestyle data are needed to clarify this relationship. Full article

Down syndrome (DS), stemming from the triplication of human chromosome 21, results in intellectual disability, with early mid-life onset of Alzheimer’s disease (AD) pathology. Early interventions to reduce cognitive impairments and neuropathology are lacking. One modality, maternal choline supplementation (MCS), has shown beneficial effects on behavior and gene expression in neurodevelopmental and neurodegenerative disorders, including trisomic mice. Loss of basal forebrain cholinergic neurons (BFCNs) and other DS/AD relevant hallmarks were observed in a well-established trisomic model (Ts65Dn, Ts). MCS attenuates these endophenotypes with beneficial behavioral effects in trisomic offspring. We postulate MCS ameliorates dysregulated cellular mechanisms within vulnerable BFCNs, with attenuation driven by novel gene expression. Here, choline acetyltransferase immunohistochemical labeling identified BFCNs in the medial septal/ventral diagonal band nuclei of the basal forebrain in Ts and normal disomic (2N) offspring at ~11 months of age from dams exposed to MCS or normal choline during the perinatal period. BFCNs (~500 per mouse) were microisolated and processed for RNA-sequencing. Bioinformatic assessment elucidated differentially expressed genes (DEGs) and pathway alterations in the context of genotype (Ts, 2N) and maternal diet (MCS, normal choline). MCS attenuated select dysregulated DEGs and relevant pathways in aged BFCNs. Trisomic MCS-responsive improvements included pathways such as cognitive impairment and nicotinamide adenine dinucleotide signaling, among others, indicative of increased behavioral and bioenergetic fitness. Although MCS does not eliminate the DS/AD phenotype, early choline delivery provides long-lasting benefits to aged trisomic BFCNs, indicating that MCS prolongs neuronal health in the context of DS/AD. Full article