Search Results (477)

Background: Takotsubo cardiomyopathy (TTC) has been historically considered a contraindication for heart donation due to its transient left ventricular dysfunction. However, emerging evidence supports that hearts from donors with fully recovered Takotsubo Cardiomyopathy can be safely transplanted. Methods: This case series describes seven heart transplantations performed between January 2022 and September 2025 using donors with previously diagnosed Takotsubo cardiomyopathy. Donor characteristics, intraoperative data, echocardiography data and postoperative outcomes were analyzed. Results: The mean donor age was 33.5 years (range 18–58), with a male-to-female ratio of 6:1. All donors exhibited echocardiographic evidence of Takotsubo Cardiomyopathy at the time of brain death, with full or partial recovery before procurement. Coronary angiography excluded obstructive coronary disease. Echocardiographic follow-up demonstrated the mean LVEF increased to 52 ± 6%, reaching 58 ± 4% at 12 months, global longitudinal strain (GLS) improved progressively (from −14.2 ± 2.8% to −18.5 ± 1.9%), confirming normalization of myocardial deformation and the right ventricular function, assessed by TAPSE, rose from 15 ± 3 mm at discharge to 20 ± 2 mm at 12 months. All patients transplanted with donors who had Takotsubo cardiomyopathy are alive at the 12-month follow-up. Conclusions: Hearts from donors with resolved Takotsubo Cardiomyopathy can be safely used for transplantation without compromising early- or mid-term outcomes. Expanding donor eligibility criteria to include selected TTC donors may contribute to mitigating organ shortages in advanced heart failure patients. Full article

Complete or partial loss of smell (anosmia), sometimes in association with distorted olfactory perceptions (parosmia), is a common neurological symptom affecting nearly 60% of patients suffering from post-acute neurological sequelae of COronaVIrus Disease of 2019 (COVID-19) syndrome, called long COVID. Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) may gain access from the nasal cavity to the brain (neurotropism), and the olfactory route has been proposed as a peripheral site of virus entry. COVID-19 is a risk factor for developing Alzheimer’s Disease (AD), an age-dependent and progressive neurodegenerative disorder characterized in affected patients by early olfaction dysfunction that precedes signs of cognitive decline associated with neurodegeneration in vulnerable brain regions of their limbic system. Here, we summarize the recent literature data supporting the causal correlation between the persistent olfactory deterioration following SARS-CoV-2 infection and the long-delayed manifestation of AD-like memory impairment. SARS-CoV-2 infection of the olfactory neuroepithelium is likely to trigger a pattern of detrimental events that, directly and/or indirectly, affect the anatomically interconnected hippocampal and cortical areas, thus resulting in tardive clinical dementia. We also delineate future advancement on pharmacological and rehabilitative treatments to improve the olfactory dysfunction in patients recovering even from the acute/mild phase of COVID-19. Collectively, the present review aims at highlighting the physiopathological nexus between COVID-19 anosmia and post-pandemic mental health to favor the development of best-targeted and more effective therapeutic strategies in the fight against the long-term neurological complications associated with SARS-CoV-2 infection. Full article

Type 2 Diabetes Mellitus (T2DM) is a recognized risk factor for Alzheimer’s Disease (AD), as epidemiological research indicates that those with T2DM have a markedly increased risk of experiencing cognitive decline and dementia. Chronic hyperglycemia and insulin resistance in T2DM hinder cerebral glucose metabolism, reducing the primary energy source for neurons and compromising synaptic function. Insulin resistance impairs signaling pathways crucial for neuronal survival and plasticity, while high insulin levels compete with amyloid-β (Aβ) for breakdown by insulin-degrading enzyme, promoting Aβ buildup. Additionally, vascular issues linked to T2DM impair blood–brain barrier functionality, decrease cerebral blood flow, and worsen neuroinflammation. Elevated oxidative stress and advanced glycation end-products (AGEs) in diabetes exacerbate tau hyperphosphorylation and mitochondrial dysfunction, worsening neurodegeneration. Collectively, these processes create a robust biological connection between T2DM and AD, emphasizing the significance of metabolic regulation as a possible treatment approach for preventing or reducing cognitive decline. Here, we review the relationship between T2DM and AD and discuss the roles insulin, hyperglycemia, and inflammation therapeutic strategies have in successful development of AD therapies. Additionally evaluated are recent therapeutic advances, especially involving the polyflavonoid anthocyanin, against T2DM-mediated AD pathology. Full article

Liver fibrosis, the progressive accumulation of scar tissue resulting from chronic liver disease, is increasingly recognized as a multi-system condition, the effects of which extend beyond the liver, affecting brain health. Dementia, characterized by progressively impaired cognition sufficient to impede daily functioning, is a major global health issue with incompletely defined risk factors and pathogenic precursors. To examine the relationship between liver fibrosis and cognitive outcomes, we conducted a comprehensive PubMed literature search, and human studies published in English were included. Evidence is synthesized on the pathophysiology and clinical significance of liver fibrosis, types of dementia, and studies supporting the association between liver fibrosis and cognitive impairment. Meta-analytic data indicate that liver fibrosis is associated with an approximately 30% increased risk of incident dementia (pooled hazard ratio ~1.3), with progressively higher risks across more advanced fibrosis stages. Putative pathomechanisms, potentially modulated by age and sex, include chronic systemic and neuro-inflammation, insulin resistance, vascular dysfunction, and a perturbed intestinal microbiota–liver–brain axis. Non-invasive liver fibrosis diagnostics, advanced neuroimaging, and biomarkers represent key tools for assessing risk. In conclusion, liver fibrosis is a systemic condition that can affect brain health. Early detection, thorough risk assessment and interventions, such as lifestyle changes, metabolic therapies, and antifibrotic treatments, may help protect neural function. Key research gaps are identified, with suggestions for improving understanding of liver fibrosis’s connection to dementia or cognitive impairment. Full article

As global population aging accelerates, the growing burden of age-related diseases is driving a shift in medical research from single-disease treatment to interventions targeting the aging process itself. Organ-specific interventions have emerged as a promising strategy to modulate systemic aging. Among organs, the brain, muscle, and gut have attracted particular attention due to their central roles in neural regulation, metabolic homeostasis, and immune balance. In this review, we focus on these three key organs, systematically summarizing their roles and regulatory mechanisms in organismal aging and discussing how exercise influences the aging process by affecting these organs. Crucially, we propose a novel “local-to-global” regulatory model, positing that preserving homeostasis in these specific tissues is sufficient to orchestrate systemic anti-aging effects. This work represents a conceptual advance by providing the theoretical rationale to move beyond non-specific systemic treatments toward precise, organ-targeted interventions. Full article

Late-onset sporadic Alzheimer’s disease (LOAD) is the most common form of dementia. The disease is characterized by progressive loss of memory and behavioral changes followed by neurodegeneration of all cortical areas. While the contribution of genetic and environmental factors is important, advanced aging remains the most important disease risk factor. Because LOAD does not naturally occur in most animal species, except humans, studies have traditionally relied on the use of transgenic mouse models recapitulating early-onset familial Alzheimer’s disease (EOAD). Hence, the development of more representative LOAD models through reprograming of patient-derived cells into neuronal, glial, and immune cells became a necessity to better understand the disease’s origin and pathophysiology. Herein, and focusing on neurons, we review current work in the field and compare results obtained with two different reprograming methods to generate LOAD patient’s neuronal cells: the induced pluripotent stem cell and induced neuron technologies. We also evaluate if these models can faithfully mimic cellular and molecular pathologies observed in LOAD patients’ brains. Full article

The integration of omics technologies, including genomics, proteomics, metabolomics, and microbiomics, has transformed sports science, particularly soccer, by providing new opportunities to optimize player performance, reduce injury risk, and enhance recovery. This systematic literature review was conducted in accordance with PRISMA 2020 guidelines and structured using the PICOS/PECOS framework. Comprehensive searches were performed in PubMed, Scopus, and Web of Science up to August 2025. Eligible studies were peer-reviewed original research involving professional or elite soccer players that applied at least one omics approach to outcomes related to performance, health, recovery, or injury prevention. Reviews, conference abstracts, editorials, and studies not involving soccer or omics technologies were excluded. A total of 139 studies met the inclusion criteria. Across the included studies, a total of 19,449 participants were analyzed. Genomic investigations identified numerous single-nucleotide polymorphisms (SNPs) spanning key biological pathways. Cardiovascular and vascular genes (e.g., ACE, AGT, NOS3, VEGF, ADRA2A, ADRB1–3) were associated with endurance, cardiovascular regulation, and recovery. Genes related to muscle structure, metabolism, and hypertrophy (e.g., ACTN3, CKM, MLCK, TRIM63, TTN-AS1, HIF1A, MSTN, MCT1, AMPD1) were linked to sprint performance, metabolic efficiency, and muscle injury susceptibility. Neurotransmission-related genes (BDNF, COMT, DRD1–3, DBH, SLC6A4, HTR2A, APOE) influenced motivation, fatigue, cognitive performance, and brain injury recovery. Connective tissue and extracellular matrix genes (COL1A1, COL1A2, COL2A1, COL5A1, COL12A1, COL22A1, ELN, EMILIN1, TNC, MMP3, GEFT, LIF, HGF) were implicated in ligament, tendon, and muscle injury risk. Energy metabolism and mitochondrial function genes (PPARA, PPARG, PPARD, PPARGC1A, UCP1–3, FTO, TFAM) shaped endurance capacity, substrate utilization, and body composition. Oxidative stress and detoxification pathways (GSTM1, GSTP1, GSTT1, NRF2) influenced recovery and resilience, while bone-related variants (VDR, P2RX7, RANK/RANKL/OPG) were associated with bone density and remodeling. Beyond genomics, proteomics identified markers of muscle damage and repair, metabolomics characterized fatigue- and energy-related signatures, and microbiomics revealed links between gut microbial diversity, recovery, and physiological resilience. Evidence from omics research in soccer supports the potential for individualized approaches to training, nutrition, recovery, and injury prevention. By integrating genomics, proteomics, metabolomics, and microbiomics data, clubs and sports practitioners may design precision strategies tailored to each player’s biological profile. Future research should expand on multi-omics integration, explore gene–environment interactions, and improve representation across sexes, age groups, and competitive levels to advance precision sports medicine in soccer. Full article

Accurate brain tumor segmentation in both adult and pediatric populations remains a challenge due to substantial differences in brain anatomy, tumor distribution, and subregion size. This study proposes a unified segmentation framework based on nnU-Net, integrating encoder-level self-supervised pretraining with a lightweight, boundary-aware decoder. The encoder is initialized using a large-scale 3D masked autoencoder pretrained on brain MRI, while the decoder is trained with a hybrid loss function that combines region-overlap and boundary-sensitive terms. A harmonized training and evaluation protocol is applied to both the BraTS-GLI (adult) and BraTS-PED (pediatric) cohorts, enabling fair cross-cohort comparison against baseline and advanced nnU-Net variants. The proposed method improves mean Dice scores from 0.76 to 0.90 for adults and from 0.64 to 0.78 for pediatric cases, while reducing HD95 from 4.42 to 2.24 mm and from 9.03 to 6.23 mm, respectively. These results demonstrate that combining encoder-level pretraining with decoder-side boundary supervision significantly enhances segmentation accuracy across age groups without adding inference-time computational overhead. Full article

Multiple sclerosis (MS) is a chronic, heterogeneous, multifactorial, immune-mediated neurodegenerative disease of the central nervous system that affects the working-age population. Its development is influenced by both genetic and environmental factors. A pathological hallmark of MS is the formation of demyelinating lesions in the brain and spinal cord, which are associated with neuronal damage caused by autoaggressive immune factors (T cells, B cells, and myeloid cells). Focal lesions are believed to be caused by the infiltration of immune cells into the central nervous system (CNS) parenchyma with concomitant tissue damage. Multiple sclerosis represents a significant social problem due to the high cost of available treatments, as well as the deterioration of employment prospects and job retention for both patients and their caregivers. Advances in MS diagnostic methods have enabled disease detection at early stages and correction of immune response impairments. Concurrently, treatments for MS patients are actively being studied, with the ongoing development of novel methods for targeted and cellular immunotherapy. This review primarily discusses approaches to cellular immunotherapy and methods of influencing the cellular arm of immunopathogenesis in multiple sclerosis. Full article

Brain age has been widely recognized as an important biomarker for monitoring adolescent brain development and assessing dementia risk. However, existing model visualization methods primarily highlight brain regions associated with aging, making it difficult to comprehensively reveal broader brain changes. In this study, we developed a VGGNet-based brain age prediction model and proposed the Softmax-Derived Brain Age Mapping algorithm to simultaneously identify brain regions associated with both youthful and aging features. The resulting saliency maps provide explicit representations of developmental and degenerative processes across different brain regions. Brain Age Map analysis revealed that aging features in the healthy group were primarily confined to the frontal cortex, aligning with findings that the frontal lobe is the earliest region to undergo natural senescence. In contrast, the dementia group exhibited widespread aging across the frontal, temporal, parietal, and occipital lobes, as well as the ventricular regions. These results suggest that the spatial distribution of brain aging can serve as a critical biomarker for distinguishing normal aging trajectories from pathological degeneration. From an application perspective, we further explored the potential of the proposed framework in neurodegenerative diseases. The analysis reveals that dementia patients generally exhibit an advanced brain age, with cortical aging being markedly more pronounced than in age-matched healthy samples. Notably, although dementia cases were not included in the training set, the model was still able to localize abnormalities in relevant brain regions, underscoring its potential value as an assistive tool for early dementia diagnosis. Full article

Melanin pigments are ubiquitous biopolymers across diverse life forms and play multifaceted roles in cellular defense and environmental adaptation. The specialized neuromelanin in human brains accumulates mainly within catecholaminergic neurons of the substantia nigra and locus coeruleus, serving as a crucial modulator of brain homeostasis, metal detoxification, and oxidative stress responses. The intricate processes of human melanogenesis, encompassing both cutaneous and neuronal forms, are governed by complex genetic networks. Concurrently, melanin in fungi (synthesized through distinct genetic pathways) confers remarkable resistance to environmental stressors, including ionizing radiation. Recent advancements in omics technologies—including transcriptomics, proteomics, metabolomics, and epigenomics—have profoundly enhanced our understanding of neuromelanin’s molecular environment in health, aging, and neurodegenerative conditions such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and other neurological disorders. This article reviews the genetic underpinnings of human melanogenesis and fungal melanogenesis, explores the convergent and divergent evolutionary pressures driving their functions, and synthesizes the rapidly accumulating omics data to elucidate neuromelanin’s critical, and often dual, role in human brain pathology. Moreover, we discuss the intriguing parallels between neuromelanin and fungal melanin, highlighting radioprotection and its potential implications for neuroprotection and astrobiology, with a special emphasis on the need to investigate neuromelanin’s potential for radioprotection in light of fungal melanin’s remarkable protective properties. Full article

Background/Objectives: Alzheimer’s disease (AD) has a prolonged preclinical phase and marked heterogeneity. Brain age and the Brain Age Gap (BAG), derived from neuroimaging and machine learning (ML), offer a non-invasive, system-level indicator of brain integrity, with potential relevance for early detection, risk stratification, and intervention monitoring. This review summarizes the conceptual basis, imaging characteristics, biological relevance, and explores its potential clinical utility of BAG across the AD continuum. Methods: We conducted a narrative synthesis of evidence from morphometric structural magnetic resonance imaging (sMRI), connectivity-based functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and diffusion tensor imaging (DTI), alongside recent advances in deep learning architectures and multimodal fusion techniques. We further examined associations between BAG and the Amyloid/Tau/Neurodegeneration (A/T/N) framework, neuroinflammation, cognitive reserve, and lifestyle interventions. Results: BAG may reflect neurodegeneration associated with AD, showing greater deviations in individuals with mild cognitive impairment (MCI) and early AD, and is correlated with tau pathology, neuroinflammation, and metabolic or functional network dysregulation. Multimodal and deep learning approaches enhance the sensitivity of BAG to disease-related deviations. Longitudinal BAG changes outperform static BAG in forecasting cognitive decline, and lifestyle or exercise interventions can attenuate BAG acceleration. Conclusions: BAG emerges as a promising, dynamic, integrative, and modifiable complementary biomarker with the potential for assessing neurobiological resilience, disease staging, and personalized intervention monitoring in AD. While further standardization and large-scale validation are essential to support clinical translation, BAG provides a novel systems-level perspective on brain health across the AD continuum. Full article

Background/Objectives: Parkinson’s disease (PD) is an adult-onset neurodegenerative disorder whose pathogenesis is still not completely understood. Several lines of evidence suggest that alterations in epigenetic architecture may contribute to the development of this condition. Here, we present a pilot DNA methylation study from peripheral blood in a cohort of Sicilian PD patients and matched controls. Peripheral tissue analysis has previously been shown to reflect molecular and functional profiles relevant to neurological diseases, supporting their validity as a proxy for studying brain-related epigenetic mechanisms. Methods: We analyzed 20 PD patients and 20 healthy controls (19 males and 21 females overall), matched for sex, with an age range of 60–87 years (mean 72.3 years). Peripheral blood DNA was extracted and processed using the Illumina Infinium MethylationEPIC v2.0 BeadChip, which interrogates over 935,000 CpG sites across the genome, including promoters, enhancers, CpG islands, and other regulatory elements. The assay relies on sodium bisulfite conversion of DNA to detect methylation status at single-base resolution. Results: Epigenome-wide association study (EWAS) data allowed for multiple levels of analysis, including immune cell-type deconvolution, estimation of biological age (epigenetic clocks), quantification of stochastic epigenetic mutations (SEMs) as a measure of epigenomic stability, and differential methylation profiling. Immune cell-type inference revealed an increased but not significant proportion of monocytes in PD patients, consistent with previous reports. In contrast, epigenetic clock analysis did not reveal significant differences in biological age acceleration between cases and controls, partially at odds with earlier studies—likely due to the limited sample size. SEMs burden did not differ significantly between groups. Epivariations reveal genes involved in pathways known to be altered in dopaminergic neuron dysfunction and α-synuclein toxicity. Differential methylation analysis, however, yielded 167 CpG sites, of which 55 were located within genes, corresponding to 54 unique loci. Gene Ontology enrichment analysis highlighted significant overrepresentation of pathways with neurological relevance, including regulation of synapse structure and activity, axonogenesis, neuron migration, and synapse organization. Notably, alterations in KIAA0319, a gene involved in neuronal migration, synaptic formation, and cortical development, have previously been associated with Parkinson’s disease at the gene expression level, while methylation changes in FAM50B have been reported in neurotoxic and cognitive contexts; our data suggest, for the first time, a potential epigenetic involvement of both genes in Parkinson’s disease. Conclusions: This pilot study on a Sicilian population provides further evidence that DNA methylation profiling can yield valuable molecular insights into PD. Despite the small sample size, our results confirm previously reported findings and highlight biological pathways relevant to neuronal structure and function that may contribute to disease pathogenesis. These data support the potential of epigenetic profiling of peripheral blood as a tool to advance the understanding of PD and generate hypotheses for future large-scale studies. Full article

Background: The clinical–radiological paradox in multiple sclerosis (MS) underscores the need for biomarkers that better reflect neurodegenerative pathology. Serum neurofilament light chain (sNfL) is a dynamic marker of neuroaxonal injury, while brain volumetry provides structural assessment of disease impact. However, the precise link between sNfL and regional atrophy patterns, as well as their combined utility for patient stratification and prediction, remains underexplored. Objective: This study aimed to establish a multimodal biomarker framework by integrating sNfL with comprehensive volumetric MRI to define neurodegenerative endophenotypes and predict neuroaxonal injury using Bayesian inference and machine learning. Methods: In a cohort of 57 MS patients, sNfL levels were measured using single-molecule array (Simoa) technology. Brain volumes for 42 regions were quantified via automated deep learning segmentation (mdbrain software). We employed (1) Bayesian correlation to quantify evidence for sNfL–volumetric associations; (2) mediation analysis to test whether grey matter atrophy mediates the EDSS–sNfL (Expanded Disability Status Scale) relationship; (3) unsupervised K-means clustering to identify patient subtypes based on combined sNfL–volumetric profiles; and (4) supervised machine learning (Elastic Net and Random Forest regression) to predict sNfL from volumetric features. Results: Bayesian analysis revealed strong evidence linking sNfL to total grey matter volume (r = −0.449, BF₁₀ = 0.022) and lateral ventricular volume (r = 0.349, BF₁₀ = 0.285). Mediation confirmed that grey matter atrophy significantly mediates the relationship between EDSS and sNfL (indirect effect = 0.45, 95% CI [0.20, 0.75]). Unsupervised clustering identified three distinct endophenotypes: “High Neurodegeneration” (elevated sNfL, severe atrophy, high disability), “Moderate Injury,” and “Benign Volumetry” (low sNfL, preserved volumes, mild disability). Supervised models predicted sNfL with high accuracy (R² = 0.65), identifying total grey matter volume, ventricular volume, and age as top predictors. Conclusions: This integrative multi-method analysis demonstrates that sNfL is robustly associated with global grey matter and ventricular volumes, and that these measures define clinically meaningful neurodegenerative subtypes in MS. Machine learning confirms that a concise set of volumetric features can effectively predict neuroaxonal injury. These findings advance a pathobiology-driven subtyping framework and provide a validated model for using routine MRI volumetry to assess neuroaxonal health, with implications for prognosis and personalised therapeutic strategies. Full article

Introduction: This study investigates how early aging affects the rat brain, focusing on aquaporin-4 and IL-17 levels in the whole brain, as well as glial cell alterations in the hippocampus. The hippocampus, essential for learning and memory, undergoes age-related changes contributing to cognitive decline and neuroinflammation. Glial cells—particularly microglia and astrocytes—are central to these processes. Most research focuses on advanced aging; in this study, we examine early aging effects. Methods: Male Wistar rats (13 weeks and 13 months old) were used. Whole-brain IL-17 and aquaporin-4 levels were assessed by ELISA. Immunohistology targeting GFAP, Iba1, and CD31 was performed on hippocampal sections to assess glial and vascular changes in CA1, CA2/3, and the dentate gyrus (DG). Results: Middle-aged rats brains showed significantly higher IL-17 and aquaporin-4 levels, confirming low-grade inflammation and metabolic alteration. In the hippocampus, microglia, astrocytes, and cerebral microvessels increased in CA2/3, with no significant changes in CA1 or DG. Conclusions: Early aging induces whole-brain neuroinflammation and metabolic changes and region-specific hippocampal alterations, with CA2/3 being particularly susceptible. These findings advance understanding of early brain aging and highlight CA2/3 as a potential target for intervention. Full article