Search Results (6,350)

The link between neurodevelopment in infants exposed to maternal gestational diabetes mellitus (GDM) and fetal DNA methylation remains unexplored. We conducted this hypothesis-generating study to investigate the association between fetal DNA methylation and neurodevelopmental outcomes in children of mothers with GDM. We carried out a prospective, observational pilot cohort study comparing infants exposed to maternal GDM with an unexposed control group. Umbilical cord blood DNA methylation was assessed using targeted methylome sequencing covering 3.34 million CpG sites. Infant neurodevelopment was evaluated at age two years using the Bayley-III Scales. Bioinformatics processing identified differentially methylated regions (DMRs), followed by multiple enrichment analyses of DMR-associated genes and partial correlation analyses. Multi-dimensional enrichment analysis of the 1053 identified DMR-associated genes revealed a significant convergence of pathways related to neurogenesis, synaptic components, and axonal guidance. Infants born to mothers with GDM exhibited lower scores in cognitive, language, and motor domains, which were associated with identifiable DNA methylation signatures at birth. Significant correlations were observed in genes essential for brain scaffolding and synaptic circuitry, most notably WNT4, the PCDHG alpha/beta clusters, and PALM. Additionally, methylation patterns in FOXF2 and CHFR suggest a potential impact on blood–brain barrier integrity, while associations with FSTL3 and H6PD highlight a systemic metabolic ‘cross-talk’ influencing neurodevelopment. Although these pilot findings are hypothesis-generating and require further functional validation, this study provides pioneering evidence that neurodevelopmental alterations in the offspring of mothers with GDM are potentially associated with intrauterine epigenetic modifications detectable at birth. Full article

Background/Objectives: Mild cognitive impairment (MCI), the prodromal stage of Alzheimer’s disease, may be influenced by nutritional status and genetic susceptibility. This systematic review synthesised evidence on how nutritional biomarkers interact with genetic variants, particularly APOE ε4, to influence cognitive outcomes in individuals with MCI. Methods: Following PRISMA 2020 guidelines, seven studies were included (three longitudinal, two randomised controlled trials, and two cross-sectional) involving adults aged ≥55 years with MCI. Nutritional exposures comprised plasma or serum concentrations of vitamins A, D, E, the vitamin B group, lipids, selenium, and ketogenic medium-chain triglycerides. Genetic risk was assessed primarily through APOE ε4 status. Risk of bias was assessed using RoB 2 and ROBINS-I, and certainty of evidence using GRADE. Due to heterogeneity in biomarkers, cognitive tools, and study designs, findings were synthesised narratively. Results: Across nutrient categories, higher concentrations of vitamin D, selenium, and antioxidants were associated with better cognitive outcomes. kMCT supplementation improved episodic memory and brain energy metabolism. Evidence for nutrient–gene interactions was mixed: APOE ε4 modified responses to vitamin B group and selenium but showed limited influence on vitamin D, lipids, or kMCT effects. Heterogeneity in biomarker assays, cognitive tools, and genetic stratification limited comparability across studies. Conclusions: Nutritional biomarkers appear to influence cognitive trajectories in MCI, and some associations may differ by APOE ε4 status. However, small samples and limited genetic stratification constrain interpretation. Future research should prioritise standardised biomarker measurement, genetically stratified cohorts, and individual participant data meta-analyses to clarify nutrient–gene interactions in MCI. Full article

Background: Postoperative neurocognitive disorders (PND) are frequent complications in the elderly surgical patients, with aging recognized as a major risk factor. This study aimed to identify electrophysiological markers and establish an exploratory machine learning framework for PND-related vulnerability prediction using anesthetic electroencephalography (EEG) features in aged mice. Methods: Young and aged mice underwent laparotomy under isoflurane anesthesia with EEG recording. Neurocognitive performance was quantified by 16 standardized behavioral fractions. A semi-supervised K-means algorithm, anchored on young-surgery mice, stratified aged-surgery mice into PND and non-PND clusters. EEG dynamics during anesthesia maintenance and emergence were analyzed, and machine learning models were trained to predict PND from EEG features. Results: At baseline, neurocognitive function was comparable across groups. After anesthesia/surgery, aged mice exhibited selective spatial and contextual memory impairments, with two-thirds classified as PND. During emergence, PND mice displayed elevated δ power and reduced α and β ratios. A Multi-layer Perceptron classifier showed discriminatory performance for PND classification in one evaluation setting (AUC = 0.94). Conclusions: This study identifies emergence-related EEG features associated with postoperative neurocognitive vulnerability in aged mice and provides an exploratory machine learning framework for preclinical risk stratification. These findings support further mechanistic investigation and warrant future validation in human perioperative EEG datasets. Full article

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

Background/Objectives: Constipation is a common gastrointestinal problem in older adults and is associated with reduced quality of life, functional decline, frailty, and an increased risk of delirium and cognitive impairment. Its pathogenesis is multifactorial, involving age-related changes in gastrointestinal motility, neural regulation, comorbidities, and polypharmacy. However, this condition has traditionally been regarded as a localized gastrointestinal disorder, which may not fully reflect its systemic clinical significance in older populations. While prior narrative reviews have described multifactorial contributors to constipation, none have formally applied a geriatric syndrome framework to integrate these dimensions. This review proposes a three-criterion operational definition—multifactorial pathogenesis, association with functional decline and frailty, and contribution to adverse systemic outcomes—to characterize constipation in older adults as a “systemic geriatric syndrome,” and evaluates available evidence against each criterion. Methods: A narrative literature search was conducted using PubMed to identify relevant studies published between 1 January 2023, and 31 December 2025. MeSH terms included “Constipation” [Major Topic] and “Aged” [MeSH Terms]. Eligible articles included English-language original studies, systematic reviews, and clinical or epidemiological studies involving individuals aged ≥65 years. Results: Diagnosis in older adults is often complicated by secondary causes, including medications and neurological disorders, as well as atypical symptom presentations in individuals with cognitive impairment. Key pathophysiological mechanisms include reductions in interstitial cells of Cajal, impaired smooth muscle contractility, dysfunction of the enteric and autonomic nervous systems, and gut microbiota dysbiosis, which may promote chronic low-grade inflammation. Major contributing factors include physical inactivity, sarcopenia, dehydration, inappropriate defecation posture, and polypharmacy, particularly opioids and anticholinergic agents. Importantly, these factors interact through the brain–gut–microbiota axis, contributing not only to gastrointestinal dysfunction but also to systemic outcomes such as frailty, cognitive decline, and increased healthcare burden, thereby supporting a multidimensional disease framework. Conclusions: The available evidence collectively supports the plausibility of framing constipation in older adults as a systemic geriatric syndrome, though formal validation of this classification requires further longitudinal and mechanistic research. Comprehensive and individualized management strategies, extending beyond simple laxative use, are essential to reduce complications and preserve functional health in aging populations. Further studies are required to validate this framework. Full article

Background: The care and management of a pregnant woman suffering from end-stage brain cancer is surrounded by medical, legal, and ethical controversies. When this brain pathology leads to brain death (BD), continuation of life-sustaining treatments has been considered futile and unethical. An exception could be the case of pregnancy, in order to deliver a healthy neonate. Aim: The presentation of a pregnant woman with a terminal stage brain astrocytoma, admitted in the intensive care unit (ICU) to support the pregnancy, until optimal fetal viability, after she had neurological deterioration and confirmed BD, and a brief literature review of previously relevant published cases. Case Presentation: A 36-year-old woman with a medical history of brain astrocytoma in the last 2 years was admitted in ICU for the first time due to status epilepticus, six months after she stopped anticonvulsant therapy. Her epilepsy was controlled, and a pregnancy of 14 weeks was confirmed. Two weeks later, she deteriorated. After a multidisciplinary approach, it was decided to mechanically ventilate the patient and support the pregnancy. Brain death was determined after a couple of days. Results: A cesarean section was performed 11 weeks after BD diagnosis (at 27 weeks of gestational age) resulting in the delivery of a live, premature infant, weighing 549 gr. Conclusions: Maternal corporeal support can maximize the chances for survival in the neonate by prolonging the pregnancy of a brain-dead woman. Full article

Leucine-rich repeat kinase 2 (LRRK2) is a multidomain serine/threonine kinase and a major genetic contributor to Parkinson’s disease (PD). Although LRRK2 has been extensively studied in neurodegeneration, emerging evidence indicates that it also plays a critical role in systemic metabolism. LRRK2 regulates glucose homeostasis through modulation of insulin signaling, vesicle trafficking, mitochondrial function, and inflammatory responses. Studies using LRRK2 knockout and knock-in models, including the pathogenic G2019S mutation, have revealed abnormalities in insulin sensitivity, adipose tissue inflammation, hepatic glucose production, and skeletal muscle metabolism. Mechanistically, LRRK2 phosphorylates Rab GTPases, thereby controlling insulin receptor trafficking and GLUT4 translocation. In addition, LRRK2 influences mitochondrial dynamics and reactive oxygen species production, linking metabolic stress to inflammatory signaling. Importantly, LRRK2 also regulates innate immune pathways, including TLR4–NFκB signaling and inflammasome activation, thereby connecting peripheral metabolic dysfunction to neuroinflammation. Here, we propose an integrated metabolic–neuroinflammatory crosstalk model in which LRRK2 functions as a molecular coordinator linking peripheral metabolic dysfunction to central neurodegeneration. In this framework, systemic metabolic stress—characterized by insulin resistance, chronic inflammation, advanced glycation end product (AGE) accumulation, and blood–brain barrier disruption—drives microglial activation and neurodegenerative processes. Understanding this systemic axis may provide new therapeutic opportunities targeting both metabolic dysfunction and neurodegeneration in PD. Full article

Background/Objectives: Poorly soluble aluminium (Al) compounds have successfully been used for decades as adjuvants in vaccines, enabling an effective immune response. Yet the safety of Al exposure from vaccines is consistently questioned, especially regarding infants. Since toxicokinetic data of aluminium after vaccination in humans are not available, model-informed predictions are needed for risk assessment. Methods: Using a physiologically-based toxicokinetic model, we predicted the Al exposure from i.m. injections of Al-adjuvanted vaccines for full-term neonates to 50-year-old adults following the recommended vaccination schedule in Germany 2025 in addition to the continuous oral background Al exposure from dietary intake. Results: During the first two years of life, moderate (max. 2-to-3-fold) but transient increases of Al concentrations in plasma and in the relevant target organs liver and bone due to vaccinations were predicted. Increase in brain Al content was 4%. Most importantly, in all tissues, maximum Al levels did not exceed normal levels observed in infants soon after birth or known from adults. In children and adults, the rise in Al concentrations in plasma and tissues due to single vaccinations was marginal. The calculated contribution of vaccinations to the Al body burden at age 50 was negligible. Conclusions: From a toxicokinetic perspective, the additional Al exposure in full-term infants, children and adults from vaccinations with Al-adjuvanted vaccines according to the current recommended schedules is considered safe. The model has proven a valuable tool for predictions of Al exposure from vaccinations. Full article

Parkinson’s disease (PD) is a common neurodegenerative disorder marked by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies, intracellular inclusions enriched in α-synuclein. Synphilin-1 interacts with α-synuclein, localizes to Lewy bodies, and has been implicated in inclusion formation and neuroprotection in cellular and animal models; however, its physiological function in vivo remains poorly defined. Here, we generated and characterized a synphilin-1 knockout (Sph-1 KO) mouse by targeted genetic deletion of the Sph-1 locus and performed a comprehensive phenotyping battery including behavioral testing as well as biochemical, histological, structural, and ultrastructural analyses. Sph-1 KO mice survived to nearly two years of age and showed normal body weight, lifespan, motor performance, learning and memory, anxiety-like behavior, attention, and gross brain morphology. Western blot analyses indicated that levels of α-synuclein and synaptic proteins were largely unchanged. While outer mitochondrial membrane proteins were unaffected, the mitochondrial matrix protein HSP60 was reduced, consistent with altered mitochondrial proteostasis in the absence of synphilin-1. Strikingly, histochemical analyses, magnetic resonance imaging, and electron microscopy revealed early-onset hydrocephalus in Sph-1 KO mice associated with severe loss and disorganization of motile ependymal cilia in the ventricular lining, a cell type that normally expresses high levels of synphilin-1. Ultrastructural and immunohistochemical analyses revealed disrupted ependymal architecture, mislocalization of acetylated α-tubulin to the cytoplasm, cellular swelling, and enlarged, aberrant mitochondria, whereas cortical neurons appeared largely structurally unaffected. Together, these findings identify synphilin-1 as a key regulator of microtubule organization and cytoskeletal/organelle homeostasis in ependymal cells, required to maintain motile ciliogenesis, cerebrospinal fluid flow, and ventricular integrity. This unexpected role for synphilin-1 in ciliated brain epithelia, along with a reduction in the critical mitochondrial chaperone HSP60, broadens our understanding of synphilin-1 biology and provides a new framework for its potential relevance to PD-associated pathology. Full article

Alzheimer’s disease is a complex neurodegenerative condition characterized by progressive cognitive decline, neuroinflammation, metabolic dysregulation, and abnormal protein deposition. While genetic factors and amyloid-beta-focused hypotheses have been extensively investigated, they fail to fully account for the prolonged prodromal phase or the early susceptibility of olfactory and limbic regions. Emerging evidence suggests chronic peripheral and mucosal infections may influence disease risk; however, mechanisms by which microbial activity outside the central nervous system contributes to persistent neuropathology remain poorly understood. This review explores the emerging concept that bacterial outer membrane vesicles act as mobile, lipid-rich vectors linking peripheral microbial reservoirs to neuroimmune and metabolic dysfunction in the aging brain. We discuss evidence suggesting vesicles originating from oral, olfactory, and upper airway niches can access the central nervous system via vascular routes and direct neural pathways, including olfactory and trigeminal nerves, where they influence glial and endothelial cell function. We also propose the Accumulative Vesicle Load Hypothesis, which describes how cumulative lifetime exposure to bacterial vesicles shapes disease onset, anatomical vulnerability, and progression, and incorporates components of other hypotheses proposed for Alzheimer’s disease. This offers a system-level perspective for early diagnosis and upstream therapeutic strategies, including minimally invasive vesicle profiling in nasal fluid, saliva, blood, and cerebrospinal fluid. This work is a conceptual review that summarizes current evidence in a hierarchically organized manner and proposes a testable model; it does not assert causality where direct human evidence is currently limited. Full article

With population aging, motor vehicle accidents involving older drivers have increased. Age-related cognitive decline affects driving performance; however, the underlying neural mechanisms remain unclear. This scoping review explored neurophysiological characteristics associated with driving in older adults, including those at risk of dementia. Following PRISMA-ScR guidelines, we searched PubMed, Scopus, and CINAHL for studies examining driving-related neurophysiological measures in older adults aged ≥60 years. Twelve studies were included. Findings converge on load-dependent neural compensation failure: older adults maintain driving performance under low-to-moderate demands, but compensatory mechanisms break down under high cognitive load. Electroencephalography (EEG) studies revealed blunted midfrontal theta upregulation during high-load conditions, associated with reduced steering precision and delayed responses. Event-related potential studies demonstrated that reduced P3b amplitude was associated with missed braking responses and that abnormal visual evoked potentials in Alzheimer’s disease predicted unfit-to-drive classifications. fNIRS studies during driving-related tasks and an fMRI study using a laboratory-based visual task consistently showed prefrontal hyperactivation in older adults. Although some older adults maintained comparable performance to younger adults, the brain–behavior associations observed in younger adults were absent, suggesting that this hyperactivation does not necessarily serve a functional compensatory role. Combined with EEG evidence of impaired oscillatory modulation, these findings suggest that prefrontal hyperactivation does not necessarily compensate for diminished neural synchronization under high-load conditions. Neurophysiological markers hold promise for fitness-to-drive assessments. Future research should employ high-load scenarios and multimodal neuroimaging to verify prefrontal compensatory mechanisms. Full article

Background: Breast cancer brain metastases (BCBMs) are clinically challenging, and treatment decisions are influenced by tumor biology. Because receptor profiles may differ between primary breast tumors and brain metastases and brain biopsy may be impractical, non-invasive imaging biomarkers may provide useful biologic correlates. We evaluated whether diffusion-weighted imaging (DWI)-derived apparent diffusion coefficient (ADC) histogram metrics from BCBM were associated with primary tumor estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status; the Ki-67 proliferation index; and luminal status. Methods: This retrospective exploratory single-center study included 72 adults with BCBM who underwent standardized 1.5T brain magnetic resonance imaging. The largest lesion in each patient was segmented on ADC maps in FireVoxel. ADC histogram features, including percentiles, were extracted. Using primary tumor biomarker status as the reference, candidate metrics were screened by univariable logistic regression. Parsimonious multivariable models included age, log-transformed lesion volume, and a single selected ADC percentile scaled by ×10. Discriminatory performance was assessed using area under the receiver operating characteristic curve (AUC); thresholds were derived with the Youden index. No external validation was performed. Results: Low-percentile ADC metrics were associated with ER positivity, PR positivity, and luminal disease, whereas no meaningful ADC histogram discrimination was observed for HER2. In multivariable models, ADC10×10 predicted ER positivity (odds ratio [OR] 0.441; AUC 0.847) and PR positivity (OR 0.478; AUC 0.819). Ki-67 positivity was best predicted by ADC75×10 (OR 3.095; AUC 0.905), although this finding should be interpreted cautiously. Luminal status (non-luminal vs. luminal) was predicted by ADC10×10 (OR 2.251; AUC 0.832). Conclusions: ADC histogram analysis from DWI in BCBM showed exploratory associations with primary tumor hormone receptor status and luminal subtype, but not HER2. These findings support ADC histogram features as candidate imaging biomarkers, but the Ki-67 result and all model performance estimates require cautious interpretation and independent external validation in multicenter cohorts. Full article

Background/Objectives: Abnormalities in the partial pressure of carbon dioxide (PCO₂) can occur during respiratory support and may contribute to adverse neonatal outcomes. This study aimed to assess the incidence of early hypocapnia and hypercapnia in mechanically ventilated preterm infants and their major associated outcomes. Methods: A single-center retrospective cohort study (2017–2024) was conducted in preterm infants < 32 weeks’ gestation who required > 24 h of invasive ventilation within the first 3 days of life. Perinatal–neonatal data were retrieved from the medical database. Admission blood gas values (arterial and capillary–venous) and the maximum and minimum PCO₂ in the first 72 h were evaluated. Normocapnia was defined as PCO₂ 35–45 mmHg, hypocapnia as < 35 mmHg, and hypercapnia as > 45 mmHg. Primary outcomes were the incidence of PCO₂ abnormalities; secondary outcomes included death or severe brain injury (SBI), SBI alone, and bronchopulmonary dysplasia (BPD) among survivors. Logistic regression identified independent predictors of the secondary outcomes. Results: Among the 134 infants evaluated, most experienced both hypercapnia and hypocapnia. Hypercapnia occurred in 81.3% of infants, and hypocapnia in 93.2%. Death or SBI was observed in 51.5%, and SBI alone in 42.5%. Gestational age < 28 weeks, air-leak syndromes, and pulmonary hemorrhage were independent predictors of death or SBI. Among survivors, hypercapnia and gestational age < 28 weeks independently predicted BPD. Infants with adverse outcomes had higher maximum PCO₂ values and greater PCO₂ variability, although these were not independent predictors of SBI or death. Conclusions: PCO₂ instability is highly prevalent in ventilated preterm infants, underscoring the need for individualized ventilation strategies. Extreme prematurity emerged as the primary risk factor for adverse outcomes, while hypercapnia was independently associated with BPD. Full article

Background/Objectives: Aging is associated with declines in cognitive function and neurotrophic support. Brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) are peripheral biomarkers discussed in relation to brain health and aging. This study investigated changes in serum BDNF, IGF-1, and cognitive screening scores after a 16-week Hatha Yoga program performed twice or four times per week in older women. Methods: Fifty-one community-dwelling women aged 70–79 years were allocated to a twice-per-week yoga group (2YG; n = 17), a four-times-per-week yoga group (4YG; n = 17), or a non-exercise control group (CON; n = 17) based on availability and participant preference; forty-three participants completed the study. Serum BDNF and IGF-1 were analyzed using enzyme-linked immunosorbent assay and chemiluminescent immunoassay, and cognitive status was evaluated using the Cognitive Impairment Screening Test (CIST). Outcomes were analyzed using two-way repeated-measures ANOVA and additional ANCOVA models adjusting for corresponding baseline values. Exploratory correlations were examined between biomarker changes and CIST changes. Effect sizes and 95% confidence intervals were reported. Results: BDNF showed a significant main effect of time (p < 0.05) without a significant group × time interaction; ANCOVA adjusting for baseline BDNF showed no significant group effect (p = 0.270). IGF-1 showed a significant group × time interaction (p < 0.01) with increases in both yoga groups; ANCOVA adjusting for baseline IGF-1 showed a significant group effect (p = 0.001). CIST showed a significant main effect of time (p < 0.01), but changes were small and the group × time interaction was not significant; ANCOVA adjusting for baseline CIST showed no significant group effect (p = 0.114). Biomarker changes were not clearly correlated with CIST changes (ΔBDNF–ΔCIST: r = −0.244, p = 0.115; ΔIGF-1–ΔCIST: r = −0.050, p = 0.750). Conclusions: In this quasi-experimental study with non-random allocation and limited covariate information, changes in peripheral neurotrophic factors and only small changes in cognitive screening scores were observed after participation in a 16-week Hatha Yoga program. However, frequency-dependent conclusions are limited, and findings should be interpreted cautiously as screening-level, hypothesis-generating reference data. Nevertheless, the program is considered a feasible, low-risk health promotion activity for older women and may inform future randomized or well-controlled studies. Full article

The transjugular intrahepatic portosystemic shunt (TIPS) is a cornerstone intervention for complications of portal hypertension, including variceal bleeding and refractory ascites. As the population with cirrhosis ages, clinicians increasingly face the question of whether and how to perform TIPS safely in older adults. We reviewed observational cohorts, registry analyses, and systematic reviews/meta-analyses. Existing evidence does not support chronological age as an absolute contraindication; however, multiple studies suggest that advanced age is associated with higher rates of post-TIPS hepatic encephalopathy (HE), early mortality, and readmissions. These findings underscore the need to shift from a binary “eligible vs. ineligible” paradigm to a structured, actionable framework that addresses modifiable risks and anticipates age-related vulnerabilities. Recent clinical practice guidance emphasizes comprehensive pre-TIPS assessment and vigilant post-procedure care, with specific attention to HE risk factors (e.g., prior HE, hyponatremia, renal dysfunction, sarcopenia) and cardiopulmonary reserve. In this narrative review, we propose an elderly-focused clinical pathway built around a four-domain assessment (Liver–Brain–Body–Heart/Kidney) and a traffic-light risk tiering system to guide patient selection, procedural strategy, follow-up scheduling, and triggered management of HE, cardiac decompensation, and renal dysfunction. This pathway aims to preserve the benefits of portal decompression while reducing preventable complications and improving outcomes that are meaningful to older patients, including functional status and quality of life. This narrative review emphasizes that outcomes after TIPS in older adults are determined not by chronological age alone but by multidomain physiological reserve. The proposed pathway informs patient selection, procedural planning, and early post-discharge monitoring in older adults. Full article