Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cerebral small-vessel disease caused by NOTCH3 mutations, yet its pathogenic mechanisms remain incompletely understood due to limited disease models. The NOTCH3 R544C mutation is a prevalent hotspot in East Asian populations, but patient-derived iPSC models are lacking. Here, we generated an iPSC line from peripheral blood mononuclear cells of a middle-aged CADASIL patient carrying a heterozygous NOTCH3 c.1630C > T (p.Arg544Cys, R544C) mutation using a Sendai virus (SeV)-based reprogramming approach. The iPSCs exhibited typical morphology, normal 46, XY karyotype, expressed pluripotency markers (OCT4, NANOG, TRA-1-60, SSEA-4), and cleared SeV vectors after passaging. They differentiated into derivatives of all three germ layers, and STR analysis confirmed donor identity. Functionally, CADASIL iPSCs showed abnormal accumulation of the NOTCH3 extracellular domain (NOTCH3ECD) with unchanged NOTCH3 full-length and intracellular domain levels, and upregulation of canonical downstream genes HEY1, NRARP, and HES1, indicating activation of the NOTCH3 signaling pathway. This study establishes and characterizes a NOTCH3 R544C patient-derived iPSC line, providing a valuable model for investigating CADASIL pathogenesis and potential therapeutic strategies, with novel insights into early NOTCH3ECD accumulation and pathway activation.

Coordinated cell-to-cell communications is crucial for the proper functioning and maintenance of brain activities, and its disruption contributes to neurological disorders, including Alzheimer's disease (AD). Altered astrocyte-neuron communications have been implicated in AD progression, yet the underlying regulatory networks remain poorly understood. Given that secretory proteins mediate both local and long-range intercellular signaling, we constructed a spatiotemporal profile of the astrocyte-derived secretome using in vivo TurboID proximity labeling in mice of amyloid pathology. Early alterations in the entorhinal cortex secretome were identified and enriched in metabolic pathways, whereas changes in the hippocampus were observed later, correlating with neuronal and synaptic maintenance. These findings suggest that early remodeling of the astrocyte secretome in the entorhinal cortex may be involved in AD pathogenesis, while later changes in the hippocampus contribute to neurodegeneration and cognitive decline. This work provides a systematic map of the dynamic, region-specific remodeling of the astrocyte secretome in AD, identifying novel spatiotemporal vulnerabilities and potential therapeutic targets.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. A hallmark pathological feature of PD is the abnormal aggregation of α-synuclein (αSyn) into insoluble Lewy bodies. Consequently, developing strategies to inhibit αSyn aggregation in the brain has been a major research focus for PD treatment. This study developed a therapeutic approach using engineered neuronal exosomes. These exosomes were modified to extend their blood circulation half-life to 3.8 h and enhance targeting, with a 2.15 ± 0.09% brain signal proportion (vs. 0.78 ± 0.07% for free dye). They were then loaded with a self-developed αSyn aggregation-blocking peptide (sPep) as well as the antioxidant pyrroloquinoline quinone (PQQ). We investigated the therapeutic efficacy of this system in both in vitro and in vivo models of PD. Our experiments confirmed that the screened sPep effectively targeted and blocked αSyn aggregation both in vitro and in vivo. Neuronal exosomes, isolated by ultracentrifugation and hybridization, demonstrated strong abilities to cross the blood-brain barrier. In vivo studies revealed that the treatment significantly improved motor and cognitive functions in PD model mice. The underlying neuroprotective mechanisms included reducing αSyn aggregation, enhancing antioxidant capacity, ameliorating mitochondrial dysfunction, and suppressing cell apoptosis, collectively promoting the survival of dopaminergic neurons. These findings demonstrate that the engineered exosome-mediated delivery system exerts a protective effect against PD pathology.

BACKGROUND: Neurite Orientation Dispersion and Density Imaging (NODDI) has advanced the study of cortical microstructure. However, its application to participants with cerebral microbleeds (CMBs) to explore cognitive impairment mechanisms and potential imaging biomarkers remains underexplored. METHODS: This observational study used NODDI to assess cortical microstructural changes in three groups: 52 participants with cerebral small vessel disease and CMBs (CSVD-c), 78 CSVD participants without CMBs (CSVD-n), and 37 healthy controls. Multivariable regression analysis examined the correlation between altered NODDI metrics, CMB severity, and cognitive function. Cox regression analysis evaluated the association between altered NODDI metrics and dementia risk. RESULTS: The CSVD-c group showed a significant decrease in Intracellular Volume Fraction (ICVF) in the bilateral caudate nucleus and an increase in Isotropic volume fraction (ISOVF) in the right precuneus compared to both the controls and CSVD-n groups. Decreased ICVF in the bilateral caudate nucleus correlated with the number of CMBs (P = 0.023), lower logical memory scores (P = 0.003), and higher Rey Auditory Verbal Learning Test and Clinical Dementia Rating-Sum of Boxes scores (P = 0.011; P < 0.001). Increased ISOVF in the right precuneus was significantly associated with a higher risk of dementia (P = 0.039), but this significance was lost after adjusting for age, sex and years of education. CONCLUSION: Participants with CMBs exhibit decreased ICVF in the bilateral caudate nucleus and increased ISOVF in the right precuneus, associated with cognitive impairment and increased dementia risk. NODDI metrics may serve as valuable markers for investigating CMB-related cognitive impairment.

Alzheimer's disease (AD) causes progressive cognitive decline, and current therapies provide limited benefit. This study evaluated the neuroprotective effects of lenalidomide (LLM), a thalidomide derivative, in a scopolamine-induced mouse model of cognitive impairment, with emphasis on its acetylcholinesterase (AChE) inhibitory potential. Mice received LLM (5, 10, and 20 mg/kg), donepezil (DNP) (3 mg/kg), or a combination and were assessed using Y-maze, passive avoidance, novel object recognition, and Morris water maze tests. In silico analysis, including molecular docking, 100 ns molecular dynamics simulation and ADMET profiling were performed to investigate the interaction of LLM with AChE. Memory performance showed a significant and dose-dependent improvement after the treatment of LLM. The 20 mg/kg dose exhibited effects comparable to DNP. LLM and DNP work together to increase effectiveness. Docking and simulation analyses revealed strong, stable binding to AChE while ADMET values indicated good drug-likeness. LLM exhibits neuroprotective and cognition enhancing effects in the scopolamine-induced model. In silico study also shows its potential as an AChE inhibitor. The study's anti-inflammatory mechanisms might also be helpful but need more exploration.

Ferroptosis, a unique form of regulated cell death driven by iron-dependent lipid peroxidation, and macrophage polarization, which reflects the high plasticity of the immune system, represent two prominent frontiers in contemporary life sciences. Emerging evidence suggests a profound bidirectional interplay between these processes, mediated by iron metabolism reprogramming, lipid signaling molecules, and complex molecular axes such as RAGE-STAT3. This review systematically summarizes the biological mechanisms of ferroptosis and macrophage polarization, delving into their interaction within the tumor microenvironment, inflammatory responses, and cardiovascular and neurodegenerative diseases (e.g., Alzheimer's and Parkinson's). We highlight how M1 macrophages induce ferroptosis through pro-inflammatory cytokines and reactive oxygen species, while M2 macrophages inhibit it by modulating iron homeostasis and antioxidant capacity. Finally, we discuss therapeutic strategies targeting the ferroptosis-macrophage polarization axis, providing a theoretical foundation and novel perspectives for developing precise medical interventions.

Approximately 50 million people are living with dementia worldwide, a number projected to reach more than 150 million by 2050. Dementia has emerged as one of the most pressing public health challenges globally, and it is increasingly recognized that dementia share several modifiable risk factors with cardiovascular diseases. It is now suggested that 45% of all dementia cases can be prevented by acting on midlife cardiovascular risk factors such as hypertension, dyslipidemia, physical inactivity, and diabetes. To successfully prevent dementia, it is important to discriminate true causal modifiable risk factors from non-causal associations. This can be facilitated by the application of robust Mendelian randomization (MR) strategies on individual level data in large-scale population biobanks. Once identified, the causal risk factors can be included in risk prediction tools to identify those high-risk individuals that will benefit the most from intensive early preventive interventions. In this review, we explore the scientific human evidence on well-established and emerging cardiovascular risk factors and risk of dementia. We discuss the important genetic risk factors for dementia and how they can be used in future risk prediction strategies. We further highlight the statistical caveats when assessing diseases of late-life and with long prodromal phases such as dementia. We conclude that the scientific evidence supports midlife low educational level, hypertension, diabetes, smoking, high BMI, and high concentrations of LDL cholesterol and triglycerides as causal risk factors of dementia. Furthermore, the overlap between cardiovascular and dementia risk factors encourages genomics-informed drug discovery as a therapeutic approach for dementia.

The 14-3-3 protein family, with over 1300 binding partners, is one of the largest regulators of protein-protein interactions (PPIs) in eukaryotic cells. They recognise and bind to phosphorylation-related motifs in their partner proteins, creating scaffolds to stabilise proteins and allowing or inhibiting kinases' access to their targets. 14-3-3 consists of seven isoforms (β, γ, ε, ζ, η, θ and σ), which are expressed across all tissues. Given their important role in PPIs, their dysregulation can contribute to a variety of diseases, such as cancer or neurodegenerative disorders like Creutzfeldt-Jakob's, Parkinson's or Alzheimer's diseases. Pathological effects can arise due to loss of function, aberrant interactions or protein aggregation. Notably, 14-3-3 aggregates have been detected in Lewy bodies or cerebrospinal fluid, mirroring the presence of amyloid proteins, such as α-synuclein (α-syn) or β-amyloid. Toxic amyloid aggregation signals the onset of neurodegeneration, which can occur through misfolding of proteins or liquid-liquid phase separation (LLPS) - a process during which proteins condense into membraneless organelles. Unlike other amyloidogenic proteins, there is little information on the conditions under which the 14-3-3 protein family members undergo LLPS or their relationship with amyloid aggregation. To address this gap, we examined all isoforms of 14-3-3 in vitro and observed the formation of amyloid aggregates, phase-separated droplets and spheroid-like structures. Our results revealed that the ε and θ isoforms form amyloid-like fibrils that can accelerate α-syn aggregation. Furthermore, molecular crowding conditions promoted phase separation and aggregation in most 14-3-3 proteins. Finally, 14-3-3s incorporated together with α-syn generate heterotypical droplets.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which tau pathology correlates more strongly with clinical progression than amyloid-β (Aβ). Zinc (Zn²⁺) is known to promote tau-mediated neurotoxicity; however, the underlying mechanisms remain incompletely understood. Our previous work demonstrated that Zinc ions (Zn²⁺) binds to the third microtubule-binding repeat (R3) of tau, inducing oligomerization and enhancing neurotoxicity. Here, we demonstrated that Zn²⁺+R3 elevated phosphorylated tau (p-tau) levels, impaired dendritic spine morphology, reduced synaptophysin expression, and disrupted autophagic flux. Mechanistically, Zn²⁺+R3 was associated with suppression of the Akt/mTOR signaling pathway, concurrent with autophagy initiation and impaired autophagosome-lysosome fusion. However, the present findings are associative in nature, as pharmacological or genetic rescue experiments were not performed; such experiments will be required to formally establish causality. Collectively, these findings suggest that targeting the Zn²⁺ and R3 interaction may represent a potential therapeutic strategy for AD.

OBJECTIVE: Examine the prevalence of select chronic health conditions by self-reported vision difficulty status among middle-aged and older adults in the United States. DESIGN: Cross-sectional, population-based analysis. PARTICIPANTS: U.S. adults aged ≥45 years METHODS: Self-reported data were from the 2020-2024 National Health Interview Survey (N=85,026). Conditions included self-reported hypertension, heart disease, high cholesterol, stroke, arthritis, cancer, weak/failing kidneys, dementia, diabetes, depression, and obesity. Adjusted prevalence ratios (APRs) were estimated using multivariable logistic regression models for each condition by vision difficulty status (none, some, severe) stratified by age group (45-64, ≥65 years). MAIN OUTCOME MEASURES: Unadjusted and adjusted prevalence and APRs of 11 chronic health conditions by vision difficulty status. RESULTS: Overall, 20.2% of adults aged ≥45 years reported some vision difficulty and 2.1% reported severe vision difficulty. Among adults aged 45-64 years, the adjusted prevalences of most chronic conditions were higher among those with some or severe vision difficulty compared to those with no vision difficulty. For example, the adjusted prevalence of hypertension was 32.9% (95% confidence interval [CI]: 31.0-34.5) among those with no vision difficulty compared to 47.8% (95% CI: 42.4-53.2) among those with severe vision difficulty, with an APR of 1.45 (95% CI: 1.32-1.60). Similar patterns were observed among adults aged ≥65 years. CONCLUSIONS: Our findings highlight the importance of integrating vision health into chronic disease prevention and management strategies, considering the condition type, severity of vision difficulty and age when developing and tailoring these strategies.

BACKGROUND: Continuation treatment with sertraline plus olanzapine is associated with lower risk of relapse of remitted psychotic depression than sertraline plus placebo. We examined the effect of continuation pharmacotherapy on health-related quality of life (HRQOL) in remitted psychotic depression. METHODS: One hundred and twenty-six men and women, aged 18 to 85 years, who had achieved sustained remission of psychotic depression with open-label treatment with sertraline plus olanzapine were randomized to continue sertraline plus either olanzapine or placebo. HRQOL was measured with the 36-item Short Form Health Survey (SF-36) at randomization baseline and study termination. The primary outcome was change in each of the eight SF-36 domains. Linear regression examined the relationship between randomized treatment and change in SF-36 domain scores. RESULTS: Sertraline plus olanzapine was associated with better outcomes in the Role Emotional (RE) and Mental Health (MH) domains than sertraline plus placebo. Relapse was associated with marked decline in both RE and MH scores. RE and MH scores at study termination were more than two standard deviations below the population mean in approximately one quarter of participants in the sertraline plus placebo group. CONCLUSIONS: In individuals with remitted psychotic depression, continuation treatment with sertraline plus olanzapine was associated with better outcomes in HRQOL domains directly relevant to mental health than treatment with sertraline plus placebo. These findings suggest that the benefit of sertraline plus olanzapine in preventing relapse of psychotic depression is associated with benefit in HRQOL.

BACKGROUND: Cardiovascular disease is a major global health burden, emphasizing the importance of blood pressure medications and lipid-modifying agents in prevention and treatment. Accurate self-reported data on the use of these drugs are vital for epidemiological research, yet the influence of age, sex, and cognitive function on reporting validity is not well understood. This study assesses self-reported use of these two drug classes within a large population-based Norwegian cohort and examines how demographic and cognitive factors affect reporting accuracy. METHODS: Cross-sectional study using data on self-reported medication use in the fourth wave of the population-based Trøndelag Health Study (HUNT4, 2017-19). Sensitivity, specificity and Cohen´s Kappa Statistics were calculated to assess accuracy using the Norwegian Prescribed Drug Registry as the gold standard. Analyses were stratified by age and sex, and by cognitive function for participants aged 70 years or older in the substudy HUNT4 70+. RESULTS: A total of 55,086 participants (54.3% women) were included in this study, and the mean age (SD) was 54.0 (17.4) years. Out of these, 8,762 also participated in the substudy HUNT4 70+ (2017-2019), where 3,132 participants had mild cognitive impairment and 779 had dementia. In the total sample, sensitivity and specificity were >90% for both blood pressure medication and lipid-modifying agents. Kappa statistics indicated substantial agreement for blood pressure medication (0.74-0.79), and substantial to almost perfect agreement for lipid-modifying agents (0.79-0.81). Agreement was highest among middle-aged participants and lower in the oldest. Chi-square tests revealed significant sex differences for both medication groups (p<0.001), demonstrating higher agreement among women. Furthermore, cognitive function was strongly associated with reporting accuracy, with the highest agreement among cognitively healthy participants. CONCLUSION: Self-reported data on the use of blood pressure medication and lipid-modifying agents were highly reliable. However, agreement was influenced by age, sex, and cognitive function.

BACKGROUND: Air pollution has been linked with poor cognitive and brain health, including Alzheimer's Disease and Related Dementia (ADRD). However, whether specific individuals are more susceptible than others remains unclear. PURPOSE: We aimed to review potential modifiers of the air pollution-cognitive/brain health association and identify subgroups potentially susceptible to adverse effects of air pollution exposure. METHODS: We identified published, peer-reviewed articles in the Embase and Medline databases through the Ovid and PubMed search platforms and used Covidence, an online software tool, to extract relevant data from eligible articles. We then systematically reviewed and summarized the evidence on how health behaviors, genetic/molecular factors, environmental factors, and individual factors modify the association between ambient air pollution and cognitive/brain health. RESULTS: Seventy-four publications, out of 6,372 relevant publications, met the eligibility criteria and were included in this review. Available studies suggested that race/ethnicity, geographic location, apolipoprotein E (APOE) e4 allele, socioeconomic status (SES), body mass index (BMI), and diet may modify the air pollution-ADRD association, and that age and education do not, although the available evidence precludes firm conclusions. Limited reporting precludes conclusions about other modifiers. CONCLUSION: Efforts to reduce the harmful effects of air pollution exposure should consider sensitive groups. The current literature suggests differential susceptibility to the adverse effects of air pollution on cognitive and brain health. Future studies should include standardized reporting of effect modification for the likely modifiers identified here, allowing for more robust conclusions.

CLK1 is one of the four human isoforms of the cdc2-like (CLK) kinases that has been suggested as a therapeutic target in diverse diseases based on its important role regulating mRNA splicing. For example, CLKs and closely related kinases such as DYRK1A have been targeted in Alzheimer's disease and other diseases in which splice site selection contributes to the disease development. Here we have developed an efficient in silico fragment-based ligand design approach to identify novel CLK1 inhibitors with excellent ligand efficiency based on an imidazo[2,1-b][1,3,4]thiadiazole fragment. More than one million docking poses were generated from 26,225 unique virtual compounds, and after applying several filtering steps, 11 compounds were selected, synthesized and their CLK1 inhibition and cellular potency were evaluated. Gratifyingly, inhibitor potencies were in excellent agreement with predicted values and crystallographic data of an inhibitor bound to CLK1 confirmed the unusual binding mode of the compounds.

The role of dietary fat in human health remains debated, particularly in aging. The diet-heart hypothesis of the 1950s linked saturated fat to cardiovascular disease (CVD), shaping nutrition guidelines for decades. However, later trials yielded inconsistent results, and recent reviews have questioned the strength of this association. At the same time, studies of ketogenic and other high-fat diets suggest that, in specific metabolic contexts, higher fat intake may offer metabolic and vascular benefits. These findings highlight the need to move beyond simplified views of dietary fat by considering fat type, metabolic state, and eating patterns. Beyond cardiovascular outcomes, interest has grown in how diet influences brain aging and cerebrovascular health. Cerebrovascular dysfunction is central to vascular cognitive impairment and dementia (VCID), yet dietary effects on these mechanisms remain incompletely understood. This review examines evidence on how dietary fat composition and eating strategies affect endothelial function, cerebral blood flow, blood-brain barrier integrity, inflammation, and mitochondrial function within the aging neurovascular unit, identifying pathways that may support cerebrovascular resilience and cognitive health.

Neurodegenerative diseases (NDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by progressive neuronal loss within the central nervous system, affecting more than 64 million individuals worldwide. Degeneration of cholinergic and dopaminergic neurons leads to cognitive impairment, motor dysfunction, and neuropsychiatric disturbances. Currently available pharmacotherapies provide only symptomatic relief, largely targeting single mechanistic pathways without halting disease progression. Increasing evidence supports the therapeutic potential of plant-derived bioactive compounds owing to their multitargeted pharmacological properties. Among these, cyanidin (CN), a naturally occurring flavonoid, exhibits potent antioxidant, anti-inflammatory, anti-apoptotic, and senolytic activities. CN has been shown to mitigate mitochondrial dysfunction and protect cholinergic and dopaminergic neurons, thereby addressing key pathological features of AD and PD. However, its clinical translation is limited by poor aqueous solubility (log P 2.41), reduced systemic bioavailability, and inadequate brain penetration. Nanotechnology-based novel drug delivery systems (NDDS), including lipid-based, polymeric, and inorganic nanoparticles, offer promising strategies to enhance CN solubility, stability, bioavailability, and blood-brain barrier permeability. This review discusses the pathophysiological mechanisms of AD and PD, the neuroprotective potential of CN, limitations associated with its conventional delivery, and the emerging role of nanoformulations in optimizing brain-targeted therapy.

BACKGROUND: Patient-reported outcome measures (PROMs) are critical for evaluating health-related quality of life (HRQoL) among people living with HIV (PLHIV). This study explores HRQoL using PROMs and assesses the prevalence and implications of HIV-associated neurocognitive disorders (HAND) within the HIV Reference Centre (HRC) of Ghent University Hospital, a tertiary outpatient clinic providing routine multidisciplinary HIV care. METHODS: Between November 2021 and June 2023, 836 of 1,473 PLHIV followed completed a PROMs questionnaire assessing physical and mental health, sleep, social support, sexual health, stigma, and substance use. Screening for HAND was conducted using the European AIDS Clinical Society (EACS) guidelines, Montreal Cognitive Assessment (MoCA), and International HIV Dementia Scale (IHDS). RESULTS: Seventy-seven percent of the participants were male and mean age was 52 years (SD = 11.68). Satisfaction rates were high for physical (77%) and mental health (71%). Notably, 47% reported significant sleep disturbances, and 18.5% regularly used substances. Forty-four percent reported one or more neurocognitive complaints on the EACS screening questions, of whom 14% had impairment across all three cognitive domains. Of those reporting complaints, 36% underwent formal cognitive screening; within this screened subgroup, impaired scores were identified in 45% on the MoCA and 63% on the IHDS. Regression analyses indicated that negative feelings, sleep difficulties, low social support, and neurocognitive functioning significantly predicted overall HRQoL. CONCLUSIONS: Sleep, substance use, and neurocognitive functioning emerge as points of interest among Belgian PLHIV. Systematic identification of cognitive difficulties-when integrated with appropriate referral pathways, cardiovascular risk management, and psychosocial support rather than as isolated screening-may contribute to preserving HRQoL. The potential benefits of screening must be weighed against the risk of increasing anxiety among PLHIV.

This study develops a fractional-order model of Alzheimer's disease using a [Formula: see text]-generalized Atangana-Baleanu-Caputo (ABC) operator to capture the spatiotemporal dynamics of amyloid-beta and tau protein spread, coupled with a neuron regeneration mechanism. The fractional parameters α, [Formula: see text], and τ control memory depth, deformation of the kernel, and temporal scaling, respectively. Numerical simulations demonstrate that: (i) intermediate fractional orders [Formula: see text] produce biologically realistic propagation delays, (ii) lower [Formula: see text] values enhance nonlocal interactions and accelerate tau diffusion across the connectome, and (iii) increasing the scaling parameter τ slows accumulation, mimicking effective clearance or treatment response. Incorporating a treatment term with drug diffusion and decay reveals that sustained low decay rates ([Formula: see text]) markedly reduce tau concentrations and protect neuron populations. These findings show that the [Formula: see text]-ABC framework not only captures the hereditary and memory effects of Alzheimer's progression but also provides a flexible platform for simulating therapeutic interventions and predicting disease trajectories using real brain connectome data.

We present the case of a 64-year-old woman who was evaluated for progressive behavioral and cognitive decline. Her clinical presentation was characterized by marked personality changes, apathy, and disinhibition, accompanied by irritability, executive dysfunction, and memory impairment. Neuropsychological assessment revealed significant cognitive impairment, with a Mini-Mental State Examination (MMSE) score of 14 and a Montreal Cognitive Assessment (MoCA) score of 11. Brain MRI revealed prominent asymmetric fronto-temporo-parietal atrophy, worse on the right. A heterozygous pathogenic granulin (GRN) mutation (c.302_315del) was identified via whole-exome sequencing and was also found in one of her sons. This case expands the mutational spectrum of and underscores its diagnostic relevance in behavioral variant frontotemporal dementia (bvFTD).

Alzheimer's disease (AD) is characterized by progressive cognitive decline and cerebral glucose hypometabolism. Emerging evidence suggests that modulating brain glucose metabolism represents a promising therapeutic strategy for AD. Here, we demonstrate that electroacupuncture (EA) improves cognitive function in 5×FAD mice by enhancing glucose metabolism in the hippocampus. EA treatment significantly attenuated learning and memory deficits and reduced β-amyloid (Aβ) deposition in 5×FAD mice. Further analysis revealed that these improvements were associated with enhanced hippocampal glucose metabolism and optimized information processing in the brain metabolic network. In addition, EA specifically activated the IGF1/IGF1R signaling pathway in the hippocampus, which promoted membrane translocation of GLUT3 and consequently enhanced neuronal glucose uptake. The glucose metabolic enhancement boosted tricarboxylic acid cycle activity and improved synaptic plasticity. Our findings establish a novel mechanism by which EA improves the learning and memory through the IGF1/IGF1R pathway, providing both theoretic and experimental support for the clinical application of EA in AD treatment.

Existing studies suggest that cardiometabolic multimorbidity (CMM) affects cognitive function, but the role of systemic inflammation in this association remains unclear. Therefore, investigating the mechanistic role of systemic inflammation in the link between CMM and cognitive decline is crucial. This study included 2492 adults aged ≥60 years from the 2011 to 2014 National Health and Nutrition Survey. Cognitive function was assessed using 3 validated tests. Inflammatory biomarkers - systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-platelet ratio (NPR), and white blood cell count - were integrated into a Comprehensive Inflammation Score (CIS) using principal component analysis. Weighted multivariate linear regression model were used to examine the associations among CMM, cognitive function, and inflammatory biomarkers. Restrictive cubic splines were used to explore the nonlinear relationship between systemic inflammation and cognitive function, and the bootstrap method was applied to examine the mediating role of systemic inflammation in the CMM-cognition relationship. Results showed that CMM was significantly associated with poorer Digit Symbol Substitution Test (DSST) performance (β = -6.57, 95% confidence interval [CI]: -8.44 to -4.70, P < .001), and higher systemic inflammation (NLR: β = 0.075, 95% CI: 0.040 to -0.111, P < .001). Systemic inflammation was also associated with poorer cognitive performance (NPR-Consortium to Establish a Registry for Alzheimer Disease: β = -2.21, 95% CI: -3.58 to -0.84, P = .007; LMR-Animal Fluency Test: β = 1.56, 95% CI: 0.25 to 2.87, P = .034; NPR-DSST: β = -5.93, 95% CI: -10.67 to -1.18, P = .017), and nonlinear associations were observed between inflammation and cognitive outcomes. Mediation analyses revealed that the SII, NLR, and LMR significantly mediated the association between CMM and DSST (SII: β = 0.053, 95% CI: 0.002 to 0.128; NLR: β = 0.133, 95% CI: 0.043 to 0.248; LMR: β = 0.118, 95% CI: 0.036 to 0.226), while NPR and CIS mediated the CMM-Consortium to Establish a Registry for Alzheimer Disease relationship (NPR: β = -0.051, 95% CI: -0.104 to -0.004; CIS: β = -0.034, 95% CI: -0.074 to -0.001). These results indicate that systemic inflammation may be a central pathway through which CMM contributes to cognitive dysfunction.

RATIONALE: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare and highly fatal neurodegenerative disorder with heterogeneous clinical presentations, making accurate early diagnosis challenging. Furthermore, there is a critical paucity of epidemiological and clinical data regarding sCJD in the Xinjiang region, contributing to frequent misdiagnoses. PATIENT CONCERNS: We present 3 patients who exhibited rapidly progressive dementia alongside multifocal neurological signs, including ataxia, extrapyramidal symptoms, and visual disturbances. DIAGNOSES: Comprehensive evaluations revealed positive cerebrospinal fluid 14-3-3 protein and the M/M genotype at prion protein gene codon 129 without pathogenic mutations in all cases. Cranial magnetic resonance imaging findings varied from early focal restrictions to typical widespread cortical "ribbon signs," while electroencephalograms lacked classic periodic sharp-wave complexes. All 3 patients fulfilled the 2017 National CJD Research and Surveillance Unit diagnostic criteria for probable sCJD. INTERVENTIONS: The patients received multifaceted symptomatic and supportive treatments, including measures to improve cerebral circulation and metabolism, as well as comprehensive nutritional and neurological support. OUTCOMES: Despite targeted treatments, no significant clinical improvement was observed. All patients experienced rapid and fatal disease progression, passing away between 1 month and 1.5 years following hospital discharge. LESSONS: The absence of classic electroencephalogram findings, such as periodic sharp-wave complexes, should not delay an sCJD diagnosis. Recognizing clinical "red flags" and utilizing multimodal diagnostic approaches are essential for early recognition and minimizing misdiagnosis, especially in regions with limited clinical data.

Unpaid dementia caregivers face high stress and significant coordination burden. We developed Caregiver Connect, a dementia-focused mobile application that consolidates shared scheduling, medication administration logging, daily tracking, and caregiver communication. In a two-week field pilot (n=12), participants completed brief caregiving-related stress ratings three times daily (1-5). Mean daily stress decreased from Day 1 to Day 14 (3.81→1.79). Surveys and interviews suggested perceived improvements in coordination and medication-management confidence, with the shared calendar and medication features rated most useful. Given the small sample, short duration, lack of control group, and use of a single-item stress rating, results are preliminary and motivate longer controlled studies with validated instruments.

Professional caregivers for dementia experience high levels of stress, as illustrated by 60% working full-time alongside caregiving and two-thirds reporting anxiety or depression. Available mobile applications have key gaps in comprehensive stress management. Here, we present CaregiverConnect, an application developed on Flutter and Firebase that integrates stress tracking with evidence-based relief mechanisms and care coordination tools. Requirements were gathered through stakeholder interviews and an analysis of literature. Core features include temporal stress monitoring based on validated Likert scales, guided breathing exercises, peer support groups, consultations with experts, and patient health logging. System validation was also conducted that proved functionality, usability, and compliance with security standards. We further did a two-week pilot study with professional caregivers in two nursing facilities. CaregiverConnect fills crucial gaps by combining real-time monitoring with interventions that are multimodal in nature within a secure, user-centered interface.

This study examined the relationship between health literacy and dementia-preventive behaviors among rural older adults in Northeastern Thailand. A community-based cross-sectional survey was conducted among 124 older adults (aged ≥ 60 years) in Maha Sarakham province. The questionnaire included demographic characteristics, six domains of health literacy, and dementia-preventive behaviors. Data were analyzed using correlation, ANOVA, Chi-square, and multivariable logistic regression. Results showed that total health literacy was positively associated with preventive behaviors (r = 0.25, p = 0.0047). After adjustment for covariates, high general health literacy (aOR = 2.11, 95% CI: 1.02-4.36) and high digital health literacy (aOR = 2.73, 95% CI: 1.21-6.12) remained significant predictors of strong preventive behaviors. Enhancing digital and self-management literacy within community health systems may support dementia prevention among rural aging populations.