Search Results (633)

Background/Objectives: Self-awareness constitutes a key metacognitive construct supporting self-regulation and adaptive functioning in aging. This systematic review examined how self-awareness fluctuates across the Alzheimer’s disease (AD) continuum and explored its associations with cognitive performance and neuroimaging markers. Methods: A systematic search was conducted in databases including PubMed, Scopus, Science Direct and Web of Science covering the period from 2016 to 2026, and the review was registered on the Open Science Framework (OSF). The selection process followed PRISMA guidelines, and a total of 334 studies were screened for eligibility while 42 met the inclusion criteria. Studies were eligible if they examined self-awareness in relation to cognitive and/or neuroimaging parameters, with individuals in the preclinical and clinical spectrum of AD as the reference population. Results: The included studies highlighted self-awareness as a dynamic construct closely linked to cognitive performance and neural integrity, with measurable deviations emerging along the continuum from subjective cognitive decline to dementia. Accordingly, the findings suggest that alterations in self-awareness may reflect the stage-dependent cognitive and neurobiological changes that characterize the progression of AD. Conclusions: Converging evidence suggests that assessing fluctuations of self-awareness, ranging from heightened awareness to reduced awareness, may contribute to the early identification of individuals at risk of progression across the AD continuum. However, the substantial methodological heterogeneity across studies precludes definitive conclusions regarding its clinical utility. Future longitudinal studies employing standardized assessment protocols are needed to determine whether these changes can reliably predict disease progression. Full article

Nitrogen-containing fused tetracyclic systems, exemplified by the synthetic 11H-indeno[1,2-b]quinoxalin-11-one core and the natural alkaloid tryptanthrin (indolo[2,1-b]quinazolin-6,12-dione), constitute structural scaffolds whose rigid, planar architecture enables high-affinity interaction with nucleic acids and kinase active sites. Converting the exocyclic carbonyls at C-11 and C-6, respectively, into oximes has become a productive strategy in medicinal chemistry. This transformation modulates frontier orbital energies, installs N,O- and N,N-chelating pharmacophores, and enables nitric oxide (NO) release. Here, we summarize current knowledge of the synthesis, stereochemical characterization, and diverse biological activities of these tetracyclic ketoximes and related derivatives. Microwave, sonochemical, visible-light photocatalytic, and multicomponent methods now afford efficient, economical routes to the parent ketones and their oximes. X-ray crystallography, spectroscopy, and density functional theory have firmly established the thermodynamic preference for the E-oxime configuration and clarified how this geometry, along with potential target-induced isomerization, shapes binding. The oximes bind c-Jun N-terminal kinases (JNK1–3) with high affinity, a property that accounts for their neuroprotective effects in models of cerebral ischemia and Alzheimer-like pathology, their dual JNK inhibition and NO-mediated cardioprotection in hypertension and myocardial infarction, and their anti-inflammatory activity via suppression of NF-κB/AP-1 signaling. Broader studies also document anticancer, antimicrobial, antiviral, and antidiabetic activities arising from DNA intercalation, topoisomerase inhibition, metal-ion coordination, and kinase blockade. Compelling preclinical profiles notwithstanding, low oral bioavailability and rapid hepatic clearance remain major pharmacokinetic obstacles. Ongoing work on new formulations, prodrug strategies, and structure–activity optimization seeks to slow systemic elimination. Precise stereochemical definition combined with pleiotropic pharmacology positions tetracyclic ketoximes as attractive candidates for next-generation agents against complex multifactorial diseases. Full article

Background/Objectives: Evaluating noninvasive, accessible ocular and blood-based biomarkers could aid in early risk stratification and disease detection during the preclinical phase of Alzheimer’s disease. This study investigates associations between plasma biomarkers of neurodegeneration and retinal structural and microvasculature parameters in cognitively normal adults with familial or genetic risk factors for Alzheimer’s disease. Methods: Forty-one participants underwent plasma sampling for glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), amyloid-beta42 (β42), amyloid-β42/40 ratio, and phosphorylated-tau217 (p-tau217), and also underwent optical coherence tomography (OCT) and OCT angiography (OCTA) imaging. Apolipoprotein E genotyping and family history of Alzheimer’s disease were recorded. Generalized estimating equations adjusting for age, sex, race, treated hypertension, Alzheimer’s disease family history, and APOE ε4 carrier status assessed associations between plasma biomarker concentrations and OCT and OCTA measurements. Results: Higher plasma GFAP and NfL concentrations were significantly associated with reduced superficial capillary plexus perfusion density and vessel density on macular OCTA. In additional analyses restricted to participants with plasma biomarker and retinal imaging assessments obtained within 9 months, associations with GFAP remained significant, whereas NfL associations no longer remained significant after correction for multiple comparisons. Conclusions: Retinal OCTA and OCT metrics may reflect general neurovascular aging in cognitively normal individuals with familial or genetic risk factors for Alzheimer’s disease. Full article

The discovery of the glymphatic system and meningeal lymphatic vessels established that the brain possesses an organized lymphatic clearance network that drains to the deep cervical lymphatics. Disruption of this system has been suggested to contribute to the accumulation of pathogenic proteins implicated in neurodegeneration. Cervical lymphatic reconstruction has been associated with some neurological benefit in Alzheimer’s and Parkinson’s disease, and preclinical work has demonstrated that noninvasive manipulation of superficial cervical lymphatics can increase cerebrospinal fluid outflow. Whether noninvasive cervicofacial lymphedema therapy can produce comparable neurological effects remains unknown. We report two men with Parkinson’s disease (Hoehn and Yahr stages 2.5 and 3) treated with a standardized cervicofacial lymphedema therapy protocol targeting cervical and facial lymphatic pathways. Total MDS-UPDRS scores decreased by 19 points (34.5%) in Patient 1 and 5 points in Patient 2. The reduction in Patient 1 exceeded the published threshold for clinically meaningful total-score improvement. Benefits were reproducible and session-linked, and were accompanied by motor and non-motor gains in cognition, alertness, mood, energy, and sleep; interruption of therapy was associated with return toward baseline. Cervicofacial lymphedema therapy may represent a low-risk, noninvasive intervention hypothesized to influence brain lymphatic clearance in Parkinson’s disease. Full article

Mesenchymal stromal cells (MSCs) have emerged as a promising therapeutic platform for central nervous system disorders, including neurodegenerative diseases and lysosomal storage disorders (LSDs). This review examines MSC mechanisms of action—paracrine activity, immunomodulation, antioxidant effects, TFEB-mediated autophagy regulation, and enzymatic cross-correction in LSDs—while critically assessing translational challenges. We provide a comparative analysis of MSC sources, administration routes, dosing regimens, and safety profiles, with emphasis on hemocompatibility and thrombotic risks. The evidence base for MSC efficacy in amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and LSDs is systematically reviewed, highlighting both promising signals and limitations. MSC-derived extracellular vesicles are discussed as a cell-free alternative with improved safety and potential blood–brain barrier interaction. We propose an individualized monitoring framework integrating clinical scales, biomarkers, and neuroimaging. Despite preclinical promise, the field faces major hurdles: product standardization, optimal dosing, and the need for large, randomized controlled trials. The most rational path forward lies in combination strategies—MSCs as adjuncts to gene or enzyme replacement therapy—and engineered platforms for sustained delivery. This review provides a roadmap for translational decision-making and identifies critical gaps that must be addressed before MSC-based therapies can be integrated into routine neurological practice. Full article

Drosophila melanogaster shares approximately 75% of human disease-related genes and possesses sophisticated genetic toolkits, including GAL4/UAS, CRISPR-Cas9, and RNA interference (RNAi), making it a rapid, cost-effective, and genetically tractable in vivo platform for natural products (NPs) discovery. This review systematically summarizes the modeling strategies, pathological mechanisms, and therapeutic applications of Drosophila models for six major human diseases, including type 2 diabetes, nephrolithiasis, inflammatory bowel disease, cancer, Alzheimer’s disease, and Parkinson’s disease. Cross-disease analysis identifies five evolutionarily conserved signaling networks—IIS/PI3K/Akt/FOXO, JNK/JAK/STAT, Nrf2/Keap1, mTOR/TORC1, and IMD/Toll—as common molecular targets of bioactive NPs, providing a unified mechanistic framework for understanding their multi-target pharmacological activities and broad therapeutic potential. Critically, we propose a generalizable integrated stepwise pipeline: high-throughput fly screening of crude extracts, bioassay-guided isolation of active monomers, genetic mechanistic dissection via RNAi and mutant rescue, and layered validation in human cells and selective mammalian models. This pipeline addresses key challenges in NPs research, including the identification of bioactive constituents and mechanistic validation, while improving screening efficiency and translational potential. Overall, this review establishes a multi-disease-applicable framework linking disease modeling, conserved signaling mechanisms, and translational pharmacology, providing practical guidance for future mechanism-driven NP discovery and preclinical development using Drosophila. By leveraging Drosophila genetics to bridge evolutionary conservation and human pathology, this framework offers a powerful, paradigm-shifting strategy to accelerate mechanism-driven NP discovery and preclinical development. Full article

Background: Memantine, an uncompetitive and voltage-dependent N-methyl-D-aspartate (NMDA) receptor antagonist, is clinically established for moderate-to-severe Alzheimer’s disease. Its pharmacodynamic profile, low-to-moderate affinity, rapid open-channel block, and strong voltage dependency allows selective inhibition of pathological NMDA overactivation while preserving physiological neurotransmission. Increasing evidence shows that these same mechanistic principles operate in the peripheral nervous system, where NMDA receptors contribute to excitotoxicity, oxidative stress, neuroinflammation, and maladaptive nociceptive signaling. Purpose: To synthesize emerging preclinical and clinical evidence demonstrating memantine’s modulatory and neuroprotective actions in peripheral neurons and glia and to outline implications for drug repurposing across neurology, pain medicine, oncology, supportive care, and ophthalmology. Methodology: A narrative integration of mechanistic studies, in vivo preclinical models, and heterogeneous clinical trials evaluating memantine’s effects on peripheral sensory neurons, autonomic neurons, Schwann cells, retinal ganglion cells, and neuromuscular junction physiology. Evidence was examined across conditions involving excitotoxicity, oxidative injury, mitochondrial dysfunction, apoptotic signaling, neuroinflammation, and neuropathic pain amplification. Results: Memantine consistently attenuates peripheral excitotoxic calcium influx, suppresses NOX-2–mediated ROS generation, stabilizes mitochondrial membrane potential, modulates Bax/Bcl-2 signaling, and reduces neuroinflammatory cytokine activity. It also inhibits dorsal horn wind-up selectively under neuropathic conditions. These convergent mechanisms yield protective effects across chemotherapy-induced peripheral neuropathy (CIPN), diabetic neuropathy, traumatic nerve injury, phantom limb pain, retinal ganglion cell excitotoxicity, and organophosphate-induced neuromuscular toxicity. Clinical evidence includes improved multimodal neuropathy outcomes in diabetic neuropathy when combined with gabapentin, reduced phantom limb pain prevalence and intensity at six months, and a five-fold reduction in post-mastectomy neuropathic pain with pre-emptive administration. Conclusions: Memantine should be conceptually reframed as a system-wide neuroprotective agent with substantial translational potential beyond the CNS. Priorities for future development include NR2B-selective peripheral NMDA antagonists, peripherally restricted formulations, single-cell transcriptomic mapping of peripheral NMDA receptor subtypes, and adequately powered PNS-specific randomized trials. Full article

Background/Objectives: The blood–brain barrier (BBB) remains a major obstacle to effective gene therapy for neurological disorders by limiting delivery of viral vectors, nanoparticles, and biologics to the central nervous system. Multiple strategies have been developed to transiently disrupt or bypass the BBB, including focused ultrasound (FUS) with microbubbles, osmotic agents, biochemical modulators, and receptor-mediated transport systems. Among these approaches, FUS-mediated BBB opening has emerged as the most spatially precise and clinically advanced strategy. Methods: This narrative review synthesizes recent preclinical and clinical literature on BBB microdisruption technologies for central nervous system gene therapy, with primary emphasis on FUS combined with microbubbles. We review BBB physiology, gene delivery platforms, the development of FUS technologies, optimization parameters, and translational evidence across neurological diseases from animal models through early-phase human studies. Results: FUS-mediated BBB opening has emerged as the leading method for transient barrier modulation. Preclinical studies in Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, glioblastoma, amyotrophic lateral sclerosis, and lysosomal storage disorders demonstrate enhanced gene delivery, increased transgene expression, and improved functional outcomes. Large-animal studies and early clinical trials indicate that BBB opening is reversible, spatially controlled, and generally well tolerated. Clinical investigations have demonstrated successful delivery of therapeutic agents across neurological indications, with preliminary efficacy signals including improved drug penetration, metabolic changes, and potential survival benefits. Optimization of acoustic parameters, microbubble characteristics, and real-time cavitation monitoring remains critical for maximizing safety and therapeutic efficacy. Conclusions: BBB microdisruption, particularly through FUS with microbubbles, represents a transformative platform for central nervous system gene therapy. Continued research is needed to standardize treatment protocols, characterize long-term safety, and facilitate broader clinical translation. Full article

Alzheimer’s disease (AD) remains a major neurodegenerative disorder lacking effective long-term disease-modifying therapies. Current pharmacological approaches provide primarily symptomatic benefit, while recently approved anti-amyloid monoclonal antibodies offer only modest clinical efficacy and are constrained by safety concerns, high costs, and limited blood–brain barrier (BBB) penetration. In this context, exosome-based strategies have emerged as potential therapeutic platforms in AD research. As endogenous nanovesicles, exosomes exhibit favorable biocompatibility, intrinsic BBB-crossing capacity, and the ability to deliver diverse therapeutic cargo across multiple pathological pathways. Through bioengineering approaches, exosomes may additionally be optimized for targeted brain delivery and therapeutic personalization. Nevertheless, despite their conceptual and preclinical advantages, exosome-based therapies remain at an early translational stage, with unresolved challenges related to large-scale production, standardization, biodistribution, and long-term safety. This review provides a comparative translational analysis of conventional and exosome-based therapeutic strategies in AD, focusing on mechanistic targeting, delivery efficiency, safety and tolerability, therapeutic personalization, and translational readiness. We critically evaluate the extent to which exosome-based platforms may address the limitations of current therapies while highlighting the key barriers that continue to limit their clinical translation and real-world applicability. Full article

Background: Nose-to-brain delivery offers a noninvasive route to bypass the blood–brain barrier for the treatment of neurodegenerative diseases. AmyP53 is a first-in-class adaptive 12-mer peptide that prevents the formation of neurotoxic amyloid oligomers by competitively targeting lipid raft gangliosides on brain cell membranes, thereby blocking the shared pathological mechanism underlying both Alzheimer’s and Parkinson’s diseases. Objective: Here, we report the identification of optimal spray devices for the nose-to-brain delivery of AmyP53, ahead of a planned Phase 1 clinical trial. Method/Results: Among six devices evaluated (four commercial systems and two novel devices specifically engineered for nose-to-brain delivery), two systems were identified as optimal for further clinical development (narrower plume angles and significantly higher deposition in the olfactory region): the Neurospray™ and Neurospray™ Preservative-Free (PF). AmyP53 was quantitatively and reproducibly delivered by both Neurospray™ systems, retaining full recognition of its therapeutic target (gangliosides), as assessed by a surface pressure-based ganglioside-binding assay. In a rabbit preclinical model, intranasal administration of AmyP53 with the Neurospray™ resulted in rapid and sustained brain delivery, detectable at 10 min and persisting at 24 h post-administration, without significant systemic exposure. Conclusions: These results validate the Neurospray™ drug delivery systems as optimal drug delivery systems for the clinical development of AmyP53. Full article

While Alzheimer’s disease (AD) is primarily considered a disorder of protein aggregation, converging evidence from clinical, neuropathological, and mechanistic studies strongly supports the notion that brain endothelial dysfunction is a primary and early event in AD pathogenesis. Brain endothelial pathways are among the most differentially expressed in human AD brains. Brain endothelial alterations precede amyloid deposition and cognitive deficits in experimental AD models and closely parallel the degree of neuronal loss in human AD brains. Despite growing evidence to support brain endothelial contributions to neurodegeneration, studies examining the potential of the brain endothelium as a druggable target in AD have been scarce. Further, there has been a relative paucity of validated fluid biomarkers that can reliably measure brain endothelial injury in AD, independently of overt vascular disease or disruption to other cerebrovascular constituents. In this perspective, we propose a brain endothelial glycocalyx-centric model of AD in which brain endothelial dysfunction, driven predominantly by non-enzymatic glycation and carbonyl stress, acts as a key upstream regulator of aberrant protein trafficking, blood–brain barrier instability, and dysregulated neuro-immune cascades. Further, recent evidence suggests the presence of direct interactions of the brain endothelium with key pathways involved in neuronal survival and synaptic signaling, highlighting potential direct contributions of brain endothelial disturbances to cognitive impairment. Within this framework, we identify several brain endothelial axes, including reduction in carbonyl stress, improved glycation-dependent signaling, attenuation of advanced glycation end-product (AGE)-mediated toxicity, and enhanced endothelial glycocalyx stability and resilience as potential therapeutic approaches in AD. Modulating brain endothelial glycation has potential as a novel therapeutic strategy in AD which may complement other disease-modifying treatments, particularly in the earliest preclinical stages. In conclusion, this framework positions the brain endothelium as a mechanistic hub linking metabolic stress to aberrant protein aggregation and neurodegeneration in AD with potential therapeutic implications in AD and other neurodegenerative disorders. Full article

Background: Preventive strategies, including adherence to specific dietary patterns, have received increasing attention as approaches to reduce cognitive decline and dementia risk. However, findings remain inconsistent, partly due to differences in dietary assessment methods, cognitive outcomes, and THE consideration of genetic susceptibility factors such as apolipoprotein E (APOE) genotype. Methods: This study examined associations between dietary patterns and longitudinal cognitive change in 185 older adults without dementia from the Western Australia Memory Study. Participants completed a food frequency questionnaire at baseline and underwent comprehensive neuropsychological assessments at baseline and up to five follow-up visits at 18-month intervals. Composite scores were generated for six cognitive domains and the Preclinical Alzheimer’s Cognitive Composite (PACC). Results: Western and Prudent dietary pattern scores were analysed using linear mixed-effects models stratified by APOE ε4 carrier status. Among APOE ε4 carriers, greater adherence to a Western dietary pattern was associated with a faster decline in attention (p = 0.016), whereas no significant associations were observed for the Prudent dietary pattern or among APOE ε4 non-carriers. This association was attenuated after excluding participants with possible baseline cognitive impairment (MoCA < 23). Conclusion: These findings suggest that adherence to a Western dietary pattern may accelerate cognitive decline in individuals genetically at risk for Alzheimer’s disease, highlighting the importance of considering gene–diet interactions when developing dietary strategies for dementia prevention. Full article

Background/Objectives: Mental and neurological disorders contribute substantially to the global burden of disease, affecting people of all ages and backgrounds. As their prevalence increases with age, their overall impact is expected to grow in the coming decades. Although psychological and pharmacological treatments are available, many patients fail to achieve satisfactory outcomes, underscoring the need for improved therapeutic strategies. Cannabis sativa L. has been used for medicinal purposes for centuries, and cannabidiol (CBD) has attracted increasing attention because of its broad therapeutic potential. Scientific studies indicate that CBD may be beneficial in several mental and neurological disorders. Methods: A comprehensive literature search was conducted to identify articles investigating the therapeutic potential of CBD and cannabis in selected disorders. Results: Evidence from preclinical and clinical studies, together with findings from the broader cannabis literature, indicates that CBD may offer therapeutic benefits in a range of conditions, including Alzheimer’s and Parkinson’s disease, anxiety disorders, and epilepsy. Emerging data also support its potential use as an adjunctive therapy for COVID-19. Current research has improved understanding of the neurobiological mechanisms underlying these disorders and the molecular pathways through which CBD may exert its effects. CBD has demonstrated good tolerability, with predominantly mild adverse effects and a favorable safety profile. Conclusions: Despite promising findings, many available studies are preclinical or involve small patient cohorts, and the mechanisms underlying the therapeutic effects of CBD remain incompletely understood. Further well-designed, randomized, controlled, multicenter trials are needed to establish the efficacy and safety of CBD and support its integration into clinical practice. Full article

A single-chain variable fragment (scFv) is an engineered antibody derivative that retains antigen-binding specificity while having a much smaller size than an antibody, improved tissue penetration, and enhanced versatility for genetic manipulation. When an scFv is fused with diverse protein payloads, multifunctional biologics can be created for targeted delivery and therapy. Over the past decade, scFv fusion proteins have gained significant traction in oncology, where they have been incorporated into immunotoxins, immunocytokines, bispecific antibodies, Chimeric Antigen Receptor (CAR)-T cells constructs, and immune cell engagers. In addition, advances in blood–brain barrier (BBB)-targeting strategies have enabled the exploration of scFv-based therapeutics for neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Despite promising preclinical and clinical outcomes, challenges such as structural instability, short half-life, immunogenicity, and manufacturing complexity remain. This review provides an in-depth and up-to-date overview of scFv fusion protein engineering and its therapeutic applications in cancer and neurodegenerative disorders. We also highlight the clinical translations and design principles of scFv fusion proteins. Full article

Microplastics and nanoplastics (MNPs) are emerging environmental pollutants due to their persistence and bodily accumulation. Recently, functional foods have received much attention for their ability to reverse or block MNP damage for therapeutic purposes and the potential risk of developing oral–gut–brain axis disorders. Among these, artichoke, spirulina algae, Opuntia ficus-indica, pterostilbene, hydroxycinnamic acids, and quinic acid are rich sources of polyphenols. These bioactive ingredients, especially when combined with probiotics and prebiotics, exhibit significant antioxidant and anti-inflammatory potential by activating nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and cellular resilience enzymes. Nrf2 activation enhances cellular resilience response, and it may preserve oral epithelial barrier (OEB), intestinal epithelial barrier (IEB), and blood–brain barrier (BBB) integrity, while modulating oral pathogens, gut microbial dysbiosis, and neuroinflammatory processes. However, most of the available evidence supporting these mechanisms derives from in vitro and animal studies, whereas clinical evidence in humans remains limited. Perturbations of Nrf2 due to circulating MNPs may exacerbate selective susceptibility to oral, gut, and nervous system disorders, including Alzheimer’s disease (AD). Although these findings are biologically plausible, the causal relationships and their clinical relevance have not yet been fully established. This review discusses the role of functional foods in maintaining oral–gut–brain health through Nrf2-mediated mechanisms that may mitigate MNP-induced inflammation and reactive oxygen species (ROS). The review also examines emerging concepts in precision nutritional medicine, including individual variability in dietary responses, microbiome-related factors, and future personalized strategies for populations exposed to MNPs. Finally, current knowledge gaps, the scarcity of human studies, and the challenges in translating preclinical findings into clinical practice are highlighted, emphasizing the need for further translational and clinical research. Full article