BACKGROUND: Agitation and aggression in Alzheimer's disease (AD) are highly distressing behavioral symptoms traditionally managed with off-label atypical antipsychotics, despite boxed warnings for increased mortality in elderly patients. The emergence of Auvelity (dextromethorphan-bupropion) provides a critical, non-antipsychotic therapeutic alternative. MECHANISM: This combination utilizes bupropion as a CYP2D6 inhibitor to achieve therapeutic central nervous system concentrations of dextromethorphan. Dextromethorphan acts as an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, bypassing dopaminergic blockade to promote synaptic plasticity via glutamatergic and monoaminergic modulation. EFFICACY: Key clinical trials (ADVANCE-1 and ACCORD) demonstrate that dextromethorphan-bupropion produces rapid, statistically significant reductions in Cohen-Mansfield Agitation Inventory (CMAI) scores. Furthermore, it offers robust long-term maintenance, demonstrating a 3.6-fold lower risk of agitation relapse compared to placebo. SAFETY: The combination therapy was generally well-tolerated in trials, successfully avoiding the sedation, cognitive blunting, and heightened fall risks characteristic of antipsychotics. Clinicians must, however, monitor for blood pressure changes and potential CYP2D6 drug-drug interactions. CONCLUSION: Dextromethorphan-bupropion represents a highly efficacious, safer paradigm shift in the pharmacological management of AD-associated agitation, offering targeted symptom relief while minimizing the severe risks associated with standard antipsychotic use.

Alzheimer's disease (AD) is increasingly recognized as a multicellular disorder involving neurovascular unit dysfunction. Investigating glial and vascular biomarkers together may provide a more integrated view of AD biology. This study characterized baseline distributions, interrelationships, and longitudinal trajectories of plasma glial (GFAP, sTREM2) and vascular/endothelial (VEGF, sICAM-1, sVCAM-1) biomarkers across the AD continuum. Using Alzheimer's Disease Neuroimaging Initiative (ADNI) data, this retrospective longitudinal cohort study included a covariate-complete clinical cohort of 2650 participants classified as cognitively unimpaired (CU), mild cognitive impairment (MCI), or AD dementia. Biomarker-specific analytic samples were determined by assay availability and complete-case requirements. Associations were evaluated using covariate-adjusted linear regression and linear mixed-effects models with participant random intercepts, adjusted for baseline age, sex, education, and APOE ε4 status. Vascular models were additionally refitted with body mass index, systolic blood pressure, antihypertensive and antidiabetic medication use, smoking history, and estimated glomerular filtration rate. Baseline GFAP showed a robust stepwise elevation from CU to MCI to AD (56.3% higher in AD than CU,  = 1.7 × 10; area under the curve 0.82), whereas sTREM2 distributions overlapped across groups. VEGF and sVCAM-1 were higher in AD than CU (14.1%,  = 0.014; 14.7%,  = 0.002), with areas under the curve of 0.61 and 0.63 and more than 80% distribution overlap. GFAP increased by 4.50% per year in CU participants and sTREM2 by 2.99% per year, with no significant diagnosis-by-time interactions for either. Over a 12-month interval, sICAM-1 declined in CU participants, and this decline was attenuated in MCI and AD, while sVCAM-1 increased in CU participants and showed negative diagnosis-by-time interactions. The vascular longitudinal findings were unchanged by adjustment for cardiometabolic and renal covariates, by time-varying diagnosis, and by separating stable MCI from MCI-to-AD converters. Correlations among vascular markers were consistent and well estimated, whereas glial-vascular correlations were based on 64 to 94 overlapping participants and were not significant. Glial and vascular plasma biomarkers did not progress synchronously across the AD continuum. GFAP showed the strongest and most discriminating diagnosis-associated elevation. Vascular markers showed statistically robust but small group-level differences with no individual-level discriminative utility, and their divergent 12-month trajectories require replication over longer follow-up before they can be interpreted as stage-dependent regulation.

Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive decline, with core pathological mechanisms including β-amyloid (Aβ) deposition, tau protein hyperphosphorylation, neuroinflammation, and impaired synaptic plasticity. Although exercise has neuroprotective effects, the molecular mechanisms by which it mediates peripheral-central communication remain unclear. The concept of the 'muscle-brain dialogue' offers a new perspective on this process. irisin, secreted by skeletal muscle in response to exercise, forms a molecular link between peripheral exercise and central neuroprotection by specifically regulating brain-derived neurotrophic factor (BDNF). This review summarizes the molecular cascade mechanisms of the irisin-BDNF axis in mediating the muscle-brain dialogue: Irisin is synthesized via the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)/fibronectin domain-containing protein 5 (FNDC5) pathway. Current evidence suggests that peripheral irisin may communicate with the central nervous system through mechanisms related to the blood-brain barrier, including potential αVβ5 integrin-mediated interactions, thereby participating in the regulation of BDNF. As a core effector molecule, BDNF improves cognitive decline in AD by enhancing neuroplasticity, reducing Aβ deposition, inhibiting tau hyperphosphorylation, and alleviating neuroinflammation. However, oxidative stress and mitochondrial dysfunction associated with AD pathology negatively regulate this axis, creating a vicious cycle. Therefore, this paper explores potential intervention strategies and the prospects for future translational research, including upstream exercise interventions, midstream barrier-crossing enhancing peptides, and downstream small-molecule TrkB agonists. Targeting this axis provides a new theoretical foundation and translational direction for the early prevention and treatment of AD, as well as for drug development.

Recent evidence suggests that prenatal environmental factors, particularly maternal infection or maternal immune activation (MIA), may influence the progression of brain aging and lifetime risk for neurodegenerative disorders. The hypothesis is that even a short-lived inflammatory event during pregnancy may leave a lasting imprint on the developing brain and immune system of the fetus, such that aging or subsequent insults may later unmask neurodegenerative disorders. Support for this hypothesis comes largely from animal studies, where gestational inflammation has been shown to potentiate the onset of Alzheimer's and Parkinson's diseases (AD/PD), by increasing amyloid/tau pathology, reducing synaptic connections, and damaging nigrostriatal dopaminergic neurons. We review convergent mechanisms, including microglial priming, chronic cytokine excess, oxidative stress, epigenetic marks and proteostatic deficits, through which maternal immune activation may embed a latent "hit" that synergizes with aging to precipitate AD or PD. Furthermore, we appraise experimental models and available human data linking MIA to AD versus PD, noting shared and distinct pathways. Despite growing preclinical evidence, translation to human cohorts remains limited by heterogeneity in MIA exposure timing and outcome measures. An understanding of MIA's impact on neurodegeneration could suggest preventive strategies and interventions for early diagnosis and treatment.

Progressive mitochondrial dysfunction coupled with calcium dyshomeostasis is a hallmark of aging and neurodegenerative conditions, yet the molecular links to cognitive decline remain unclear. Moreover, although sex differences in susceptibility to neurodegeneration are well recognized, their molecular basis remains poorly defined. In our previously engineered mouse model, systemic depletion of Tusc2 (Fus1), a mitochondrial calcium-regulatory protein, accelerates aging and recapitulates key features of human aging, including sex-specific cognitive decline. Here, we identify Tusc2 as a key modulator of hippocampal (HP) resilience to aging. To define the impact of Tusc2 loss on molecular determinants of cognition, we profiled HP transcriptomes in both sexes and proteomes in males at 4 months of age, when sex-specific differences in cognitive behavior first emerge. Male knockout HP exhibited broad mitochondrial dysfunction, including suppression of oxidative phosphorylation (OxPhos) proteins, activation of the ATF4 branch of the integrated stress response (ISR), and coordinated downregulation of translational, proteasomal, and synaptic pathways. These molecular alterations were accompanied by increased protein aggregate size, consistent with impaired proteostatic capacity, and reduced PSD-95 neuropil intensity, indicative of compromised synaptic integrity in the HP. In contrast, female knockout HP exhibited comparatively modest transcriptional alterations and preferential activation of adaptive ATF6-associated unfolded protein response (UPR) pathways, consistent with a protective response that may be influenced by estrogen signaling, sex chromosome complement, epigenetic regulation, and other sex-dependent mechanisms. Comparative analysis with aging human HP datasets revealed significant and broad overlaps, suggesting that Tusc2 deficiency recapitulates key molecular features of human brain aging. Together, these findings identify TUSC2 as a principal regulator of mitochondrial calcium homeostasis that contributes to maintenance of proteostatic and synaptic integrity of the HP during aging, and reveal marked sex differences in mitochondrial stress resilience. These results establish Tusc2 deficiency as a mechanistically defined model for investigating early, potentially reversible stages of mitochondrial and proteostatic decline in brain aging.

OBJECTIVE: To evaluate the diagnostic performance, internal consistency, and construct validity of the Spanish Stanford Proxy Test for Delirium (S-PTD) in non-intubated critically ill Mexican patients admitted to intensive and intermediate care units. BASIC PROCEDURES: We conducted a single-site cross-sectional psychometric study in adult patients admitted to intensive care and intermediate care units within the first 48 hours of admission. Trained nursing staff administered the Spanish S-PTD at the end of the clinical shift, and results were compared with an independent delirium assessment performed by consultation-liaison psychiatrists using DSM-5 criteria. Patients with endotracheal intubation or Richmond Agitation-Sedation Scale (RASS) scores ≤ -3 were excluded by protocol. Diagnostic accuracy, receiver operating characteristic curve performance, internal consistency, and exploratory factor structure were examined. MAIN FINDINGS: A total of 120 patients were analyzed. Mean age was 62.5 ± 18.1 years, 64 (53.3%) were men, and 87 (72.5%) were admitted for medical conditions. DSM-5 delirium was identified in 21 patients (17.5%), whereas 27 patients (22.5%) screened positive using the S-PTD cutoff of ≥3. At this cutoff, the S-PTD demonstrated an AUC of 0.87, accuracy of 88.3% (95% CI, 81.4%-92.9%), sensitivity of 81.0% (95% CI, 60.0%-92.3%), specificity of 89.9% (95% CI, 82.4%-94.4%), positive predictive value of 63.0% (95% CI, 44.2%-78.5%), and negative predictive value of 95.7% (95% CI, 89.5%-98.3%). Internal consistency was high (Cronbach's α = 0.948). Exploratory factor analysis provided preliminary evidence supporting construct validity and a predominantly unidimensional structure (KMO = 0.84; Bartlett's test p < .001). The first factor had an eigenvalue of 7.71 and explained 64.2% of the variance, whereas the second eigenvalue was 0.97. PRINCIPAL CONCLUSIONS: In this non-intubated ICU/IMCU Mexican cohort, the Spanish S-PTD demonstrated promising diagnostic accuracy and psychometric properties when administered by trained nursing staff. Findings should be interpreted cautiously because of the single-site design, limited number of delirium cases, exclusion of mechanically ventilated and moderately/deeply sedated patients, absence of formal inter-rater reliability testing, and the small number of patients with documented cognitive impairment or dementia. Further multicenter studies, including mechanically ventilated patients, are needed before broad implementation in critically ill populations.

Missense mutations in UBQLN2 are linked to dominant inheritance of amyotrophic lateral sclerosis (ALS) which is frequently accompanied by frontotemporal dementia (FTD). The encoded UBQLN2 protein functions to maintain proteostasis, collapse of which is increasingly being realized as the cause of many neurodegenerative diseases. During investigations of our UBQLN2 mouse models of ALS/FTD, we observed a significant decline in Tank-binding kinase 1 (TBK1) protein in end-stage mice. The decline could be significant, as haploinsufficiency of TBK1 expression is linked to ALS/FTD. To determine whether the reduction in TBK1 levels is responsible for driving pathogenesis, we crossed P497S UBQLN2 transgenic (Tg) mice with BacTBK1 Tg mice that overexpress TBK1 and analyzed the progeny for signs of pathology. The analysis revealed that double transgenic mice had a significant reduction in neurodegeneration in both the brain and spinal cord (SC) compared to P497S single-Tg mice. Double immunofluorescence staining of P497S mouse tissue revealed TBK1 colocalizes with UBQLN2 aggregates in spinal motor neurons. Biochemical extraction studies of mouse brain tissue revealed increased enrichment of TBK1 along with wild type and mutant UBQLN2 proteins in detergent-insoluble material, suggesting TBK1 gets sequestered by UBQLN2 aggregates. GST-pulldown assays revealed that UBQLN2 binds directly with TBK1, but paradoxically the P497S mutation was found to reduce TBK1 binding. Turnover studies indicated that loss of UBQLN2 destabilizes TBK1, providing another route for its reduction. These findings lead us to propose that efforts directed toward increasing TBK1 expression may provide a therapeutic approach for treating ALS/FTD caused by UBQLN2 mutations.

Neuropsychiatric symptoms can emerge early in Alzheimer's disease (AD), but whether innate fear is altered prior to amyloid plaque deposition remains unclear. This study aimed to examine innate fear responses in young adult male APP/PS1 mice and to evaluate whether D-cycloserine (DCS) rescues such deficits via GluN2B-containing NMDA receptors. Male APP/PS1 mice (2-3 months old) exhibited impaired innate fear responses in the looming disk test, while their motor function and contextual fear memory remained intact. Hippocampal Grin2b expression was reduced in the APP/PS1 mice. DCS restored normal fear responses, an effect blocked by GluN2B antagonists but unaffected by GluN2A inhibition. Our results demonstrate that innate fear deficits emerge early in male APP/PS1 mice and are rescued by DCS through activation of hippocampal GluN2B-containing NMDA receptor, highlighting a potential target for early AD-related neuropsychiatric symptoms.

Mitophagy and mitochondrial quality-control pathways are impaired in Alzheimer's disease (AD), but the relevance of peripheral mitophagy markers and their regulation during sustained amyloid-β (Aβ) stress remain unclear. We investigated whether serum optineurin, a mitophagy receptor, is altered in mild cognitive impairment (MCI) and AD, and explored mitophagy dynamics in an in vitro model of Aβ-induced mitochondrial stress. To achieve this aim, serum optineurin was measured in 458 older individuals, including controls and patients with AD, mild cognitive impairment (MCI), and mixed Alzheimer's disease/ vascular dementia (MIXED). Complementary in vitro experiments were performed in SH-SY5Y neuroblastoma cells exposed to Aβ over time, to evaluate mitochondrial function, oxidative stress, lipid peroxidation, lactate release, Parkin/optineurin recruitment, mitophagy, mitochondrial quality-control markers, apoptosis, and cell viability. Serum optineurin was markedly lower in MCI and AD groups than in controls (p < 0.001 for both) and was also reduced in MIXED (p < 0.001). Serum 4-HNE was increased in MCI and AD, consistent with systemic oxidative stress. In vitro, Aβ induced an early increase in mitophagy and optineurin expression, followed by a later decline associated with impaired mitochondrial quality-control markers, apoptotic activation, and reduced cell viability. In conclusion, optineurin emerges as a candidate peripheral biomarker associated with AD and MCI. In vitro, Aβ exposure was associated with an early increase in mitophagy-related responses followed by progressive mitochondrial dysfunction, oxidative stress, apoptotic activation, and reduced cell viability. These findings support the relevance of optineurin within mitochondrial quality-control pathways under AD-related stress.

BACKGROUND: Drivers of frequent emergency department (ED) presentations and patient-reported care experiences for older adults remain unclear. METHOD: A retrospective population-based cohort study of adults aged ≥65 years in New South Wales, Australia, using linked hospital and mortality records and patient-reported ED care experiences. Individuals with an index ED presentation in 2018 who survived the ascertainment period were followed for five years. ED presentation frequency during the remainder of 2018 was classified as low (1-3 ED presentations) or frequent (≥4 ED presentations). Demographic and clinical characteristics were compared. Generalised estimating equation and survey logistic regression models identified factors associated with frequent presentation and negative care experiences. RESULTS: There were 336,283 index presentations in 2018; 10.6% were frequent presenters, mostly aged 75-84 years (38.3%). Frequent ED use was more common among those aged 75-84 years in the first four years (ORs 1.06; 95%CI 1.01-1.11 to 1.27; 95%CI 1.23-1.31) and those aged ≥85 years in the first year (OR 1.33; 95%CI 1.28-1.38). Multimorbidity, rurality, living in aged care, and triage below resuscitation were associated with frequent presentations. Female, dementia, osteoporosis, frailty, non-urgent presentation, and hospitalisation were associated with lower odds of frequent presentation. For patient experience (n=47,461), negative ED experience was associated with long waits (≥60 minutes; OR 1.70; 95%CI 1.19-2.42), complications (OR 1.63; 95%CI 1.16-2.28), and poor communication or involvement in decisions, with insufficient treatment information showing the strongest association (OR 5.17; 95%CI 3.48-7.69). CONCLUSIONS: Frequent ED use in older adults reflects persistent issues in complex health and social needs, communication and shared decision-making.

The ABCC9 gene and its cognate protein SUR2 play important roles in neurovascular coupling and are implicated in hippocampal sclerosis of aging (HS-Aging). However, prior studies have not focused on human brain SUR2 expression or SUR2 in glial cells. Here we analyzed cell type-specific ABCC9/SUR2 expression patterns, and correlation with known genetic risk variants, using multiple data sets and a novel antiserum. Existing single-nucleus RNA sequencing data sets and new spatial transcriptomics data indicated that SUR2 transcripts were expressed primarily in human brain pericytes, astrocytes, smooth muscle cells, and endothelial cells. Evaluation of Sur2 expression in a sample of mice brains showed similar results except Sur2 was not detected in the mice astrocytes. In a SUR2-enriched subcluster of human astrocytes, the pattern of transcript expression suggested responsiveness to thyroid hormone signaling: SUR2-correlated gene products were enriched for thyroid hormone-sensitive transcripts and SLCO1C1, the astrocyte thyroid hormone importer, was the transcript with the strongest correlation with SUR2 expression. Cells in the SUR2 + astrocyte cluster tended to have been derived from individuals lacking severe Alzheimer's disease pathology. An ABCC9 single nucleotide variant (rs1914361, also a HS-Aging risk allele) was associated with increased SUR2 expression in astrocytes, but not other cell types. SUR2 mRNA splicing differed between cell types; astrocytes preferentially expressed the SUR2B variant. A novel SUR2 antiserum immunolabeled blood vessel walls and some astrocyte-morphology cells in human brain. Overall, human brain SUR2 expression was enriched among different cell types of the gliovascular unit. A SUR2-enriched, possibly-homeostatic astrocyte subcluster suggested connections to thyroid hormone signaling.

The search for effective therapeutics that can bring hope to patients and families affected by rare prion diseases is ongoing. Self-propagating, misfolded proteins underlie a broad range of neurodegenerative disorders that include prion diseases as well as more common conditions such as Parkinson's and Alzheimer's disease. Byron Caughey was a pioneer in the field of prion therapeutic discovery. His seminal contributions in drug development included elucidating disease biochemistry, understanding the need to target conformational changes, and developing cell-free conversion assays to monitor protein misfolding in real time. These advances laid the foundation for therapeutic strategies aimed at preventing, slowing or reversing the conversion of native protein into a pathogenic, seed-competent conformer and/or its assembly into amyloid fibrils. Within the Caughey laboratory, small molecule inhibitors targeting the misfolded prion, the process of conversion and aggregation, or stimulating disassembly were studied intensively. More recent approaches targeted the relocation, removal or downregulation of the normal protein substrate. These efforts in combination with high-resolution structural characterization of the infectious prions now offer new opportunities for intelligent drug design. Equally important to drug discovery have been advances in the development of sensitive and reliable methods to detect the agent and its clearance, which is necessary to validate that putative treatments are efficacious. Herein, we highlight 4 decades of Byron Caughey's contributions and dedication to the search for anti-prion therapeutics.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive impairment, synaptic malfunction, oxidative stress, cholinergic deficits, and a lack of effective disease-modifying therapeutics. In this study, we integrated in silico approaches with network pharmacology to identify novel multi-target ligands against three key AD-associated proteins: acetylcholinesterase (AChE), protein kinase B (AKT1), and monoamine oxidase B (MAO-B). Structure-based e-pharmacophore modeling and virtual screening were conducted using Pharmit, a large compound library from the ZINC and COCONUT databases, followed by stringent ADMET filtering to obtain drug-like candidates. Network pharmacology analysis identified AKT1 as the best hub gene between predicted hit compounds and AD-associated gene-enriched pathways, such as PI3K-Akt, FoxO, calcium, and cAMP signaling pathways. Four hits (1-4) were screened for binding affinity evaluation using molecular docking, followed by MM-GBSA, and molecular dynamics (MD) simulations. Hit1 (N-(2-(1H-indol-3-yl)ethyl)-7-hydroxy-5,6-dimethoxy-[1,2,4]triazolo[4,3-a]quinazoline-3-carboxamide) (ZINC000033435965) demonstrated the strongest binding affinities across all complexes, with docking scores of - 11.4, - 11.8, and - 12.1 kcal/mol for hAChE, AKT1, and MAO-B, respectively. MD simulations over 100 ns for Hit1 revealed stable interaction as described by RMSD, RMSF, Rg, SASA, and HB profiles. E-pharmacophore and validation demonstrated strong predictive performance across the complexes, especially for AKT1 and MAO-B with high enrichment factors and ROC-AUC values (0.95 and 0.94). Additionally, DFT analysis of Hit1 revealed a favorable electronic stability energy (- 1479.283992 Eh). ADMET profiling predicted favorable oral bioavailability, BBB permeability, drug-likeness, and low predicted toxicity. The findings of this study suggest that Hit1 could be a promising multi-target molecule capable of modulating cholinergic transmission, neuronal survival pathways, and oxidative stress in AD. Experimental validation, including in vitro enzymatic assays and in vivo evaluations, is essential to further establish the therapeutic potential of Hit1.

BackgroundSubjective cognitive impairment (SCI) predicts Alzheimer's disease and related dementias (ADRD). Identifying SCI correlates may identify cognitive risk earlier in the ADRD continuum. We examined SCI correlates among older non-Hispanic Black (NHB) and non-Hispanic White (NHW) men.MethodCross-sectional data were from 669 men in the 2012 National Health and Aging Trends Study. Logistic regression was used to identify SCI correlates, accounting for complex sampling and attrition.ResultHigher education (OR = 0.33, 95% CI: 0.13-0.87) and former smoking (OR = 0.38, 95% CI: 0.16-0.91) were associated with lower SCI odds. Sleep difficulties (OR = 2.81, 95% CI: 1.22-6.47), multimorbidity (OR = 2.16, 95% CI: 1.09-4.29), and ADL disability (OR = 4.19, 95% CI: 2.03-8.61) were associated with higher odds.DiscussionEducation, smoking status, sleep, multimorbidity, and functional status may be important SCI correlates among older NHB and NHW men. Addressing modifiable correlates may support cognitive health earlier in the ADRD continuum.

Brain-age estimates the brain's biological age from neuroimaging data and has been proposed as a biomarker of brain health and disease risk. While brain-age estimation commonly uses high-field (HF) magnetic resonance imaging (MRI) ( T), this is costly and inaccessible, limiting its applicability. Emerging ultra-low-field (ULF) MRI ( T) is cheaper and more accessible, but its lower resolution may limit the reliability of biomarkers such as brain-age. We assessed different brain-age pipelines in 23 adults scanned on one HF system (GE Signa Premier at 3 T) and two identical ULF systems (Hyperfine Swoop at 64 mT) located at two different sites, hereafter referred to as ULF1 and ULF2. We used 14 distinct acquisitions defined by T1- or T2-weighting, resolution, and preprocessing: raw anisotropic orientations (axial, coronal, sagittal), isotropic scans, and super-resolution derivatives from multi-resolution registration (MRR) and SynthSR. These inputs (a total of = 573 scans) were analyzed with five brain-age software packages (BrainageR, SynthBA, MIDI, DeepBrainNet, PyBrainAge). Performance evaluation entailed validity (brain-age vs. actual age), correspondence (ULF brain-age vs. HF brain-age) and test-retest reliability (ULF1 brain-age vs. ULF2 brain-age). Overall, results were mixed across pipelines, although several ULF pipelines performed comparably to HF. The four best-performing combinations were SynthBA on T2 scans without SynthSR, MIDI on T2 scans without SynthSR, PyBrainAge on T1 scans with SynthSR and using FreeSurfer recon-all-clinical, and BrainageR on T1 scans with SynthSR. These showed moderate-to-strong validity ( -0.92, -0.64, Mean Absolute Error [MAE] -8.21 years), moderate-to-strong correspondence to HF ( -0.93, Intraclass Correlation Coefficient [ICC] -0.92), and excellent test-retest reliability ( -0.99, ICC -0.99). Moreover, some anisotropic acquisitions achieved comparable validity and reliability to MRR images when tested with the best-performing model, SynthBA ( -0.62, ICC [CI] [0.97-1.00], for coronal T2). This first systematic evaluation of brain-age at ULF demonstrates that accurate and reliable estimates can be achieved across multiple pipelines, without necessarily requiring image enhancement. Performance depended on the combination of model, scan type, and preprocessing. ULF brain-age estimation could be a practical and scalable tool for clinical decision-making, population research, and long-term patient monitoring, thereby helping to make advanced neuroimaging biomarkers more accessible worldwide.

The number of older adults living with dementia in the United States and worldwide continues to rise. Identifying elevated dementia risk decades before potential onset can help individuals prepare and enable healthcare providers and policymakers to target resources that may delay onset or mitigate consequences. Using nationally representative data from the U.S. Health and Retirement Study (1992-2016), we estimated the probability of dementia at around age 80 as a function of 110 risk factors measured at around age 60, using a recently developed and validated probabilistic dementia measure and longitudinal regression models. Poor physical health, low cognitive ability, fewer than 12 years of education, and greater functional limitations at around age 60 were the strongest predictors of dementia at age 80. Additional predictors included being born in the Southeastern U.S., lacking private health insurance, non-veteran status, having poor vision or hearing, limited work history, disability, diabetes, body mass index ≥ 35, prior stroke, and both alcohol abstention and heavy drinking. Several predictors, such as geographic origin, veteran status, and work history, have received limited attention in prior prediction research. Future research should examine whether these candidate predictors represent causal risk factors rather than simply associations.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and neuronal loss, primarily associated with β-amyloid plaque deposition, tau hyperphosphorylation, and cholinergic dysfunction. Since the disruption of cholinergic neurotransmission is a key pathological feature of AD, the cholinesterase (ChE) inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) remain the mainstay of symptomatic treatment by enhancing synaptic acetylcholine levels. However, the currently approved small molecules, including tacrine, donepezil, rivastigmine, and galantamine, are limited by their modest efficacy, poor selectivity, and adverse effects, necessitating the development of improved therapeutic agents. Among emerging scaffolds, isatin (1-indole-2,3-dione) has attracted considerable research attention owing to its structural versatility, synthetic accessibility, and favorable pharmacological properties. Recent studies have reported diverse isatin-based derivatives, including hydrazones, Schiff bases, thiosemicarbazones, spirooxindoles, and molecular hybrids, exhibiting potent AChE and BChE inhibitory activities, often in the submicromolar or nanomolar ranges. Structure-activity relationship studies have revealed the critical influence of electronic effects, linker optimization, -substitution, and molecular hybridization on inhibitory potency and selectivity. This review summarizes the most promising isatin-based cholinesterase inhibitors reported from 2020 to the present, highlighting their biological activities, structure-activity relationships, and potential for the development of next-generation anti-Alzheimer therapeutics.

INTRODUCTION: The precuneus (Pc) is a central hub integrating diverse brain functions, and it is early involved in Alzheimer's disease (AD) pathophysiology, yet its subregional vulnerability remains poorly understood. This study aims to delineate the differential involvement and vulnerability of these subdivisions in the early stages of AD. METHODS: We conducted a resting-state FC analysis of Pc subregions in 32 cognitively unimpaired carriers of the PSEN1 E280A mutation compared to 25 noncarriers using seed-based analyses. RESULTS: As compared to noncarriers, we found that the group of asymptotic carriers had increased connectivity from the 7Am subregion toward the entorhinal cortex, superior temporal gyrus, insula-operculum, dlPFC, and somatosensory areas. Moreover, the POS2 subregion significantly decreased connectivity with the anterior insula and dlPFC. Higher MoCA scores correlated with increased connectivity within and between the Pc and frontoparietal networks. DISCUSSION: These results reveal distinct patterns of early functional reorganization and support the subregional Pc analysis in identifying sensitive biomarkers for preclinical AD, often overlooked in conventional whole-region analyses.

Dementia caregiving is associated with elevated psychological distress, yet limited research has examined how caregiving demands shape mental health among East Asian American caregivers, a rapidly growing but understudied population. Guided by the stress process framework, this study examined three temporal dimensions of objective caregiving demands - time intensity, frequency, and chronicity - and their associations with subjective caregiving demands and depressive symptoms among older East Asian American caregivers of individuals living with Alzheimer's disease and related dementias (AD/ADRD). Survey data were collected from 82 East Asian American caregivers aged 50 years or older who were providing care to individuals with dementia in the United States. Participants were recruited through community-based organizations and ethnic community settings. Ordinary least squares regression models were estimated to examine associations among temporal caregiving demands, subjective caregiving demands, and depressive symptoms. An exploratory post hoc structural equation model was also estimated to examine indirect associations. Caregivers in this sample reported substantial caregiving involvement, averaging more than 10 hours of care per day, five days per week, over a period exceeding five years. In adjusted regression models, time intensity and chronicity were not directly associated with depressive symptoms, while caregiving frequency was negatively associated with depressive symptoms. Subjective caregiving demands were strongly and positively associated with depressive symptoms. Temporal caregiving demands were positively associated with subjective caregiving demands when examined separately. An exploratory post hoc analysis suggested that chronicity was indirectly associated with depressive symptoms through subjective caregiving demands. Findings suggest that the mental health implications of dementia caregiving may depend less on objective time exposure alone and more on caregivers' subjective appraisal of caregiving demands. Culturally and linguistically responsive interventions should address perceived caregiving burden, improve access to formal support, and attend to the long-term caregiving experiences of East Asian American dementia caregivers.

We performed machine learning analysis of population data to determine the major determinants of 1-year mortality among geriatric patients undergoing hip arthroplasty. The data of 17,290 patients aged ≥ 65 years who underwent hip arthroplasty in 2019 were extracted from the Korea National Health Insurance Service claims database. With 1-year mortality as the dependent variable, random forest variable importance and Shapley Additive Explanations (SHAP) were used to identify the major predictors among 31 included predictors and their associations with mortality. The area under the curve of the random forest model was 74.6%. The top 10 predictors were age, red blood cell transfusion, male sex, dementia, low socioeconomic status, presence of solid tumors, history of congestive heart failure, history of chronic kidney disease, statin use, and history of peripheral vascular disease. Univariate analysis and SHAP analysis identified age (maximum SHAP value 0.17), red blood cell transfusion (0.10), male sex (0.09), dementia (0.04), low socioeconomic status (0.03), presence of solid tumors (0.06), history of congestive heart failure (0.04), history of chronic kidney disease (0.05), general anesthesia (0.02), and iron use (0.02) as positive contributors to model predictions of mortality. Higher SHAP values indicate greater contributions to model output relative to the baseline prediction. We constructed an effective prediction model for predicting mortality among patients undergoing hip arthroplasty. Appropriate interventions should be provided for high-risk patients (i.e., advanced age, multiple comorbidities, or anticipated transfusion needs).

BACKGROUND AND PURPOSE: Degeneration of the pontine noradrenergic and midbrain dopaminergic systems contributes to cognitive-behavioural disturbances during the prodromal stages of Alzheimer's disease (AD). We developed a genetically engineered, programmable probiotic Escherichia coli Nissle 1917 strain (EcN ) capable of producing L-3,4-dihydroxyphenylalanine (L-DOPA) in a sustained and titratable manner, thus offering a novel gut-brain delivery mechanism to increase brain levels of noradrenaline and dopamine during the early stages of AD. EXPERIMENTAL APPROACH: We replicated locus coeruleus (LC) projection system degeneration in AD by administering dopamine-β-hydroxylase IgG-saporin immunotoxin into the prefrontal cortex of 6-months-old Tg344-19 AD rats. The animals then received EcN /benserazide or placebo by daily gavage for 6 weeks. We assessed cognitive-behavioural function prior to postmortem assessments of amyloid-β plaque load, glial cell activation and neuronal and synaptic markers. Gut colonization, along with plasma and brain L-DOPA, dopamine, noradrenaline and metabolite levels, were also measured. KEY RESULTS: EcN displayed stable gut colonization and resulted in sustained therapeutic levels of L-DOPA in plasma and brain, resulting in increased cortical and hippocampal noradrenaline levels. EcN reduced anxiety-like behaviour improved spatial and working memory. The treatment reduced forebrain Aβ plaque and MHC-II antigen-presenting microglial load. Additionally, EcN increased protein levels of the dendritic spine marker PSD95. CONCLUSIONS AND IMPLICATIONS: This translational study suggests that EcN modifies AD by boosting brain catecholamine production, reducing Aβ accumulation and neuroinflammation, promoting synaptic health, and enhancing cognitive function. Collectively, these results highlight EcN as a promising preclinical engineered gut microbiome-based therapeutic strategy for early-stage AD.

Alzheimer's disease (AD) biomarkers may be associated with decline in non-cognitive domains of intrinsic capacity (IC), but such evidence has not been synthesized. This narrative review, based on a structured PubMed search (last search: December 31, 2025), included 119 human studies examining associations of core AD biomarkers (e.g., amyloid-beta (Aβ) and tau protein) and biomarkers of non-specific processes involved in AD pathophysiology (including neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), structural magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography (FDG-PET)) with composite IC scores and non-cognitive IC domains. Among included studies, 2 investigated composite IC scores, 49 depressive symptoms, 30 locomotion, 29 hearing impairment, 19 vitality, and 1 vision impairment. The very limited longitudinal evidence on composite IC scores suggests that lower IC was associated with increased p-tau181 levels and that higher baseline NfL predicted steeper IC decline, whereas plasma Aβ42/Aβ40 showed no clear association. At the IC domains' level, higher cerebral Aβ deposition was associated with poorer locomotion, especially slower gait, more consistently than other biomarker modalities. Higher levels of tau biomarkers and NfL were more often associated with lower or declining handgrip strength. Depressive symptoms represented the most investigated non-cognitive IC domain, showing consistent longitudinal associations with lower fluid Aβ42, greater cerebral amyloid deposition, and subsequent brain atrophy. Hearing impairment was linked mainly to higher tau and NfL, reduced glucose metabolism, and brain atrophy; evidence for vision impairment was almost totally absent. Overall, the pattern of associations varied by biomarker modality, IC domain, and study design, suggesting that AD-related pathology and neurodegeneration have functional correlates beyond cognition. Methodological quality, formally appraised with the Newcastle-Ottawa Scale and the JBI checklist, was acceptable for most included studies.

The ability to initiate stepping promptly and accurately is critical for safe mobility in later life. Choice stepping reaction time (CSRT) is an independent predictor of recurrent falls in older adults and is often prolonged in dementia. Although the prefrontal cortex (PFC) is crucial for rapid response execution, existing studies primarily focus on regional activation, leaving the topological reorganization of prefrontal functional networks poorly understood. In this study, twenty-six healthy older adults (HOAs) and 25 older adults with mild-to-moderate dementia (MMD) completed four blocks each of a simple stepping task and a choice stepping task in randomized order. Prefrontal hemodynamic responses were recorded using a 48-channel functional near-infrared spectroscopy (fNIRS) system. We quantified task-evoked regional activation and derived graph-theoretic network metrics within the PFC. Finally, we investigated their associations with CSRT. Compared with HOAs, the MMD group showed higher right DLPFC activation during simple stepping (p = 0.005), yet the activation decreased from simple to choice stepping (p = 0.032) in MMD. Graph analysis revealed a significantly greater prefrontal clustering coefficient (C) in MMD (p = 0.005) compared with HOAs, whereas other global network metrics were comparable between groups. Moreover, higher C during choice stepping was associated with shorter CSRT (r = -0.55, p = 0.021) in MMD, suggesting that greater prefrontal network segregation may correlate with faster stepping reaction time. Our findings suggest altered task-evoked prefrontal activation alongside localized topological reconfiguration in older adults with dementia, with greater prefrontal network segregation linked to faster volitional stepping execution.