Search Results (216)

Chronological age incompletely captures neurodegenerative burden and functional vulnerability in multiple sclerosis (MS). Brain-predicted age difference (Brain-PAD; predicted minus chronological age) provides an MRI-derived index of accelerated brain aging, but links to mobility and real-world behavior remain unclear. Forty-three adults with MS completed structural MRI, mobility testing, and six months of free-living physical activity monitoring. Brain age was estimated using PyBrainAge applied to FreeSurfer-derived cortical thickness and subcortical volumes. Hierarchical regressions tested whether Brain-PAD explained additional variance in mobility (Mini-BESTest total and subscores; forward/backward walking velocity) and moderate-to-vigorous physical activity (MVPA) beyond age and disability (PDDS). Predicted brain age exceeded chronological age (Brain-PAD = 8.4 ± 11.1 years; p < 0.001). After accounting for age and PDDS, Brain-PAD explained additional variance in Mini-BESTest total (ΔR² = 0.05, p = 0.042) and anticipatory control (ΔR² = 0.08, p = 0.034), with a trend for sensory orientation. Brain-PAD was not associated with walking velocity beyond PDDS. Higher Brain-PAD was associated with lower MVPA (β = −0.91, p = 0.005) and explained additional variance (ΔR² = 0.19). Brain-PAD is elevated in MS and relates to balance control and real-world physical activity beyond age and disability, highlighting its potential to identify functional vulnerability. Full article

Purpose: No prior clinical studies have quantitatively evaluated the effect of low-dose radiation therapy (LDRT) on Alzheimer’s disease (AD) brain changes using multi-modal MRI. This study examined the feasibility of using conductivity, diffusion, and brain tissue volume measures to detect treatment effects in patients with AD receiving LDRT. Methods: Nine patients with mild AD were enrolled in three groups. Three patients in each group were assigned to the control group (0 cGy) and the treated groups [24 cGy/6 fractions (4 cGy for each fraction) and 300 cGy/6 fractions (50 cGy for each fraction)]. Conductivity, diffusivity, and brain tissue volume were acquired at baseline and 6 months post-treatment and were evaluated to assess within-group MRI changes and evaluate associations between MRI measures and Mini-Mental State Examination (MMSE) scores. Results: Region-of-interest (ROI) analyses identified substantial changes in high-frequency conductivity (HFC) (e.g., left insula), cerebrospinal fluid (CSF) volumes (e.g., anterior cingulate, limbic regions), and diffusion tensor imaging (DTI) metrics, such as axial diffusivity (AxD) and fractional anisotropy (FA), in fusiform, thalamic, hippocampal, and occipital areas. Correlation analysis showed strong associations between MRI measures and cognition, most notably HFC in the left fusiform gyrus (r = 0.843, p = 0.0043) after treatment. Diffusion indices across multiple regions also showed significant positive or negative correlations with MMSE. Conclusions: This exploratory clinical study demonstrates that LDRT induces measurable physiological and microstructural alterations in the brain detectable via conductivity and diffusion MRI. Conductivity emerged as the sensitive biomarker, showing strong cognitive correlations. These exploratory findings suggest that multi-modal quantitative MRI can serve as an effective tool for evaluating treatment response in clinical LDRT for AD. Full article

Aging is a complex biological process characterized by progressive loss of cellular homeostasis, impaired regenerative capacity, and accumulation of senescent cells that collectively predispose tissues to disease. Traditional two-dimensional culture systems and animal models have provided valuable insights but fail to fully recapitulate the spatial organization, cellular heterogeneity, and microenvironmental cues of aging human tissues. Organoid technology—three-dimensional self-organizing structures derived from adult stem cells or pluripotent stem cells has emerged as a transformative platform to model aging in vitro. These mini-tissues retain the architecture, signaling dynamics, and lineage hierarchy of native organs, making them powerful systems to interrogate age-associated cellular phenotypes, DNA damage responses, and senescence programs. This review discusses how organoid models are advancing our understanding of aging biology across multiple organ systems, from the intestines and liver to the brain and lung. We highlighted key molecular pathways driving cellular senescence within organoids—including p16INK4a/p21CIP1 signaling, SASP activation, mitochondrial dysfunction, and epigenetic drift—and how these can be targeted to restore tissue homeostasis. We further discussed how organoids derived from aged tissues, induced pluripotent stem cells, and engineered oncogene systems reveal new therapeutic opportunities to modulate senescence in age-related disorders, cancer, and regenerative medicine. Finally, we discussed emerging integrative tools such as organoid co-cultures, single-cell omics, and senolytics drug screening that are expanding the potential of organoids as translational platforms for anti-aging and disease intervention. Full article

Background: Age-related cognitive deccline is a significant health issue in Spain, especially among adults over 60 years of age. Addressing this involves establishing intervention guidelines and identifying early diagnostic biomarkers. Objective: To evaluate changes in urine of Brain-Derived Neurotrophic Factor, concentration and cognitive performance after the implementation of the multicomponent CESPORT program (incorporating a Mediterranean Diet, nutritional education, and continuous support). Methods: This controlled trial included 76 older adults, divided into an experimental group (n = 58; mean age 66.9 years; 75.9% female) that participated in the CESPORT program, and a control group (n = 18; mean age 68.8 years; 72.2% female). Cognitive performance was assessed using the Mini-Mental State Examination (MMSE) and the Cognifit^® battery. Urinary BDNF concentrations were quantified via ELISA. Results: After adjusting for baseline scores via ANCOVA, the experimental group demonstrated significantly higher post-intervention outcomes compared to the control group (p < 0.001). Substantial improvements with medium-to-large effect sizes were observed in global cognition, reasoning, attention, coordination and perception. Furthermore, urinary BDNF levels were significantly elevated in the experimental group. Positive correlations were found between Brain-Derived Neurotrophic Factor concentrations and cognitive performance in multiple domains (p < 0.05), particularly regarding global status and reasoning. Conclusions: The multicomponent CESPORT intervention demonstrates a potential protective effect against age-related cognitive decline. Furthermore, urinary BDNF emerges as a promising, non-invasive early biomarker for cognitive health. Further research is warranted to validate these findings. Full article

Objectives: This randomized, double-blind, placebo-controlled 12-week clinical trial evaluated the efficacy and safety of a standardized ethanol extract of purple perilla leaves (Perilla frutescens Britton var. acuta Kudo; PE) in adults with cognitive impairment. Methods: Subjects who met the inclusion criteria were randomly assigned in a 1:1 ratio to one of two groups and received PE (n = 50, 500 mg/day) or placebo (n = 50) for 12 weeks. The primary efficacy outcomes included cognitive function, which was assessed by the Korean mini-mental status examination–2 (K–MMSE–2) and the Alzheimer’s disease assessment scale–cognitive subscale (ADAS–Cog), and plasma amyloid β (Aβ) and brain-derived neurotrophic factor (BDNF) levels, which were measured as secondary biochemical markers. The safety biomarkers were also assessed before and after the intervention. Results: After 12 weeks of intervention, the K–MMSE–2 total score, the K–MMSE–2 subdomain scores (attention and calculation and language), the ADAS–Cog total score, and the ADAS–Cog subscale scores (word recall, commands, delayed word recall, naming, word recognition, and recall instructions) showed statistically significant between-group improvements compared with the placebo group. Improvements were observed in both groups, whereas the magnitude of cognitive enhancement was greater in the PE group, indicating an effect beyond placebo-related responses. No statistically significant between-group differences were observed in plasma Aβ or BDNF levels. The safety evaluation found no clinically significant changes. Conclusions: Twelve-week administration of PE significantly improved cognitive outcomes without safety concerns, suggesting its potential as a standardized botanical ingredient for supporting cognitive function in individuals with early cognitive impairment. Full article

Head injuries remain one of the major health concerns in contact sports such as boxing. Despite the widespread use of protective gloves and helmets, their biomechanical effectiveness in mitigating head acceleration and reducing brain injury risk remains uncertain. This study aims to biomechanically assess available boxing equipment solutions and identify the brain–skull system’s response to physical forces from a boxing punch. A dedicated experimental setup was developed using mini triaxial accelerometers and a high-speed camera to measure head accelerations in a Primus unbreakable dummy. Tests were performed using gloves of different masses (0 oz, 10 oz, and 16 oz) and three head protection configurations: no helmet, rugby helmet, and boxing helmet. The resultant accelerations were analyzed and compared across test conditions. Peak wrist accelerations ranged from 195.00 to 271.77 m/s², while head accelerations did not exceed biomechanical injury thresholds. The boxing helmet, composed of multilayer polyurethane foam, did not consistently decrease acceleration; in some cases, it produced higher overloads due to increased head mass and moment of inertia. A rugby helmet made of open-cell EVA (ethylene vinyl acetate) foam with lower density exhibited more favorable energy-dissipation characteristics under low-impact conditions. Glove mass also influenced acceleration differently between male and female participants, likely due to variations in punch velocity and force generation. This work is a pilot study using two trained adult volunteers to validate the combined IMU–video measurement framework. The results serve as hypothesis-generating mechanistic observations rather than population-level effect estimates. Protective effectiveness in boxing depends on a complex interaction between material properties, geometry, and user biomechanics. Optimal equipment design should balance energy absorption and mass to minimize both linear and rotational accelerations. Future studies should integrate advanced material modeling and finite element simulations to support the development of adaptive, lightweight protective systems. Full article

Background/Objectives: The incidence of dementia and the concurrent burden on healthcare will increase with a population that continues to age. Pharmaceutical interventions for dementia carry negative side effects, ineffectively treat underlying causes, and fail to prevent disease onset. Therefore, non-pharmaceutical interventions such as music therapy should to be explored as a standalone or co-therapy for dementia. Music therapy improves cognitive symptoms of dementia; however, the neural mechanisms underpinning these improvements are not fully understood. Methods: To investigate potential neural mechanisms, six participants with dementia completed the Standardised Mini Mental State Examination, an n-back task, and magnetoencephalography (MEG) scanning before and after a music therapy program structured around improving executive functioning. Results: After music therapy, scores on an n-back task improved, and the MEG data revealed increased connectivity in neural networks and areas associated with compensation during executive functioning tasks. Connectivity results suggest there is preliminary evidence that music therapy improves cognitive symptoms of dementia by activating compensatory neural networks and areas; however, given the small sample size, these results should be interpreted with caution. Conclusions: The results of this hypotheses study present music therapy as a potentially viable short-term intervention which may operate by targeting compensatory neural networks and could be a long-term intervention that incorporates positive modifiable lifestyle factors, protecting the brain from dementia. Full article

Background: Survivors with chronic sequelae of carbon monoxide (CO) poisoning after the 1963 Miike–Mikawa coal mine disaster can exhibit persistent higher brain dysfunction in late life. We examined whether serum metabolic alterations remained detectable ~60 years later and assessed serum brain-derived neurotrophic factor (BDNF). Methods: In this cross-sectional case–control study, outpatients with chronic CO-poisoning sequelae (CO; n = 14) and former miners without CO exposure (CON; n = 16), all aged ≥ 75 years, underwent targeted serum metabolomics (1183 metabolites) and clinical assessments. Between-group differences were evaluated using Welch’s t-test, and age-matched propensity-score matching (1:1) served as a sensitivity analysis. BDNF was additionally compared using a linear regression/ analysis of covariancemodel adjusting for age and Mini–Mental State Examination (MMSE). Results: Relative to controls, the CO group showed higher valine, alanine, and betaine and lower 3-hydroxybutyric acid, inosine, and hypoxanthine; these contrasts persisted with concordant direction after matching. Serum BDNF was lower in the CO group (unadjusted trend) and was significantly reduced after age/MMSE adjustment (p = 0.0252). Exploratory correlations between clinical measures and selected metabolites/BDNF were attenuated after accounting for group. Conclusions: Six decades after exposure, chronic CO sequelae were associated with a reproducible serum profile combining amino-acid elevations with relative suppression of ketone-body and purine-related metabolites, suggesting enduring alterations in systemic substrate handling and bioenergetics. If replicated in larger cohorts, such signatures—potentially alongside BDNF—should be regarded as hypothesis-generating; biomarker development would require external validation, longitudinal tracking, and assessment of intervention responsiveness before any clinical use is considered. Full article

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Compared with traditional two-dimensional (2D) models, patient-derived CRC organoids more faithfully preserve the genomic, transcriptomic, and architectural features of primary tumors, making them a powerful intermediate platform bridging basic discovery and clinical translation. Over the past several years, organoid systems have rapidly expanded beyond conventional epithelial-only cultures toward increasingly complex architectures, including immune-organoid co-culture models and mini-colon systems that enable long-term, spatially resolved tracking of tumor evolution. These advanced platforms, combined with high-throughput technologies and clustered regularly interspaced short palindromic repeats (CRISPR)-based functional genomics, have substantially enhanced our ability to dissect CRC mechanisms, identify therapeutic vulnerabilities, and evaluate drug responses in a physiologically relevant context. However, current models still face critical limitations, such as the lack of systemic physiology (e.g., gut–liver or gut–brain axes), limited standardization across platforms, and the need for large-scale, prospective clinical validation. These gaps highlight an urgent need for next-generation platforms and computational frameworks. The development of high-throughput multi-omics, CRISPR-based perturbation, drug screening technologies, and artificial intelligence-driven predictive approaches will offer a promising avenue to address these challenges, accelerating mechanistic studies of CRC, enabling personalized therapy, and facilitating clinical translation. In this perspective, we propose a roadmap for CRC organoid research centered on two major technical pillars: advanced organoid platforms, including immune co-culture and mini-colon systems, and mechanistic investigations leveraging multi-omics and CRISPR-based functional genomics. We then discuss translational applications, such as high-throughput drug screening, and highlight emerging computational and translational strategies that may support future clinical validation and precision medicine. Full article

The oxoglutarate dehydrogenase-like (OGDHL) gene encodes a brain-enriched, rate-limiting enzyme in the tricarboxylic acid cycle, playing an essential role in mitochondrial energy metabolism. Mutations in OGDHL are linked to a broad spectrum of neurodevelopmental disorders, characterized by developmental delay, intellectual disability, epilepsy, corpus callosum dysgenesis, and sensory deficits. This mini-review systematically summarizes the discovery, structural features, and molecular functions of OGDHL, and provides a comprehensive catalog of all reported pathogenic mutations and their clinical phenotypes. By linking mitochondrial energy metabolism and neural pathogenesis, this work positions OGDHL as a potential key regulator in neural development and function. Ultimately, this review aims to advance further research on OGDHL in the nervous system, enhance the understanding of metabolic regulation in neurodevelopment, and lay the groundwork for elucidating the mechanisms underlying OGDHL-related neurological diseases. Full article

Background/Objectives: In clinical practice, Explainable AI (XAI) enables non-specialists and general practitioners to make precise diagnoses. Current XAI approaches are limited, as many rely solely on either presenting explanations of clinical data or presenting explanations of MRI, or presenting explanations in unclear ways, reducing their clinical utility. Methods: In this paper, we propose a novel Hybrid Explainable AI (HXAI) framework. This framework uniquely integrates both model-agnostic (SHAP) and model-specific (Grad-CAM) explanation methods within a unified structure for the diagnosis of Alzheimer’s disease. The dual-layer explainability constitutes the main originality of this study, as it provides the possibility of interpreting quantitative (at the feature level) and spatial (at the region level) data within a single diagnostic framework. Clinical features (e.g., Mini-Mental State Examination (MMSE), normalized Whole Brain Volume (nWBV), Socioeconomic Status (SES), age) are combined with MRI-derived features extracted via ResNet50, and these features are integrated using ensemble learning with a logistic regression meta-model. Results: The corresponding validation reflects the explainability accuracy of these feature-based explanations, with removal-based tests achieving 83.61% explainability accuracy, confirming the importance of these features. Model-specific information was used to explain MRI predictions, achieving 58.16% explainability accuracy of visual explanations. Conclusions: Our HXAI framework integrates both model-agnostic and model-specific approaches in a structured manner, supported by quantitative metrics. This dual-layer interpretability enhances transparency, improves explainability accuracy, and provides an accurate and interpretable framework for AD diagnosis, bridging the gap between model accuracy and clinical trust. Full article

Pediatric drug delivery presents unique challenges due to physiological and pharmacological differences across age groups, requiring specialized formulation approaches beyond simple dose adjustments of adult medications. This review synthesizes recent advances in polysaccharide-based pediatric drug delivery and highlights novel findings that may accelerate clinical translation. It summarizes how chitosan, alginate, hyaluronic acid, dextran, modified starches, and other polysaccharides are engineered into nanoparticles, hydrogels, films, and orodispersible/mini-tablet formulations to improve stability, bioavailability, taste masking, and controlled release across neonates to adolescents. These systems can accommodate developmental variations in absorption, distribution, metabolism, and excretion processes across pediatric subpopulations, with particular emphasis on oral and alternative administration routes. Evidence supporting unexpectedly high acceptability of mini-tablets, successful integration of modified polysaccharides in 3D-printed personalized low-dose therapies, and the emergence of blood–brain barrier-penetrating and RGD-functionalized polysaccharide nanocarriers for pediatric oncology are emphasized as novel, clinically relevant trends. This review also addresses regulatory considerations, safety profiles, and future perspectives. By integrating developmental insights with innovative formulation strategies, polysaccharide polymers offer promising solutions to improve medication adherence, safety, and efficacy across the pediatric age spectrum. Full article

Background/Objectives: Myotonic dystrophy type 1 (DM1) is a multisystem disorder that affects the central nervous system. Despite previous studies, blood-based biomarkers have not been sufficiently characterized. This study investigated plasma neurofilament light chain (NfL), phosphorylated tau (p-tau181), amyloid-β (Aβ42/40), and glial fibrillary acidic protein (GFAP) in a Japanese cohort with DM1 to assess their potential as biomarkers. Methods: Forty patients with genetically confirmed DM1 were enrolled in this study. Plasma NfL, p-tau181, Aβ42/40, and GFAP were quantified using single-molecule array technology. Clinical and genetic variables, including age, CTG repeat size, Mini-Mental State Examination (MMSE) score, modified Rankin Scale (mRS) score, and creatine kinase levels, were analyzed for correlations. Results: NfL and p-tau181 were significantly elevated in patients with DM1 compared with controls, with 95% exceeding the p-tau181 cut-off. NfL was moderately correlated with age, age at onset, and mRS, and no significant associations were observed between p-tau181 and other biomarkers, although a correlation was noted with serum creatine kinase. Conclusions: These findings support that NfL is a marker of disease severity in DM1 and identified plasma p-tau181 as a potential novel biomarker. While the mechanisms underlying the increased p-tau181 levels remain unclear, they may reflect DM1-related pathologies in the brain and possibly in skeletal muscle. Study limitations include a small sample size and lack of age-matched controls, highlighting the need for longitudinal validation. This study demonstrates the utility of NfL and suggests that p-tau181 is an emerging biomarker for DM1, supporting future work toward biomarker-guided monitoring and therapeutic evaluation. Full article

Background and Objectives: Difficulties in language production and comprehension constitute clinical symptoms characterizing patients diagnosed with Primary Progressive Aphasia (PPA). Thorough assessment of language domains can detect specific deficits commonly observed in different PPA variants, but brief and practical instruments capable of screening for language impairment are lacking. The present study aimed to examine the ability of the Mini Linguistic State Examination (MLSE) to distinguish between healthy individuals and PPA patients, as well as to differentiate among PPA subtypes, within Greek clinical practice. Materials and Methods: Τhe Mini Linguistic State Examination (MLSE), a 15-min detailed examination of different language domains, was administered to a group of clinically diagnosed PPA patients and a group of healthy participants. In addition, PPA patients completed a neuropsychological test battery assessing memory, language, executive, and visuospatial functions. Patterns of patients’ brain perfusion were also explored with single-photon emission computed tomography. Results: Comparisons between PPA patients and healthy controls revealed significant differences across all MLSE domains (all p < 0.001), and receiver operating characteristic analyses demonstrated excellent diagnostic accuracy, with AUC values exceeding 0.90 across language domains and perfect classification for the total MLSE score (AUC = 1.00, p < 0.001). Conclusions: These findings indicate that the MLSE is able to detect distinct patterns of deficits and to provide a comprehensive overview of patients’ linguistic profiles, supporting its clinical utility and diagnostic potential for differentiating PPA variants. Full article

Background: The purpose of this study was to investigate differences in cognitive well-being and brain activity between older women with and without mild cognitive impairment (MCI) across varying levels of physical activity. Method: A total of 126 female participants aged over 65 years were recruited and categorized into MCI and non-MCI groups. Cognitive health was evaluated using the Korean versions of the Mini-Mental State Examination (MMSE-K) and the Montreal Cognitive Assessment (MoCA-K), while physical activity levels were quantified with the Physical Activity Scale for the Elderly (PASE-K). Brain activity was assessed through electroencephalography (EEG). Data were analyzed using two-way ANOVA. Results: Results indicated that non-MCI participants consistently demonstrated higher cognitive scores across all physical activity levels. Moreover, individuals with higher physical activity exhibited greater theta wave activity compared with those in the MCI group. Significant group differences were also observed in concentration and stress levels. Conclusion: These findings suggest that higher physical activity levels are associated with better cognitive performance and brain activity in older women. Promoting physical activity may therefore contribute to strategies aimed at supporting healthy cognitive aging, although longitudinal research is required to establish causal relationships. Full article