Neighborhood disadvantage in later life is associated with poorer cognition and increased vulnerability to dementia. Cognitive reserve (CR), an individual's total cognitive resources, may foster cognitive resilience against dementia in the face of neighborhood disadvantage. However, whether the neighborhood disadvantage-cognition association varies across older adults remains understudied and its moderators remain underexplored. We examined associations between late midlife neighborhood disadvantage and five domain-specific cognitive functions as well as the moderating role of young adult CR on these associations. In 1149 community-dwelling men age 61-73 living across the United States, we assessed neighborhood-level socioeconomic disadvantage using the area deprivation index and cognitive performance in executive function, episodic memory, processing speed, verbal fluency, and visual-spatial ability. General cognitive ability assessed at average age 20 was used as a measure of young adult CR. Years of education was included as another potential moderator for comparison. Greater late midlife neighborhood disadvantage was associated with poorer executive function (β = -.09, p < .05) and processing speed (β = -.12, p < .05). Moreover, those with higher young adult CR showed a weaker association between neighborhood disadvantage and executive function (β = .07, p < .02). The same moderation effect was not observed for years of education. Findings are consistent with the idea that neighborhood disadvantage negatively associates with executive function, albeit less so among those with higher young adult CR. Fostering cognitive development to enhance CR earlier in life may buffer against environmental threats to later-life executive function, which is among the earliest cognitive functions affected in aging, and may, in turn, decrease vulnerability to dementia.

Current Alzheimer's disease therapies offer limited efficacy and are often accompanied by significant side effects, underscoring the urgent need for new treatment strategies. Enhancing autophagy represents a promising therapeutic approach, yet most known autophagy inducers act through the mTOR-dependent pathway, which broadly affects cellular metabolism and proliferation, and their clinical potential is further limited by poor blood-brain barrier (BBB) penetration. To address these twin challenges, an artificial intelligence (AI)-driven platform named DeepDrugDiscovery was developed, shifting the focus from traditional structure-based screening toward a mechanism-centric strategy for identifying mTOR-independent autophagy enhancers with brain penetrability. The platform screened over one million molecules and identified two lead compounds, Ombuin and 2-Hydroxycinnamic acid, which were experimentally shown to clear pathogenic tau and amyloid-β aggregates and restore memory function in both worm and mouse models of Alzheimer's disease. Notably, Ombuin exhibited robust brain exposure, confirming accurate BBB prediction. Released as an open-source resource, DeepDrugDiscovery demonstrates a scalable, AI-powered pipeline for discovering mechanism-based therapeutics.

Targeting disease-specific chemical signals enables precise therapeutic control over complex pathologies. In Alzheimer's disease (AD), elevated hydrogen peroxide (HO) accompanies hallmark features, including amyloid-β (Aβ) aggregate deposition and metal ion dyshomeostasis, creating an oxidative milieu primed for selective chemical activation. Here, we show a rationally designed prodrug platform that harnesses HO as an endogenous trigger for redox-based therapy. Boronic ester-masked precursors (BE-1 and BE-2) remain inert under physiological conditions but undergo rapid oxidative deboronation in the presence of HO, releasing redox-active aminophenols. These activated molecules exhibit multimodal pathological modulation, as revealed by molecular-level biochemical and biophysical analyses: scavenging reactive oxygen species, inducing residue-specific oxidative modifications of Aβ, and redirecting aggregation pathways of both metal-free and metal-bound Aβ. In AD transgenic mice, BE-1 undergoes conversion to its active form within the brain tissue. Long-term administration of BE-1 markedly reduces hippocampal oxidative stress, lowers amyloid plaque burden, and improves cognitive performance. This pathology-responsive, activity-based prodrug strategy provides a chemically precise framework for simultaneously modulating multiple, interconnected drivers of neurodegeneration.

BACKGROUND: Reproductive factors have been associated with cognition in older women, yet findings have been inconsistent. Moreover, recent studies have also found similar associations in men. OBJECTIVE: Examine the relationship between reproductive and cognitive factors in both sexes, controlling for multiple covariates. METHODS: We analyzed data from 914 women with natural menopause ( = 72.655.57) and 811 men ( = 74.435.37) from the HELIAD study. Participants provided reproductive, medical, and social histories and had a comprehensive neuropsychological assessment, including Mild Cognitive Impairment and dementia diagnosis. Covariates included age, education, medical, genetic, lifestyle, and socioeconomic factors. RESULTS: Controlling for age and education, in women, later menarche, earlier menopause, fewer menstrual years, shorter interpregnancy intervals, and menstrual regularity were associated with poorer cognitive outcomes. Earlier first childbirth (<25y), greater parity (especially, before 20y), and older age at fourth childbirth were linked to better cognition (.95-2.20). In men, older age at third and fourth child birth, having more children at ages 20-29 or 40+, the last child at >35y, and childlessness were associated with poorer cognition, while having the first child at >35y (language tasks) and having more children overall were associated with better cognition (:1.37-2.20). After full-adjustment and Bonferroni correction, no associations remained. CONCLUSIONS: Reproductive patterns may affect cognition differentially based on sex. Moderate reproductive activity may be protective, whereas extreme patterns (e.g. very early/late childbirth, childlessness) may be linked to cognitive decline. These associations attenuate after statistical adjustment and correction, necessitating further controlled and longitudinal studies to clarify these relationships.

Recent advances in biomarker testing for Alzheimer's disease (AD), most notably the introduction of blood-based biomarkers (BBMs), have prompted a revision in diagnostic criteria for AD. In comparison to other established neurodiagnostic testing (i.e. amyloid positron emission tomography [PET] and cerebral spinal fluid [CSF] assays), AD BBMs offer a scalable, low-cost, and accessible method to aid in the diagnosis of AD which, in turn, may offer more expedient intervention. Despite this headway in AD diagnosis, several concerns about the clinical implementation of BBMs remain--and specifically, who should be receiving them. Palmqvist et al. (2025) recently published clinical practice guidelines to clarify the use of BBMs in specialty care settings; however, there remains variability in the administration and interpretation of test results to patients. As BBMs expand, it is critical that clinicans do not overlook the consideration of alternative causes of cognitive decline, which can lead to misdiagnosis of AD. This article expands on current clinical guidelines for biomarker testing, discussing ethical and practical considerations of AD BBMs, and offering a shared decision-making (SDM) framework to encourage patient-centered care when considering appropriateness of BBMs in specialty care settings. The framework includes 1) patient education, 2) clarifying patient values, and 3) offering clinical guidance. Future directions of AD BBMs and health disparities are also discussed.

PURPOSE: White matter (WM) signal on ¹⁸F-florbetapir positron emission tomography (PET) is often regarded as nonspecific, yet its biological significance remains unclear. This study aimed to characterize the trajectory, clinical significance, and biomarker correlates of normal-appearing white matter (NAWM) ¹⁸F-florbetapir retention across the Alzheimer's disease (AD) continuum. METHODS: We analyzed NAWM ¹⁸F-florbetapir retention in 672 participants across the AD continuum from the Alzheimer's Disease Neuroimaging Initiative and two Chinese cohorts. Longitudinal PET, plasma, and cerebrospinal fluid (CSF) biomarkers, as well as lecanemab treatment effects, were evaluated. RESULTS: NAWM retention followed a distinct trajectory from cortical amyloid, increasing during preclinical stages and plateauing in symptomatic phases. Elevated NAWM ¹⁸F-florbetapir retention independently predicted cognitive decline, correlated with plasma p-tau217 and CSF p-tau/Aβ42 ratio, and showed significant reductions following lecanemab therapy. Combined assessment of cortical and NAWM PET improved diagnostic accuracy for amyloid positivity to 92%. NAWM retention also correlated strongly with plasma and CSF biomarkers in preclinical stages, and mediation analyses indicated that these fluid markers partly explained NAWM-cognition associations. CONCLUSION: NAWM ¹⁸F-florbetapir retention represents a biologically valid and dynamic biomarker of AD progression, with potential utility for early detection, prognostication, and therapeutic monitoring.

BACKGROUND: Latinos are disproportionately affected by dementia but remain underrepresented in dementia research. Engaged research approaches, characterized by co-leadership between academic and community partners, can strengthen the representativeness, responsiveness, and impact of scientific evidence. There is a need to better understand how methods of engagement may deepen partnerships with underrepresented communities. This study examined engagement with a Community Council of research partners who were co-conducting dementia research among Latino communities in South Texas. METHODS: An explanatory sequential mixed-methods study assessed Council member engagement over two years. The Research Engagement Survey Tool (REST), measuring engagement quality and quantity across eight engagement principles and levels, was administered at three time points. Repeated measures ANOVA and pairwise t-tests assessed changes; Bonferroni correction was applied for significance. Semi-structured interviews with a Council member subset (N = 10) were analyzed using thematic content analysis and integrated with survey findings. RESULTS: Council members (N = 13), including caregivers, persons living with dementia, community health workers, community organizations, clinicians, and dementia researchers, completed all survey administrations. Overall REST quality scores increased from baseline to study end (mean 4.18 to 4.77 on a 1-5 scale; p=.003). Significant increases after Bonferroni correction were observed in: focusing on community perspectives (p=.008), valuing partner input (p=.015), co-learning and capacity building (p=.017), fostering collaborative partnerships (p=.015), and involving partners in dissemination (p=.013). When examined by engagement level, 'collaboration' remained highest across all time points; the largest increases occurred in 'partnership' (quality +6.9; quantity +6.8, each out of 20). Qualitative findings reinforced survey results across three themes: (1) establishing partnerships through diversity, shared experiences, and leadership; (2) building capacity through co-learning, trust, and being heard; and (3) sustaining the work. Together, findings illustrate a trajectory in which structural diversity and inclusive processes produced stronger trust, partnership, and sustained community leadership. CONCLUSION: The Council model can effectively support and deepen engagement with Latino community partners when structured around cultural values and community-centeredness. Through the Council's structural diversity, relational processes, and shared leadership, engagement strategies strengthened trust and fostered a sustained partnership. These findings contribute to the engagement sciences and provide a model for reducing underrepresentation in dementia research.

BACKGROUND: There is increasing awareness that many long-term care (LTC) residents may have experienced trauma or post-traumatic stress disorder (PTSD) in their lifetimes, conditions that can be comorbid with dementia and/or complex mental health conditions. In Canada, health care aides provide the vast majority of direct care to such residents. This qualitative study explored their experiences working with residents whose responsive behaviors may indicate past trauma or PTSD. METHODS: In Fall 2024, we conducted open-ended interviews with 24 care aides from 6 urban LTC homes in Alberta, Canada. Initial interview topics built on insights from 13 separate interviews conducted in 2023. Questions were iterated throughout data collection and the data analyzed using Braun and Clarke's reflexive thematic analysis approach. RESULTS: Our participants broadly reflected the demographic make-up of Alberta's care aide workforce: 91.7% female, 79.2% from racialized groups and 70.8% speaking English as an additional language. We identified 3 overarching themes in their experiences: (1) care aides regularly suspected some responsive behaviors to be trauma-related but seldom named these as such; (2) their strategies for managing these behaviors and providing personalized care involved adapting existing skills and innovating new ones; and (3) resident care connected to possible past trauma was complex and compounded current workplace challenges and struggles. CONCLUSIONS: Two improvements could help care aides working with residents with suspected trauma backgrounds: greater understanding of trauma and knowledge of trauma terminology, and use of a trauma-informed care framework. Such changes would likely improve resident quality of life by helping care aides better differentiate responsive behaviors, deliver targeted and individualized care, and avoid resident retraumatization. Implementation of trauma-informed care, however, needs to build on existing care aide expertise to facilitate uptake and ensure sustainability.

BACKGROUND: Dementia is frequently underdiagnosed in its early stages, but changes in healthcare utilization may precede diagnosis by several years. We examined healthcare patterns and chronic conditions before cognitive impairment among the Atherosclerosis Risk in Communities (ARIC) study participants to better understand this pre-diagnostic period. METHODS: We included ARIC visit 6 (2016-2017) participants with continuous 5-year prior Medicare coverage (2011-2018) and used negative binomial regression to compare longitudinal trends in hospitalization in participants with Part A coverage, and emergency department (ED) and ambulatory care use in participants with Part A&B coverage, in the 5 years prior to and 1 year following an incident dementia according to ARIC syndromic classification. Inverse probability weights were used to balance participants with and without incident dementia on baseline age, race, sex, education, and prevalent comorbidities. Principal diagnosis discharge codes were used to assess chronic conditions associated with hospitalization and ED visits, whereas all available diagnosis codes were used for ambulatory care visits. RESULTS: Among 3,923 eligible participants (mean age 79.6 ± 4.8 years; 59% women; 24% Black), 325 (8.3%) were classified as incident dementia at ARIC visit 6 or 7. During 5 years prior to visit 6, participants with incident dementia compared with non-dementia participants, had on average higher use of inpatient (0.12 vs. 0.08 hospitalizations per 6-month) and ED services (0.28 vs. 0.18 visits per 6-month) but lower ambulatory care use (3.53 vs. 3.76 visits per 6-month). Participants with incident dementia experienced more frequent hospitalizations for acute myocardial infarction (3.8% vs. 1.7%), chronic kidney disease (4.1% vs. 2.6%), congestive heart failure (4.7% vs. 1.6%), and stroke/TIA (8.5% vs. 2.6%), and more frequent ambulatory care visits for atrial fibrillation (23% vs. 15%), than non-dementia participants within 5 years prior to incident dementia. CONCLUSIONS: Compared with non-dementia participants, those with incident dementia had higher average hospitalization and ED utilization but lower ambulatory care visits, with differences observable 3 years before incident dementia. Cardiovascular disease and concomitant cerebrovascular disease are important contributors to dementia. Close monitoring of healthcare-seeking patterns may help identify individuals at high risk of dementia earlier in the disease course. TRIAL REGISTRATION: Not applicable.

BACKGROUND: This study aimed to assess healthcare professionals' perceived knowledge, attitudes, and practices (KAP) toward the use of noninvasive neuromodulation technology as an adjunctive treatment for cognitive disorders. METHODS: A cross-sectional survey was conducted at The First Affiliated Hospital of Henan Medical University, enrolling healthcare professionals from multiple centers from April 2025 to August 2025. KAP scores were measured using a structured questionnaire. Factors associated with practice were identified using multivariable logistic regression. A path analysis within a structural equation modeling (SEM) framework, incorporating mediation effects, was conducted to explore the interrelationships among the KAP dimensions. RESULTS: A total of 479 valid responses were included. The mean perceived knowledge, attitude, and practice scores were 5.36 ± 5.10 (possible maximum: 16; 33.50% of maximum score), 21.32 ± 3.25 (possible maximum: 25; 85.28% of maximum score), and 20.05 ± 4.07 (possible maximum: 25; 80.20% of maximum score), respectively. Both perceived knowledge (OR = 1.284, 95% CI: 1.156-1.427, P < 0.001) and attitude (OR = 2.635, 95% CI: 2.180-3.186, P < 0.001) were independently associated with practice. SEM analysis revealed that perceived knowledge exerted a direct positive effect on attitude (β = 0.489, P = 0.012) and practice (β = 0.261, P = 0.009), while attitude directly influenced practice (β = 0.642, P = 0.005). Additionally, perceived knowledge indirectly affected practice through its influence on attitude (β = 0.314, P = 0.008). CONCLUSION: Although healthcare professionals demonstrated positive attitudes and practices toward noninvasive neuromodulation technology, their level of perceived knowledge remained insufficient. Targeted educational and training initiatives are warranted to enhance knowledge, which may further strengthen attitudes and practices related to this emerging therapeutic approach. CLINICAL TRIAL NUMBER: Not applicable.

PURPOSE: Dehydration is common among those admitted to hospital with delirium or dementia and may itself contribute to cognitive impairment. Agitated behaviors are also common in such patients and may lead to difficulty in maintenance of peripheral IV cannulas. In this paper, we examine the potential advantages and drawbacks of subcutaneous (SC) compared with intravenous (IV) hydration in patients with cognitive impairment and mild-to-moderate dehydration. METHODS: We reviewed and summarized the available literature on SC versus IV hydration in patients with cognitive impairment and the impact on agitation and cannula maintenance in particular. RESULTS: Compared with IV hydration, SC hydration is faster to establish and associated with fewer adverse effects. A meta-analysis of randomized controlled trials found that SC hydration in patients with cognitive impairment results in a lower risk of agitation (relative risk 0.40 [95% CI 0.22-0.72]) compared with IV hydration. Furthermore, there is an 80% reduced risk of catheter dislodgment. It is likely that the reduced risk of agitation and catheter dislodgment is causally related to the fact that subcutaneous access is less traumatic approach for a population at high risk for agitation. CONCLUSION: SC hydration has many advantages and few disadvantages for those with mild-to-moderate dehydration and cognitive impairment who need parenteral hydration. It should, in our opinion, always be considered in this population. It is important, however, that ease of use does not lead to overuse, especially where low-intake dehydration may represent part of the natural course of advanced illness.

Cryo-electron microscopy (cryo-EM) structure determination relies on preparing thin, vitreous films of sample solution on EM grids. Cryo-EM is a mature technology, but preparing the grids remains a major bottleneck. Here, we evaluate the cryoWriter, a blotting-free, microfluidic grid-preparation robot that writes nanoliter volumes onto EM grids in a controlled environment. Using capillary-writing in spiral or line patterns, we prepared high-quality grids from minimal sample volumes and obtained near-atomic reconstructions for test specimens, including TMV, apoferritin, and the membrane protein TRPM4. We further demonstrate programmable deposition modes, such as writing the sample twice to boost particle density, or two-line writing for on-grid mixing to visualize time-resolved protein-ligand binding. In a challenging case (NrS-1 DNA polymerase), the cryoWriter grids exhibited reduced orientation bias relative to conventional blotting, enabling a more isotropic reconstruction. These results show that the cryoWriter provides a versatile platform for reproducible low volume cryo-EM grid preparation and for on-grid biochemical workflows.

Cerebral small vessel disease (CSVD) is an important contributor to stroke and dementia, yet the role of venous dysfunction in its pathophysiology remains poorly understood. Resting-state fMRI captures spontaneous low-frequency oscillations (sLFOs), reflecting cerebral blood flow dynamics primarily in the venous system. We applied sLFO lag-time mapping to investigate venous perfusion alterations in covert CSVD. We stratified 572 community-dwelling individuals into controls and CSVD subtypes based on MRI markers, and compared voxel-wise lag-time-derived perfusion indices-mean positive lag-time, mean negative lag-time, and spatial lag-time distribution-between groups. Participants with ischemic CSVD exhibited significantly prolonged positive lag times, indicating altered perfusion timing in regions corresponding to the superficial venous drainage system. Voxel-wise analyses revealed heterogeneous alterations in perfusion timing and spatial distribution across CSVD subtypes, with both delayed and advanced venous timing observed in distinct regions of the superficial and deep venous systems. Hierarchical clustering analyses identified a distinct perfusion pattern in the strictly-lobar cerebral microbleeds subgroup, suggestive of cerebral amyloid angiopathy. These results suggest that altered venous perfusion timing is an early hallmark of CSVD, and that rs-fMRI lag-time mapping may serve as a non-invasive biomarker to detect early perfusion changes and distinguish between different CSVD pathophysiological processes.

The European research landscape for developing new diagnostic, preventive, and therapeutic interventions is fraught with challenges. Scarcity of qualified talent, limited funding for laboratories and research infrastructure, geopolitical competition, and increasing complexity of data systems all require creativity, leadership, and vision to advance science and translate research results into effective solutions. This paper aimed to identify research priorities across the seven member organisations of the European Science for Health (EurSci4Health) community. The leadership of the membership organisations was surveyed, in total 150 individuals, yielding 38 valid responses (response rate of 21.7%). Three factors emerged as drivers of research: opportunities for collaboration, addressing unmet medical needs, and contributing to European excellence and competitiveness. In terms of disease areas, respondents identified neurological disorders (e.g., Alzheimer's disease, Parkinson's disease), cancer (e.g., brain, lung cancer), and global health threats (e.g., antimicrobial resistance, pandemics) as the highest priorities. Among scientific domains and enabling technologies, data science, artificial intelligence (AI), big data, and robotics emerged as the highest-priority areas for future research investment. There was also a plea for cross-disciplinary funding spanning fields such as data science and chemical biology, nanotechnology and clinical pharmacology, and regulatory science and health technology assessment (HTA). The survey findings are discussed through the perspective of fostering trust, collaboration, and a shared vision within the EurSci4Health research communities. The results underscore a strong preference for enabling talented, independent researchers to pursue curiosity-driven basic science, while remaining responsive to compelling health questions on the horizon. This paper seeks to contribute constructively to the broader dialogue on future health research priorities and innovation policy. Ultimately, progress in the field will depend not on passive adaptation to external developments, but on proactive engagement and strategic advocacy.

BACKGROUND: Dementia-related affective symptoms and social withdrawal increase vulnerability to suicidal behaviour. This study evaluates the magnitude of this risk and its determinants, focusing specifically on suicide attempts and deaths. METHODS: A systematic review and meta-analysis of observational studies was conducted. Eight English- and Chinese-language databases were searched from inception to May 2025. Pooled odds ratios (OR) were estimated using random-effects models to compare people with dementia (PwD) with controls and to identify risk factors within the dementia population. RESULTS: Thirty-seven studies met the inclusion criteria. Dementia was associated with a 62% increased risk of suicidal behaviour compared with non-dementia controls (pooled OR = 1.62; 95% CI 1.32-1.98). Risk was notably concentrated in specific subgroups: younger patients were nearly three times more likely to die by suicide than older patients, and men faced 28% higher odds of suicide attempts and 188% increased odds of suicide deaths compared to women. Social isolation and psychiatric history-particularly depression-were robust risk markers. Notably, the exhaustive search of Chinese-language databases yielded no eligible publications, revealing a significant geographical evidence gap. CONCLUSIONS: PwD face a significant increase in suicidal behaviour, concentrated within subgroups with psychiatric and social vulnerabilities. Prevention should prioritise younger patients, men, and socially isolated individuals. The identified lack of diverse data necessitates future cross-cultural qualitative research in English and Chinese to bridge the gap between Western and Eastern perspectives and capture culturally situated risk factors currently missing from the literature.

Disruption of the blood-brain or blood-retinal barrier (BBB/BRB) is a common phenomenon in neurodegenerative diseases of the central nervous system (CNS). While many existing reviews focus on the link between BBB disruption and neuronal degeneration in the brain, a similar analysis of the BRB integrity in retinal degeneration is currently unavailable. Like the BBB, the inner BRB is established by retinal blood vessels encapsulated in a neurovascular unit (NVU). The retinal NVU and BRB are affected not only in retina-specific neurodegenerative diseases (e.g. diabetic retinopathy, retinitis pigmentosa etc.) but also in neurodegenerative diseases that primarily affect the brain (e.g. Alzheimer's disease, Parkinson's disease etc.). In this review, we will discuss the link between vascular abnormalities (including BRB disruption) and retinal neurodegeneration in these diseases to highlight the pivotal role of BRB integrity in neuronal homeostasis and health.

As individuals age, changes in cognitive health can alter how they engage with their environments, with disruptions in daily life participation potentially signaling emerging challenges. Life-space, which quantifies the spatial extent and frequency of an individual's movement, provides a lens to capture changes. While life-space has been studied among community-dwelling older adults, its application in dementia remains limited, despite the unique ways cognition may shape mobility and interactions with place. Most Global Positioning System (GPS)-based life-space studies rely on aggregate metrics that describe how far people travel but provide limited insight into what kinds of places they visit or how mobility is structured by activity context. This proof-of-concept study explores the feasibility of integrating GPS mobility data with contextual information to create zoned life-space maps and examines whether this framework can reveal interpretable mobility patterns in a small sample of older adults with and without dementia. Seventeen participants (10 cognitively intact, 7 with dementia) were monitored for four weeks, generating over 34,000 location points. An updated stop-segmentation algorithm identified stops and trajectories, while activity types were inferred using OpenStreetMap and a probability-based method. Stops were colour-coded by activity and mapped within three zones (neighbourhood, town, beyond) to produce life-space visualizations. In this small sample, participants with dementia tended to exhibit shorter travel distances, fewer unique destinations, and lower location entropy in the neighbourhood and town zones. Life-space maps illustrated differences in engagement, routine, and purpose not readily captured by aggregated metrics alone, supporting the feasibility of place-based GPS life-space mapping.

Aging is accompanied by several neurophysiological changes. Of recent interest are age-related changes in brain energetics-how the brain produces and uses energy. In vitro, preclinical, and genetic investigations point to a general decline in the efficiency of brain energetics in aging, which may help explain age-related changes in mood, cognition, movement, and behaviour, as well as an increased likelihood of developing neurodegenerative disorders. We hypothesized that age-related alterations to brain energetics are observable using functional neuroimaging data from healthy individuals (N = 24, 35-80 years), and that alterations may occur in regions associated with neurodegenerative pathology. Specifically, we jointly analyzed cerebral glucose metabolism and blood flow data, defining novel metrics that capture regional variability in processes related to relative energy production (rEP) and relative aerobic glycolysis (rAG), an energy production mechanism. By applying Scaled Subprofile Modeling Principal Component Analysis (SSM-PCA) to these metrics, we identified spatial covariance patterns that capture a widespread age-related restructuring of brain energetics. Broadly, an age-related rEP pattern (r = 0.72) consisted of rEP increases in frontal, basal ganglia, and brainstem regions, coupled with decreases in occipitoparietal regions, while an age-related rAG pattern (r = 0.65) revealed rAG increases in substantia nigra and occipitoparietal regions and decreases in caudate and frontal regions. Finally, by comparing these patterns to well-known metabolic patterns related to Parkinson's and Alzheimer's disease, we identified the strongest topological similarity and covarying pattern expression between the age-related rEP pattern and the Parkinson's Disease Related Pattern (PDRP). These results provide in vivo support for altered brain energetics with age and potential neurophysiological similarities between aging and neurodegeneration.

TNF-α (Tumor Necrosis Factor) is a proinflammatory cytokine that amplifies inflammatory response and promotes leukocyte recruitment. TNF-α is primarily produced by activated macrophages, among others, in response to infection, inflammation, or tissue damage. Given its central role in normal and abnormal immune responses, it is the target of several therapeutics, such as adalimumab and etanercept. TNF-α is also a prognostic and diagnostic biomarker associated with rheumatoid arthritis, Alzheimer's disease, multiple sclerosis, several kidney diseases, cancers, type 2 diabetes, sepsis, and others. Because TNF-α levels change dynamically during inflammatory responses, tools capable of sensitive and spatially resolved detection could enable improved monitoring of immune activity and disease progression. Single-walled carbon nanotubes (SWCNT) are cylindrical carbon lattices that emit distinct near-infrared bandgap photoluminescence. In this work, we evaluated three aptamer-based sensor constructs, plus an additional two iterations of one aptamer sequence, and two antibody-based sensor constructs for TNF-α that use SWCNT near-infrared photoluminescence signal transduction. Several, but not all, of these aptamer and antibody-based sensors sensitively and selectively detected TNF-α in human and bovine serum in a physiologically relevant range, and we found that their sensing was impacted by both passivation and incorporating an exogenous quencher onto the aptamer sequence. This study highlights the importance and challenges of translating previously-validated molecular recognition elements to new detection conditions, in this case on the surface of SWCNT and in challenging serum conditions. It also validated a lead sensor, the VR11-SWCNT aptamer construct with or without quencher chemistry and with surface passivation, that builds upon constructs that failed in serum. These results demonstrate a strategy toward synthesis of nanoscale optical sensors capable of detecting TNF-α. We anticipate that the sensors evaluated here will have utility in both the diagnosis and study of inflammation-driven chronic disease, while the sensor assessment framework will help drive the broader field of molecularly specific diagnostics.

Psychiatric disorders frequently co-occur with endocrine, nutritional, and metabolic disorders, complicating diagnosis, treatment, and prognosis. To date, no umbrella review (UR) has summarized the corresponding evidence. We conducted a UR of meta-analyses of observational studies reporting the prevalence and outcomes of comorbid endocrine, nutritional, metabolic, and psychiatric disorders (DSM/ICD criteria, PubMed/Medline/Scopus/Embase/Web of Science, 13/10/2025). Meta-analytic prevalence and association estimates were recalculated/and graded using quantitative criteria. The methodological quality of the meta-analyses was assessed with AMSTAR-2. Subgroup and meta-regression were conducted. Eighty-one meta-analyses (records=254,154,533, k=1,780) yielded 119 meta-analytic estimates. Among 64 prevalence estimates drafted from the original meta-analyses, 10(6.4%) had strong credibility, namely (among adults unless otherwise specified): obesity in autism spectrum disorder(17.0%, 95%C.I.=13.0-22.0); Vitamin-D deficiency in schizophrenia(65.3%, 95%C.I.=46.4-84.2); major depressive disorder(MDD) in diabetic foot ulcer(47.0%, 95%C.I.=26.0-85.0), in diabetes mellitus(61.8%; 95%C.I.=56.6-66.7%), in metabolic syndrome (30.5%; 95%C.I.=26.3-35.1), and in polycystic ovary syndrome(PCOS)(37.0%; 95%C.I.=29.0-44.0%); anxiety in PCOS(48.0%, 95%C.I.=37.0-59.0), in type-1 diabetes(21.3%, 95%C.I.=17.8-26.7); type-2-diabetes in MDD(8.7%; 95%C.I.=7.3-10.2%); and mild cognitive impairment in type-2-diabetes(45.0%; 95%C.I.=36.0-54.0%). Five of 43(11.7%) outcomes met strong credibility criteria. Comorbid-MDD vs. non-comorbid-MDD posed a higher risk for all-cause mortality (relative risk/RR=1.48, 95%C.I.=1.4-1.6) and dementia (RR=2.1, 95%C.I.=1.7-2.6) among diabetic people. ADHD-comorbidity increased glycate hemoglobin-A1C levels among type-I diabetes children (SMD=0.7, 95%C.I.=0.5-0.9) and type-2 diabetic females (SMD=0.6, 95%CI=0.4-0.7). Diabetes increased the risk of 30-day hospital readmission (RR=1.2, 95%C.I.=1.1-1.3) in people with dementia. This study provides a comprehensive atlas of the prevalence and outcomes associated with multimorbidity across endocrine, nutritional, metabolic, and psychiatric diseases, assessing credibility and prompting integrated, multidisciplinary care.

Among all the neural diseases Alzheimer's disease (AD) represents a major and critical global health challenge, along with limited diseases-altering therapeutic interventions efficacy. This study deploys collective approaches of in silico study which includes molecular docking, ADMET profiling, density functional theory (DFT), and MD simulations simulation to evaluate pyridine-based dual inhibitors which can target acetylcholinesterase (AChE PBD ID: 4EY7) and butyrylcholinesterase (BChE PDB ID: 6I0B). From a curated library of 55 ZINC-derived compounds, virtual screening using AutoDock Vina identified lead candidates exhibiting superior binding affinities (-11.5 to - 8.0 kcal/mol for AChE; - 10.9 to - 7.4 kcal/mol for BChE) compared to marketed drugs donepezil and tacrine. Compound 46 emerged as the top AChE inhibitor, while compound 49 demonstrated optimal BChE inhibition. DFT analysis at the B3LYP/6-31G(d) level revealed distinct electronic properties: compound 46 exhibited a wider HOMO-LUMO gap (5.32 eV) correlating with enhanced kinetic stability, whereas compound 49 displayed a narrower gap (5.10 eV) and elevated dipole moment, supporting target-selective binding. Extended MD simulations with 200 ns of total duration confirmed that compounds 46 and 49 (two complexes) have structurally stable conformations compared with each other; however, compound 49 was found to be thermodynamically more stable according to MM-PBSA predicted binding free energy (-54.96 ± 4.36 kcal/mol) than compound 46 (-44.73 + 4.85 kcal/mol). ADMET predictions showed good intestinal absorption and CNS permeability; however, it will be necessary to improve both the solubility of these compounds as well as their CYP3A4-related liability. This multi-tiered computational strategy was able to identify both compounds 46 and 49 as highly promising candidates for further experimental validation as dual cholinesterase inhibitors that will be incorporated into efforts to develop new AD treatment approaches.

Although cardiac arrests are common, most survivors do not develop post-hypoxic myoclonus (Lance-Adams syndrome, LAS), suggesting that hypoxia alone may be insufficient. We retrospectively identified LAS cases from electronic records and video archives (2000-2025) and reviewed the literature. Among 17 patients, 12 had peri-event blood gases, all showing severe acidemia (mean pH, 7.08), with respiratory acidosis in seven and metabolic acidosis in five; the remaining five had respiratory failure. In published reports, respiratory events commonly preceded LAS. Systemic acidemia associated with respiratory insufficiency frequently accompanies hypoxic injury in LAS and may explain its rarity after isolated cardiac arrest.

BACKGROUND: Periodontitis has gained attention as a key factor associated with cognitive decline and Alzheimer's dementia. However, the relationship between periodontitis-related oral microbiota shifts and brain health in the general population remains unclear. METHODS: We investigated the oral microbiome-brain axis in 1026 participants from the population-based PAROMIND Study. Using 16S rRNA gene amplicon sequencing of subgingival crevicular fluid, we inferred via topological data analysis a microbiota similarity network. This network, which distills the complex high-dimensional data into an interpretable map of microbial similarity, revealed a continuous disease gradient mirroring the microbial pathogenicity spectrum, from taxa of low periodontal pathogenicity (e.g., Streptococcus) to periodontitis-associated taxa (e.g., Porphyromonas, Fusobacterium). Leveraging this network, we systematically examined associations between periodontal microbiota profiles and 40 brain health-related phenotypes, including cognition, brain structure, mental health, inflammatory biomarkers, diet, vascular risk factors, and demographics. FINDINGS: Higher abundance of periodontitis-related bacterial taxa was associated with poorer cognitive performance, elevated leucocyte counts, and lower MIND diet adherence after covariate adjustment. Complementary forward model selection analysis supported the links to cognitive performance and inflammation, and additionally identified a significant association with brain structure (cortical thickness and subcortical volume). We identified associations with both established genera (Porphyromonas) and taxa not previously implicated in brain health (Fretibacterium, Tannerella, Dialister). INTERPRETATION: These findings from a large cohort advance the understanding of the oral microbiome-brain axis, highlighting specific microbial profiles linked to subclinical cognitive, structural, and inflammatory brain health markers. By demonstrating these links in a non-demented population, our study suggests that monitoring the oral microbiome could inform early risk assessment for cognitive decline, positioning periodontal health as an accessible target for early intervention strategies. FUNDING: Deutsche Forschungsgemeinschaft.