BACKGROUND: Digital health technology has the potential to increase access to home-based reablement programmes for people living with dementia (PLwD) or mild cognitive impairment (MCI) to support everyday living. Digital Voice Assistants (DVAs) offer a possible solution to overcome usability issues with traditional technologies due to associated cognitive, motor and visual impairments. This paper describes the co-design of a personalised reablement programme to be delivered via DVA. METHODS: PLwD or MCI (n = 9), their care partners (n = 9) and health professionals (n = 8) participated in the co-design via online workshops and semi-structured interviews. Phases 1-7 of the IDEAS (Integrate, Design, Assess and Share) framework guided this iterative process to develop a product for future feasibility testing. Consensus on essential functions and features was facilitated using the MoSCoW prioritisation method. Transcripts were analysed using a modified thematic framework to inform the reablement programme. RESULTS: Thematic requirements of a cognitive reablement program to be delivered via DVA included (1) Daily Living (self-care, household and cooking), (2) Activity Participation (leisure activities, home hobbies and ad hoc appointments), (3) Emotional Well-being (social connection and coping strategies) and (4) technical requirements (activation, adaptable content, adherence, auditory processing, awareness and training). CONCLUSIONS: The IDEAS framework successfully facilitated meaningful engagement from PLwD or MCI, their care partners, and health professionals to integrate user insights and feedback to co-design a personalised reablement program via DVA for subsequent pilot feasibility testing. PATIENT OR PUBLIC CONTRIBUTION: PLwD and/or MCI, and their care partners contributed by sharing lived experiences for researchers to gain insights; collaboratively identifying behaviours requiring support; creating ideas for solutions; feeding back on prototypes and prioritising program features and functions. Health professionals fed back improvements on prototypes, identifying potential barriers and solutions to implementation of the program.

INTRODUCTION: No published studies have evaluated the application of Generative Pre-trained Transformer-5 (GPT-5) in the analysis of memory clinic patient clinical notes or the interpretation of plasma phosphorylated tau (P-tau) 217 values. We compared Alzheimer's disease (AD) probability estimates generated by GPT-5 before and after incorporating plasma P-tau 217 with pre- and posttest probabilities. METHODS: This was a retrospective study comprising 74 patients from a memory clinic in Queen Mary Hospital, Hong Kong. Final diagnoses were made by physicians, supported by medical history, physical examination, neuroimaging and amyloid positron emission tomography. Extracted clinical data included cognitive, functional and neuropsychiatric assessments. Pretest AD probabilities were derived from a published meta-analysis, while posttest probabilities were calculated using a Bayesian approach. These values were compared with those estimated by GPT-5. The diagnostic performance of GPT-5 and physicians was assessed using accuracy and Kappa coefficient, with final diagnosis as reference. RESULTS: There were 40 amyloid-positive (A+) and 34 amyloid-negative (A-) patients. In A+ patients, Bayesian posttest probabilities were higher than GPT-5 estimates (median 97.0% vs. 80.0%, P = 0.003), while those of A- patients were lower than GPT-5 estimates (median 3.0% vs. 27.5%, P < 0.001). With application of plasma P-tau 217, physicians achieved higher diagnostic accuracy than GPT-5 (81.1% vs. 45.9%, P < 0.001), while GPT-5 suggested mixed aetiologies more frequently (23.0% vs. 8.1%, P = 0.04) and inappropriate anti-amyloid therapy in 31% (11/36) of scenarios. CONCLUSION: Our findings show that GPT-5 has limitations in analysing clinical information of real-life memory clinic patients.

UNLABELLED: Alzheimer's disease (AD) remains a debilitating neurodegenerative disorder with limited therapeutic options, necessitating novel approaches to target its underlying mechanisms. The NLRP3 inflammasome has emerged as a critical player in AD pathogenesis, driving neuroinflammation and amyloid-beta aggregation, yet existing inhibitors face challenges such as hepatotoxicity and poor blood-brain barrier (BBB) penetration. We conducted a computational drug repurposing study to identify FDA-approved drugs with NLRP3 inhibitory potential and favourable BBB permeability. Using molecular docking we screened a library of 2600 FDA approved compounds against the NLRP3 structure (PDB ID:8WSM), followed by molecular dynamics (MD) simulations and binding free energy calculations to validate top hits. Our results identified Flavoxates as the most promising candidate, exhibiting a high docking score (- 10.241 kcal/mol) and stable binding affinity (- 52 kcal/mol via MMPGBSA). MD simulations confirmed its robust interaction with NLRP3, demonstrating low RMSD (0.168 +/- 0.019 nm) and RMSF (0.088 +/- 0.035 nm) values over 100 ns. Moreover, Flavoxate showed optimal pharmacokinetic properties, including BBB permeability and low toxicity, as predicted by SwissADME and ProTox 3.0 The study highlights the efficacy of in silico methods in accelerating drug repurposing, bypassing the need fo de novo drug development. By repurposing Flavoxate, we propose a clinically translatable strategy to mitigate NLRP3-mediated neuroinflammation in AD, offering a potential disease modifying therapy with an established safety profile. This work underscores the significance of computational approaches in bridging the gap between preclinical discovery and therapeutic application for neurodegenerative diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-026-00696-3.

BACKGROUND: Diaphragmatic hernia in horses is a rare condition, most commonly presenting with signs of colic and, less frequently, respiratory compromise. Hepatic herniation through a diaphragmatic defect with secondary hepatic failure and encephalopathy has rarely been documented in horses. CASE PRESENTATION: A 5-year-old Mangalarga Marchador stallion was evaluated for progressive neurological deterioration, including obtundation, head pressing, ataxia, and circling. Serum biochemistry revealed severe hepatobiliary dysfunction, characterised by increased gamma-glutamyl transferase and alkaline phosphatase activities, hyperbilirubinaemia and hypertriglyceridaemia. The horse died within 12 h of admission. Post-mortem examination revealed a chronic pleuroperitoneal diaphragmatic defect with herniation of the left lateral, left medial, and quadrate hepatic lobes into the thoracic cavity. The herniated portion showed severe atrophy, haemorrhagic necrosis, cholestasis, and ductular proliferation, while the non-herniated hepatic mass exhibited bridging fibrosis and nodular regenerative remodelling. Histopathological examination of the brain confirmed the presence of Alzheimer type II astrocytes in the cerebral cortical grey matter, consistent with hepatic encephalopathy. CONCLUSIONS: This case documents an unusual manifestation of equine diaphragmatic hernia in which extensive chronic hepatic incarceration resulted in severe hepatobiliary dysfunction and hepatic encephalopathy. The findings suggest that diaphragmatic hernia with hepatic involvement should be considered in the differential diagnosis of horses presenting with severe hepatopathy and neurological signs compatible with hepatic encephalopathy, particularly when classical signs of colic are absent.

Alzheimer's disease (AD) is characterised by the intraneuronal aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles and by the extracellular deposition of β-amyloid (Aβ). Tau pathology restricted to the hippocampal formation is frequently observed in the elderly brain in the absence of any Aβ deposition and considered as "primary age-related tauopathy" (PART). Here, we applied an unbiased proteomic approach to determine how concomitant Aβ pathology modifies the neurofibrillary tangle proteome. Neurofibrillary tangles were isolated by dissecting Tau pSer202/pThr205 "AT8" immunopositive neuronal profiles, combining chromogenic immunohistochemistry with laser capture microdissection, from hippocampal sections of 17 post-mortem brains spanning three groups: PART (n = 5; A0, B1-2, C0 scores), intermediate AD (n = 6; A1-2, B2-3, C1-2 scores) and advanced AD (n = 6; A3, B3, C3 scores). A label-free quantitative liquid chromatography-mass spectrometry based proteomic analysis, using data independent acquisition (DIA) on a Bruker timsTOF, was performed. A conserved core of 63 proteins was identified as enriched in tangles across all groups, mostly associated with "RNA binding" and "regulation of mRNA metabolic process", based on the Gene Ontology database. Group-specific signatures were also observed: 33 proteins were significantly enriched only in tangles collected from PART cases and were predominantly linked to "structural molecule activity", whereas Aβ-positive cases showed specific enrichment of "RNA binding" and "cytoplasmic translation" pathways-with intermediate AD cases displaying a transitional profile. Our findings are consistent with PART having distinct tangle proteomic features; however, the majority of its proteomic signature is in common with tangles within the AD continuum. By addressing how Aβ accumulation alters the tangle proteome, this study provides mechanistic insights into the expansion of Tau pathology, paving the way towards the identification of biomarkers and therapeutic strategies that would allow for stabilisation of Tau pathology in the elderly.

This review delves into the advancements in Alzheimer's Disease (AD) research in China, focusing on insights, innovations, and future directions derived from the Chinese Preclinical Alzheimer's Disease Study (CPAS). With an aging population, AD prevalence has risen, increasing societal and economic burdens. CPAS, initiated in 2019, aims to identify early Alzheimer's pathology using plasma biomarkers and PET imaging. The study includes participants across the cognitive spectrum, including cognitively unimpaired individuals, patients with mild cognitive impairment (MCI), and patients with dementia, undergoing comprehensive assessments. Key findings include the impact of Aβ-PET on diagnosis and management, risk factors for amyloid pathology, and the expansion of biomarkers to include synaptic and other PET imaging markers. Future directions involve exploring disease-modifying therapies and applying multi-omics approaches to enhance the understanding and treatment of AD. These efforts are crucial for advancing personalized medicine and improving therapeutic outcomes in China and globally.

OBJECTIVE: People living with dementia (PLWD) take more medications than those without dementia, increasing their risk of medication-related harm, defined as any negative outcome related to medication use, encompassing both harm events and outcomes. This systematic review aimed to determine the prevalence of medication-related harm in PLWD and evaluate its impact across a range of outcomes. METHODS: Twelve databases were searched from inception to April 2025. Studies of any design reporting the prevalence and/or outcomes of medication-related harm in PLWD were included. Study quality was assessed using appropriate risk of bias tools. A meta-analysis was conducted to determine combined hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In total, 115 studies were included (110 observational, five randomised controlled trials). Most studies (n = 73) were at low risk of bias. Adverse drug events were the most commonly reported harm event (n = 92), with prevalence ranging from 2.5 to 93.0%. Adverse health outcomes were measured in 55 studies, with 32 reporting increased risk associated with medication use. Psychoactive medications were frequently implicated (n = 59 studies), with 43 reporting a link with negative outcomes. Six studies (n = 25,715 participants) were included in an exploratory meta-analysis, which suggested an association between antipsychotic use and increased mortality (HR = 1.42; 95% CI = 1.10-1.84; p = 0.008). CONCLUSIONS: This review provides a comprehensive synthesis of medication-related harm in PLWD, highlighting its breadth and complexity across care settings and medication classes. The findings support the need for improved medicines optimisation strategies, including medication review and deprescribing approaches, to reduce harm in this vulnerable population.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, neuroinflammation, and cholinergic dysfunction. Increasing evidence suggests that gut microbiota disturbances contribute to AD progression, encouraging the investigation of microbiota-modulating approaches such as probiotics and paraprobiotics. This study evaluated the effects of Lactobacillus casei probiotic and its thermally inactivated paraprobiotic on cognitive, behavioral, oxidative, cholinergic, and inflammatory alterations in a sporadic AD model induced by intracerebroventricular streptozotocin (STZ-ICV; 3 mg/3 μL/site) in female rats. From day 4, animals received daily oral treatment with probiotic L. casei (1 × 10 CFU), paraprobiotic (100 mg/kg), or saline for 14 days. Behavioral assessments of memory and exploratory activity were performed alongside biochemical analyses of oxidative stress markers, antioxidant defenses, acetylcholinesterase (AChE) activity, and neuroinflammatory parameters in central and peripheral tissues. STZ-ICV administration induced impairments in working and long-term memory, increased oxidative stress and neuroinflammation, elevated AChE activity, and promoted intestinal and behavioral alterations. Both probiotic and paraprobiotic treatments attenuated memory deficits, reduced lipid peroxidation, inhibited AChE activity, and decreased inflammatory markers. However, their effects differed in magnitude and tissue specificity. The probiotic mainly improved peripheral antioxidant defenses, whereas the paraprobiotic exerted broader neuroprotective effects, reducing cerebral oxidative stress, restoring non-enzymatic antioxidant levels in the hippocampus and colon, improving jejunal catalase activity, and attenuating hippocampal astrogliosis. These findings demonstrate that modulation of the gut-brain axis through L. casei-based interventions mitigates key pathological features of sporadic AD, with paraprobiotics emerging as a promising and stable alternative with enhanced neuroprotective potential independent of bacterial viability.

Ceramides (Cer) are lipid signaling molecules regulating cell proliferation, differentiation, senescence and apoptosis, whose metabolic disturbance disrupts organismal homeostasis. Accumulating evidence links ceramide imbalance to psychiatric and neurodegenerative diseases, yet few systematic reviews summarize subtype-specific ceramide functions. This review outlines ceramide anabolic and catabolic pathways, compares functional distinctions among ceramides with distinct acyl chain lengths, describes substrate preferences of ceramide metabolic enzymes, and introduces ceramide detection techniques. On this basis, we discuss regulatory roles and underlying molecular mechanisms of ceramides in schizophrenia, Alzheimer's disease, epilepsy, depression, bipolar disorder and anxiety disorders, identify disease-specific effects of distinct ceramide subtypes, and provide theoretical evidence for lipid-targeted pharmacological research on psychiatric disorders.

Non-communicable diseases (NCDs) account for a major share of global mortality and disability, while their development and outcomes reflect interactions among behavioral, metabolic, socioeconomic, environmental, infectious, and non-modifiable factors. This issue of the Biomedical Journal highlights the breadth of contemporary research across NCD epidemiology, mechanisms, diagnosis, prevention, and treatment. A study from northern Peninsular Malaysia examines age- and sex-specific patterns in the burden of cardiovascular disease, respiratory disease, and diabetes, while a review considers the complex association between diabetes, vascular complications, and dementia. Further reviews address strategies to improve glioblastoma vaccines through enhanced antigen presentation and combination immunotherapy, as well as ultrasound-guided interventions for adhesive capsulitis, including stage-specific and structure-oriented approaches to pain relief and functional recovery. The original articles explore a single-dose, non-waiting neoadjuvant immunotherapy strategy for resectable hepatocellular carcinoma; emerging evidence on problematic ChatGPT use; genomic surveillance following an outbreak of carbapenem-resistant Serratia marcescens; the stage-specific role of miR-7974 in colorectal cancer; and the potential diagnostic relevance of DEC-1 in ischemic stroke. Other contributions investigate extracorporeal shockwave therapy as a means of reducing inflammation in experimental psoriasis and Fu's subcutaneous needling as a potential modulator of mitochondrial quality control and inflammatory signaling in a rat model of sciatica. A correspondence exchange on molecular diagnostic platforms for primary mitochondrial diseases discusses the validation, sensitivity, terminology, clinical practicality, and particular advantages of long-read nanopore sequencing.

Amyloid-β (Aβ) accumulation begins many years before the onset of clinical symptoms in Alzheimer's disease (AD). Studies in humans suggest that unimpaired individuals with elevated Aβ exhibit subtle changes in cognitive trajectories over time, particularly in memory. Identifying animal models that recapitulate these early changes is critical for translational research on preclinical AD. Here, we hypothesized that aging dogs, which naturally accumulate Aβ, show similar patterns to those observed in humans. Forty-three beagles underwent longitudinal cognitive testing on tasks assessing spatial memory, landmark discrimination, and reversal learning, while Aβ burden was measured using cerebrospinal fluid Aβ42/40. Parallel analyses were conducted in cognitively unimpaired older adults from the Harvard Aging Brain Study (n = 287) using Aβ PET imaging and neuropsychological assessments. Despite no baseline differences, dogs with lower CSF Aβ42/40 showed worse longitudinal trajectories on a spatial memory task. No comparable effects were observed for landmark discrimination or reversal learning. Using a data-driven approach, Low CSF Aβ42/40 dogs were more likely to be classified in the Lower trajectory group than High CSF Aβ42/40 dogs. A similar pattern emerged in humans: Aβ+ individuals showed lower memory trajectories compared to Aβ- individuals. Across species, memory deficits were characterized by reduced benefits of practice effects rather than abrupt decline. Together, these findings suggest that aging dogs show Aβ-associated memory trajectories that parallel patterns observed in cognitively unimpaired older adults and support the canine model as a valuable translational platform for studying the earliest stages of AD.

INTRODUCTION/OBJECTIVES: We aimed to investigate associations between menopausal characteristics, including age at menopause and cause (natural vs. artificial), with long-term outcomes in women with rheumatoid arthritis (RA), incident Alzheimer's disease and related dementias (ADRD), RA severity, and overall mortality. We hypothesized that atypical menopausal characteristics increase ADRD risk and disease severity. METHODS: Women with incident RA in 1980-2014 who were ≥50 years of age at RA incidence were included. Menopause cause and age at menopause (categorized as <45, 45-54, ≥55 years) were abstracted from medical records. Associations between menopausal characteristics and ADRD, extra-articular manifestations (ExRA), erosions, cardiovascular events, and mortality were evaluated using Cox models. Associations with clinic visits for flares and remissions were assessed using mixed-effects models. Data were collected using the Rochester Epidemiology Project medical records-linkage system. RESULTS: Both early/premature and late menopause were associated with nonsignificant near two-fold increases in ADRD risk. In addition, early/premature (HR 2.40; 95% CI 1.15-5.01) and late menopause (HR 2.17; 95% CI 1.01-4.66) significantly increased severe ExRA risk. Menopausal characteristics were not associated with presence of erosions or mortality. Artificial menopause was associated with fewer cardiovascular events and fewer visits for RA remission. Early/premature menopause was associated with fewer remission visits (OR 0.50; 95% CI 0.29-0.87). CONCLUSION: Women with early/premature and late menopause had nonsignificant, increased risk of incident ADRD. Menopausal characteristics had significant associations with RA severity and cardiovascular events, and may be relevant contextual factors in long-term risk assessment for women with RA.

In Alzheimer's disease (AD), amyloid beta (Aβ) plaques and hyperphosphorylated tau tangles drive neurodegeneration and cognitive decline. Disrupted calcium homeostasis-particularly via transient receptor potential canonical-1 (TRPC1) channels-contributes to tauopathy and disease progression. This study investigated the therapeutic potential of 2-aminoethoxydiphenyl borate (2-APB), a modulator of TRP channels, in a scopolamine-induced rat model of AD. Adult Wistar rats were assigned to six groups: normal control, disease control (scopolamine 2.5 mg/kg), three 2-APB treatment groups (2.5, 5.0 and 10.0 mg/kg) and a donepezil group (5.0 mg/kg), each with six animals. Treatments lasted three weeks. Cognitive performance was assessed using the Morris water maze, memory consolidation and open field tests. Biochemical assays measured acetylcholinesterase (AChE), calcineurin, oxidative stress markers (GSH, MDA) and inflammatory cytokines (TNF-α, IL-6, IL-1β). Protein and gene expression analyses (Western blot, qRT-PCR) evaluated tau, GSK-3β, TRPC1, MARK2, and calcineurin A/PPP3CA, alongside histopathological and immunohistochemical studies. 2-APB treatment significantly reduced pro-inflammatory cytokines, alleviated neuroinflammation, and decreased oxidative stress. Cognitive function improved, correlating with normalized AChE activity and preserved neuronal structure. At the molecular level, 2-APB reduced tau hyperphosphorylation at Ser396 and Thr231, likely through suppression of TRPC1-associated calcium entry and consequent modulation of calcium-dependent kinases (MARK2) and phosphatases (calcineurin), as well as the GSK-3β pathway. However, given that 2-APB is a broad-spectrum calcium signaling modulator - known to act on IP₃ receptors, SOCE/ORAI pathways, and multiple TRPC subtypes in addition to TRPC1-the present findings provide supportive evidence linking TRPC1 modulation to the observed neuroprotective effects. Although, the involvement of additional interconnected signaling mechanisms cannot be excluded and these findings should be interpreted within the context of 2-APB's pleiotropic pharmacological profile. Downregulation of TRPC1 and calcineurin A/PPP3CA gene expression supported 2-APB's role in restoring calcium balance and mitigating tau pathology. These results highlight 2-APB's potential in addressing key AD features-tauopathy, oxidative stress, neuroinflammation and cognitive impairment-warranting further preclinical and clinical research as a potential therapeutic for AD and related tauopathies.

Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose an urgent global health challenge. Growing evidence establishes microglia-driven neuroinflammation as a key driver of disease onset and progression, with mitochondrial dysfunction emerging as an early trigger of microglial activation. This review comprehensively summarizes current progress on how mitochondrial alterations regulate microglial activation across AD, PD, and ALS. We identify conserved mechanisms including metabolic reprogramming, impaired mitophagy, and inflammatory signaling, though Aβ, α-synuclein, and TDP-43 engage these pathways through disease-specific molecular routes. Therapeutic strategies targeting microglial mitochondria, including cGAS-STING and NLRP3 inhibitors, TREM2 agonists, and mitochondrial transplantation, remain largely preclinical. Emerging targets such as OLFML3 and GPNMB require functional validation in microglia. Collectively, this review underscores that preserving microglial mitochondrial health represents a promising therapeutic frontier and identifies key priorities for translating these strategies toward clinical application.

Recent studies suggest that impairment of the glial autophagy-lysosomal pathway (ALP) critically contributes to the sustained neuroinflammatory response and neurodegenerative processes in Alzheimer's disease (AD). Glial cells, comprising microglia, astrocytes, oligodendrocytes, and ependymal cells, serve as key immune regulators in the central nervous system, where they are essential for maintaining ALP homeostasis, promoting proteostasis, and modulating neuroinflammatory responses. Here, we systematically review the regulatory roles of glial ALP in AD pathology, emphasizing its involvement in amyloid accumulation, tau hyperphosphorylation, synaptic impairment, white matter damage, and mitochondrial as well as other organelle dysfunction, and provide an in-depth analysis of key signaling pathways including TFEB, mTOR, and NLRP3. Furthermore, we outline therapeutic strategies aimed at restoring lysosomal function, regulating autophagic flux, and suppressing inflammation, along with a discussion of the multi-target regulatory potential of acupuncture and natural bioactive agents. We also highlight emerging ALP-associated biomarkers and their potential utility in early diagnosis and treatment response assessment. The objective of this review is to uncover the mechanistic interplay between glial ALP dysregulation and the pathological cascade of AD, offering a conceptual framework for the development of novel therapeutics that integrate neuroprotection with immune modulation.

Aging-related neurological disorders, including stroke, Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, and various neuroinflammatory conditions, affect over three billion individuals worldwide and constitute leading causes of morbidity, disability, and socioeconomic burdens. Aging contributes not only to the increased incidence of these disorders but also to their progression through interconnected mechanisms, including endothelial dysfunction, oxidative stress, chronic inflammation, mitochondrial dysfunction, cellular senescence, metabolic imbalance, and gut microbiota dysbiosis. These processes collectively impair neuronal survival, synaptic plasticity, and cognitive and motor functions. Traditional Chinese medicine (TCM), with its characteristic multi-component and multi-target therapeutic strategies, has emerged as a promising approach to counteract age-associated neurological decline. Accumulating preclinical studies suggest that TCM interventions may exert neuroprotective, anti-inflammatory, and antioxidant effects, modulate autophagy, restore metabolic homeostasis, and potentially delay cellular senescence. However, high-quality clinical evidence on safety and efficacy remains limited. This review summarizes current insights into the molecular interplay between aging and neurological disorders and highlights the therapeutic potential of TCM in targeting hallmarks of aging, providing perspectives for integrative prevention and treatment strategies for neurodegenerative and neurovascular diseases.

PURPOSE: To investigate the sources of variability in Centiloid (CL) calculations, particularly the influence of image reconstruction and reference region selection, and to examine the relationship between baseline CL scores, visual interpretation and subsequent disease progression. METHODS: 162 aMCI patients who underwent amyloid PET at a single center were retrospectively analyzed. Visual assessment was performed by two nuclear medicine physicians and Centiloid scoring was determined using syngo.MI Neurology Cortical Analysis, using different reference regions (RR) and image reconstruction settings. The CL values were compared against visual interpretation, using a ROC analysis. The value of CL in predicting the onset of Alzheimer's dementia was assessed. RESULTS: The use of the whole cerebellum as RR provided the most robust and consistent CL values across reconstruction methods. The RR was critical in the case of flutemetamol, as CL varied in more than 20 units between pons and whole cerebellum. Visual classifications and CL values showed strong concordance (area under the ROC curve: 0.9786) and the CL cut-off value that maximized agreement with visual reading was 28 CL. During follow-up, 49% of patients progressed to AD dementia and CL-based amyloid positivity was a significant predictor of progression. CONCLUSION: Standardized CL quantification using the whole cerebellum as RR enhances the reliability of amyloid PET interpretation across tracers and reconstruction settings. CL values strongly correlate with visual assessment and are predictive of clinical progression. These findings suggest the potential utility of CL quantification in both clinical and research settings.

Neurobiobanks focused on the study of major cognitive impairment constitute a strategic infrastructure for translational research and personalized medicine in the neurosciences. In Mexico and the Dominican Republic, the National Dementia Biobank (BND) at the Universidad Politécnica de Pachuca and the National Brain Bank at the Universidad Nacional Pedro Henríquez Ureña (BNC-UNPHU) have developed integrated mechanisms for the collection, processing, and preservation of human brain tissue, as well as other tissues such as kidney, liver, intestine, pancreas, and skin, intended exclusively for biomedical research. Both institutions share research lines centered on the molecular pathological study of the tau protein and the amyloid-β peptide, key markers of Alzheimer's disease and other dementias. Protocols for immunohistochemistry, silver staining, single and multiple immunofluorescences, as well as staining with fluorochromes such as thiazine red and thioflavin-S, have been standardized for the precise detection of neuropathological lesions. Transgenic animal models, including the triple transgenic mouse with mutations in presenilin-1, amyloid-β protein precursor, and tau, have served as complementary tools to dissect the temporal sequence of protein aggregation. In parallel, both institutions have implemented sustained scientific outreach programs, including a traveling museum of neurodegenerative diseases, Brain Awareness Week, Alzheimer's fairs, and media campaigns, aimed at reducing stigma, promoting altruistic tissue donation, and building public trust. Collectively, these neurobiobanks represent an emerging model of research contextualized within Latin American populations, with the potential to integrate into regional and international networks that contribute to reducing knowledge gaps in neurodegeneration.

BackgroundMild cognitive impairment (MCI) is an intermediate stage between normal aging and Alzheimer's disease (AD). Because there is no treatment for AD, it is vital to establish which patients are at a higher risk of disease progression, and might benefit from early intervention.ObjectiveThis study investigates whether a score based on clusters of MRI and lipidomic variables can predict the time to moderate progression in MCI.MethodsWe analyzed MRI and lipidomics data from 480 individuals with MCI (mean age 72.14 years, range 55-90 years). Moderate progression was defined as a ≥ 2.5-point increase in the Clinical Dementia Rating Scale Sum of Boxes (baseline mean CDR-SB of 1.2, range 0-10 points). Multi-source data integration and clustering methods were used to derive predictive scores.ResultsThe MRI-based score outperformed the lipidomics score (c-index: 0.754 versus 0.666). A 1-unit increase in the MRI score was linked to a 13% higher risk of moderate progression. Individuals in the top 25% of MRI scores had a 3-fold greater risk of decline.ConclusionsAn MRI-based score offers a simple, effective tool to predict moderate MCI progression and identify high-risk individuals for AD.

BackgroundPhysical exercise is widely recognized for its cognitive benefits; however, the effect of menopausal status in modulating the cognitive effects of exercise is not definitively established.ObjectiveTo examine the cognitive benefits of two 6-month physical exercise programs in cognitively healthy older women across adulthood, and whether menopause status moderates these benefits.MethodsIn a post hoc analysis of a randomized controlled trial, 93 cognitively healthy women (aged 20-67; 43% at post-menopause) were assigned to either aerobic exercise (AE) or stretching/toning (ST) 4 days a week for six months. Neuropsychological assessment, cardiorespiratory exercise test, and blood draw were performed at baseline, 3-months, and 6-months. Linear mixed-effects regression models assessed whether menopausal status moderated the impact of exercise on executive functions and processing speed.ResultsSeventy-six participants (81.7%) completed the intervention. A time-by-group-by-menopause interaction emerged after 3 months (β = -0.89;  = 0.001) and 6 months (β = -0.67,  = 0.016). Post-menopausal women in the AE group showed greater improvement in executive functions compared to the ST group and pre-menopausal women. Models controlled for age, education, and baseline cognitive performance.ConclusionsOur results provide novel evidence that AE improves cognition with pronounced executive functions benefits in post-menopausal women, a population at higher risk for dementia. Since women are at a higher risk of developing Alzheimer's disease compared to men, these findings support AE as a relevant strategy to promote women's brain health. Although this is a secondary analysis, it may inform future exercise trials targeting women.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease. Despite advances in the understanding of the genetics of AD, environmental risk factors are still under investigation, and the etiology is still not completely understood. The environmental component of AD, which we explore in the first part of this review, takes on greater importance with more advanced disease onset. Moreover, genetics does not explain all of AD. Environmental risk factors are divided into modifiable and nonmodifiable risk factors. Among the modifiable risk factors, nutrition seems to play a predominant role. One-carbon metabolism (OCM) is involved in this food-related component, notably through B vitamins. Homocysteine, a sulfur-containing amino acid, is at the crossroads of OCM. Abnormal increases in homocysteine levels (hyperhomocysteinemia) are associated with deleterious effects on cognition. Various mechanisms can lead to hyperhomocysteinemia, including genetic factors associated with different polymorphisms, dietary deficiencies targeting vitamins B9 and B12, and renal insufficiency. The second part of the review details OCM and the role of homocysteine. Finally, part 3 highlights the numerous studies in the literature describing the association between hyperhomocysteinemia and cognitive decline. However, the mechanistic links between hyperhomocysteinemia and cognitive decline in AD are poorly understood. Several hypotheses have been proposed in the literature. The toxic effects of homocysteine could be mediated by N-homocysteinylation, a nonenzymatic reaction leading to the irreversible accumulation of N-homocysteinylated proteins. Finally, we detail some therapeutic trials targeting one-carbon metabolism in AD, notably vitamin B9 and B12 supplementation.

BackgroundAlzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation with impaired lymphatic clearance, yet therapies targeting lymphatic dysfunction remain underexplored. The Neurolymphatic Formula (NLF), a traditional Chinese medicine, demonstrates lymphatic modulation potential, but its mechanistic role in AD remains unknown.ObjectiveThis study aimed to elucidate NLF's therapeutic efficacy in AD and investigate whether it enhances central and peripheral lymphangiogenesis via VEGF receptor 3 (VEGFR3) activation.MethodsWe evaluated NLF's pharmacological effects on behavior and AD pathology in APP/PS1 mice, including sunitinib-induced lymphatic impairment models. Underlying mechanisms were explored using network pharmacology, molecular docking, and in vitro assays on human lymphatic endothelial cells (HLECs).ResultsIn APP/PS1 mice, 4-week NLF treatment reduced Aβ plaque burden by 43% ( < 0.01) and improved spatial memory latency by 35% ( < 0.05). NLF restored meningeal and mesenteric lymphatic density in sunitinib-treated mice to 82% and 133% of baseline, respectively ( < 0.01), while upregulating serum VEGFR3 2.3-fold ( < 0.01). To validate NLF's molecular basis, coptisine was identified as a representative VEGFR3 ligand (-7.1 Kcal/mol). In vitro, coptisine (25 μM) enhanced HLEC viability by 60%, accelerated wound closure 2.5-fold, and increased tube junctions by 75% (all  < 0.01) alongside VEGFR3 upregulation.ConclusionsNLF alleviates AD pathology by promoting Aβ clearance through VEGFR3-mediated dual modulation of central and peripheral lymphatic systems. The in vitro efficacy of its constituent, coptisine, mechanistically validates this pro-lymphangiogenic pathway, highlighting NLF's therapeutic potential as a holistic lymphatic-targeted AD treatment.

BACKGROUND: Multi-system impacts of long COVID remain unknown. We aimed to compare multi-system deficits between people with long COVID and controls. METHODS: We conducted a case-control study and recruited participants from two UK population-based cohorts: the Avon Longitudinal Study of Parents and Children (ALSPAC) and TwinsUK. Participants provided samples for SARS-CoV-2 serology between 2020 and 2021 and were asked about duration of COVID-19 symptoms between July and December 2021. Cases had long COVID (evidence of COVID-19 infection and persistent symptoms ≥4 weeks post infection); controls comprised 3 groups: acute COVID-19 only (symptoms reported for <4 weeks) and serological evidence of infection; self-reported long COVID-like symptoms but without wild-type SARS-CoV-2 virus antibodies; no symptoms or history of COVID-19 infection. People who were severely unwell or pregnant were excluded. Participants attended a clinic follow-up visit between 2021 and 2023 and underwent multi-system MRI, (cardiac, brain, lung, kidney), measurement of blood pressure and autonomic function, spirometry, renal function, exercise tests, strength and physical capability. Severity of deficit was then scored for each system as 0 (none) to 3 (severe). Primary outcome was a single composite multi-domain score summing each of nine domains: autonomic, brain, exercise capacity, heart, lungs, physical, renal, strength and vascular, with a maximum score of 27. FINDINGS: In total, 349 participants, 141 with long COVID (40%) and 208 (60%) controls were recruited. Overall deficit score in cases was 0.22 (95% CI -0.44, 0.88) units greater than controls, adjusted for age, sex, ethnicity, cohort membership and relatedness. This estimate was little changed (0.32 (-0.34, 0.98)) when additionally adjusted for educational status, index of multiple deprivation, physical activity, smoking and co-morbidity. Restricting cases to those reporting symptoms including fatigue (n = 46) increased the excess deficit score to 0.81 (-0.19, 1.81) units in the minimally adjusted model. A difference was only observed in the vascular domain, largely attributable to elevated blood pressure, showing a 1.76 (1.04, 2.97) multivariable adjusted odds ratio excess in cases, and 3.04 (1.36, 6.80) when restricted to cases with fatigue. INTERPRETATION: There was no evidence of marked residual subclinical deficits in most systems in people with long-COVID, although there was evidence of persistent deficits in the vascular system, largely related to elevated blood pressure. Mechanisms unrelated to organ dysfunction may contribute to symptoms. Blood pressure measurement and control should be included in clinical follow-up. FUNDING: Jointly funded by the National Institute for Health and Care Research and UK Research and Innovation (CONVALESCENCE, COV-LT-0009, MC_PC_20051).

BACKGROUND: Early diagnosis of Alzheimer's disease (AD) is critical for improving patient outcomes. The laboratory-developed blood test of AlzoSure measures the unfolded conformational variant of p53 (U-p53AZ) in plasma and has shown promise as a screening tool for AD risk. We aimed to evaluate the association between U-p53AZ with established cerebrospinal fluid (CSF) and neuroimaging measures, and to determine its diagnostic performance in distinguishing cognitively normal (CN) individuals from those with mild cognitive impairment (MCI). METHODS: Participants included CN and MCI individuals aged 55-90 years with complete baseline and 24-month follow-up assessments. Associations between U-p53AZ, CSF biomarkers, standardized uptake value ratio (SUVR) of glucose measured by fluorodeoxyglucose positron emission tomography (FDG-PET), and cognition were examined with multivariable regression models adjusted for age, sex, and status. Diagnostic performance was assessed with receiver operating characteristic (ROC) analysis. RESULTS: At baseline, no significant group differences were observed in plasma U-p53AZ, FDG SUVR, or CSF biomarkers between CN and MCI. Longitudinally, FDG SUVR significantly declined in MCI ( = 0.040), while CSF t-tau and p-tau181 increased in both groups (all  < 0.05). Higher U-p53AZ levels were independently associated with elevated CSF t-tau ( = 0.38;  = 0.033) and p-tau181 ( = 0.37;  = 0.033) at baseline, and these associations persisted at follow-up ( range 0.43-0.48; all  < 0.02). No significant associations were found with FDG SUVR or cognitive scores. The discriminative ability of U-p53AZ to distinguish CN from MCI was modest (AUC = 0.617, 95% CI 0.518-0.716). CONCLUSION: AlzoSure measurements are significantly associated with CSF tau values but demonstrate limited utility in differentiating CN from MCI. Although promising as a marker of tau-related neurodegeneration, AlzoSure has a modest diagnostic performance as a stand-alone assessment.