The objective of this study was to investigate the effects of pulsed magnetic field (PMF) at different frequencies on phagocytosis, migration, and the expression of inflammatory factors in microglia. BV2 microglia were subjected to PMF at different frequencies for 3 d, twice daily. The changes of cell viability, phagocytosis and migration after magnetic stimulation were detected. The mRNA and protein levels of TNF-α and IL-1β were determined using RT-PCR and ELISA. The nuclear translocation of NF-κB P65 and intracellular Ca2+ level was detected through immunofluorescence. PMF at different frequencies did not affect microglial viability. Stimulation at all frequencies enhanced the ability of microglia to phagocytosis and migration. The mRNA expression level of IL-1β and TNF-α was significantly decreased by magnetic stimulation at 20 Hz and 40 Hz. However, only the protein level of IL-1β was significantly reduced by magnetic stimulation at 20 Hz, while TNF-α remained unaffected. Magnetic stimulation at 20 Hz and 40 Hz inhibited the nuclear translocation of NF-κB P65 and increased the intracellular Ca2+ level. Repetitive magnetic stimulation can modulate the secretion of inflammatory cytokines and enhance the phagocytosis and migration capacity of microglia in a frequency-dependent manner. This variation may be linked to differences in the activation of NF-κB and calcium in microglia.

BACKGROUND: Accumulation of Annexin A11 (ANXA11) aggregates is a distinct pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While genetic studies have linked ANXA11 mutations (e.g., D40G) to disease, the precise molecular events converting aggregation into neurotoxicity and intercellular propagation remain elusive. We hypothesize that lysosomal integrity serves as a critical checkpoint in ANXA11 proteinopathy and that its failure drives disease progression. METHODS: To model the human pathology of ANXA11, we generated pre-formed fibrils (PFFs) of wild-type and FTLD/ALS-linked D40G mutant ANXA11. Human iPSC-derived neurons, 3D cerebral organoids, and bulk RNA-sequencing were employed to investigate neurotoxicity. High-resolution imaging, lentiviral knockdown, and biochemical assays were performed to delineate the lysosomal damage response and the subsequent "prion-like" spreading of aggregates. RESULTS: The internalized ANXA11 fibrils accumulated in lysosomes, triggering lysosomal membrane permeabilization (LMP). The D40G mutation exacerbated this toxicity, leading to severe LMP, mitochondrial depolarization, and specific transcriptional downregulation of the dynactin subunit ACTR10. Mechanistically, we identified a protective signaling axis involving p38 MAPK, MK2, and HSP27 that senses ANXA11-induced lysosomal damage and initiates lysophagy. Notably, in human cerebral organoids, failure of this lysophagic clearance facilitated the cytoplasmic escape of ANXA11, thereby accelerating its seeding activity and propagation to neighboring cells. Pharmacological or genetic modulation of this pathway significantly altered neuronal survival. CONCLUSIONS: Our study established lysosomal rupture as a primary driver of ANXA11-associated neurodegeneration and validated the p38/MK2/HSP27 axis as a crucial defense mechanism in human neural tissue. These findings provide a novel mechanistic link between lysosomal quality control and ANXA11 propagation, highlighting that enhancing lysophagic flux represents a promising translational strategy to halt the progression of FTLD and ALS.

BACKGROUND: Given the risk of progression to dementia ranging from 6 to 44.8% over approximately 4 years of follow-up, nonpharmacological multicomponent interventions are emerging as promising strategies to improve or maintain cognitive function and quality of life in individuals with mild cognitive impairment (MCI). This pilot study aims to evaluate the feasibility and potential efficacy of a multicomponent and transdisciplinary intervention focused on the dyad of older adults with MCI-family study partner to promote cognitive function in older adults. METHODS: A pilot, randomized, controlled, and double-blind clinical trial will be conducted with 102 dyads consisting of an older adult with MCI and their family study partner. The participants will be randomly assigned to two groups: the intervention group (INTERCOG) and the control group. The INTERCOG group will receive a 12-week home-based intervention (twice weekly) with the support of a healthcare professional. The intervention components consist of cognitive training and stimulation, nutritional counseling, and physical exercises. Simultaneously, family members will participate in a training program on care and self-care. The control group will receive an Enhanced Standard of Care with educational messages on infection prevention. The feasibility of the study will be assessed through an analysis of recruitment, data collection, intervention acceptability, and implementation challenges; also, changes in global cognition and changes in specific cognitive domains will be measured as exploratory results. Secondary outcomes will include changes in health-related quality of life, caregiver burden, social support for family members, as well as changes in functional independence, frailty, physical capacity, family functioning, and nutritional status in patients, with follow-up at 3, 6, and 9 months. In a subsample of 40 participants, the diversity of the gut microbiota will be characterized, and the frequency of the APOE-ε4 allele will be determined. DISCUSSION: Multicomponent and transdisciplinary interventions focused on the family member-patient dyad have the potential to optimize cognitive outcomes and quality of life. This pilot study will allow us to identify key aspects of the feasibility and potential efficacy of INTERCOG intervention, crucial information for the design of future larger-scale studies. TRIAL REGISTRATION: NCT06408103. December 6, 2024, at clinicaltrials.gov. In recruitment.

BACKGROUND: In 2023, a majority (86%) of open-heart surgeries was performed at Thorax Centrum Twente (TCT) via a full median sternotomy. Currently, there is no consensus on postoperative sternal precautions following full median sternotomy. Research from the USA and Canada suggests that existing restrictive sternal precautions may not be necessary. More lenient sternal precautions, such as the "Keep Your Move in the Tube" principle, have shown positive outcomes, with no significant complications. Patients following this approach experienced fewer mobility issues and reported improved quality of life and reduced anxiety. This study explores the potential benefits of fewer restrictions, which could reduce patient anxiety and lead to fewer follow-up visits. This study aims to determine whether the Thoracic Surgical Rehabilitation Experts Twente (T-REX Twente) sternal precautions have a small positive effect on the Modified MacNew Quality of Life after Myocardial Infarction questionnaire (QLMI-2), physical activity, and reduction of movement-related anxiety in patients after full median sternotomy, compared to standard restrictive sternal precautions. It also assesses whether the T-REX sternal precautions result in no negative effects on pain, wound healing, or postoperative complications. METHODS: This prospective, randomized, controlled, single-blind study will include adult patients undergoing full median sternotomy at TCT between June 2024 and June 2026, all participating in outpatient cardiac rehabilitation. Exclusion criteria include intensive care unit stays over 72 h, delirium, dementia, severe cognitive impairments, language barriers, or treatment by an external referring cardiologist. The control group will adhere to current restrictive sternal precautions, whereas those in the intervention group will follow the T-REX sternal precautions, which allow lifting, pushing, or pulling as long as arm movement remains within a defined "tube." The primary endpoint is the change in QLMI-2 from baseline (T) to start of phase II cardiac rehabilitation (T). DISCUSSION: The T-REX Twente sternal precautions may improve quality of life, physical activity, and reduce movement-related anxiety, supporting the idea that less restrictive postoperative sternal precautions can enhance patient outcomes. TRIAL REGISTRATION: CCMO Trial Register NL78107.100.23, registered on 29 February 2024. CLINICALTRIALS: gov: NCT06115759.

BACKGROUND: Visual illusions are misperceptions of real external stimuli and, when persistent, may indicate underlying neurological or metabolic disorders. Delusional parasitosis is characterized by a fixed belief of infestation without medical evidence and may occur secondary to medical conditions. However, the relationship between visual illusion-related perceptual abnormalities and delusion formation, particularly in reversible metabolic states such as vitamin B12 deficiency, remains unclear. CASE PRESENTATION: An 80-year-old man presented with a persistent belief that mites infested his body and environment. His delusion was preceded by misinterpretation of real stimuli, including lint and skin debris, consistent with visual illusions. Cognitive assessment indicated mild cognitive impairment. His wife gradually came to share his delusional beliefs. Laboratory findings revealed marked vitamin B12 deficiency. Brain perfusion imaging demonstrated hypoperfusion in the medial occipital and parietal association cortices. Treatment with low-dose quetiapine and mecobalamin resulted in rapid resolution of visual illusions and subsequent disappearance of delusional parasitosis. Quetiapine was discontinued without relapse, and follow-up imaging showed improvement in cerebral perfusion. The wife's shared beliefs resolved following clinical improvement and separation. CONCLUSIONS: This case suggests that visual illusions due to reversible metabolic disturbances may precipitate delusional parasitosis in cognitively vulnerable individuals and highlights the importance of evaluating all suspected patients and closely associated individuals.

BACKGROUND: The utility of various cognitive assessment tools for distinguishing between mild impairment and dementia, as well as for determining cutoff values for specific populations, continues to be the subject of extensive research. Here, we assessed the utility and feasibility of these tools in the first Slovak memory clinic cohort. METHODS: We enrolled a Slovak memory clinic cohort of patients with MCI and dementia (MCI, n = 84; dementia, n = 55). The participants were characterized using a range of cognitive assessment tools-Auditory Verbal Learning (AVLT), Category and Letter Fluency (CFT, LFT), Digit Span (DSF, DSB), Digit-Symbol Coding (DS-C), Frontal Assessment Battery (FAB), MMSE, MoCA, Rey Osterrieth Complex Figure (ROCF), and Trail Making Test (TMTA, TMTB); clinical assessments-Amsterdam Instrumental Activities of Daily Living (A-IADL) and 5-level EuroQol questionnaire with 5 dimensions (EQ-5D-5 L); and scales for anxiety, dependency, depression, dignity, and MRI volumetry. The ability of the various assessments to distinguish between MCI and dementia was evaluated. RESULTS: Over the course of three years, at a single memory clinic, it was feasible to enrol and evaluate a total of 150 participants, 139 of whom fulfilled the definition of either MCI or nonvascular dementia. Of the employed cognitive and clinical assessment tools, the best differentiation between MCI and dementia was observed for the AVLT and A-IADL. The DSF and DSB tests did not reveal differences between the populations. No differences were observed in education, vital signs, or anthropometric measurements. Participants with dementia had greater degrees of brain atrophy in the hippocampi and frontal, parietal, and temporal cortex; lower total brain volumes; and greater ventricular dilation. CONCLUSIONS: This study confirms the utility of a range of cognitive assessment tools and scales for differentiating between MCI and dementia but reveals that some commonly employed tools, such as the DSF and DSB, may not be sensitive to these differences. This study highlights the importance of accurate assessment of the ability to perform activities of daily living and supports the development of objective, ecologically valid assessments of IADL.

BACKGROUND: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) co-occur frequently, and growing evidence, including neuropathology, supports synergistic interplay between the diseases. We tested whether a single T1-weighted MRI scan may differentiate neuropathologically confirmed comorbid AD/DLB and AD controls using heterogeneously acquired neuroimaging. METHODS: We obtained structural neuroimaging, on two groups, AD with and without DLB pathology. Convolutional neural networks are trained across dimensions. We introduce a triple-ensemble strategy consisting of majority voting schemes within a variety of plane permutations. In addition, we conduct voxel-wise statistical analyses. RESULTS: Here we show convolutional neural networks record a classification accuracy of 0.820 and an f1 score of 0.79 in identifying comorbid DLB/AD from AD patients. Prediction accuracy is higher proximal to date of death, while the trained model largely outperforms clinical baseline diagnosis. The slice-level performance varies depending on the sampled brain location, with sensitivity highest in the temporal lobe and specificity highest in the occipital lobe. In DLB/AD, gray matter is relatively preserved though atrophy is observed in the occipital lobe, suggesting that the comorbidity differentially affects brain loss and may accelerate it in the occipital lobe. CONCLUSIONS: This study demonstrates how machine learning approaches can address diverse neuroimaging data from clinical sources to differentiate neurodegenerative diseases using a true gold standard of neuropathological confirmation. The frameworks utilized here can be extended to other diseases that are frequently co-occurring and feasibly extend to single scan diagnostic clinical utility of scans already being acquired.

Glycogen Synthase Kinase-3 Beta is a multifunctional serine/threonine kinase, involved in regulating multiple cellular processes. Its dysregulation plays a key role in progression of Alzheimer's disease and no FDA-approved GSK3β inhibitors for AD therapy are available, due to challenges in isoform selectivity, safety and pharmacokinetic limitations. Here, an OECD guideline-compliant, two-stage machine learning-based virtual screening framework is developed for GSK3β inhibitors. A chemically diverse dataset from different databases were pre-processed and used for model development and validation. A comparative study confirmed the superiority of this two-stage approach over standard multiclass models, by yielding significantly higher balanced accuracy on the internal test set (0.86 against 0.74) and specificity. The best predictive models were deployed as an open-access web tool and were used for screening ASINEX Synergy Library. In the structure-based approach, molecular docking with a validated docking protocol was performed and the best molecules were subjected to molecular dynamics simulation, binding free energy and per-residue decomposition analysis. Principal component analysis of trajectories confirmed global stability and consistent binding modes. Cross-screening against the homologous GSK3α isoform and the structurally distinct Cyclin-dependent kinase 2 (CDK2) by molecular docking revealed distinct mechanistic interaction profiles. Rather than exhibiting strict single-target exclusivity, the top hits showed binding affinity profiles consistent with potential CMGC family Multi-Target Directed Ligands (MTDLs), warranting experimental kinome validation. This presumed polypharmacological profile is advantageous for Alzheimer's therapeutics, positioning these compounds as robust candidates for simultaneously mitigating multiple kinase pathways that drive Tau hyperphosphorylation. Overall, this integrated ML model development, validation, screening, protein selection, molecular docking and molecular dynamics workflow provides a reproducible, interpretable, and high-confidence method for identification of GSK3β inhibitors for Alzheimer's disease.

BACKGROUND: Evidence linking total and specific types of vegetable and fruit intake to dementia remains scarce. This study examined associations between total and subgroup intake of vegetables and fruits and dementia risk across three prospective cohorts and a meta-analysis. METHODS: Data were drawn from the Health and Retirement Study (HRS), the Framingham Heart Study Offspring cohort (FOS), and Whitehall II study (WHII). Average daily intakes of total vegetables and fruits and seven subgroups were assessed using food frequency questionnaires. Incident dementia was identified using cohort-specific definitions. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). We also performed a meta-analysis that incorporating our results and findings from 13 previous cohort studies. RESULTS: Among 18,339 participants aged ≥45 years (HRS: 6,750; FOS: 3,068; WHII: 8,521), 949 dementia cases occurred over an average of 7-13 years' follow-up. After multivariable adjustment, intake of fruits and vegetables combined was associated with a lower risk of dementia in the highest versus the lowest tertile (HR was 0.74, 95%CI: 0.61, 0.89, P-trend=0.165). Additionally, green leafy vegetables demonstrated a protective association (pooled HR per serving increment: 0.82; 95% CI: 0.70, 0.96, P -trend=0.015). No significant pooled associations were observed for other vegetable or fruit subgroups. Findings pooled from a meta-analysis of 222,108 participants showed that a higher intake of fruits and vegetables was associated with a lower risk of dementia compared to a lower intake (pooled HR : 0.80; 95% CI: 0.71, 0.91). Significant inverse associations were also observed for vegetable intake (pooled HR : 0.87; 95% CI: 0.82, 0.92) and fruit intake (pooled HR : 0.90; 95% CI: 0.85, 0.95). CONCLUSIONS: Our study supports an inverse association of vegetable and fruit intake with dementia risk. Further studies on specific subgroups are warranted.

OBJECTIVE: To evaluate the action selection, production, and execution of familiar tool use in patients with cognitive impairment, and to report the prevalence of Familiar Tool Use Impairment (FTUI) and its association with cognitive impairment and functional disability. DESIGN: Cross-sectional, observational study. SETTING: The outpatient memory clinic in a tertiary care hospital. PARTICIPANTS: A total of 66 patients with mild cognitive impairment and 80 patients with dementia were consecutively recruited, along with 85 healthy controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Familiar tool test (FTT) and their association with multiple cognitive domains and basic activity of daily living in patients with cognitive impairment. RESULT: Early signs of FTUI were observed in the mild cognitive impairment stage, with a FTUI rate of 6.0%. The prevalence of FTUI increased significantly from the healthy controls to the dementia group to approximately 65.0% (p < 0.001). Canonical correlation analysis (r = 0.529, p = 0.006) indicated that semantic and visuospatial impairment contributed substantially to the canonical variables and showed a prominent association with the Selection Scale in FTT (FTT-S) deficits. Multiple linear regression analyses revealed that tool selection was associated with the degree of bathing dependency (R²= 0.471, 95% CI: -0.49∼-0.13) and dressing (R²= 0.429, 95% CI: -0.35∼-0.05). CONCLUSION: This study characterized the prevalence of FTUI in patients with cognitive impairment and its underlying cognitive factors, based on the familiar tool test. The findings provided a new perspective for understanding the cognitive impairment and functional disability, suggesting that FTUI may serve as an early warning indicator of functional decline, and offer a practical clinical tool for individualized cognitive rehabilitation in apraxia.

Early diagnosis remains a major challenge in Alzheimer's disease (AD), as clinical symptoms often appear after irreversible pathological progression. This study aimed to identify early diagnostic biomarkers and clarify metabolic regulatory mechanisms in AD by integrating metabolomic profiling from a mouse model with validation using public human datasets. AD models were established in 42 C57BL/6J mice by intraperitoneal injection of D-galactose (120 mg/kg) combined with intragastric administration of aluminum chloride (20 mg/kg) for 8 weeks. Plasma samples were collected at weeks 0, 3, 6, and 8 for untargeted metabolomic profiling. Public plasma/cerebrospinal fluid metabolomic datasets and brain transcriptomic datasets from AD patients were further analyzed for validation. Time-dependent metabolic alterations were observed in AD mice, characterized by predominant metabolite depletion at weeks 3-6 and compensatory accumulation at week 8. The metabolic profile of AD mice was clearly separated from that of controls at week 8. Nicotinamide metabolism and sphingosine-related pathways showed dynamic dysregulation during AD progression. Notably, nicotinamide and sphingosine were persistently increased in AD mice and were also elevated in plasma samples from AD patients, whereas metabolites such as N,N-diethyl-m-toluamide were decreased. Transcriptomic analysis revealed abnormal expression of key genes involved in nicotinamide metabolism (NMNAT1 and SIRT1) and sphingosine metabolism (SPTSSA and SPHK1) in brain tissues from AD patients. In conclusion, AD is characterized by stage-dependent metabolic dysregulation, featuring early depletion followed by late compensation. Dysregulated nicotinamide and sphingosine metabolism may contribute to AD pathogenesis, and related metabolites and regulatory genes may serve as potential diagnostic biomarkers and therapeutic targets.

Mitochondrial dysfunction is recognized as a key pathogenic mechanism of Alzheimer's disease (AD), involving a self-perpetuating feedback loop with three aspects: upstream β-amyloid protein (Aβ), downstream calcium ion (Ca) and reactive oxygen species (ROS). However, current therapeutic strategies only focus on one aspect and fail to address multiple factors within this cycle. Moreover, the lack of targeted approaches to the mitochondria within damaged neurons further limits their application. Herein, we developed a sequential targeting nanochaperone to selectively target damaged neuronal mitochondria and disrupt this vicious cycle for AD treatment. In this strategy, with the sequence mediation of damaged neuron-targeting and mitochondria-targeting peptides decorated on surface, the nanochaperone can first localize to the damaged neurons in AD brain and then translocate to mitochondria within them. Subsequently, this nanochaperone can effectively bind upstream Aβ proteins and inhibit their aggregation toxicity to mitochondria through the synergic effect of chaperone-mimicking microdomains and Aβ-targeting peptide on surface, thereby halting downstream mitochondrial Ca dyshomeostasis and ROS overload in the damaged neuron. Furthermore, the modified mitochondria-targeting peptide with antioxidant property can further scavenge overproduced ROS and regulate Ca homeostasis, which in turn contributes to reducing the Aβ-induced mitochondrial damage. Consequently, the nanochaperone efficiently restores the mitochondrial dysfunction by disrupting the self-amplifying feedback loop of "Aβ-Ca-ROS" in the AD mitochondrial microenvironment, resulting in the significant alleviation of neuronal damage and cognitive deficits in 5xFAD transgenic mice. Taken together, our work presents a novel therapeutic strategy against mitochondrial dysfunction for AD treatment.

UNLABELLED: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial outcomes on the renal and cardiovascular system in diabetes mellitus (DM) patients. As most clinical trials were performed in Type 2 DM, the effects of SGLT2 inhibition in Type 1 DM are not completely clarified. OBJECTIVE: To evaluate the effects of long-standing SGLT2 inhibitor dapagliflozin on the protein profile in rats with a Type 1 DM model. METHODS: Male Wistar rats were divided into Control (C), DM, and DM treated with dapagliflozin (DM+DAPA) for 30 weeks. DM was induced by a single injection of streptozotocin (40 mg/kg); dapagliflozin was added to chow (5 mg/kg/day). Label-free mass spectrometry was used to assess left ventricular proteome. The bioinformatic tools used were STRING, Cytoscape, Cluster Marker, and ClueGO. STATISTICAL ANALYSIS: ANOVA and Tukey or Kruskal-Wallis and Dunn. RESULTS: Dapagliflozin attenuated body weight loss (C 574 ± 43; DM 339 ± 31*; DM+DAPA 413 ± 30*# g; p < 0.05 * vs C; # vs DM) and reduced glycemia [C 108 (101-111); DM 554 (529-562)*; DM + DAPA 343 (237-416)*# mg/dL; p < 0.05 * vs C; # vs DM]. Most proteins identified in the networks downregulated in DM vs C were upregulated in DM + DAPA vs DM. Proteins related to energy metabolism (CKm, Ak1, Atp5pf, Mdh1, Idh2), excitation-contraction coupling (Actc1, Casq2, Serca1, Serca2a), and oxidative stress (Sod1, Sod2) were upregulated in DM + DAPA. KEGG pathways enriched in DM vs Control included gap junction, necroptosis, and fatty acid degradation (upregulated), and Alzheimer's disease, cardiac contraction, and glycolysis/gluconeogenesis (downregulated). In DM + DAPA vs DM, upregulated pathways included Parkinson's disease, cardiac contraction, citrate cycle, necroptosis, and cyclic guanosine monophosphate-dependent protein kinase (PKG) signaling pathway; downregulated proteins were linked to ketone body metabolism. CONCLUSION: Dapagliflozin modulates cardiac protein abundance by attenuating DM-induced changes in Type 1 DM rats.

Radiometal-based radiopharmaceuticals have become central to the advancement of molecular imaging and targeted radionuclide therapy, offering powerful tools for the diagnosis and treatment of diseases affecting the brain. The unique chemical versatility of radiometals - encompassing a broad range of coordination chemistries, physical half-lives, and emission properties - combined with an expanding repertoire of targeting biomolecules enables highly tunable and increasingly modular imaging and therapeutic platforms. In particular, positron emission tomography (PET) using radiometal-labelled tracers provides sensitive, quantitative, and non-invasive assessment of molecular processes in vivo, while radiometal-based therapeutic agents enable the selective delivery of cytotoxic radiation to diseased tissue. This review examines recent progress in the application of radiometal-based radiopharmaceuticals for brain disorders, with a focus on neuro-oncology - including primary brain tumours and brain metastases - as well as neurodegenerative diseases such as Alzheimer's disease and Parkinsons disease. Key challenges unique to brain applications are discussed, including the restrictive nature of the blood-brain barrier, heterogeneous target expression, and off-target biodistribution. Recent advances in chelator development, emerging antigen targets, alternative routes of administration, and strategies to improve brain delivery are highlighted. While imaging agents continue to lead therapeutic development in this space, reflecting the need for accurate disease characterisation, recent progress underscores the potential of radiometal-based therapies for brain disease. In particular, immunoPET has emerged as a powerful tool for evaluating target expression, biodistribution, and treatment response. Collectively, these developments position radiometal-based radiopharmaceuticals as a promising and evolving platform enabling personalised treatment strategies for neurological disorders.

PURPOSE: Vitamin D deficiency (VDD) is common in older adults with osteoporosis, but its prevalence, determinants, and clinical impact in hip fracture (HF) patients remain incompletely defined. This study investigated the prevalence of VDD, associated factors, and 12-month outcomes in HF patients managed within a Fracture Liaison Service program. METHODS: In this prospective cohort study, 934 patients hospitalized for HF were enrolled between March 2023 and March 2025. VDD was defined as serum 25-hydroxyvitamin D [25-(OH)D] < 50 nmol/L. Clinical characteristics, laboratory parameters, and 12-month outcomes were assessed. RESULTS: Overall VDD prevalence was 53.6%, with a median 25-(OH)D concentration of 22 nmol/L among deficient patients. Independent predictors of VDD were male sex (p < 0.001), diabetes mellitus (p = 0.003), dementia (p = 0.013), and active smoking (p = 0.045), while prior vitamin D supplementation was negatively associated (p < 0.001). Decision tree analysis showed VDD prevalence ranging from 17.2% to 86.3% across patient phenotypes. Patients with VDD showed higher levels of bone turnover markers. In unadjusted analyses, VDD was associated with higher 12-month mortality (HR 1.65, 95% CI 1.12-2.42, p = 0.010), an association attenuated and no longer significant after adjustment for age, sex, and comorbidity burden (HR 1.31, 95% CI 0.88-1.96, p = 0.188). No associations were observed between VDD and rehospitalization or refracture rates. CONCLUSION: VDD is highly prevalent in HF patients. Although associated with higher mortality in unadjusted analyses, this relationship appears largely explained by comorbidity burden. These findings highlight the importance of recognizing VDD and implementing targeted vitamin D supplementation strategies in high-risk HF populations.

OBJECTIVE: Social cognition, particularly emotion recognition, can be impaired in neurological disorders involving brain damage and neurocognitive deficits. However, it remains unclear whether distinctive profiles of social versus general cognitive impairments exist across neurological patient groups: moderate-severe traumatic brain injury (mod-sevTBI), acute ischaemic stroke (AIS), aneurysmal subarachnoid haemorrhage (aSAH), frontal low-grade glioma (LGG), advanced Parkinson's disease (PD), and behavioural variant frontotemporal dementia (bvFTD). METHODS: Data were obtained from scientific studies and clinical records in four Dutch research centres. Neuropsychological testing included emotion recognition [Eckman 60-Faces test (EFT): total score and subscores], memory [Dutch Rey Auditory Verbal Learning Test (DRAVLT): encoding and retrieval], information processing speed, and cognitive control (Trail Making Test A and B). Scores were transformed into Z-scores using normative data and compared across groups. RESULTS: Included were 710 patients: 118 mod-sevTBI, 93 AIS, 121 aSAH, 100 LGG, 147 PD, 131 bvFTD. EFT-total was impaired in all groups (p < .001), with significant group differences (F(5,704) = 30.8, p < .001). Emotion recognition was the most severely affected domain in bvFTD, mod-sevTBI, AIS, and LGG. Only bvFTD and mod-sevTBI showed impairments in specific emotions, mainly sadness and fear. MANOVA showed overall group differences in general cognition (Wilks' Lambda = .69, p < .001). Memory encoding was impaired in all groups, but retrieval in none. Information processing speed and cognitive control were impaired only in bvFTD, mod-sevTBI, AIS, and PD. INTERPRETATION: Emotion recognition is significantly affected across six neurological patient groups, with distinct profiles relative to general cognition. These findings support tailored neuropsychological assessment in clinical practice.

The renin-angiotensin system (RAS), traditionally recognized for its role in regulating blood pressure and fluid homeostasis, is increasingly understood to exert important effects across multiple organ systems, including the central nervous system (CNS). A local brain RAS contributes to neurovascular regulation, inflammation, oxidative stress, synaptic plasticity, and cognitive function. This review critically summarizes the neurotherapeutic relevance of the protective RAS arm, particularly the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis, the angiotensin II type 2 receptor (AT2R), and the alamandine/Mas-related G protein-coupled receptor D (MrgD) pathway. Experimental evidence suggests that these pathways may counterbalance angiotensin II type 1 receptor signaling by reducing neuroinflammation, oxidative injury, vascular dysfunction, and neuronal loss in models of ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The strongest evidence remains preclinical, with most data derived from cell culture and animal models, whereas human evidence is still indirect and largely based on observational or early translational studies of RAS-modifying drugs. Important uncertainties remain regarding blood-brain barrier penetration, receptor-specific signaling, disease-stage dependency, systemic vascular effects, and reproducibility across models. Therefore, protective RAS signaling should be considered a promising but still exploratory therapeutic framework rather than an established treatment strategy for neurological disease. Future work should prioritize selective brain-penetrant agonists, validated biomarkers of central RAS activity, and rigorously designed clinical trials to determine whether modulation of ACE2-angiotensin-(1-7)-Mas, AT2R, or alamandine/MrgD signaling can produce clinically meaningful neuroprotection.

Histone deacetylase 3 (HDAC3) is increasingly implicated in Alzheimer's disease (AD), yet its precise pathogenic role and therapeutic value remain unresolved. This mini-review critically examines the current evidence for HDAC3 in AD, with a focus on what is established, what remains uncertain, and what is needed for translation. We review the data linking HDAC3 to amyloid-β (Aβ) accumulation, Tau pathology, neuroinflammation, and synaptic dysfunction, while highlighting key limitations in the field, including weak causal evidence, inconsistent cell type-specific findings, insufficient human brain validation, and the lack of proof that HDAC3 serves as a central mechanistic node across AD-related pathways. We also discuss major translational challenges, including poor inhibitor selectivity, uncertain brain penetrance, potential safety concerns, and the absence of standardized preclinical benchmarks. We propose that future progress will require human evidence, cell type-specific causal studies, integrated mechanistic models, and more rigorous pharmacological validation. Together, these considerations define a clearer roadmap for evaluating HDAC3 as a biologically credible and clinically actionable target in AD.

The present study aims to examine the language impairments observed across various stages of Alzheimer's Disease (AD) in Turkish-speaking individuals. The study involved 24 participants diagnosed with AD (12 women, 12 men; mean age = 82.00 ± 6.75) and a control group of 24 healthy adults (12 women, 12 men; mean age = 80.71 ± 8.61). All participants completed the Test Your Memory-Turkish (TYM-TR) and the Aphasia Language Assessment Test (ADD). Data analysis was conducted using SPSS 24 software with descriptive statistics, Spearman's correlation coefficient, and the Mann-Whitney test. Participants with AD scored lower on the TYM-TR and ADD than healthy participants. A strong positive correlation was observed between scores on the TYM-TR and ADD tests in both participant groups. The test scores decreased as AD stages progressed. This study provides a framework for SLTs to identify AD stages and tailor language interventions accordingly.

Colony-stimulating factor 1 receptor (CSF1R) is a receptor tyrosine kinase involved in cell growth and differentiation, particularly in macrophages and microglia. CSF1R inhibitors are under investigation for various diseases, including cancer, autoimmune/inflammatory diseases, and neurodegenerative disorders. PLX5622 is a highly specific, brain-penetrant, and orally bioavailable CSF1R inhibitor that is being evaluated in a clinical trial for rheumatoid arthritis and considered as an attractive candidate for the treatment of Alzheimer's disease (AD). Drug metabolism significantly influences both the efficacy and safety of therapeutic agents. In particular, bioactivation leading to the formation of reactive metabolites is often implicated in adverse drug effects. In this study, we investigated the metabolism and potential bioactivation of PLX5622 in mouse and human liver microsomes (MLM/HLM) and mice using LC-MS-based metabolomic approaches. Reduced glutathione (GSH) and methoxyamine (NHOMe) were used to capture reactive intermediates. In total, 12 PLX5622-GSH adducts and five NHOMe adducts were identified in both HLM and MLM, along with 22 nontrapped metabolites generated from demethylation, hydroxylation, and carbon-carbon cleavage reactions. PLX5622-GSH-related adducts in mice were also assessed and 8 GSH adducts were detected in mouse liver, confirming the occurrence of bioactivation in vivo. Using recombinant human cytochrome P450 (CYP) enzymes and selective chemical inhibitors in liver microsomes, CYP3A was determined to be the primary enzyme responsible for the metabolic activation of PLX5622. These insights into the metabolic pathways of PLX5622 are valuable for further study of its safety and potential drug interactions of CYP3A. Future studies using human primary hepatocytes or physiologically human-relevant models such as liver-on-a-chip systems are warranted to confirm clinical relevance and better predict in vivo outcomes.

OBJECTIVES: Although growing evidence indicates that ecosystems shape human health, their effects on older adults-a group highly sensitive to environmental stressors-remain underexplored. This study examines the effect of China's National Key Ecological Function Zones (NKEFZs), a large-scale ecosystem improvement program, on the cognitive function of older adults and explores the underlying mechanisms. METHODS: Using five waves (2011-2020) of data from the China Health and Retirement Longitudinal study (CHARLS;  = 16,003), this study employes a staggered difference-in-differences design to estimate the effects of policy on cognitive health. RESULTS: NKEFZs significantly enhanced cognitive function and episodic memory by 0.467 and 0.372 points, respectively. Mechanism analysis identifies reductions in industrial smoke and dust emissions and a higher likelihood of using clean fuels for cooking or heating as possible channels through which NKEFZs contribute to improved cognitive health. Heterogeneity analyses indicate that the beneficial effects varied by gender, education, marital status, household size, health status, and smoking or drinking behaviors. CONCLUSION: These findings highlight the role of ecosystem improvements in maintaining cognitive health and reveal disparities in the effects of such population-level interventions across individual characteristics. These insights inform other countries in developing upstream environmental strategies for dementia prevention and risk reduction.

BackgroundSubjective cognitive decline (SCD) is a common early complaint in mild cognitive impairment (MCI). Evidence for the 21-item SCD-Questionnaire (SCD-Q21) to discriminate MCI from normal controls (NCs) is limited.ObjectiveTo investigate the discrimination performance of Chinese SCD-Q21 and compare it with SCD-Q9 for community-based MCI early detection, assess the added value of simple covariates, and determine an optimal SCD-Q21 cut-off.Methods294 NCs and 83 people with MCI were assessed and collected demographic and clinical data. Participants completed SCD-Q21, SCD-Q9, Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD) scale; clinical adjudication used Montreal Cognitive Assessment-Basic, Clinical Dementia Rating, and Activities of Daily Living. Group comparison, logistic regression and ROC analyses were applied. Optimal cut-offs were derived using the Youden index and AUCs were compared using DeLong tests. Within-MCI analyses contrasted screen-positive versus screen-negative subgroups.ResultsTotal SCD-Q21 scores were higher in MCI, although five items [question 1 (Q1), Q2, Q3, Q11, and Q17] did not differ between groups. In multivariable binary logistic regression models, lower education (OR = 0.786), higher body mass index (BMI) (OR = 17.874), and higher SCD-Q21 total scores (OR = 1.114) were independently associated with MCI, whereas SCD-Q9 was not. Standalone AUCs were 0.662 (SCD-Q21) and 0.640 (SCD-Q9). Combing age, sex, education, BMI, and HAMA/HAMD with SCD instrument yielded AUC ∼0.91. SCD-Q21 ≥ 7 gave 69.88% sensitivity and 62.93% specificity. Screen-negative MCI cases showed lower vascular/metabolic comorbidity and lower HAMA/HAMD scores.ConclusionsSCD-Q21 provides independent information but modest stand-alone discrimination. As part of a brief multivariable triage including education, BMI, vascular risk review, and anxiety rating, it supports efficient case-finding in community settings.

BackgroundWhile large language models (LLMs) have a potential to simulate public-opinion, their reliability for sensitive medical topics like novel Alzheimer's disease (AD) treatments remains unclear.ObjectiveThis study compared LLM-generated and human answers on AD-therapy dilemmas; assessed model and prompting parameter influences; and identified demographic bias.MethodsUsing survey data on late 2023 from 1671 Japanese Trial Ready Cohort Webstudy participants who are presumably cognitively unimpaired, LLM persona profiles guided four LLMs (Gemini-1.5-flash, Gemini-2.0-flash, GPT-4.1-mini, GPT-4o-mini). The models answered a binary question about acceptance towards patient-prioritization or a 5-point Likert question on concern about amyloid-related imaging abnormalities (ARIA) under varied prompt settings. Aggregate similarity was measured with Jensen-Shannon Divergence (JSD) for binary and Earth Mover's Distance (EMD) for Likert scale; while individual agreement used Cohen's κ and Spearman's ρ.ResultsWhile some LLM models achieved fair group-level agreement in both tasks (JSD ≤ 0.05, EMD < 1.0), individual agreement was negligible across any LLM settings (κ, ρ ≈ 0). Adding detailed attributes like living condition, clinical status, or related personal opinions offered limited improvement. Performance was largely stable for most demographic levels, but deteriorated for minority subgroups, such as those with low education or requiring long-term care.ConclusionsOur study demonstrates that current LLMs can approximate aggregate attitudes toward novel AD therapies but cannot predict individual opinions. They can amplify biases in some small subgroups. LLMs may be useful for pre-testing public survey in the field of AD/dementia treatment but should not replace authentic human data.

BackgroundWhile Alzheimer's disease (AD) is a known risk factor for falls, the association between falls and incident AD is a growing area of study.ObjectiveThe primary aim of this analysis was to examine associations between new-onset falls in older adults and neuroimaging and plasma biomarkers of AD. A secondary aim was to evaluate associations between new-onset falls and neuroimaging markers of motor dysfunction.MethodsData from the UK Biobank study was utilized. Participants were 70 years of age or older at the date of neuroimaging and had no reported history of falls at study enrollment. To determine falls status, participants self-reported data on falls history within the last year prior to neuroimaging.Results15,447 individuals were included in our analysis (No falls, N = 12,522; One fall, N = 2,199, Multiple falls, N = 726). Compared to individuals in the No falls group, individuals in the One fall and Multiple falls group had significantly higher volumes of white matter hyperintensities, while individuals in the Multiple falls group had significantly lower left and right hippocampal volumes. One or more fall was associated with higher plasma levels of pTau181, which did not remain significant after adjusting for multiple comparisons. Plasma amyloid-β 42/amyloid-β 40 ratio did not differ significantly between groups.ConclusionsIn a sample of older adults without history of falls at study enrollment, new-onset falls were associated with decreased hippocampal volumes, which is associated with prodromal AD, as well as an increased volume of white matter hyperintensities, which may also emerge secondary to AD pathology.

BackgroundLecanemab is an anti-amyloid monoclonal antibody, approved for early Alzheimer's disease (AD), with evidence indicating greater benefit at earlier stages. Sensitive cognitive measures are needed to identify underlying amyloid pathology.ObjectiveTo investigate whether the Logical Memory (LM) subtest of the Wechsler Memory Scale-Revised (WMS-R) can help characterize amyloid positivity in lecanemab-eligible individuals.MethodsWe retrospectively analyzed 91 individuals who attended our center between December 2023 and March 2025; 45 met eligibility criteria (Mini-Mental State Examination ≥ 22, Clinical Dementia Rating 0.5 or 1.0, magnetic resonance imaging compatibility). Amyloid status was determined by positron emission tomography, classified as amyloid-positive (Aβ+, n = 35) or amyloid-negative (Aβ-, n = 10). All participants underwent neuropsychological assessment, including LM. Groups were compared, and LM Aβ status discrimination was evaluated using receiver operating characteristic analyses and multivariable logistic regression.ResultsGroups did not differ in age, sex, or education. LM immediate (LMIR) and delayed recall (LMDR) scores were lower in the Aβ+ group (LMIR median: 5.0 versus 9.0, p = 0.011; LMDR: 0.5 versus 3.0, p = 0.017). Receiver operating characteristic analyses identified cutoffs of 7.5 for LMIR (area under the curve [AUC]: 0.79, sensitivity: 79%, specificity: 77%) and 1.5 for LMDR (AUC: 0.76, sensitivity: 75%, specificity: 77%). Lower LM scores were associated with increasing amyloid positivity. Logistic regression showed significant associations for both LMIR and LMDR (odds ratio: 0.80 and 0.64, 95% confidence interval: 0.64-0.95 and 0.38-0.91, respectively).ConclusionsWMS-R LM scores were significantly associated with amyloid-β accumulation in individuals with early AD meeting lecanemab eligibility criteria.