INTRODUCTION: Accelerated brain volume loss has been observed following trials of anti-amyloid beta immunotherapy (AAT); however, there is limited understanding of this paradoxical phenomenon in early-onset Alzheimer's disease (EOAD) versus late-onset Alzheimer's disease (LOAD). METHODS: We retrospectively analyzed brain volume changes over a 1-year period following initiation of AAT. Annualized rates of brain volume alteration were calculated, and linear mixed-effects models were performed to assess brain volume trajectories in EOAD versus LOAD. RESULTS: One hundred fourteen participants (35 with EOAD; 79 with LOAD; mean baseline MMSE: 27) were analyzed. Ventricular expansion, measuring ∼15%/year, and whole-brain atrophy occurred in both groups. LOAD showed ∼1.7× greater hippocampal atrophy compared with EOAD, independent of baseline cerebral amyloid burden, though global cortical amyloid burden predicted whole-brain and hippocampal atrophy (< 0.001). DISCUSSION: Brain atrophy with prominent ventricular expansion occurs in early-stage EOAD and LOAD following AAT. Additional studies are needed to elucidate the mechanisms and implications of this post-immunotherapy effect.

INTRODUCTION: Alzheimer's disease (AD) risk is strongly modified by biological sex and apolipoprotein E () genotype, yet these factors are rarely incorporated into drug discovery efforts. We hypothesized that sex- and -specific transcriptomic signatures define distinct molecular endotypes of AD which can be therapeutically targeted through precision drug repurposing using an integrative data framework. METHODS: We analyzed frontal cortex RNA sequencing data from 369 individuals in the Religious Orders Study Rush Memory and Aging Project cohort ( ε3/ε3 and ε3/ε4) to derive sex- and genotype-specific AD gene expression signatures. Differential expression and Gene Ontology enrichment analyses identified biological processes uniquely or differentially perturbed across groups. Drug-induced perturbation signatures from the Library of Integrated Network-Based Cellular Signatures database were queried to identify US Food and Drug Administration-approved compounds predicted to reverse AD-associated signatures. Top candidates were validated using the PearlDiver-Mariner claims database to assess AD risk associations. RESULTS: Transcriptomic dysregulation varied markedly across groups. Female ε3/ε3 AD brains exhibited the greatest number of differentially expressed genes ( = 8903), whereas male ε3/ε3 showed the fewest ( = 640). ε4 carriers demonstrated enrichment of immune and inflammatory pathways, including cytokine signaling and extracellular signal-regulated kinase cascade activation, whereas ε3/ε3 groups exhibited downregulation of synaptic organization, vesicle trafficking, and bioenergetic processes. Drug reversal analysis identified four candidates: riluzole, chloroquine, acetazolamide, and anagrelide. In population-level validation, riluzole (relative risk [RR] = 0.52; 95% confidence interval [CI]: 0.40-0.68), chloroquine (RR = 0.56; 95% CI: 0.55-0.58), and acetazolamide (RR = 0.76, 95% CI: 0.73-0.79) were associated with significantly reduced AD risk, whereas anagrelide exhibited increased risk. Protective associations for riluzole, chloroquine, and acetazolamide held in both sexes, with stronger effects in women. DISCUSSION: Sex and genotype define biologically distinct AD transcriptomic states, with subgroup-specific and shared pharmacologic reversibility. Integrating stratified transcriptomics with population-scale validation identified clinically actionable candidates supporting an AD precision drug repurposing framework.

BACKGROUND: Ankle arthrodesis (AA) remains a reliable surgical treatment option for end-stage ankle arthritis in appropriately selected patients. Although traditionally performed in an inpatient (IP) setting, interest in these surgeries being done as an outpatient (OP) and ambulatory surgery center (ASC) settings has increased. We compared costs and post-operative complication rates for AA performed across these settings. METHODS: Using Medicare fee-for-service claims (2016-2021), we retrospectively identified patients ≥65 years of age who underwent AA. Using subsequent inpatient and Part B (provider) claims, we evaluated postoperative complications within 1 year, defined by () codes, including infection, thromboembolic events, and device-related issues. We also evaluated total episode and post-acute care costs within 90 days. We tested for differences in perioperative safety indicators and costs through multivariate regressions, controlling for age, sex, race, and Charlson Comorbidity Index (CCI), dementia, and the involvement of a surgical assistant. A propensity-matched analysis was performed to minimize selection by indication bias. RESULTS: We included 7104 initial AA cases across surgical settings: 262 (3.7%) in ASC, 3047 (42.9%) in OP, and 3795 (53.4%) in IP. Compared with IP cases, OP and ASC surgeries were performed in younger, healthier (as assessed by CCI) patients and more frequently in male patients ( < .001). In multivariate analyses, IP cases had the highest infection rates (+7.2 percentage points compared with ASC,  = .001; +4.2 percentage points compared to OP,  = .016) and the highest 90-day total episode costs of $19 817 (95% CI: $18 137 to $21 497). Propensity-matched analyses were consistent with multivariable results, confirming the same directional associations but with modestly larger effect sizes. CONCLUSION: AA performed in ASC settings was associated with lower complication rates and substantially lower episode-of-care costs compared with IP and OP settings in this Medicare fee-for-service population, particularly among appropriately selected patients. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that involves the formation of amyloid-β (Aβ) aggregates, and the development of targeted therapeutic strategies is needed. In the current work, we report the rational design of H102-CP05, a 22-residue chimeric peptide that integrates the β-sheet breaker peptide H102 with the CD63-targeting anchor CP05 to enable extracellular vesicle (EV)-mediated delivery of an Aβ-inhibitory payload. Computational analysis confirmed favorable physicochemical properties and a non-allergenic profile. In silico immunogenicity assessment and C-IMMSIM simulation demonstrated a low risk of anti-drug antibody formation under chronic dosing conditions. Homology modelling and HADDOCK docking (score: -147.2 ± 4.6) predicted a computationally favourable CD63 binding configuration, while 100 ns molecular dynamics simulations confirmed structural stability in both aqueous and EV-mimetic lipid bilayer environments. In vitro cytotoxicity against HEK-293 cells revealed no significant toxicity (10-100 µM). Zebrafish embryo studies indicated acceptable developmental safety at lower concentrations, with concentration-dependent bradycardia observed at higher doses warranting further cardiovascular evaluation. Thioflavin T fluorescence assays demonstrated dose-dependent inhibition of Aβ fibrillation, with near-complete suppression at 100 µM. These findings collectively support H102-CP05 as a promising EV-displayed therapeutic candidate for AD.

Alzheimer's disease (AD) is increasingly recognized as a disorder driven by dysregulated innate immunity rather than merely amyloid‑β accumulation. Microglia, the brain's resident innate immune cells, acquire long‑term functional memory, a process known as trained immunity or innate immune memory, through epigenetic and metabolic reprogramming. In AD, chronic exposure to amyloid‑β and tau aggregates locks microglia into a maladaptive primed state characterized by altered histone modifications (H3K4me3, H3K27ac), sustained glycolysis via the HIF‑1α/mTOR axis, and impaired phagocytic function, perpetuating neuroinflammation and neurodegeneration. This review critically synthesizes recent advances that define the molecular architecture of microglial immune memory, including epigenetic rewiring, immunometabolic shifts, and intercellular crosstalk with astrocytes and the gut microbiome. We evaluate the emerging immunopharmacological toolbox designed to reverse maladaptive priming and restore neuroprotective resilience, focusing on small‑molecule NLRP3 inflammasome inhibitors (HT‑6184, DFV890, BGE‑102), TREM2 agonists (VG‑3927, MNA‑001), metabolic modulators (metformin, rapamycin), trained immunity‑based vaccination (BCG), specialized pro‑resolving mediators (maresin 1, resolvin D1, lipoxin A4), and senolytics. Clinical‑stage agents and their mechanisms of action are highlighted. We argue that the next generation of AD therapeutics must move beyond target suppression toward the functional reprogramming of brain innate immunity, and we propose a biomarker-guided, patient-stratified framework that integrates multimodal immunopharmacology, combining NLRP3 inhibition, TREM2 agonism, metabolic reprogramming, and resolution pharmacology to restore immune homeostasis. Harnessing the plasticity of innate immune memory offers a transformative paradigm for disease‑modifying therapy in AD.

BACKGROUND: Alzheimer's disease (AD) is characterized by pathological changes in Aβ&Tau, cognitive impairment, and may also manifest psychiatric symptoms. Zonisamide (ZNS) has been demonstrated its improvement of cognitive dysfunction in T2DM mice in our previous study. However, the efficacy and mechanism of ZNS in treating AD remain unclear. AIM: We aims to investigate the therapeutic efficacy of ZNS for AD and its potential molecular mechanisms. METHODS: Three-month-old 5xFAD mice were treated with ZNS (20 mg/kg, i.p.) for 12-week. The behavioral test assesses cognitive function and psychiatric symptoms. Aβ-PET/CT, immunofluorescence, and Thioflavine-S stainin staining assessed the levels of Aβ plaques. Proteomics and Western blot analyses evaluated synapse-associated proteins, amyloid precursor protein (APP) related proteins and phosphorylated tau. RESULTS: We discovered for the first time that ZNS significantly improved spatial learning and memory, and also alleviated psychiatric symptoms in 5xFAD. Besides, ZNS increased PSD95, SYP, BDNF, and SAP90/PSD-95-related protein 3 (SAPAP3), which plays a crucial role in compulsive-like behaviors. Importantly, siRNA-mediated knockdown of SAPAP3 in N2A/APP cells inhibited the regulatory effect of ZNS on PSD95 and NMDAR2A (NR2A). In addition, ZNS treatment reduced Aβ deposition in the brain. It also downregulated APP, p-APP (Thr668), BACE1, and PS1, and attenuated tau phosphorylation at Ser396 by inhibiting its upstream kinase ERK1/2 activity. CONCLUSION: ZNS exerts neuroprotective effects in 5xFAD mice and improves AD-related cognitive impairment and AD-like lesions, which establishes ZNS as a promising therapeutic avenue for AD and its associated psychiatric symptoms.

This systematic review investigates the mediating factors in the relationship between ambient air pollution exposure and cognitive aging. We identified 16 studies examining 72 unique exposure-mediator-outcome associations for six pollutants (PM2.5, PM10, NO2, NOX, black carbon, and PM1 components). The most studied pollutant was PM2.5 (65% of analyses). Cognitive outcomes included memory, cognitive processing speed, and clinically diagnosed conditions such as dementia incidence. Potential mediators spanned mental health outcomes (depression, anxiety, stress), lung function (FEV1, FVC, PEF), vascular diseases (stroke, hypertension), inflammation (CRP), metabolic factors (type 2 diabetes), sleep, and neuroanatomical changes. The quality of mediation analysis reporting was generally good, but most studies had some risk of bias, particularly in outcome assessment and confounding adjustment. Cardio and Cerebro-vascular diseases emerged as a potential key mediator. Mental health outcomes, sleep, and lung function also showed mediating potential, but further research is needed to confirm these findings. This review highlights the need for rigorous causal mediation analyses and standardized reporting to better understand the complex pathways linking air pollution to cognitive aging, in order to identify targeted preventive measures to reduce the negative impact of ambient air pollution on cognitive health.

AIMS: To identify BMI trajectories after type 2 diabetes (T2D) diagnosis and examine associations with laboratory measures, medication use, comorbidities, and healthcare utilization. METHODS: We analyzed BMI trajectories in 3,539 adults with T2D in North Karelia (2011-2014) and followed until 2024. BMI trajectory classes were estimated using growth mixture modeling. Regression models were used to assess differences in measurement activity, treatment intensity and diabetes medication use between the classes. RESULTS: Three BMI trajectories were identified: stable (77.7 %), increasing (14.6 %), and decreasing (7.7 %). HbA1c and LDL cholesterol measurement activity was lowest in the decreasing class. Use of glucagon-like peptide-1 agonists varied over time, peaking in the decreasing class in 2015 and in the increasing class in 2024. Comorbidities increased in all classes but differed in pattern: the increasing class accumulated more chronic kidney and urinary tract diseases, obesity related diagnoses, sleep disorders, and chronic lower respiratory diseases, whereas the decreasing class had higher prevalence of dementia and cardiovascular and pulmonary diseases. Healthcare utilization was highest in the decreasing class. CONCLUSIONS: These findings reveal considerable heterogeneity in long-term outcomes among people with T2D and highlight the need for continuous monitoring and targeted support to maintain metabolic control and manage comorbidity burden.

Alzheimer's disease and related dementias represent a significant and growing health care burden in the United States. This article describes the implementation of a rehabilitation-driven, interdisciplinary care model and its impact on antipsychotic medication use and emergency department visits among individuals with dementia in skilled nursing facilities. The approach integrates a research-based dementia staging protocol into occupational, physical, and speech therapies to create individualized care plans that leverage preserved function and the development of customized care strategies. These plans are integrated into facility-wide practices through staff training and ongoing monitoring. Data from 3 affiliated skilled nursing facilities demonstrate significant reductions in antipsychotic use and emergency department visit rates following program implementation. The data suggest that a therapy-forward, person-centered care model can meaningfully reduce the risks associated with pharmacologic interventions and acute hospitalizations, offering an effective strategy for improving dementia care outcomes.

To systematically review longitudinal studies examining the evidence of multimorbidity on the incidence of frailty. The systematic review with meta-synthesis we searched four databases Scopus, PubMed, Virtual Health Library, Web of Science, and CINAHL for literature published prior to December 2023 using a prespecified search strategy. The quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale for longitudinal studies. Three studies examining the role of multimorbidity on frailty incidence were included. All the included studies assessed patterns of multimorbidity, and frailty was operationalized through Fried's phenotype. Two of the three studies indicated that multimorbidity was associated with an increased risk of frailty and the most prevalent patterns of multimorbidity linked with the incidence of frailty were cardiometabolic and dementia-neuro patterns. In conclusion, two of the three included studies suggest that multimorbidity is a risk factor for frailty.

Monitoring butyrylcholinesterase (BuChE) activity is crucial for tracking Alzheimer's disease (AD) progression and evaluating therapeutics; however, high-performance near-infrared (NIR) probes with rapid response and clear design principles remain scarce. Here, we report a series of dicyanoisophorone-based NIR fluorescent probes engineered via a "halogen effect" to systematically tune reactivity toward BuChE. Through spectroscopic screening, the CF-substituted probe DCNC7 emerged as the optimal candidate, benefiting from the strong electron-withdrawing and hydrophobic nature of the trifluoromethyl group, which enhances binding affinity and catalytic recognition. DCNC7 exhibits over 120-fold NIR fluorescence enhancement upon the BuChE reaction, with fast kinetics (∼15 min), high sensitivity (detection limit 0.0206 U/L), and excellent selectivity. We validated DCNC7 for in situ imaging of BuChE in AD mouse cells and brain tissues, enabling both identification of natural inhibitors and longitudinal assessment of AD progression. Moreover, the screened inhibitor was evaluated for its suppressive effect on BuChE activity in brain tissue and its therapeutic efficacy in vivo. Collectively, DCNC7 offers a reliable tool for AD monitoring, drug screening, and efficacy evaluation, and the halogen effect-based design strategy provides a generalizable route to develop rapid-response, high-affinity enzyme probes for complex disease models.

BACKGROUND: Older adults are vulnerable to mental health disorders, and hospitalization typically indicates severity. This study aimed to identify the most common mental health disorders leading to hospitalization among older adults in Ecuador. The frequency of different types of dementia, including Alzheimer's disease, vascular dementia, and other forms of dementia, as well as non-alcohol-induced delirium, was also analyzed. METHODS: Nine years of nationwide data were examined, including sociodemographic factors, types of disorders, and lengths of hospital stays for each mental health disorder based on ICD-10 criteria. The Ecuadorian National Institute of Statistics and Censuses provided the dataset for analysis based on hospitalization data. RESULTS: A logistic regression model was used to calculate adjusted odds ratios (aOR). Between 2015 and 2023, Ecuador recorded 10,949 hospitalizations for mental health disorders among the older adult population. The highest hospitalization rates observed were 10.17 per 100,000 inhabitants for mental and behavioral disorders due to psychoactive substance use, predominantly among males. Depressive disorder rates were 9.35 per 100,000 inhabitants, with higher odds in women (aOR 1.78, 95% CI 1.59-1.99). Adults aged 75-79 and 80+ had higher odds of hospitalization for Alzheimer's disease (aOR 7.64 and 10.81, respectively). Hospitalizations due to mental and behavioral disorders related to psychoactive substance use were typically shorter (less than 2 d), while schizophrenia spectrum and bipolar disorders were associated with longer stays (more than 11 d). CONCLUSIONS: Our findings reveal critical patterns of hospitalizations among older adults due to substance use and depression, providing data for public health policy and future research in similar settings.

BACKGROUND: Interventions for mild cognitive impairment (MCI) can delay cognitive decline. Sensory deprivation is a risk factor for the development of dementia. Providing multisensory stimulation (MSS) based on 'virtual tourism', a dynamic presentation of natural tourist landscapes to visitors through internet technology that allows them to experience immersive travel experiences without leaving their homes, may constitute an effective management strategy. OBJECTIVE: To evaluate a 'virtual tourism' MSS intervention for older adults with MCI using a mixed-methods design to assess attitudes and perceived benefits. METHODS: Sixty-six older adults with MCI were randomized to either the experimental group receiving 'virtual tourism' MSS for 8 weeks or the waitlist control group. Cognitive function, neuropsychiatric symptoms (NPSs), quality of life, and sleep were assessed using scales at baseline and at 4, 8, 12, and 16 weeks. Semistructured interviews were conducted at 8 weeks. RESULTS: The attrition and activity attendance rates were 6.06% and 81.25%, respectively. According to the questionnaire results, cognitive function, NPSs, quality of life and sleep significantly improved in the intervention group and continued to improve for up to 16 weeks. Many respondents said that their participation improved their cognition, mood, sleep, physical fitness, and social support and provided suggestions for content enrichment and technological updates. CONCLUSIONS: 'Virtual tourism' MSS is effective for older adults with MCI. Eight weeks of MSS can effectively improve cognitive function, NPSs, quality of life and sleep for >16 weeks. These results contribute to the development of novel strategies to slow cognitive decline.

We investigated the joint associations of circulating neurodegeneration markers-neurofilament light (NfL) and glial fibrillary acidic protein (GFAP)-ambient air pollution, and plasma metabolomic profiles with transitions from a healthy state to dementia, Parkinson's disease (PD), and all-cause mortality in the UK Biobank. The analytic sample included 19,645 participants aged ≥ 50 years with complete proteomic, metabolomic, and environmental data. Time-to-event analyses used Cox proportional hazards and multistate Weibull models to evaluate associations and statistical interactions across health transitions. Higher NfL concentrations were associated with increased risks of transitions from healthy to PD, dementia, and death, whereas higher GFAP concentrations were specifically associated with dementia (HR = 2.65, 95% CI: 2.17-3.25). At the nominal level, particulate matter (PM, PM) showed positive statistical interactions with NfL for mortality, while nitrogen oxides (NO₂/NO) showed negative interactions with GFAP. There was little evidence of interaction between PM and either biomarker for dementia. Metabolomic principal components reflecting lipid, amino acid, and energy pathways were associated with variation in the relationships of NfL and GFAP with dementia and mortality and interacted with PM for PD and dementia. A branched-chain amino acid-related component showed a negative interaction with GFAP for dementia, indicating weaker associations at higher levels. These findings highlight complex relationships linking air pollution, metabolic dysregulation, and neurodegeneration, and support integrative multi-omics approaches to identify pathways relevant to prevention of neurodegenerative diseases and premature mortality.

Hyperthermia, a physical therapeutic modality with unique advantages in treating inflammatory diseases, has evolved rapidly from empirical practice to precision medicine. Technologically, it has expanded from whole-body hyperthermia and traditional moxibustion to localized approaches, including photothermal, magnetothermal, ultrasound, and implantable platforms. Traditional moxibustion acts through heat and near-infrared radiation, while nanomaterials and smart devices now enable precise control over temperature, spatial targeting, and treatment duration. these modalities converge on conserved mechanisms: TRPV channel activation, HSF1-HSP70 induction, and immune modulation, which collectively alleviate inflammation and promote tissue repair in inflammatory bowel disease, osteoarthritis, and Alzheimer's disease. This review summarizes technological evolution, mechanistic insights and therapeutic applications, thereby providing a framework for developing precision hyperthermia strategies and multifunctional platforms for inflammatory diseases.

The number of patients living with dementia (PLWD) has steadily increased, making it the fifth leading cause of death among adults. While hospice care is standard for end-of-life symptom management, predicting 6-month survival is challenging, leaving many who could benefit ineligible. The study team conducted a single-armed pilot study implementing a nurse-practitioner-led telehealth program for caregivers at an outpatient clinic, focusing on symptom management for PLWD. The study team recruited 15 caregivers with a mean age of 68 years. Most were women (60%), non-Hispanic (80%), White (67%), and children of the patient (67%). A total of 86 tele-visits were conducted. Overall, 14 caregivers found it easy to learn how to access the tele-visits. In 85 of 86 visits, caregivers felt it addressed their concerns, and all (N = 15) were satisfied with the program. Caregiver burden (12-item Zarit Burden Interview) decreased significantly (β = -0.79 (95% CI -1.22 to -0.36), P = .001), with no significant change in anxiety (General Anxiety Disorder-7), depression (Patient Health Questionnaire-9), or pain scores (Doloplus-2). The data suggest that a nurse-practitioner-led telehealth program is a feasible and acceptable intervention for caregivers caring for PLWD, with improvement in caregiver burden scores. Future studies are needed to examine its efficacy and broader implementation.

Huntington's disease (HD) is an autosomal dominant genetic neurodegenerative disorder with features of progressive motor, cognitive, and psychiatric dysfunction. Current diagnosis relies largely on clinical presentation and genetic testing but lacks sensitivity to early disease diagnosis or progression monitoring. MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate gene expression post-transcriptionally. They are increasingly being investigated as potential diagnostic biomarkers, especially given their detectability in biofluids like plasma and cerebrospinal fluid. This review aimed to evaluate the clinical utility of miRNAs in HD, specifically defining their roles not as primary diagnostic screeners, but as dynamic biomarkers for predicting clinical conversion in premanifest individuals, tracking disease progression, and monitoring therapeutic responses. A comprehensive literature search was conducted in Medline, Embase, PubMed, Scopus, Cochrane, and ClinicalTrials.gov up to November 2024. Studies written in English including human subjects or HD models quantifying miRNA expression level for diagnostic purposes were included in this systematic review. Data was extracted onto a standard form and quality assessed with the MINORS and Cochrane tools. Thirty studies with 1889 participants were included. Dysregulated miRNAs that had been repeatedly identified in HD were miRNA-9, miRNA-124, miRNA-214, miRNA-146a, and miRNA-10b. Remarkably, Romano et al. have attained 88% sensitivity and 92% specificity for SNORD13 in plasma, and Chang et al. have achieved AUC > 0.90 for a multi-miRNA panel. While promising trends, high heterogeneity of methods and incomplete reporting of diagnostic metrics limited meta-analysis. miRNAs, particularly exosome-derived ones, possess great potential as minimally invasive biomarkers for HD diagnosis. However, while current evidence strongly supports this biomarker potential, immediate clinical implementation is not yet feasible. Future studies must resolve ongoing challenges in assay standardization, cross-cohort external validation, and integration with clinical and imaging data before clinical deployment can be realized.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects over 12 million people worldwide. A central pathological feature is the accumulation of aggregated alpha-synuclein (αS) in Lewy bodies and Lewy neurites. Engineered αS variants such as 3K (E35K+E46K+E61K) and KLK (KTKEGV→KLKEGV in 6 repeats) have been shown to enhance membrane binding and aggregation propensity, contributing to cellular toxicity. To further investigate the impact of 3K and KLK on αS biology, we developed a sensitive assay in a human neuroblastoma model to assess expression levels and cytotoxicity. Relative to wild-type αS, the 3K mutant exhibited reduced steady-state expression and increased toxicity, consistent with prior reports. In contrast, the KLK mutant showed no marked change in protein expression but induced significantly higher toxicity, more than the 3K variant. Furthermore, stearoyl-CoA desaturase (SCD) inhibition partially rescued the toxicity of 3K and KLK αS, with 3K showing greater restoration of cell growth than KLK, validating the sensitivity of our live-cell assay to detect pharmacological responses. These findings underscore the utility of our assay in dissecting disease-relevant mechanisms and highlight the potential of engineered αS variants to model pathogenic features of PD. This platform offers a versatile tool for evaluating therapeutic strategies targeting αS aggregation and toxicity in PD and related synucleinopathies.

Several lines of evidence suggest the relationship between diabetes and cognitive decline. Patients with a diagnosis of type 2 diabetes (T2D) present an increased risk of Alzheimer's disease (AD) development than the general population, and it is known that brain insulin resistance (IR) plays a key role in the conversion from mild cognitive impairment (MCI) into AD. During recent years, emerging therapeutic perspectives have been proposed with the aim of targeting T2D-related cognitive impairment, and glucose-lowering drug classes, especially glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium glucose cotransporter inhibitors (SGLT2is), demonstrated neuroprotective effects and a positive effects on cognitive function acting by several molecular mechanisms including anti-inflammatory activity, modulation of insulin signaling, and promoting the neurogenesis process. Different clinical trials showed their ability in preventing neurodegenerative decline, with numerous phase II and III trials underway in populations with AD; however, although preclinical evidence is promising and some clinical data are encouraging, translating these results into established therapeutic strategies requires larger, randomized, and controlled clinical trials with extended follow-up period, standardized cognitive assessments, and inclusion of molecular and imaging biomarkers. Addressing these gaps will be essential to determine whether glucose-lowering drug classes can be introduced into clinical practice to prevent or slow cognitive decline in patients with T2D, exerting neuroprotective activity beyond their effect on glycemic control.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the most common cause of dementia in the world. Cognitive decline, memory problems, behavioral disturbances, and, finally, loss of functional independence characterize it. AD has risen and continues to increase globally, especially among aging people. A team of researchers at the University of Alberta says that we need faster, better diagnosis and treatment of AD. It elaborates on the progressive understanding of AD pathophysiology, biomarkers, emergent targets, and the latest delivery solution. The paper covers and discusses various disease-causing mechanisms like plaque formation, tau hyperphosphorylation, etc., which causes AD. Research is also being undertaken on the role of genetic and epigenetic factors in the pathogenesis and evolution of diseases, including but not limited to APOE polymorphisms, DNA methylation, modifications of histones, and non-coding RNAs. Researchers have discovered biomarkers relevant to AD, particularly those found in CSF and blood. The biomarkers include Aβ42, phosphorylated tau, neurofilament light chain, GFAP, and TREM2. Other biomarkers include salivary, urinary, neuroimaging, and digital. Next come the therapeutic strategies targeting amyloid aggregation, tau pathology, and other types of dysfunctions. Recent developments in monoclonal antibodies, kinase inhibitors, anti-inflammatory agents, neurotrophic agents, and antioxidant therapies are stressed. Moreover, nanotechnology-based and targeted delivery systems being developed for drugs include, but are not limited to, liposomes, polymeric nanoparticles, dendrimers, nanoemulsions, and intranasal formulations to enhance blood-brain barrier permeability. A combination of biomarker-guided diagnostics with mechanism-based therapies might enable precision medicine approaches and improve clinical outcomes in AD.

PURPOSE: Informal carers ('proxies') are often asked to report on the health of individuals who cannot self-report, either from their own ('proxy-proxy') or the patient's ('proxy-person') perspectives. It remains unclear which perspective proxies find most useful. Understanding this is important for designing measures that proxies can complete. We conducted an exploratory study on which perspective proxies find most useful and why, when reporting pain and physical function in dementia and symptoms in multiple sclerosis (MS). METHODS: This study used data from two cross-sectional online surveys: one for proxies of people with MS and another for people with dementia. Proxies were asked to indicate which perspective they found most useful and why for communicating symptoms in MS, and pain or physical function in dementia, to healthcare professionals (HCPs). Quantitative responses were summarised using percentages; qualitative responses were analysed using content analysis. RESULTS: 55 proxies reported on MS symptoms, 29 on pain in dementia, and 33 on physical function in dementia. The most selected perspectives were: 35% (19/55) proxy-proxy for MS symptoms, 38% (11/29) proxy-person for pain and 39% (13/33) either of the perspectives for physical function. Proxy-person was valued for empathy and person-centredness, especially in reporting pain and MS symptoms. Proxy-proxy was appreciated for objectivity and reducing conflict, particularly in physical function. Using either perspective was considered most useful for balancing views and reducing misinterpretation in both conditions. CONCLUSION: Proxies' most useful perspectives vary slightly by domain and condition. Incorporating an understanding of how proxies approach the challenge of reporting may improve measure design.