Search Results (12,030)

Background and Objectives: Impaired autophagy has been implicated in neurodegeneration, but circulating autophagy-related proteins have shown inconsistent associations with cognitive impairment. We compared serum autophagy-related protein 5 (ATG5) among older adults with normal cognition, mild cognitive impairment (MCI), and clinically diagnosed Alzheimer’s disease (AD), and examined its relationship with global cognitive performance. Materials and Methods: This single-centre cross-sectional study enrolled 164 older adults (55 with normal cognition, 55 with MCI, and 54 with clinically diagnosed AD). Cognitive status was determined through integrated clinical assessment rather than a single test cut-off. An enzyme-linked immunosorbent assay was employed to quantify serum ATG5, yielding quantifiable values for 156 participants, right-censored observations above the highest calibrator for six, and unmeasurable results for two. Since the two 96-well plates, drawn from one ELISA kit lot and processed on the same day, exhibited a substantial discrepancy in measurement scale across runs, they were analysed as distinct strata, with the principal group contrast estimated via a right-censored Tobit regression of log-transformed ATG5 within each plate, controlling for cognitive group, age and sex; a pooled plate-adjusted model also provided support. Supportive analyses used within-plate z-standardised ATG5. Associations with clinical variables were assessed using age- and sex-adjusted partial Spearman correlations with false discovery rate correction. Results: Across both analytical strata (plate 1 omnibus p = 0.293; plate 2 p = 0.264) and within the supportive pooled model (p = 0.143; AD vs. normal geometric mean ratio 0.89, 95% CI 0.73–1.09), serum ATG5 concentrations did not differ significantly between cognitive groups. Concentrations on plate 2 were 47% lower (GMR 0.53, 95% CI 0.45–0.62), a gap exceeding the inter-assay imprecision declared by the manufacturer and unexplained by the calibrator values from plate 2; since relative dispersion matched across both plates (likelihood ratio p = 0.730), the pattern suggests a multiplicative scale shift of unknown origin. Serum ATG5 levels were weakly associated with global cognitive performance assessed via the S-MMSE (partial ρ = 0.283, p < 0.001, FDR p = 0.010), an association that persisted after adjusting for education, albumin and folate and retained a similar magnitude within a linear model (β = 0.044, p = 0.014). Incorporating ATG5 into a model that included age, sex and education failed to enhance discrimination (ΔAUC +0.012 and +0.000). Conclusions: Serum ATG5 did not discriminate normal cognition, MCI, and clinically diagnosed AD. A weak rank-based association with S-MMSE was observed, but the effect was small. These findings do not support serum ATG5 as a diagnostic discriminator for clinically defined cognitive status. Full article

Background: This study aims to develop an amyloid-beta-induced three-dimensional (3D) Alzheimer’s disease model using the Magnetic Levitation (MagLev) technique and rat pheochromocytoma (PC-12) (rat pheochromocytoma) cells. Methods: Initially, optimization studies were performed to determine the appropriate paramagnetic agent concentration and cell number required for the formation of 3D cellular structures. The formation of these structures was monitored by light microscopy, and cell viability was evaluated using a live/dead assay. Filamentous actin (F-actin) expression was assessed by immunostaining. Subsequently, amyloid beta 1–42 (Aβ1–42) aggregates were introduced into the 3D cellular structures to establish a 3D Alzheimer’s disease model. The 3D disease model was characterized by immunostaining of Choline Acetyltransferase (ChAT). Finally, the applicability of the developed model for therapeutic evaluation was demonstrated using curcumin as a representative neuroprotective compound. Results: The optimization studies successfully enabled the formation of 3D cellular structures using the magnetic levitation technique. Immunostaining analysis showed an increase in F-actin expression in 3D structures. Following the introduction of Aβ1–42 aggregates, a significant decline in cell viability was observed by day 21. ChAT immunostaining revealed a decrease in fluorescence intensity (F.I.) to 28% of the control level, corresponding to an approximately 72% reduction in ChAT expression. Curcumin treatment increased cell viability by 22%, 23%, and 13% on days 7, 15, and 21, respectively. Conclusion: Overall, the findings showed that the 3D Aβ 1–42 induced 3D Alzheimer’s disease model can provide a valuable experimental platform for investigating neurodegenerative diseases and evaluating potential therapeutic interventions. Full article

Background/Objectives: Alzheimer’s disease (AD) is a multifactorial neurodegenerative condition characterised by cognitive impairment, cholinergic deficiency and neuroinflammation. Carvacrol and thymol are two related natural monoterpenes with reported antioxidant, anti-inflammatory, anti-apoptotic and cholinesterase-inhibiting properties. This scoping review aims to map the current evidence regarding the effects of carvacrol and thymol on AD-related pathologies and identify their mechanisms of action. Methods: A systematic literature search was conducted in February 2026 across PubMed, Scopus and Web of Science. This review included original, English-language primary research articles investigating the effects of carvacrol and thymol on AD using in vitro, in vivo, or in silico models. Results: From an initial pool of 87 unique records, 30 primary studies met the inclusion criteria, encompassing direct AD pathology models (e.g., amyloid-beta), AD-associated risk models (e.g., metabolic or hypertensive impairment), and general cognitive impairment models. Both carvacrol and thymol reduced escape latency during spatial learning acquisition training and increased time spent in the target quadrant during probe trials, indicating improvements in both learning and memory retention, although several studies reported non-linear relationships. At the cellular level, carvacrol and thymol modulated distinct redox and inflammatory pathways, including nuclear factor erythroid 2-related factor 2 upregulation and tumour necrosis factor-alpha suppression. Synthetic derivatives and nanocarrier formulations (e.g., liposomes, nanoemulsions) demonstrated enhanced acetylcholinesterase inhibition and biological stability relative to parent monoterpenes. No clinical trials were identified, and formal critical appraisal was not performed. Conclusions: Preclinical evidence indicates that carvacrol and thymol show potential multi-targeted neuroprotective activity across diverse models of cognitive dysfunction. However, clinical translation remains unproven due to heterogeneous experimental designs, pharmacokinetic limitations, a lack of human trials, and unassessed study quality. Full article

Background and Objectives: The main neurodegenerative diseases (NDs)—Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)—represent a growing global health burden with no available disease-modifying therapies. Curcumin, a polyphenol from Curcuma longa, is a promising candidate owing to its pleiotropic antioxidant, anti-inflammatory, and neuroprotective profile observed mainly in preclinical models, but the poor oral bioavailability (<1%) and negligible BBB penetration (<0.1%) have substantially limited curcumin’s clinical translation. The objective of this work was to critically examine the therapeutic potential of curcumin in NDs, focusing on advanced drug delivery systems (DDSs) designed to overcome its pharmacokinetic barriers. Methods: This is a narrative, non-systematic review of PubMed/MEDLINE, Scopus, and Web of Science. The review is organized around five complementary thematic areas selected to span the full translational pipeline of curcumin in neurodegeneration, from mechanistic rationale to clinical applicability: (1) molecular mechanisms, addressing the pleiotropic activities that justify therapeutic interest; (2) pharmacokinetic barriers, the principal obstacle to clinical translation; (3) the evolution of drug delivery systems (DDSs), documenting the technological strategies developed to overcome these barriers; (4) disease-specific applications, evaluating the available evidence across the four main NDs; and (5) translational limitations, identifying the methodological and regulatory gaps that must be closed to enable clinical implementation. Results: Curcumin exhibits neuroprotective activity in preclinical models of the four NDs analysed, acting on six interconnected mechanisms and the gut–brain axis. Four generations of DDSs have been developed, from phytosomes and clinically used lipid dispersions (Meriva^®, BCM-95^®, Longvida^®, and Theracurmin^®) to fourth-generation systems (biomimetic nanoparticles, MOFs, microneedles, 3D scaffolds, hydrogels, and carbon dots) that substantially increase the bioavailability in preclinical studies. Combination strategies, such as curcumin with resveratrol and dutasteride, show preliminary clinical signals in ALS. However, clinical translation remains limited: over 80% of positive animal findings have not been replicated in humans, formulation characterization is frequently incomplete, and most trials lack CNS-exposure biomarkers. Importantly, most of the reported bioavailability claims are based on total curcumin measurements (parent aglycone plus its inactive Phase II conjugates) rather than the active aglycone alone, a methodological limitation that should be considered when interpreting the magnitude of the bioavailability improvements reported for novel formulations. Conclusions: Curcumin exhibits pleiotropic neuroprotective activity in preclinical models of AD, PD, MS, and ALS, mediated by interconnected antioxidant, anti-inflammatory, anti-amyloidogenic, mitochondrial, and gut–brain axis mechanisms. However, its poor systemic bioavailability (<1%), minimal blood–brain barrier penetration, and extensive first-pass metabolism have limited clinical translation. Advanced drug delivery systems (including lipid-based carriers (liposomes, solid lipid nanoparticles, and nanostructured lipid carriers), polymeric nanoparticles (PLGA and chitosan), and bioinspired vesicles (exosomes)) are essential in order to overcome these barriers. Nevertheless, the formulation heterogeneity, limited long-term safety data, and reliance on preclinical models remain major obstacles; a definitive clinical translation will therefore require well-characterized formulations validated in phase II/III trials with cerebrospinal fluid exposure biomarkers, the pharmacokinetic monitoring of active aglycone (rather than total curcumin including inactive conjugates), and adaptive trial designs in neurological populations. Full article

Although dementia-related stigma is well-documented, there is a paucity of research examining intergenerational activities to reduce stigma within rural settings. Using a World Café approach, the objective of this paper was to explore rural stakeholders’ ideas and perspectives on intergenerational strategies to reduce dementia-related stigma in rural communities. Seventy-five participants engaged in a facilitated workshop held in Kamloops, British Columbia, Canada, on 14 May 2025. Discussions were transcribed and analyzed using Braun and Clarke’s thematic analysis framework. The findings highlighted three themes for reducing dementia-related stigma in rural communities: (1) contact activities that promote meaningful interactions (e.g., shared hobbies, arts programs, and reminiscence activities) between people living with dementia and others across age groups; (2) educational interventions that enhance dementia knowledge and awareness (e.g., dementia information integrated into educational institutions across the life course); and (3) mixed interventions that combine contact-based and educational approaches. Moving forward, further research is needed to co-design, implement, and evaluate the impact of specific interventions. This study provides critical insights to inform the development of dementia stigma-reduction programs, policies, and interventions in rural settings. Full article

Alzheimer’s disease (AD) is the leading cause of dementia and disproportionately affects women, who experience a higher lifetime risk and more rapid structural brain changes than men. Reliable imaging biomarkers are essential for detecting these changes, although their estimation may be influenced by voxel geometry, image resolution, and segmentation methodology. In this study, magnetic resonance imaging (MRI) scans from 40 female participants with AD obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were analyzed using the Computational Anatomy Toolbox 12 (CAT12), implemented within Statistical Parametric Mapping 12 (SPM12), and Materialise Mimics to identify structural biomarkers associated with neurodegeneration. Cortical thickness, gray matter (GM), white matter (WM), cerebrospinal fluid (CSF), and total intracranial volume (TIV) were quantified, while Brain Parenchymal Volume (BPV) and Brain Parenchymal Fraction (BPF) were calculated to assess global brain tissue preservation. The analyses demonstrated characteristic AD-related changes, including cortical thinning, GM loss, ventricular enlargement, and increased CSF volume. Significant correlations among cortical thickness, tissue volumes, BPV, and BPF further supported their complementary role in characterizing disease-related structural changes. Overall, these findings suggest that MRI-derived measures of cortical thickness, tissue volumes, BPV, and BPF provide useful structural biomarkers of AD and emphasize the importance of considering voxel geometry and segmentation methodology when evaluating neuroimaging biomarkers. Full article

Existing electroencephalography (EEG) complexity methods treat channels as independent univariate series under an isotropic Euclidean metric, which retains the magnitude of inter-channel fluctuations but not the direction of interhemispheric dominance. We reformulate fractal analysis in two-dimensional Minkowski space using the non-positive-definite Lorentzian metric instead of the Euclidean norm, thereby preserving directional information. Each increment vector between paired left–right electrodes is classified by the sign of its Lorentzian self-product as spacelike (left-dominant), timelike (right-dominant) or null, so that complexity and directional asymmetry are quantified jointly. Minkowski Higuchi Fractal Dimension (M-HFD) is a consistent extension: it reduces exactly to the classical Higuchi Fractal Dimension (HFD) under proportional coupling and remains stable under bounded perturbations of that ideal. Synthetic fractional Brownian motion experiments confirm reliable dimension estimation across the full fractal range. On an open-access cohort (36 Alzheimer’s patients, 29 controls), a Mamdani fuzzy inference system under leakage-free nested leave-one-out cross-validation attained AUCs of 0.873 (mixed), 0.883 (female) and 0.880 (male). Full article

Neurodegenerative diseases arise from interacting oxidative, inflammatory, mitochondrial, and proteostatic disturbances. Hydroxytyrosol (HT), an olive phenol, has been proposed as a multitarget neuroprotective compound. This narrative review integrates HT chemistry, parent/metabolite pharmacokinetics, blood–brain barrier (BBB) evidence, mechanisms, disorder-specific models, and human studies. Direct HT evidence is strongest for nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) activation and experimental modulation of α-synuclein; support for AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial protection, nuclear factor-kappa B (NF-κB)-related inflammation, and amyloid-β (Aβ) is predominantly preclinical, whereas tau, autophagic flux, and ubiquitin–proteasome effects remain preliminary. Oral HT is rapidly absorbed but extensively conjugated, and no study has quantified parent HT or its major metabolites in the human brain or cerebrospinal fluid after oral supplementation. Isolated-HT trials show systemic antioxidant or anti-inflammatory biomarker effects, while cognitive findings derive mainly from phenolic-rich olive matrices and cannot be assigned to HT alone. No disease-modifying efficacy has been established for isolated HT in Alzheimer’s disease (AD), Parkinson’s disease (PD), or related disorders. HT is therefore a mechanistically plausible candidate, but human brain exposure, dose–response, and efficacy require adequately powered disease-specific trials. Full article

Background: Apathy is an increasingly recognized predictor of cognitive decline. Although both poor glycemic status and apathy have been independently linked to cognitive decline, whether apathy mediates the relationship between poor glycemic status and cognitive decline remains unclear. Methods: We used data from 4571 adults aged ≥60 years without baseline memory problems from the U.S. Health and Retirement Study. Glycemic status was measured using glycosylated hemoglobin (HbA1c). Apathy-like symptoms were derived from CES-D items, reflecting diminished positive affect and motivation. Outcomes included incident cognitive impairment and incident self-reported Alzheimer’s disease and related dementias (ADRD). Accelerated Failure Time models, adjusted for age, sex, and education, estimated associations between HbA1c and time to each outcome. Mediation was tested using a product-of-coefficients approach that incorporated survey weights. Results: Over a mean 8.89 (SD 4.7) years, 938 participants developed cognitive impairment. Higher HbA1c was associated with shorter time to cognitive impairment (TR = 0.85; 95% CI 0.79–0.91). After adjustment for apathy-like symptoms, the association was attenuated (TR = 0.87; 95% CI 0.81–0.92), indicating approximately 11% mediation. Over 9.2 (SD 4.6) years, 583 participants reported incident ADRD. Higher HbA1c was associated with shorter time to ADRD (TR= 0.91; 95% CI 0.85–0.97) that was attenuated (TR = 0.93; 95% CI 0.86–0.99), suggesting 20% mediation through apathy-like symptoms. However, the mediation effects attenuated after further adjustment for baseline cognition and vascular/lifestyle factors. Conclusions: Overall, poorer glycemic status was associated with accelerated onset of adverse cognitive events, with apathy-like symptoms as a potential mediator requiring confirmation in future studies. Full article

The search for new compounds capable of inhibiting the activity of enzymes involved in the development of neurodegenerative diseases, including Alzheimer’s disease, has attracted continuing interest for many years. Natural isothiocyanates and their synthetic analogs, as well as compounds containing a 1,3,5-triazine core, constitute a group of molecules with complex mechanisms of action involving multiple molecular targets. Although literature data confirm the activity of both isothiocyanates and s-triazines, these two active fragments have not yet been combined, and it remains unclear whether a synergistic effect can be achieved. In this study, 11 novel isothiocyanate–triazine conjugates, consisting of a 1,3,5-triazine core substituted with aliphatic or cyclic secondary amines and a phosphorus analogue of isothiocyanate [6-(isothiocyanatohexyl)phosphonate)ethyl], were synthesized with yields of 46–80%. The pharmacokinetic profiles and parameters related to Lipinski’s rule of five were determined for all compounds. All compounds were evaluated as inhibitors of acetylcholinesterase (AChE) and β-secretase (BACE1). Compound 1i showed the highest inhibitory activity against AChE (IC₅₀ = 0.182 ± 0.02 µM), while compound 1b exhibited the strongest inhibition of BACE1 (IC₅₀ = 8.48 ± 2.18 µM). To explore the potential of these multifunctional derivatives, plausible enzyme-ligand binding models were proposed based on molecular docking simulations. Full article

Background/Objectives: Cognitive stimulation and cognitive training are used as non-pharmacological approaches to support people living with Alzheimer’s disease, but Alzheimer-specific evidence is dispersed across heterogeneous intervention formats. This scoping review mapped structured cognitive stimulation and training interventions evaluated in people with mild-to-moderate Alzheimer’s disease and summarized the cognitive, emotional, functional, and follow-up outcomes reported. Methods: The review was conducted using the Joanna Briggs Institute methodology and reported according to PRISMA-ScR. PubMed, SciELO, PEDro, LILACS, and Google Scholar were searched on 24 February 2025 for studies published between January 2015 and 24 February 2025 in English, Portuguese, or Spanish. Intervention studies were eligible. Two reviewers independently screened records and charted data, with disagreements resolved by a third reviewer. Results: Of 352 records identified, five studies involving 245 participants were included. Interventions comprised virtual-reality cognitive stimulation, conventional cognitive training, group reminiscence therapy, a multicomponent music–reminiscence–reality-orientation intervention, and computerized cognitive training. In the limited technology-assisted evidence, statistically significant changes were reported in global cognition or selected memory, language, attention, and executive outcomes. Conventional cognitive training showed signals of improvement in initiative and temporary stabilization of memory, whereas reminiscence-based interventions primarily reported changes in depressive and neuropsychiatric symptoms. Where longer follow-up was available, benefits diminished over time. Conclusions: The mapped evidence suggests that structured cognitive stimulation and training may produce short-term, outcome-specific benefits in mild-to-moderate Alzheimer’s disease. Given the small and heterogeneous evidence base, these findings represent modality-related patterns within the included studies and should not be interpreted as evidence of comparative effectiveness. Full article

Background/Objectives: Beginning in mid-life, age-related cognitive decline may negatively affect overall hearing health. Thus, understanding the relationship between hearing and cognition is of critical importance. Although the relationship has received considerable attention, and numerous theories have been posited to explain it, questions remain. Research indicates that 50% of older Americans grapple with severe hearing loss, affecting their daily communication, while Alzheimer’s disease, a prevailing cause of dementia, affects approximately 11% of Americans aged 65 or older. The Lancet Commission underscores hearing loss as a leading modifiable risk factor for dementia, contributing up to 7% of the risk. The purpose of this study was to advance our understanding of the specific domains of hearing and cognition that are related, thus informing theory and clinical practice. Methods: Participants were 99 older adults (mean age = 73 years) recruited from the 10-year Indicators of Cognitive Change study. Measures of peripheral hearing sensitivity (four-frequency pure-tone average [PTA4]) and auditory processing (Dichotic Sentence Identification [DSI]) were used to predict performance on multiple measures from the Montreal Cognitive Assessment (MoCA) and Cogstate Brief Battery (CBB). Results: DSI emerged as a significant predictor across both MoCA and CBB, surpassing the predictive power of PTA4. Surprisingly, relationships between hearing and cognitive measures differed for MoCA domains versus CBB subtests, highlighting the complexity of this association. Conclusions: The ability to separate and identify competing auditory information may be necessary components of healthy cognitive function. In clinical practice, assessment of binaural auditory processing may provide an early indicator of cognitive vulnerability in older adults. Full article

Background: Due to the rise in Alzheimer disease (AD) and AD-related dementias (AD/ADRD) in an aging population, millions of caregivers will be at risk for physical and mental health decline. As those they care for already have physical and cognitive impairment, it is crucial that caregivers maintain health-promoting behaviors. Because regular physical activity (PA) prevents functional loss and improves physical health and well-being, understanding how to help caregivers adopt and sustain PA despite unique time, caregiving, and self-efficacy barriers is a pressing public-health priority. Existing health-promoting interventions among dementia caregivers, including PA, have demonstrated limited success. To overcome the fragmentation and slow synthesis of behavioral science evidence, the Human Behavior-Change Project advocates theoretical grounding, systematic mapping of intervention components (e.g., behavior change techniques [BCTs]) using standardized taxonomies, and explicit specification of mechanisms of behavior change (MoBCs). Objective: To examine the limited success of health-promotion interventions among dementia caregivers we aimed to conduct a narrative review to synthesize evidence from interventions that evaluated PA in dementia caregivers across three domains: (1) use of behavioral theory to inform intervention design, (2) specification of BCTs, and (3) identification and measurement of MoBCs. Methods: Two scientific databases were searched to identify representative studies and reviews, using key terms including “physical activity”, “intervention”, “dementia”, and “caregiver” from inception to July 2025. Results: Seven primary intervention trials and six reviews were selected for inclusion. Gaps across the domains were identified to inform priority areas for future research. Conclusions: There is a need to develop tailored, theory-driven PA interventions that target empirically supported BCTs and MoBCs to improve dementia caregivers’ health and well-being. Full article

Alzheimer’s disease (AD) is the leading cause of dementia and a heterogeneous neurodegenerative disorder characterized by amyloid-β (Aβ) and tau pathology, impaired proteostasis, neurovascular dysfunction, maladaptive glial and immune responses, and synaptic dysfunction. Human genetic evidence supports an upstream role for Aβ. Anti-Aβ monoclonal antibodies substantially reduce amyloid burden and modestly slow clinical decline in early symptomatic AD. Continued decline despite plaque removal is consistent with ongoing downstream tau pathology, glial responses, and neuronal injury. This narrative review examines AD mechanisms, biomarkers, and therapeutic prospects from a geroscience perspective and applies the eight hallmarks of neurodegenerative diseases as an analytical framework. Advances in blood-based biomarkers, particularly plasma phosphorylated tau 217, may improve biological detection, but their clinical value depends on assay performance, intended use, and patient context. Gut dysbiosis and gut–brain communication are considered separately as candidate systemic modifiers because causal evidence in humans remains insufficient. The hallmarks are overlapping analytical categories, not independent primary causes, and their therapeutic relevance depends on disease stage and pathway activity. Future studies should establish which preventive strategies and biomarker-guided, stage-matched combination therapies improve clinically meaningful outcomes and identify the patients most likely to benefit. Full article

Background: Alterations in glutamatergic homeostasis have been implicated in Alzheimer’s disease, but the relationship between total hippocampal tissue glutamate and Alzheimer-like molecular alterations remains unclear. This study evaluated the early neuroprotective potential of gentisic acid (GA) and erucic acid (EA) in an intracerebroventricular streptozotocin (icv-STZ)-induced rat model of sporadic Alzheimer-like pathology. Methods: Sixty-four female Sprague–Dawley rats were randomly assigned to eight groups: control, sham, STZ, STZ + GA (100 or 200 mg/kg/day), STZ + EA (25 or 50 mg/kg/day), and STZ + memantine (10 mg/kg/day). Treatments began immediately after STZ and continued orally for 21 days. Behavioral performance was assessed by Morris water maze and passive avoidance tests. Total hippocampal tissue glutamate was quantified by LC–MS/MS. Neuronal degeneration was assessed histopathologically, whereas tau, amyloid-β, and AChE immunoreactivity and tau-, APP-, and AChE-related in situ hybridization signals were evaluated. Results: Compared with controls, STZ-treated rats exhibited poorer behavioral performance, higher total hippocampal tissue glutamate, greater neuronal degeneration, and increased molecular signals. GA and EA administration was associated with attenuation of these alterations, with generally stronger effects at higher doses. EA at 50 mg/kg/day showed the lowest mean total hippocampal tissue glutamate among treatment groups. GA at 200 mg/kg/day and EA at 50 mg/kg/day showed the most consistent preservation across behavioral, histopathological, and molecular endpoints. Conclusions: Early GA and EA administration was associated with neuroprotective effects in the icv-STZ model. Because treatment began immediately after STZ administration, the findings support early or preventive neuroprotection rather than reversal of established Alzheimer-like pathology. Total tissue glutamate measurements neither distinguish extracellular glutamate nor directly demonstrate glutamate-mediated excitotoxicity. Full article